PCORI Health Care Horizon Scanning System Volume 3 Issue 1 Horizon Scanning Status Report March 2021

Prepared for: Patient-Centered Outcomes Research Institute 1828 L St., NW, Suite 900 Washington, DC 20036

Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12

Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462

Investigators: Randy Hulshizer, MA, MS Jennifer De Lurio, MS Marcus Lynch, PhD, MBA Damian Carlson, MS Christian Cuevas, PhD Andrea Druga, MSPAS, PA-C Misha Mehta, MS Prital Patel, MPH Brian Wilkinson, MA Donna Beales, MLIS Eloise DeHaan, BS Eileen Erinoff, MSLIS Kariann Hudson, MEd Madison Kimball, MS Maria Middleton, MPH Melinda Rossi, BA Kelley Tipton, MPH Rosemary Walker, MLIS Andrew Furman, MD, MMM, FACEP

March 2021 Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI.

An intervention that potentially meets inclusion criteria might not appear in this report simply because the Horizon Scanning System has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions.

A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the Horizon Scanning System. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions.

Financial Disclosure Statement None of the individuals compiling this information has any affiliations or financial involvement that conflict with the material presented in this report.

Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated.

All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of PCORI or its Board of Governors. This publication was developed through a contract to support PCORI’s work. Questions or comments may be sent to PCORI at [email protected] or by mail to 1828 L Street, NW, Suite 900, Washington, DC 20036. ©2021 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org.

Suggested citation: Hulshizer R, De Lurio J, Lynch M, et al. PCORI Health Care Horizon Scanning System: 2021 Horizon Scanning Status Report: Volume 3, Issue 1. Patient-Centered Outcomes Research Institute; March 2021. Prepared by ECRI under Contract No. MSA- HORIZSCAN-ECRI-ENG-2018.7.12.

HORIZON SCANNING STATUS REPORT ● MARCH 2021 i

Preface

The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning of new and emerging health care technologies and innovations with high potential for disruption to the current standard of care to better inform patient-centered outcomes research investments at PCORI. The HCHSS provides PCORI with a systematic process to identify and monitor technologies and innovations in health care that are in PCORI’s priority areas of interest and to create an inventory of interventions that have the highest potential for disruption to the current standard of care in terms of patient outcomes, health disparities, care delivery, infrastructure, access, and/or costs. It is also a tool for the public to identify information on selected new health care technologies and interventions. Any investigator or funder of research can use the PCORI HCHSS to help select research topics. The health care technologies and innovations of interest for horizon scanning are those that have yet to become part of established health care practices. These interventions are in late stages of research and development or very early phases of adoption, except in the case of new applications of already-diffused technologies. Consistent with the definitions of health care interventions provided by the National Academy of Medicine and the Federal Coordinating Council for Comparative Effectiveness Research, PCORI is interested—at present—primarily in innovations in drugs and biologics, medical devices, and procedures within its selected priority areas of interest for horizon scanning. PCORI may choose, upon future consideration, to expand its focus to include a wider range of interventions (eg, systems innovations). Horizon scanning involves 2 processes. The first is identifying and monitoring new and evolving health care interventions that purportedly hold potential to diagnose, treat, or otherwise manage a disease or condition or to improve care delivery. The second is analyzing the relevant health care context in which these new and evolving interventions would exist to understand their potential for disruption to the standard of care. The goal of the PCORI HCHSS is not to predict future utilization and costs of any health care intervention; rather, the reports are intended to help inform and guide planning and prioritization of research resources. This edition of the Status Report is the first of 4 volumes planned for 2021 and lists topics (ie, interventions intended for a specific use within a specific patient population) that have been identified and are being monitored. Content in this report was current as of March 15, 2021. The reader should be aware that, although forward-looking statements were accurate as of this currency date, no warranty is provided regarding the accuracy of these statements at the time of publication. We welcome comments on this report. Send comments by mail to William Lawrence, MD, MS, Patient-Centered Outcomes Research Institute, 1828 L St, NW, Suite 900, Washington, DC 20036, or by email to [email protected].

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Contents

Introduction ...... 1 Section 1. Alzheimer’s Disease and Other Dementias: 11 Topics ...... 7 Table 1.1. Currently Monitored Alzheimer’s Disease and Other Dementias Topics: 10 Topics ...... 7 Table 1.2. Alzheimer’s Disease and Other Dementias Topics Archived Since Last Status Report: 1 Topic ...... 17 Section 2. Cancer: 91 Topics...... 18 Table 2.1. Cancer Topics Added Since Last Status Report: 6 Topics ...... 18 Table 2.2. Currently Monitored Cancer Topics: 80 Topics ...... 24 Table 2.3. Cancer Topics Archived Since Last Status Report: 5 Topics...... 99 Section 3. Cardiovascular Diseases: 17 Topics...... 104 Table 3.1. Currently Monitored Cardiovascular Diseases Topics: 17 Topics ...... 104 Section 4. Mental and Behavioral Health: 18 Topics ...... 121 Table 4.1. Mental and Behavioral Health Topics Added Since Last Status Report: 1 Topic ...... 121 Table 4.2. Currently Monitored Mental and Behavioral Health Topics: 17 Topics ...... 122 Section 5. Rare Diseases: 141 Topics ...... 139 Table 5.1. Rare Diseases Topics Added Since Last Status Report: 20 Topics ...... 139 Table 5.2. Currently Monitored Rare Diseases Topics: 114 ...... 159 Table 5.3. Rare Diseases Topics Archived Since Last Status Report: 7 Topics ...... 269 Section 6. Potentially Disruptive Trends: 37 Trends ...... 274 Table 6.1. Trends Added Since Last Status Report: 13 Trends ...... 274 Table 6.2. Currently Monitored Trends: 21 Trends ...... 283 Table 6.3. Trends Archived Since Last Status Report: 3 Trends ...... 298 Appendix. Abbreviations and Acronyms ...... 301

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Introduction

The PCORI Health Care Horizon Scanning System (HCHSS) identifies and monitors topics (ie, interventions intended for a specific use within a specific patient population) likely to be available for clinical use (ie, outside the research environment) within 3 years. For interventions subject to US Food and Drug Administration (FDA) regulatory processes, we consider those in phase 3 trials or phase 2 trials with special FDA designations (eg, Fast Track, Breakthrough Therapy) likely to accelerate time to approval. HCHSS continues to monitor topics for up to 1 year after initial clinical availability.

Status Reports The PCORI HCHSS produces quarterly Status Reports, which summarize key data elements for all topics and trends currently monitored in the system and, if applicable, topics and trends archived since the last Status Report. This Status Report is organized into 6 sections—one for each of the 5 initial PCORI-defined priority areas and one for potentially disruptive trends—titled as follows: (1) Alzheimer’s Disease and Other Dementias, (2) Cancer, (3) Cardiovascular Diseases, (4) Mental and Behavioral Health, (5) Rare Diseases, and (6) Potentially Disruptive Trends. An appendix contains abbreviations and acronyms used throughout the report. The reader should note that PCORI may choose, upon future consideration, to modify or expand its list of priority areas. In addition, the PCORI HCHSS identifies and monitors disruptive trends (ie, large, high-level disruptions) occurring across or within clinical areas from a combination of factors that, taken together, create a paradigm shift in health care. Identification of these trends is not limited to PCORI’s initially defined priority areas. Each of the 6 sections contains 1 to 3 tables, depending on the topics or trends contained in that section: (1) topics or trends added since the last Status Report, (2) currently monitored topics or trends, and (3) topics or trends archived since the last Status Report. If no topics or trends fall into a given category (ie, added, monitored, archived), no table will be included for that category in that section. For sections 1 through 5 (priority areas), tables for newly added and currently monitored topics summarize information in each row, as shown in the following columns: Potential patient population; Intervention description (including names and locations of developers/manufacturers); Potential comparators; Patient-oriented outcome measures (limited to those reported in clinical trials); and Regulatory information. Information in the first 4 columns is collectively referred to as PICO (ie, patient population, intervention, comparators, and outcomes) information. In the tables of archived topics, the Regulatory information column is replaced with a Archive reason column. Within each table, topics are sorted alphabetically by intervention name (ie, the second column, Intervention description). Potentially disruptive trends are summarized in section 6. Tables for newly added, currently monitored, and recently archived trends summarize information in each row, as shown in the following columns: Title, Description, Threats, and Opportunities. Trends are sorted alphabetically by title. Trends listed in the table of archived trends are those that ECRI internal stakeholders agreed were unlikely to significantly disrupt health care in the United States within the next 3 year.

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Horizon Scanning Process Overview The PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual (hereafter referred to as the Protocol) details the criteria we use to select topics and trends. We briefly describe our process below.

Broad Scanning to Identify Topics and Trends We scan information sources broadly within each priority area to detect leads for potential topics meeting criteria as described above. Analysts review leads to discover potential topics or trends. If they meet inclusion criteria, analysts create 1 of 2 types of records. Topic records encompass PICO (intended patient population, intervention, comparators to the intervention, and patient-oriented outcomes of interest) information and key regulatory information (if the topic is subject to a regulatory pathway). Trend records include a description of the trend, potential clinical areas affected, and lists of potential threats and opportunities posed by the trend. Analysts present potential topics and trends at nomination meetings. After a brief presentation and discussion, HCHSS team members vote in blinded fashion to include or exclude the topic or trend based on criteria described in the Protocol. All included topics and trends are reported in the quarterly Status Report.

Developing Topic and Trend Profiles Included topics with late-phase clinical data are further developed as topic profiles—reports that rely on focused searches and more robust analysis. Each topic profile is sent to stakeholders for comment with the goal of obtaining a maximum of 9, but at least 5, sets of comments and ratings before a topic is eligible for consideration for this report. Stakeholders provide varied perspectives and/or areas of knowledge in health care (eg, clinical, health systems, research, nursing). In addition, we seek at least one patient, patient representative, or caregiver perspective for each topic. The commenter reads the topic profile and completes a 6-question survey, which elicits ratings—on a scale of 1 (low disruption potential) to 4 (high disruption potential)—about the intervention’s potential to disrupt a number of key areas of health care. Commenters provide a written rationale for each rating. ECRI follows strict conflict-of-interest policies and ensures that comments and ratings received from any stakeholder with potential conflicts of interest are balanced by inputs from other neutral parties, including ECRI experts. See the Protocol for more details about ECRI’s conflict-of-interest policy. Included trends are developed into trends profiles; revised based on comments from the nomination meeting, if needed; and edited before being sent to internal ECRI stakeholders for comment. Each trend profile is posted to an internal ECRI online bulletin board, and a pool of about 50 ECRI internal stakeholders—representing health care business and finance, clinical engineering, health systems, health care generalist, information technology, nursing, physician, physician assistant, and research perspectives—is invited to provide input on each trend. Any stakeholder from the pool may self-select to review a trend, based on the stakeholder’s expertise and interest. The horizon scanning project manager monitors the process to ensure that at least 5 stakeholders representing appropriate perspectives review each trend. If a stakeholder chooses to review a trend, the stakeholder reads a trend summary, then completes a brief online survey to elicit the stakeholder’s perspectives on the trend’s potential to

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disrupt health care, the expected timing of the disruption, and the likelihood of the trend to cause disruption.

Selecting Topics and Trends for the High Potential Disruption Report The purpose of the stakeholder survey process is to help determine which topics and trends have the highest potential to significantly disrupt patient care—such as patient outcomes, access to care, health disparities, care delivery, staffing, and costs—in some manner. Twice annually, the horizon scanning team reviews all stakeholder comments and ratings (for currently included topics and trends) received in the past 12 months. This review begins a process culminating in the production and delivery of the High Potential Disruption Report, which highlights topics and trends with high potential to be significantly disruptive to patient care in the United States within the next 3 years. See the Protocol for an explanation of how we select topics and trends for inclusion in the High Potential Disruption Report.

Archiving Topics and Trends An included topic or trend may be archived if comments from stakeholders overwhelmingly suggest that it is unlikely to cause significant disruption in US health care in the next 3 years. An included topic may also be archived for one of the following reasons: (1) development of the intervention has ceased; or (2) the intervention has been clinically available outside the clinical research environment for longer than 1 year.

Reporting Period Summary The PCORI HCHSS began operating in December 2018. Since then, review of about 5000 leads has led to the identification of about 590 potential topics across the 5 PCORI priority areas and 100 high-level trends occurring in all areas of health care. After subjecting the potential topics to our inclusion criteria and nomination process, 278 topics have been selected and are being actively monitored in the system, or were being monitored but have been archived within the past 3 months. Likewise, after subjecting the potential trends to our inclusion criteria and nomination process, 37 trends have been selected and are being actively monitored or were being monitored but have been archived within the past 3 months. These 278 topics and 37 trends are reported in this Status Report.

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Topics are presented in alphabetical order according to intervention name (ie, the second column, Intervention description) within each table in each priority area’s section. As topics advance in development, their names often change from a research name to a generic name to the brand-name product. The 278 topics included in this report represent 180 diseases/conditions and span the PCORI-defined priority areas as follows (also see Figure 1): • Alzheimer’s disease and other dementias: 11 topics (4%) • Cancer: 91 topics (33%) • Cardiovascular diseases: 17 topics (6%) • Mental and behavioral health: 18 topics (6%) • Rare diseases: 141 topics (51%)

Figure 1. Percentage of Topics by Priority Area

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Across all priority areas, topics in this report represent the following therapeutic classes (also see Figure 2): • Assistive technology: 1 topic (0.4%) • Biotechnology: 24 topics (9%) • Cell therapy: 17 topics (6%) • Device (nonimplantable): 11 topics (4%) • Gene therapy: 17 topics (6%) • Immunotherapy: 4 topics (1%) • Implant: 4 topics (1%) • Monoclonal antibody: 33 topics (12%) • Pharmaceutical: 157 topics (56%) • Procedure (nonsurgical): 2 topics (0.7%) • Viral vector therapy: 8 topics (3%) Note: Total does not equal 100% because of rounding.

Figure 2. Percentage of Topics by Therapeutic Class

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Trends are presented in alphabetical order according to title. Titles and descriptions of trends will change over time as new information becomes available. Among the 37 trends presented in this report, 6 themes have emerged (also see Figure 3): • Artificial intelligence and machine learning: 15 trends (41%) • Health information technology, apps, and smart devices: 4 trends (11%) • Innovative treatment models: 10 trends (27%) • Preventive measures: 2 trends (5%) • Proteomics, genomics, and personalized medicine: 4 trends (11%) • Screening and diagnostics: 2 trends (5%)

Figure 3. Percentage of Trends by Theme

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Section 1. Alzheimer’s Disease and Other Dementias: 11 Topics

Table 1.1. Currently Monitored Alzheimer’s Disease and Other Dementias Topics: 10 Topics

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 50 to 85 years Aducanumab (BIIB037) is a recombinant human Cholinesterase inhibitors ADLs function PDUFA date: June 7, 2021; who have Alzheimer’s monoclonal antibody. It is intended to slow disease (eg, donepezil, Cognitive function Priority Review disease (AD) progression of AD by removing amyloid beta (Aβ) plaques galantamine, rivastigmine) Disease progression FDA designation(s): Fast in the brain. AD, the most common cause of dementia, is Supportive care Survival Track a progressive, neurocognitive disorder characterized by Quality of life Clinical trial(s): Phase 3b significant decline in cognitive function, changes in mood 221AD304 primary and behavior, and difficulty performing activities of daily completion October 2023; living (ADLs). There is no cure, and additional therapies phase 3 EMERGE terminated are needed. AD is associated with abnormal August 2019, top-line data accumulations of proteins in the brain called Aβ plaques presented December 2019; and neurofibrillary tangles. These accumulations are phase 3 ENGAGE terminated thought to be neurotoxic and interfere with signaling in August 2019, top-line data the brain and contribute to brain cell death, thus causing presented December 2019 the symptoms of AD. Aducanumab purportedly preferentially binds to Aβ protein to prevent new plaque formation and promotes the breakdown of existing Aβ accumulations. By lowering the amount of neurotoxic protein aggregates in the brain, it purportedly modifies the disease to slow progression. In the most recent clinical trials, aducanumab is given intravenously at a dosage of 10 mg/kg monthly for up to 100 weeks. Developer(s): Biogen (Cambridge, Massachusetts), in collaboration with Neurimmune AG (Schlieren-Zurich, Switzerland) and Eisai Co, Ltd (Tokyo, Japan)

Section 1. Alzheimer’s Disease and Other Dementias 7

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 to 85 years AGB101 is a low-dose, extended-release form of the Cholinesterase inhibitors Cognitive function Clinical trial(s): Phase 2/3 who have mild cognitive antiepileptic drug levetiracetam intended to treat MCI due (eg, donepezil, Disease progression HOPE4MCI primary impairment (MCI) due to to AD. AD is a progressive, neurodegenerative disorder in galantamine, rivastigmine; Quality of life completion July 2022 Alzheimer’s disease (AD) and which there is abnormal accumulation of amyloid beta off-label) who have the APOE4 variant (Aβ) and tau proteins in the brain, forming aggregates Supportive care (eg, of the apolipoprotein E called Aβ plaques and neurofibrillary tangles. These are cognitive training) gene, APOE thought to be neurotoxic and lead to neurodegeneration, causing AD symptoms. AD is characterized by significant cognitive function decline, changes in mood and behavior, and difficulty performing activities of daily living (ADLs). It progresses to and is the most common cause of dementia. MCI is a measurable decline in cognitive function that precedes dementia. No cure exists for AD, and there are no FDA-approved treatments for MCI. AGB101 purportedly slows overactive neuron signaling in the hippocampus area of the brain, which has been observed to predict the amount of neurodegeneration seen in MCI and the rate of progression to dementia in AD. Thus, it might help slow disease progression in AD and delay onset of AD dementia. In clinical trials, AGB101 is given orally at a dosage of 220 mg once daily for 78 weeks. Developer(s): AgeneBio, Inc (Baltimore, Maryland)

Section 1. Alzheimer’s Disease and Other Dementias 8

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 to 80 years Atuzaginstat (COR388) is a bacterial protease inhibitor. It Cholinesterase inhibitors Activities of daily living Clinical trial(s): Phase 2/3 who have mild to moderate targets the infectious pathogen Porphyromonas gingivalis (eg, donepezil, (ADLs) function GAIN primary completion Alzheimer’s disease (AD) gingipains, a bacterium purportedly linked to periodontal galantamine, rivastigmine) Cognitive function December 2021, data dementia disease and AD and linked to the production of amyloid Memantine (for moderate Disease progression reported November 2020 beta (Aβ) in preclinical and clinical models. P gingivalis AD) Survival gingipains is found in the brain tissue and cerebral spinal fluid of people with AD. Atuzaginstat purportedly could be Quality of life the first disease-modifying treatment to reduce brain infection, block Aβ production, reduce neuroinflammation, and impart neuroprotection for patients with mild to moderate AD. In clinical trials, atuzaginstat is given orally in 40- or 80-mg capsules twice daily. Developer(s): Cortexyme, Inc (San Francisco, California)

Section 1. Alzheimer’s Disease and Other Dementias 9

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 50 years or BAN2401 is a monoclonal antibody specific for amyloid Cholinesterase inhibitors ADLs function Clinical trial(s): Phase 3 older who have mild beta (Aβ) under study to treat AD. AD, the most common (eg, donepezil, Cognitive function CLARITY primary completion cognitive impairment (MCI) cause of dementia, is a progressive, neurodegenerative galantamine, rivastigmine) Disease progression June 2022; phase 2 primary or mild dementia due to disorder characterized by significant decline in cognitive completion March 2022, Supportive care Survival Alzheimer’s disease (AD) function, changes in mood and behavior, and difficulty phase 2 data reported July performing activities of daily living (ADLs). No cure exists. Quality of life 2018 Abnormal accumulations of proteins in the brain referred to as Aβ plaques and neurofibrillary tangles are seen in AD. The accumulations are thought to be neurotoxic and interfere with signaling in the brain and contribute to brain cell death, thus causing the symptoms of AD. MCI is a measurable decline in cognitive function that precedes that of dementia. In the body, Aβ exists in multiple conformations, including monomers, oligomers, protofibrils (soluble Aβ aggregates), and insoluble fibers. Recent research suggests that protofibrils may be a key mediator of AD pathogenesis. BAN2401 purportedly binds Aβ protofibrils selectively over other Aβ conformations. By neutralizing and eliminating this neurotoxic form of Aβ, BAN2401 has the potential to slow AD progression. In clinical trials, BAN2401 is given intravenously at a dosage of 10 mg/kg once every 2 weeks. Developer(s): Eisai Co, Ltd (Tokyo, Japan), in collaboration with Biogen (Cambridge, Massachusetts)

Section 1. Alzheimer’s Disease and Other Dementias 10

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 to 91 years Brexpiprazole (Rexulti) is an atypical antipsychotic Antianxiety drugs Agitation, as measured Clinical trial(s): Phase 3 who have Alzheimer’s medication that purportedly reduces agitation in patients Antidepressants by accepted clinical primary completion March disease (AD)–associated with AD by modulating serotonin-dopamine activity in the Antipsychotics (eg, ratings and scales 2022; phase 3 extension agitation brain. Although antipsychotics are sometimes used off- haloperidol) Quality of life primary completion July label to treat this condition, they carry an increased risk of 2022; phase 3 completed Atypical antipsychotics (eg, death in patients with dementia. Brexpiprazole might March 2017, phase 3 aripiprazole) have a better safety profile compared with other completed March 2017, antipsychotics. According to the manufacturer, Beta-adrenergics pooled data published April brexpiprazole is a partial agonist (ie, activator) of Caregiver intervention and 2020 environmental modification serotonin 1A (5-HT1A) and dopamine 2 (D2) receptors and Note(s): FDA has approved an antagonist of serotonin 2A (5-HT2A) receptors. (eg, removed or alleviated brexpiprazole to treat Brexpiprazole might also bind to noradrenaline α1B/2C stressors) schizophrenia and as receptors. In clinical trials, brexpiprazole is taken by Synthetic adjunctive treatment for mouth at a dosage of 1 to 3 mg once daily for 10 to 14 tetrahydrocannabinol major depressive disorder weeks. (MDD) Developer(s): Otsuka Holdings Co, Ltd (Tokyo, Japan), in collaboration with H Lundbeck A/S (Valby, Denmark)

Section 1. Alzheimer’s Disease and Other Dementias 11

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 to 79 years Cromolyn and ibuprofen (ALZT-OP1) is a combination Cholinesterase inhibitors ADLs function Clinical trial(s): Phase 3 who have evidence of early therapy intended to slow or reverse cognitive and (eg, donepezil, Cognitive function COGNITE completed Alzheimer’s disease (AD) functional decline in patients with early-stage AD. AD, the galantamine, rivastigmine) Disease progression November 2020, designed most common cause of dementia, is a progressive, under Special Protocol Memantine (off-label) Survival neurodegenerative disorder characterized by significant Supportive care Assessment decline in cognitive function, changes in mood and Quality of life behavior, and difficulty performing activities of daily living (ADLs). No cure exists. Abnormal accumulations of proteins in the brain, referred to as amyloid beta (Aβ) plaques and neurofibrillary tangles, are seen in AD. The accumulations are thought to be neurotoxic and interfere with signaling in the brain and contribute to brain cell death, thus causing the symptoms of AD. Cromolyn acts as an Aβ polymerization inhibitor to purportedly block the development of Aβ plaques. The ibuprofen component is intended to reduce neuronal inflammation caused by existing plaques. In clinical trials, cromolyn is inhaled and ibuprofen is given orally (dosage and treatment duration are unspecified for both components). Developer(s): AZTherapies, Inc (Boston, Massachusetts)

Section 1. Alzheimer’s Disease and Other Dementias 12

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 50 to 85 years CT1812 (Elayta) is a small-molecule antagonist of the Cholinesterase inhibitors Activities of daily living FDA designation(s): Fast who have mild to moderate progesterone receptor member component 1 (PGRMC1) (eg, donepezil, (ADLs) function Track Alzheimer’s disease (AD) that is intended to slow AD’s progression. AD, the most galantamine, rivastigmine) Cognitive function Clinical trial(s): Phase 2 dementia common cause of dementia, is a progressive, Memantine (for moderate Disease progression COG0201 primary neurodegenerative disorder characterized by significant AD) Survival completion June 2020; phase decline in cognitive function, changes in mood and 2 COG0202 primary Quality of life behavior, and difficulty performing activities of daily living. completion July 2021; phase No cure exists. Abnormal accumulations of proteins in the 1/2 COG0105 primary brain, referred to as amyloid beta (Aβ) plaques and completion January 2021 neurofibrillary tangles, are seen in AD. They are thought to be neurotoxic and interfere with signaling in the brain and contribute to brain cell death, thus causing the symptoms of AD. No disease-modifying treatments are available, and current treatments address only symptoms. PGRMC1 is a cell-surface protein expressed in brain synapses that acts as a receptor for oligomeric Aβ and purportedly contributes to Aβ-mediated neurotoxicity. CT1812 purportedly competes with Aβ binding to PGRMC1, potentially preventing the neurotoxicity induced by synaptic binding of Aβ in the brain. In clinical trials, patients were given CT1812 orally at a dosage of 100 or 300 mg once daily. Developer(s): Cognition Therapeutics, Inc (Pittsburgh, Pennsylvania)

Section 1. Alzheimer’s Disease and Other Dementias 13

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 90 years Leuco-methylthioninium dihydromethanesulfonate Cholinesterase inhibitors Activities of daily living Clinical trial(s): Phase 3 who have mild cognitive (LMTM) is a tau aggregation inhibitor. It is being (eg, donepezil, (ADLs) function LUCIDITY primary impairment (MCI) or mild to developed as a disease-modifying treatment for AD, the galantamine, rivastigmine) Cognitive function completion June 2022; phase severe dementia due to most common cause of dementia. AD is a progressive, Memantine (off-label for Disease progression 3 completed May 2016, data Alzheimer’s disease (AD) neurodegenerative disorder characterized by significant published November 2017; MCI and mild AD) Survival decline in cognitive function, changes in mood and Supportive care phase 3 completed behavior, and difficulty performing activities of daily living. Quality of life November 2015, data No cure exists. Abnormal accumulations of proteins in the published December 2016 brain, referred to as amyloid beta (Aβ) plaques and neurofibrillary tangles, are seen in AD. The accumulations are thought to be neurotoxic and interfere with signaling in the brain and contribute to brain cell death, thus causing the symptoms of AD. LMTM purportedly reduces levels of aggregated or misfolded tau proteins in the brain by preferentially binding to the tau protein, which might slow disease progression. In clinical trials, LMTM is taken by mouth at a dosage of 8 or 16 mg split into twice-daily doses. Developer(s): Mediforum Pharmaceutical Co, Ltd (South Korea), which acquired publishing, manufacturing, and intellectual property rights from TauRx Pharmaceuticals, Ltd (Singapore, Republic of Singapore)

Section 1. Alzheimer’s Disease and Other Dementias 14

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 years or Neflamapimod is a small-molecule inhibitor of the Alternative therapies (eg, Activities of daily living FDA designation(s): Fast older who have probable intracellular enzyme p38 alpha mitogen-activated protein music therapy, pet therapy) (ADLs) function Track Lewy body dementia and kinase (p38 MAPKα). It is intended to treat Lewy body Cholinesterase inhibitors Cognitive function Clinical trial(s): Phase 2 have received dementia, a type of neurodegenerative dementia with (off-label) Disease progression AscenD-LB primary cholinesterase inhibitor distinct features, including visual hallucinations, Parkinson disease Lewy body–specific completion June 2020, data therapy for more than 3 parkinsonism, and sleep behavior disorder. Abnormal medications (eg, carbidopa- symptoms and severity reported October 2020; months deposits of a protein called alpha-synuclein (Lewy bodies) levodopa) (eg, visual phase 3 planned are seen in the brains of patients with Lewy body hallucinations, dementia. The deposits are thought to be neurotoxic and parkinsonism, sleep contribute to symptoms of the disorder. Chronically active disturbances) p38 MAPKα purportedly plays a role in the alpha- synuclein-associated toxicity observed in the brains of Survival these patients. Neflamapimod purportedly improves Quality of life synaptic dysfunction by inhibiting chronically activated p38 MAPKα, which may slow or reverse cognitive impairment associated with Lewy body dementia. In clinical trials, the drug is given orally at a dosage of 40 mg 2 or 3 times daily with food for 16 weeks. Developer(s): EIP Pharma, Inc (Boston, Massachusetts)

Section 1. Alzheimer’s Disease and Other Dementias 15

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 to 85 years Periodic Therapeutic Plasma Exchange (Alzheimer’s Cholinesterase inhibitors Activities of daily living Clinical trial(s): Phase 2/3 who have mild to moderate Management by Albumin Replacement [AMBAR] protocol) (eg, donepezil, (ADLs) function (AMBAR) completed March Alzheimer’s disease (AD) is intended to treat AD by periodically extracting plasma galantamine, rivastigmine) Cognitive function 2018, data published July and exchanging the patient’s albumin with Albutein Memantine (off-label) Disease progression 2020 solution. Investigators theorize that, because most Survival Note(s): FDA approved a amyloid beta (Aβ) protein is bound to albumin and Biologics License Application Quality of life circulating in plasma, plasma exchange might flush Aβ for Albutein in 1978 as from the brain into the circulation, mitigating cognitive adjunctive therapy for decline. In clinical trials, treatment groups were assigned patients with hypovolemia, to receive either a high dose (total plasma exchange once cardiopulmonary bypass weekly, 2.5-3.0 L plasma removal with albumin procedures, replacement for 6 weeks) or a low dose (low-volume hypoalbuminemia, and plasma exchange monthly, 650-880 mL plasma removal plasma exchange with a low dose of albumin or immunoglobulin for 12 months). Developer(s): Grifols SA (Barcelona, Spain)

Section 1. Alzheimer’s Disease and Other Dementias 16 Table 1.2. Alzheimer’s Disease and Other Dementias Topics Archived Since Last Status Report: 1 Topic

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults aged 50 to 85 years Troriluzole (BHV-4157) is a third-generation, tripeptide- Cholinesterase inhibitors Activities of daily living In January 2021, who have mild to moderate prodrug conjugate of riluzole being developed as a (eg, donepezil, (ADLs) function Biohaven reported that the Alzheimer’s disease (AD) disease-modifying treatment for AD. In patients with AD, galantamine, Cognitive function phase 2/3 clinical trial of dementia damaged brain cells are susceptible to cellular injury by rivastigmine) Disease progression troriluzole failed to meet its overactivity of the excitatory neurotransmitter glutamate. primary end point, and the Memantine (off-label for Survival Riluzole is a sodium channel blocker and glutamate mild AD) company plans to continue modulator approved by FDA to treat amyotrophic lateral Quality of life the analysis to inform sclerosis (ALS). It purportedly reduces glutamate- its future direction. mediated excitotoxicity and nerve cell deterioration by promoting glutamate’s reuptake into nerve cells. Troriluzole purportedly has the same mechanism of action as riluzole but with improved bioavailability and tolerability. These factors could reduce adverse events typically associated with riluzole, such as fatigue, weakness, dizziness, and hepatotoxicity. Troriluzole purportedly decreases glutamate-mediated neuronal damage to reduce symptoms in patients with AD and delay AD progression by preventing the loss of synapses. In clinical trials, patients take troriluzole by mouth at a dosage of 280 mg once daily at bedtime for 48 weeks. Developer(s): Biohaven Pharmaceuticals, Inc (New Haven, Connecticut)

Section 1. Alzheimer’s Disease and Other Dementias 17 Section 2. Cancer: 91 Topics

Table 2.1. Cancer Topics Added Since Last Status Report: 6 Topics

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have locally Fam-trastuzumab deruxtecan-nxki (Enhertu) is a HER2- One or more of the Overall survival Approval date: January 15, advanced or metastatic specific antibody-drug conjugate under study for treating following: Progression-free survival 2021 gastric or gastroesophageal gastric cancer. The antibody-drug conjugate incorporates Angiogenesis inhibitors Quality of life FDA designation(s): junction adenocarcinoma a HER2-specific antibody that is designed to bind the (eg, ramucirumab) Breakthrough Therapy that has been treated with a surface receptor HER2, a protein commonly Antimetabolites (eg, Clinical trial(s): Phase 2 previous line of HER2- overexpressed by some gastric cancers. The antibody is fluorouracil) DESTINY-Gastric02 primary directed therapy conjugated to the cytotoxic drug deruxtecan, which Immune checkpoint completion September 2021, inhibits the activity of topoisomerase I, an enzyme that inhibitors (eg, data published May 2020 relieves DNA supercoiling. This enzyme inhibition leads pembrolizumab) if cells to arrest their cell cycle and die because of tumors are microsatellite replication-dependent, site-selective, DNA double-strand instability–high or breaks. Fam-trastuzumab deruxtecan-nxki purportedly mismatch repair– binds to HER2 and triggers internalization of the drug into deficient the cells. This increases the likelihood of deruxtecan targeting and killing malignant cells while minimizing Taxanes (eg, docetaxel, cytotoxicity on normal cells. The recommended dosage in paclitaxel) the FDA-approved label is 6.4 mg/kg intravenously once Topoisomerase inhibitors every 21 days until disease progression or intolerable (eg, irinotecan) toxicity. Developer(s): Daiichi Sankyo Co, Ltd (Tokyo, Japan), in collaboration with AstraZeneca (Cambridge, United Kingdom)

Section 2. Cancer 18

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adult females with Mirvetuximab soravtansine (IMGN853) is an antibody- One or more of the Overall survival FDA designation(s): Fast platinum-resistant, drug conjugate consisting of an anti-FRα antibody following: Progression-free survival Track advanced high-grade conjugated to the cytotoxic agent maytansinoid DM4. Alkylating agents (eg, Quality of life Clinical trial(s): Phase 3 epithelial ovarian, primary Although FRα expression is limited in normal tissues, cyclophosphamide) FORWARD I primary peritoneal, or fallopian tube about 60% to 80% of recurrent ovarian cancers express Angiogenesis inhibitors completion January 2019, cancers with high folate high levels of FRα. Mirvetuximab soravtansine purportedly (eg, bevacizumab) data presented September receptor-alpha (FRα) binds to FRα-expressing cells, becomes internalized, and Anthracyclines (eg, 2019; phase 3 SORAYA expression who have delivers maytansinoid DM4, a potent tubulin-targeting doxorubicin) primary completion July received 1 to 3 prior agent, to kill the tumor cells. To determine eligibility for 2021; phase 3 MIRASOL Poly adenosine systemic lines of anticancer treatment, patients are tested for tumor FRα primary completion June diphosphate-ribose therapy and for whom overexpression using immunohistochemistry. In clinical 2022 single-agent therapy is trials, mirvetuximab soravtansine is given intravenously at polymerase (PARP) appropriate as the next line a dosage of 6 mg/kg every 3 weeks. inhibitors (eg, niraparib, olaparib, rucaparib) if of treatment Developer(s): patient harbors ImmunoGen, Inc (Waltham, Massachusetts) mutations in the breast cancer genes 1 and/or 2 (BRCA1/2) Taxanes (eg, docetaxel, paclitaxel) Topoisomerase inhibitors (eg, topotecan)

Section 2. Cancer 19

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have primary Pelabresib (CPI-0610) is a small-molecule inhibitor of Hypomethylating agents Symptom control (eg, FDA designation(s): Orphan myelofibrosis or bromodomain and extra-terminal domain (BET) proteins. (eg, azacitidine, splenomegaly) Drug, Fast Track myelofibrosis arising from It is under study for treating myelofibrosis, a decitabine) Progression-free survival Clinical trial(s): Phase 3 polycythemia vera or myeloproliferative neoplasm in which bone marrow stem JAK inhibitors (eg, Overall survival primary completion essential thrombocytopenia cells develop abnormally. Two Janus kinase (JAK) inhibitors fedratinib, ruxolitinib) September 2022; phase 2 (ruxolitinib and fedratinib) have been FDA approved for primary completion August treating myelofibrosis. However, only about 50% of 2021, preliminary data patients respond to these therapies, which have not presented December 2020 demonstrated a substantial effect on limiting disease progression. BET proteins are epigenetic regulators of gene expression. The proteins promote expression patterns that regulate various myelofibrosis-associated processes, including inflammatory cytokine production and differentiation of myeloid cells into aberrant megakaryocytes. In clinical trials, pelabresib (125 mg) is taken by mouth on days 1 through 14 of a 21-day treatment cycle. The drug has been investigated as both a monotherapy and as an add-on therapy to ruxolitinib. Developer(s): Constellation Pharmaceuticals, Inc (Cambridge, Massachusetts)

Section 2. Cancer 20

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults with locally advanced Sotorasib (AMG510) is a potent and selective, small- One or more of the Overall survival PDUFA date: August 16, or metastatic non–small cell molecule inhibitor of the KRas protein, a cell membrane following: Progression-free survival 2021; Priority Review lung cancer (NSCLC) GTPase that regulates cell proliferation. The KRAS G12C Angiogenesis inhibitors Quality of life FDA designation(s): harboring a G12C mutation gene mutation promotes uncontrolled cell proliferation (eg, ramucirumab) Breakthrough Therapy in the Kirsten rat sarcoma and survival. It does this by encoding a hyperactive KRas Antimetabolites (eg, Clinical trial(s): Phase 3 gene, KRAS, that has been protein, which constantly sends downstream signaling gemcitabine, CodeBreaK 200 primary treated with one previous cascades that activate cell proliferation genes and inhibit pemetrexed) completion November 2021; line of systemic therapy tumor suppressor genes. The incidence of the KRAS G12C Immune checkpoint phase 1/2 CodeBreaK 100 gene in patients with NSCLC is about 13%. KRas G12C- inhibitors (eg, primary completion driven NSCLC is an aggressive disease with a poor atezolizumab, November 2021, data prognosis and limited treatment options. For almost 40 nivolumab, presented September 2020, years, KRas was considered an unachievable target pembrolizumab) phase 1 data published because no treatment strategy had yielded significant Taxanes (eg, docetaxel) September 2020, phase 2 success. Sotorasib is a novel targeted therapy that data reported January 2021 irreversibly binds KRas G12C and locks it in the inactive state. Sotorasib purportedly improves health outcomes by blocking downstream signaling cascades involved in NSCLC cell proliferation and survival. Because sotorasib is highly specific for KRas G12C, it purportedly has few off- target effects. Determining eligibility for this therapy requires testing for KRAS gene mutation status. In clinical trials, sotorasib is taken by mouth at a once-daily dose of 960 mg until disease progression or intolerable toxicity. Developer(s): Amgen, Inc (Thousand Oaks, California)

Section 2. Cancer 21

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults with Teclistamab is a bispecific antibody targeting B-cell One or more of the Overall survival FDA designation(s): Orphan relapsed/refractory multiple maturation antigen (BCMA) and CD3 and under study for following: Progression-free survival Drug myeloma (MM) who have treating relapsed/refractory MM. A number of agents Alkylating agents (eg, Quality of life Clinical trial(s): Phase 2 received treatment with an have been approved in recent years to treat MM, but the bendamustine, primary completion January immunomodulatory drug, a disease is considered incurable and most patients cyclophosphamide) 2022 proteasome inhibitor, and develop progressive disease. BCMA has been proposed as Anthracyclines (eg, an anti-CD38 antibody a biomarker for targeting MM because it is highly doxorubicin) expressed in malignant plasma cells. Teclistamab Antibody-drug purportedly functions as a T-cell redirecting antibody. By conjugates (eg, simultaneously binding BCMA and the T-cell epitope CD3, belantamab mafodotin- the antibody recruits and activates T cells to kill BCMA- blmf) expressing MM cells. In clinical trials, teclistamab is administered under the skin at an unspecified dose. Glucocorticoids (eg, dexamethasone) Developer(s): Immunomodulatory Janssen Pharmaceuticals, LLC (Raritan, New Jersey) agents (eg, lenalidomide, pomalidomide, thalidomide) Monoclonal antibodies (eg, daratumumab, elotuzumab) Proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib) Selective inhibitors of nuclear export (eg, selinexor) Topoisomerase inhibitors (eg, etoposide)

Section 2. Cancer 22

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults with locally advanced Zanidatamab (ZW25) is a bispecific antibody targeting 2 One or more of the Overall survival FDA designation(s): Orphan or metastatic biliary tract different epitopes on HER2 and is under study for treating following: Progression-free survival Drug, Fast Track, cancer overexpressing HER2-overexpressing biliary tract cancer. Biliary tract Fibroblast growth factor Quality of life Breakthrough Therapy human epidermal growth cancer is a rare cancer that forms in bile ducts, which receptor inhibitors (eg, Clinical trial(s): Phase 2 factor receptor 2 (HER2) that carry fluid between the liver, the gallbladder, and the pemigatinib) for FGFR2 HERIZON-BTC-01 primary has previously been treated small intestine. It is a highly aggressive cancer that is often fusion–positive tumors completion July 2022 with at least one line of diagnosed at an advanced disease stage, and patients Fluorouracil-based systemic therapy have poor outcomes with standard treatments. HER2 is chemotherapy (eg, overexpressed in about 15% of biliary tract cancers, but FOLFOX [leucovorin no HER2-specific therapies are FDA approved for treating (folinic acid), 5- the disease. A bispecific antibody, zanidatamab is fluorouracil, and intended to improve health outcomes through dual HER2 oxaliplatin]; FOLFIRI signal blockade, antibody binding, receptor clustering, and [leucovorin (folinic acid), removal of HER2 from the cell surface. To determine 5-fluorouracil, and eligibility for treatment, patients are tested for tumor irinotecan]) HER2 overexpression using immunohistochemistry or in Immune checkpoint situ hybridization methods. In clinical trials, zanidatamab inhibitors (eg, is given intravenously at an unspecified dose and pembrolizumab) for duration. microsatellite instability– Developer(s): high or mismatch repair– Zymeworks, Inc (Vancouver, British Columbia, Canada), in deficient tumors collaboration with BeiGene, Ltd (Shanghai, China) Isocitrate dehydrogenase 1 (IDH1) inhibitors (eg, ivosidenib) for IDH1 mutation–positive tumors Neurotrophic tyrosine receptor kinase (NTRK) inhibitors (eg, entrectinib, larotrectinib) for NTRK gene fusion– positive tumors

Section 2. Cancer 23 Table 2.2. Currently Monitored Cancer Topics: 80 Topics

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children who have 131I-omburtamab (131I-8H9) is a monoclonal antibody One or more of the Overall survival Submission date: Rolling leptomeningeal metastases designed to target the B7-H3 protein and radiolabeled following: Progression-free Biologics License Application from relapsed, high-risk with iodine-131. B7-H3 is a surface protein that is highly Alkylating agents (eg, survival (BLA) completed August neuroblastoma expressed in neuroblastoma cells. Neuroblastoma is a thiotepa) Quality of life 2020 type of cancer that originates in the sympathetic nervous Antimetabolites (eg, FDA designation(s): system, which is responsible for controlling involuntary cytarabine, methotrexate) Breakthrough Therapy bodily functions (eg, breathing, heart rate, digestion), and Radiation therapy Clinical trial(s): Phase 2/3 causes tumors in the abdomen, chest, neck, pelvis, or primary completion spine. In up to 70% of patients with neuroblastoma, December 2020, data metastases are present at the time of diagnosis. Even presented October 2020 though metastatic spread to the membranes surrounding Note(s): FDA issued a Refusal the brain and spinal cord is rare, the survival rate of to File letter in October 2020, patients with leptomeningeal metastases ranges between and a BLA resubmission is 2 and 6 months. 131I-omburtamab purportedly binds B7- planned for the first quarter H3-expressing cells with high affinity and exposes them to of 2021 radiation emitted by iodine-131. This novel approach to target and kill leptomeningeal metastases has potential to improve health outcomes in patients who have limited treatment options. In clinical trials, 131I-omburtamab is injected directly into the cerebrospinal fluid at a dose of 50 mCi. Eligibility for a second dose is evaluated 5 weeks after the first dose. Developer(s): Y-mAbs Therapeutics, Inc (New York, New York)

Section 2. Cancer 24

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Anlotinib (AL3818) is a potent and broad-spectrum One or more of the Overall survival FDA designation(s): Orphan advanced or metastatic receptor tyrosine kinase (RTK) inhibitor. It is designed to following: Progression-free Drug alveolar soft part sarcoma, target more RTKs than do multikinase inhibitors used as Alkylating agents (eg, survival Clinical trial(s): Phase 3 leiomyosarcoma, or synovial standard treatment for soft tissue sarcomas, including the dacarbazine, Quality of life APROMISS primary sarcoma drugs sorafenib, sunitinib, and pazopanib. Anlotinib may temozolomide) completion April 2021 provide an option for patients who have limited treatment Antimetabolites (eg, options because their disease has developed resistance. gemcitabine) Anlotinib has broad inhibition against RTKs involved in Antitumor antibiotics (eg, soft tissue sarcoma disease development including c-KIT, anthracyclines, fibroblast growth factor receptors (FGFRs), platelet- mitomycin-C) derived growth factor receptors (PDGFRs), and vascular endothelial growth factor receptors (VEGFRs). Anlotinib Microtubule inhibitors (eg, inhibits a broader range of RTKs than do available eribulin, vinorelbine) multikinase inhibitors and purportedly is better at Multikinase inhibitors (eg, preventing blood vessel formation, cell proliferation, and pazopanib, sunitinib) cancer spread (ie, metastasis). In clinical trials, anlotinib is Tropomyosin receptor taken by mouth once daily, at a dose of 12 mg, in a 2- kinase inhibitors (eg, weeks-on, 1-week-off schedule until disease progression larotrectinib) for NTRK gene or intolerable toxicity. fusion–positive sarcomas Developer(s): Advenchen Laboratories, LLC (Moorpark, California)

Section 2. Cancer 25

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Atezolizumab (Tecentriq) is a monoclonal antibody that One or more of the Overall survival Approval date: May 29, 2020; advanced or metastatic targets programmed cell death ligand 1 (PD-L1), an following: Progression-free Real-Time Oncology Review hepatocellular carcinoma inhibitory surface molecule expressed by cells to Anthracyclines (eg, survival FDA designation(s): Orphan (HCC) and have had no modulate immune responses. HCC, an aggressive cancer, doxorubicin) Quality of life Drug, Breakthrough Therapy previous systemic therapy has limited treatment options and is a major cause of Antimetabolites (eg, 5- Clinical trial(s): Phase 3 cancer deaths. A hallmark of cancer is its ability to evade fluorouracil, gemcitabine) IMbrave150 primary an immune response. Several types of cancer cells, Multikinase inhibitors (eg, completion February 2021, including HCC, activate an immune checkpoint pathway in lenvatinib, sorafenib) data published May 2020 T cells by overexpressing PD-L1, which binds to the Note(s): FDA has approved programmed cell death 1 (PD-1) coinhibitory receptor and Platinum agents (eg, atezolizumab to treat many limits the activation of cancer-specific T cells. cisplatin, oxaliplatin) other cancers. See the FDA- Atezolizumab purportedly prevents the interaction approved labeling and between PD-1 and PD-L1 to release the brake on the prescribing document for all immune checkpoint pathway. Atezolizumab treatment in approved indications. combination with bevacizumab is intended to restore anticancer immunity by inhibiting vascular endothelial growth factor–related immunosuppression. The recommended dosage in the FDA-approved label is an intravenous infusion of 1200 mg on day 1 of each 21-day cycle in combination with intravenous bevacizumab (15 mg/kg on day 1 of each 21-day cycle) until disease progression or development of unacceptable toxicity. Developer(s): Genentech, Inc (South San Francisco, California), a subsidiary of F Hoffman-La Roche AG (Basel, Switzerland)

Section 2. Cancer 26

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who are at risk of Avasopasem manganese (GC4419) is intended to treat One or more of the Incidence of severe FDA designation(s): oral mucositis (OM) after patients who are likely to develop OM. No effective following: mucositis Breakthrough Therapy, Fast chemoradiation therapy treatments are available for OM, a common side effect of Localized therapy (eg, low- Cancer treatment Track with cisplatin and intensity- anticancer therapies (eg, chemotherapy, radiation). level laser therapy, oral adherence Clinical trial(s): Phase 3 modulated radiation Avasopasem manganese is a small-molecule superoxide cryotherapy) Quality of life ROMAN primary completion therapy for locally dismutase mimetic drug intended to detoxify reactive Supportive care (eg, oral December 2021 advanced, nonmetastatic oxygen species (ROS). ROS are overproduced during hygiene protocols) head and neck cancer chemoradiation therapy, overwhelming the body’s superoxide dismutase enzymes and resulting in oxidative tissue damage that contributes to OM. Treatment with a superoxide dismutase, such as avasopasem manganese, purportedly reduces chemoradiation-induced toxicity. In clinical trials, avasopasem manganese is given intravenously at an unspecified dose before initiating intensity-modulated radiation therapy. Developer(s): Galera Therapeutics, Inc (Malvern, Pennsylvania)

Section 2. Cancer 27

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed or Axicabtagene ciloleucel (Yescarta) is a chimeric antigen Bendamustine plus CD20 Progression-free PDUFA date: March 5, 2021; refractory indolent receptor (CAR) T-cell therapy under study for treating antibody (eg, survival Priority Review non-Hodgkin lymphoma (eg, indolent non-Hodgkin lymphoma (eg, follicular lymphoma, obinutuzumab, rituximab) Overall survival FDA designation(s): follicular lymphoma, marginal zone lymphoma). Indolent non-Hodgkin CD20 monoclonal antibody Health-related quality Breakthrough Therapy marginal zone lymphoma) lymphomas are incurable B-cell lymphomas that typically Ibritumomab tiuxetan of life Clinical trial(s): Phase 2 and have received at least 2 respond to initial chemoimmunotherapy. However, for Lenalidomide plus CD20 ZUMA-5 primary completion prior lines of therapy the subset of patients whose disease progresses during monoclonal antibody February 2022, data treatment with multiple agents, limited treatment options presented December 2020 are available and prognosis is poor. To produce PI3K inhibitor (eg, Note(s): FDA previously axicabtagene ciloleucel, a patient’s own (ie, autologous) T copanlisib, idelalisib) approved axicabtagene cells are genetically modified to express a CAR fusion Tazemetostat ciloleucel to treat adults who protein with a CD19-specific antigen recognition domain have relapsed or refractory and a T-cell activation domain. These genetically modified large B-cell lymphoma after cells are grown in number in a laboratory before infusion 2 or more lines of systemic into the patient, where they purportedly induce a therapy, including diffuse cytotoxic response to CD19-expressing lymphoma cells large B-cell lymphoma and normal B cells. In clinical trials, axicabtagene (DLBCL) not otherwise ciloleucel is given as a single infusion at an unspecified specified, primary dose. mediastinal large B-cell Developer(s): lymphoma, high-grade B-cell Kite Pharma, a Gilead Company (Santa Monica, California) lymphoma, and DLBCL arising from follicular lymphoma

Section 2. Cancer 28

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Belumosudil (KD025) inhibits rho-associated coiled-coil Extracorporeal Survival PDUFA date: May 30, 2021; older and adults who have kinase 2 (ROCK2) and is under study for treating chronic photopheresis Treatment response Priority Review chronic graft-vs-host disease GVHD. A life-threatening immune disorder, GVHD is a Hydroxychloroquine rate FDA designation(s): Orphan (GVHD) that has been frequent complication of allogeneic hematopoietic stem Ibrutinib Quality of life Drug, Breakthrough Therapy treated with 2 prior systemic cell transplantation (HSCT). It arises when donor T cells Imatinib Clinical trial(s): Phase 2 GVHD therapies recognize host cells as foreign because of their expression KD025-208 primary of alloantigens and mount an immune response against mTOR inhibitors (eg, sirolimus) completion August 2021, host tissues, leading to inflammation and fibrosis in data presented February Mycophenolate mofetil multiple body tissues. The standard treatment for chronic 2020; phase 2 KD025-213 GVHD is corticosteroids; however, patients whose disease Pentostatin primary completion no longer responds to steroids have poor long-term Rituximab September 2021, interim outcomes, with a mortality rate of 70% to 80%. ROCK2 has data presented February been shown to be involved in regulating proinflammatory 2020 cytokines, such as interleukin (IL)-17 and IL-21, which are involved in the pathogenesis of chronic GVHD. Belumosudil inhibition of ROCK2 purportedly leads to downregulation of proinflammatory T helper 17 (Th17) responses and increases levels of immunosuppressive regulatory T cells, potentially moderating the antihost immune response underlying chronic GVHD. In clinical trials, belumosudil is taken by mouth at a dosage of 200 mg once or twice daily. Developer(s): Kadmon Holdings, Inc (New York, New York)

Section 2. Cancer 29

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have primary Bomedemstat (IMG-7289) is a small-molecule inhibitor of Hypomethylating agents Symptom control (eg, FDA designation(s): Orphan myelofibrosis or lysine-specific demethylase 1 (LSD1). Bomedemstat is (eg, azacitidine, decitabine) splenomegaly) Drug, Fast Track myelofibrosis arising from under study for treating myelofibrosis, a JAK inhibitors (eg, Progression-free Clinical trial(s): Phase 2b polycythemia vera or myeloproliferative neoplasm in which bone marrow stem fedratinib, ruxolitinib) survival primary completion essential thrombocytopenia cells develop abnormally. Two Janus kinase (JAK) inhibitors Overall survival December 2020, interim (ruxolitinib and fedratinib) have been FDA approved for data reported December treating myelofibrosis. However, only about 50% of 2020 patients respond to these therapies and the therapies have not demonstrated a substantial effect on limiting disease progression. LSD1 plays a role in regulating gene expression by altering the histone methylation state. Bomedemstat’s inhibition of LSD1 purportedly increases methylation of specific lysine residues in histones, altering gene expression in a manner that inhibits the production of inflammatory cytokines and impairs self-renewal and proliferation of neoplastic stem cells. In clinical trials, bomedemstat is taken by mouth once daily at an unspecified dose. Developer(s): Imago Biosciences (South San Francisco, California)

Section 2. Cancer 30

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or Burosumab-twza (Crysvita) is a fully human, recombinant One or more of the Increase in osteoid Approval date: June 18, 2020 older and adults who have monoclonal antibody against FGF23, a hormone that following: surface, thickness, and FDA designation(s): Orphan fibroblast growth factor 23 regulates phosphate and vitamin D levels. TIO is a rare Phosphate supplements volume Drug (FGF23)–related disease characterized by a reduction of phosphate and (eg, aluminum phosphate, Quality of life Clinical trial(s): Phase 2 hypophosphatemia in vitamin D levels in the blood, resulting in the weakening calcium phosphate, UX023T-CL201 primary tumor-induced and softening of bones. Tumors that release high levels of magnesium phosphate) completion July 2017, data osteomalacia (TIO) FGF23 are the underlying cause of TIO. Surgical removal Vitamin D analogues (eg, presented November 2018 associated with of the tumor typically leads to a full recovery in patients calcitriol, ergocalciferol, Note(s): FDA previously phosphaturic mesenchymal with TIO; however, patients whose tumor is too small to paricalcitol) approved burosumab-twza tumors that cannot be be localized or too large or invasive to be surgically to treat X-linked curatively resected or removed have no treatment options other than hypophosphatemia localized phosphate and vitamin D supplementation. By inhibiting FGF23, burosumab-twza purportedly increases phosphate reabsorption from the kidneys and increases the production of active vitamin D, potentially improving outcomes in patients with TIO. The recommended dosage in the FDA-approved label is a subcutaneous injection starting at 0.4 mg/kg once every 2 weeks in children or 0.5 mg/kg once every 4 weeks in adults. The dosage may be increased up to 2 mg/kg, without exceeding 180 mg, once every 2 weeks until disease progression or intolerable toxicity. Developer(s): Ultragenyx Pharmaceutical, Inc (Novato, California), in collaboration with Kyowa Kirin Co, Ltd (Tokyo, Japan)

Section 2. Cancer 31

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Canakinumab (Ilaris) is a human monoclonal antibody One or more of the Overall survival Clinical trial(s): Phase 3 advanced or metastatic that binds and neutralizes the immune mediator activity following: Progression-free CANOPY-2 primary non–small cell lung cancer of human interleukin-1β (IL-1β), a member of the ALK inhibitors (eg, alectinib, survival completion February 2021; (NSCLC) of squamous or interleukin-1 (IL-1) family of cytokines. Canakinumab is crizotinib if ALK Quality of life phase 3 CANOPY-1 primary nonsquamous origin that intended as an addition to the standard of care and is rearrangement–positive; completion July 2021 has not been treated or that designed to be a selective antibody that binds with high ceritinib, crizotinib if ROS1 Note(s): FDA has approved has been previously treated affinity to IL-1β but not to any other member of the IL-1 rearrangement–positive) canakinumab to treat many with an immune checkpoint family or IL-1β from another species. Canakinumab Angiogenesis inhibitors (eg, other diseases. See the FDA- inhibitor in combination purportedly elicits an anti-inflammatory response in the bevacizumab, approved labeling and with or after platinum-based tumor microenvironment that blocks tumor proliferation ramucirumab) prescribing document for all chemotherapy and new blood vessel formation (ie, angiogenesis). Under Anthracyclines (eg, approved indications. specific conditions, IL-1β and other inflammatory doxorubicin) cytokines, which are produced primarily by tumor- associated macrophages, play a role in the growth, Antimetabolites (eg, vascularization, progression, and spread of cancer cells. In gemcitabine, pemetrexed) clinical trials, canakinumab is given as a subcutaneous EGFR inhibitors (eg, injection at an unspecified dose in combination with afatinib, erlotinib) if EGFR intravenous docetaxel at a dose of 75 mg/m2 or rearrangement–positive intravenous pembrolizumab at a dose of 200 mg plus Immune checkpoint platinum-based chemotherapy every 3 weeks until inhibitors (eg, nivolumab, disease progression or intolerable toxicity. pembrolizumab) Developer(s): Platinum-based agents (eg, Novartis AG (Basel, Switzerland) carboplatin, cisplatin) Taxanes (eg, docetaxel, paclitaxel) Tropomyosin kinase inhibitors (eg, larotrectinib) if NTRK rearrangement– positive Vinca alkaloids (eg, vinblastine, vinorelbine)

Section 2. Cancer 32

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Capmatinib (Tabrecta) is a potent and selective, small- One or more of the Overall survival Approval date: May 6, 2020 advanced or metastatic molecule inhibitor of the hepatocyte growth factor (HGF) following: Progression-free FDA designation(s): Orphan non–small cell lung cancer receptor. A receptor tyrosine kinase encoded by the MET Angiogenesis inhibitors (eg, survival Drug, Breakthrough Therapy (NSCLC) harboring an exon gene, the HGF receptor is typically required for tissue and bevacizumab, Quality of life Clinical trial(s): Phase 3 14–skipping mutation in the organ regeneration and damage repair. The incidence of ramucirumab) CINC280A2301 primary mesenchymal-epithelial MET gene alterations in patients with NSCLC, including Anthracyclines (eg, completion September 2022; transition gene, MET MET exon 14–skipping mutation and MET amplification, is doxorubicin) phase 2 GEOMETRY mono-1 about 2% to 4%. MET-driven NSCLC is an aggressive Antimetabolites (eg, primary completion disease with a poor prognosis and limited treatment gemcitabine, pemetrexed) February 2022, data options. Approved by FDA, capmatinib is a novel targeted published September 2020 therapy intended for patients harboring a MET exon 14– Immune checkpoint Note(s): This Accelerated skipping alteration. Capmatinib is designed to interact inhibitors (eg, nivolumab, Approval requires the with tyrosine 1230 and a hinge motif in the HGF receptor’s pembrolizumab) conduct of a further clinical kinase domain, which causes it to adopt a unique Platinum agents (eg, trial to verify and describe autoinhibitory shape that prevents access to its ATP carboplatin, cisplatin) capmatinib’s clinical benefit binding site. Because capmatinib is highly specific for the Taxanes (eg, docetaxel, HGF receptor, it purportedly has fewer off-target effects. paclitaxel) In NSCLC cells, capmatinib purportedly blocks new blood Vinca alkaloids (eg, vessel formation (ie, angiogenesis), proliferation, and vinblastine, vinorelbine) survival pathways by inhibiting the HGF receptor’s constitutive ligand-independent signaling. Determining eligibility for this therapy requires testing for MET mutation status. The recommended dosage in the FDA- approved label is 400 mg capmatinib taken by mouth twice daily until disease progression or intolerable toxicity. Developer(s): Novartis AG (Basel, Switzerland), licensed by Incyte Corp (Wilmington, Delaware)

Section 2. Cancer 33

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have Cediranib plus olaparib (Lynparza) is a combination drug One or more of the Overall survival Clinical trial(s): Phase 2b platinum-resistant, regimen under study for treating platinum-resistant, following: Progression-free CONCERTO primary recurrent ovarian cancer recurrent ovarian cancer. Poly adenosine diphosphate- Angiogenesis inhibitors (eg, survival completion December 2021, with no evidence of a ribose polymerase (PARP) inhibitors (eg, olaparib, bevacizumab) Quality of life data published May 2020 deleterious germline variant rucaparib) have been approved as monotherapies for Anthracyclines (eg, in the breast cancer genes recurrent ovarian cancer. However, their use is limited to doxorubicin, pegylated BRCA1 or BRCA2 patients with deleterious BRCA1 or BRCA2 variants, which liposomal doxorubicin) sensitize cancer cells to PARP inhibition. Research has Taxanes (eg, docetaxel, demonstrated that cediranib, a small-molecule tyrosine paclitaxel) kinase inhibitor with activity against multiple receptor tyrosine kinases, can also sensitize cancer cells to PARP inhibition by suppressing the homologous recombinational repair pathway. Therefore, clinical trials are investigating whether the combined use of cediranib and olaparib is effective in treating ovarian cancer in patients who lack deleterious BRCA1/2 variants. In clinical trials, patients receive oral cediranib at a dosage of 30 mg twice daily and oral olaparib at a dosage of 200 mg twice daily until disease progression or unacceptable toxicity. Developer(s): AstraZeneca (Cambridge, United Kingdom)

Section 2. Cancer 34

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen One or more of the Overall survival Submission date: Rolling and refractory multiple receptor (CAR) T-cell therapy. It is engineered to target B- following: Progression-free Biologics License Application myeloma (RRMM) that has cell maturation antigen (BCMA) using T cells isolated from Alkylating agents (eg, survival initiated December 2020 been treated with 2 or more a patient’s own blood sample. BCMA has been proposed bendamustine, Quality of life FDA designation(s): Orphan lines of therapy including a as a potential target for CAR T-cell therapy in multiple cyclophosphamide) Drug, Breakthrough Therapy protease inhibitor, myeloma (MM) because BCMA expression is limited to Anthracyclines (eg, Clinical trial(s): Phase 3 immunomodulatory agent, malignant plasma cells and nonessential normal cells (eg, doxorubicin) CARTITUDE-4 primary or anti-CD38 antibody normal plasma cells, some mature B cells). To produce Glucocorticoids (eg, completion April 2026; ciltacabtagene autoleucel, self-donated T cells are dexamethasone) phase 1/2 CARTITUDE-1 transduced with a lentiviral vector encoding CARs with 2 primary completion unique binding domains for BCMA. The BCMA CAR- Immunomodulatory agents (eg, lenalidomide, February 2022, data transduced T cells are grown in culture to increase cell presented December 2020 numbers and then reintroduced into the patient. pomalidomide) Ciltacabtagene autoleucel is intended to target malignant Monoclonal antibodies (eg, BCMA-expressing plasma cells in patients with MM and to daratumumab, promote a robust cellular immune response against these elotuzumab) cells. In clinical trials, ciltacabtagene autoleucel is given as Proteasome inhibitors (eg, a single intravenous infusion containing 7.5 × 105 BCMA bortezomib, ixazomib) CAR T cells/kg. Topoisomerase inhibitors Developer(s): (eg, etoposide) Janssen Pharmaceutical, LLC (Titusville, New Jersey), a subsidiary of Johnson & Johnson, Inc (New Brunswick, New Jersey)

Section 2. Cancer 35

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 70 years DCVax-L is intended to treat the brain cancer GBM, which Fractionated external beam Overall survival FDA designation(s): Orphan who have glioblastoma has very limited treatment options and is associated with radiation therapy Progression-free Drug multiforme (GBM) that has poor outcomes. DCVax-L is an immunotherapy made up One or more of the survival Clinical trial(s): Phase 3 GBM been surgically removed of activated dendritic cells loaded with tumor antigens following: Quality of life primary completion and treated with adjuvant derived from the patient’s own tumor. It is intended to Alkylating agents (eg, November 2016, interim radiation therapy and improve outcomes by promoting an immune response cyclophosphamide, data published May 2018, 3- chemotherapy against residual glioblastoma cells after surgical tumor lomustine, procarbazine) year survival data reported removal. DCVax-L uses monocytes obtained from the Angiogenesis inhibitors (eg, November 2018, top-line patient’s withdrawn blood; the remainder of the blood is bevacizumab) data expected in the second returned to the patient in a process known as quarter of 2021 leukapheresis. In manufacturing, the monocytes are mTOR inhibitors (eg, differentiated into dendritic cells in a laboratory and then everolimus) activated and loaded with patient-derived antigens from Platinum agents (eg, the patient’s tumor tissue after surgical resection. The carboplatin, cisplatin) purified DCVax-L is then given to the patient to elicit Vinca alkaloids (eg, adaptive immunity from T cells and B cells. Treatment vincristine) begins at least 2 weeks before the first course of DCVax-L is given and involves total or near total tumor resection followed by conventional external beam radiation therapy and concurrent temozolomide chemotherapy. In clinical trials, DCVax-L containing 2.5 × 106 tumor lysate–pulsed dendritic cells is given as an intradermal injection in the upper arm at days 0, 10, and 20 and at weeks 8, 16, 32, 48, 72, 96, and 120. Developer(s): Northwest Biotherapeutics, Inc (Bethesda, Maryland)

Section 2. Cancer 36

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 50 years or Devimistat (CPI-613) is intended to provide a new One or more of the Overall survival FDA designation(s): Orphan older who have relapsed or treatment option for patients with AML, who have very following: Progression-free Drug, Fast Track refractory acute myeloid limited options and poor outcomes. Devimistat is a small- Anthracyclines (eg, survival Clinical trial(s): Phase 3 leukemia (AML) molecule lipoate analogue drug intended to target the daunorubicin, idarubicin) Quality of life ARMADA 2000 primary altered energy metabolism unique to many cancers, Antibody-drug conjugate completion October 2022 including AML. This altered energy metabolism frequently (eg, gemtuzumab depends on the activity of the pyruvate dehydrogenase ozogamicin) complex and the α-ketoglutarate dehydrogenase Antimetabolites (eg, complex. Devimistat purportedly inhibits the catalytic and cladribine, fludarabine) regulatory functions of these key cancer pathways, leading to tumor cell death. In clinical trials, devimistat is Cytokine (eg, granulocyte being tested in combination with a standard induction colony-stimulating factor regimen of high-dose cytarabine and mitoxantrone. [G-CSF]) Devimistat 2000 mg/m2 is given intravenously on days 1 to DNA synthesis inhibitors 5 of the induction regimen. (eg, etoposide, Developer(s): mitoxantrone) Rafael Pharmaceuticals, Inc (Cranbury, New Jersey) FLT3 inhibitor (eg, gilteritinib) Hypomethylating agents (eg, azacitidine, decitabine) IDH inhibitors (eg, enasidenib, ivosidenib) Multikinase inhibitor (eg, sorafenib)

Section 2. Cancer 37

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years Devimistat (CPI-613) is intended to treat pancreatic cancer One or more of the Overall survival FDA designation(s): Orphan who have pancreatic in the first-line setting, because only about 5% of these following: Progression-free Drug, Fast Track adenocarcinoma with patients respond to the standard of care (ie, gemcitabine Antimetabolites (eg, 5- survival Clinical trial(s): Phase 3 distant metastases that chemotherapy). Devimistat is a small-molecule lipoate fluorouracil, gemcitabine) Quality of life AVENGER 500 primary have not been treated analogue drug intended to target the altered energy Chemoprotectant (eg, completion April 2021 metabolism of many cancers, including pancreatic leucovorin) adenocarcinomas. This altered energy metabolism DNA synthesis inhibitor (eg, frequently depends on the activity of the pyruvate irinotecan) dehydrogenase complex and the α-ketoglutarate dehydrogenase complex. Devimistat purportedly EGFR inhibitor (eg, downregulates metabolic pathways in cancer cells that erlotinib) depend on α-ketoglutarate and acetyl-CoA. In clinical Platinum-based agents (eg, trials, devimistat is given by intravenous injection at a cisplatin, oxaliplatin) dosage of 500 mg/m2 on days 1 and 3 of a 14-day cycle, Taxanes (eg, docetaxel, followed immediately by intravenous modified paclitaxel) FOLFIRINOX (ie, leucovorin [folinic acid] at 400 mg/m2, 5- fluorouracil at 400 mg/m2, irinotecan at 140 mg/m2, and oxaliplatin at 65 mg/m2). Developer(s): Rafael Pharmaceuticals, Inc (Cranbury, New Jersey)

Adults who have recurrent Dianhydrogalactitol (VAL-083) is a small-molecule drug One or more of the Overall survival FDA designation(s): Orphan malignant glioma (eg, that causes N7 DNA alkylation. It is intended to treat following: Progression-free Drug, Fast Track glioblastoma multiforme recurrent malignant gliomas, which often become Alkylating agents (eg, survival Clinical trial(s): Phase 2/3 [GBM]) resistant to standard-of-care temozolomide therapy carmustine, Quality of life GBM AGILE primary because the tumor expresses high levels of an enzyme cyclophosphamide, completion December 2022; (O6-methylguanine-DNA-methyltransferase [MGMT]) that procarbazine) phase 2 DLM-16-001 primary helps repair DNA. VAL-083’s novel N7 DNA alkylation Angiogenesis inhibitors (eg, completion September 2020, activity is intended to overcome MGMT-mediated bevacizumab) data published December resistance. In clinical trials, VAL-083 is given as an mTOR inhibitors (eg, 2019, data reported intravenous infusion at a dosage of 30 mg/m2 on days 1, everolimus) November 2020 2, and 3 of a 21-day treatment cycle, for up to twelve 21- day treatment cycles. Platinum-based drugs (eg, carboplatin, cisplatin) Developer(s): Vinca alkaloids (eg, Kintara Therapeutics, Inc (San Diego, California) vincristine)

Section 2. Cancer 38

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have recurrent Eflornithine (α-difluoromethylornithine [DFMO]) is a small- One or more of the Overall survival FDA designation(s): Orphan grade 3 anaplastic molecule, irreversible inhibitor of the enzyme ornithine following: Progression-free Drug, Breakthrough Therapy astrocytoma (AA) after decarboxylase (ODC). ODC is involved in synthesis of Alkylating agents (eg, survival Clinical trial(s): Phase 3 radiation therapy and polyamines, which are essential for cell proliferation. AA is lomustine, temozolomide) Quality of life STELLAR primary completion adjuvant temozolomide a rare type of glioma, a tumor that occurs in the brain and Angiogenesis inhibitors (eg, December 2021 treatment spinal cord, originating from cells called astrocytes that bevacizumab) surround and protect neurons. Eflornithine’s inhibition of Vinca alkaloids (eg, ODC purportedly causes a cytostatic effect in rapidly vincristine) dividing cells, slowing growth of AA tumors. This novel mechanism of action has the potential to improve health outcomes in patients with recurrent AA, a patient population with few effective treatment options and poor prognosis. In clinical trials, eflornithine is taken by mouth at a dosage of 2.8 g/m2 every 8 hours in a 2-weeks-on, 1- week-off schedule in combination with oral lomustine at a dosage of 90 mg/m2 once every 6 weeks. Developer(s): Orbus Therapeutics, Inc (Palo Alto, California)

Section 2. Cancer 39

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Eryaspase (ERY001) consists of l-asparaginase One or more of the Overall survival FDA designation(s): Fast advanced or metastatic encapsulated inside donor-derived red blood cells to treat following: Progression-free Track pancreatic cancer that has metabolically active tumors. Pancreatic cancer is a Antimetabolites (eg, 5- survival Clinical trial(s): Phase 3 been treated with at least metabolically active disease associated with a poorer fluorouracil, capecitabine, Quality of life TRYbeCA-1 primary one previous line of prognosis when compared with other cancer types gemcitabine) completion August 2021 systemic therapy because of a lack of effective treatment options. L- Chemoprotectant (eg, asparaginase is an enzyme that hydrolyzes the amino acid leucovorin) asparagine into aspartic acid and ammonia, which inhibits DNA synthesis inhibitor (eg, protein synthesis. Eryaspase-mediated depletion of irinotecan) asparagine purportedly arrests cell proliferation and induces programmed cell death (ie, apoptosis). Platinum-based agents (eg, Encapsulating l-asparaginase in donor red blood cells oxaliplatin) purportedly prolongs activity and decreases adverse Taxanes (eg, albumin- events. In clinical trials, eryaspase is given as an bound paclitaxel) intravenous infusion at a dosage of 100 units/kg every 2 weeks in combination with chemotherapy until disease progression or unacceptable toxicity. Developer(s): Erytech Pharma SA (Lyon, France)

Section 2. Cancer 40

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Eryaspase (ERY001) consists of l-asparaginase One or more of the Overall survival Clinical trial(s): Phase 2/3 advanced or metastatic encapsulated inside donor-derived red blood cells to treat following: Progression-free TRYbeCA-2 primary triple-negative breast cancer metabolically active tumors. TNBC is a metabolically active Alkylating agents (eg, survival completion December 2020 (TNBC) and have had no cancer associated with a poorer prognosis when cyclophosphamide) Quality of life previous systemic therapy compared with other breast cancer subtypes because of a Anthracyclines (eg, lack of effective treatment options. L-asparaginase is an doxorubicin) enzyme that hydrolyzes the amino acid asparagine into Antimetabolites (eg, aspartic acid and ammonia, which inhibits protein capecitabine, gemcitabine) synthesis. Eryaspase-mediated depletion of asparagine purportedly arrests cell proliferation and induces Immune checkpoint programmed cell death (ie, apoptosis). Encapsulating l- inhibitors (eg, asparaginase in donor red blood cells purportedly atezolizumab) for patients prolongs activity and decreases adverse events. In clinical with tumors expressing trials, eryaspase is given as an intravenous infusion at a programmed cell death dosage of 100 units/kg on days 1 and 8 of a 3-week cycle ligand 1 (PD-L1) until disease progression or unacceptable toxicity, in Poly adenosine combination with gemcitabine (1000 mg/m2) plus diphosphate-ribose carboplatin (AUC 2). polymerase (PARP) Developer(s): inhibitors (eg, niraparib, olaparib) for patients with Erytech Pharma SA (Lyon, France) BRCA1/2 mutations Taxanes (eg, docetaxel, paclitaxel) Vinca alkaloid (eg, vinorelbine)

Section 2. Cancer 41

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Fam-trastuzumab deruxtecan-nxki (Enhertu) is a One or more of the Overall survival Clinical trial(s): Phase 3 advanced or metastatic, monoclonal antibody conjugated with a chemotherapy following: Progression-free DESTINY-Breast06 primary hormone receptor (HR)– drug (ie, deruxtecan). The conjugated drug is designed to Alkylating agents (eg, survival completion December 2022; positive or HR-negative, bind the surface receptor HER2, a protein commonly cyclophosphamide) Quality of life phase 3 DESTINY-Breast04 human epidermal growth associated with certain subtypes of breast cancer. Front- Anthracyclines (eg, primary completion January factor receptor 2 (HER2)–low line therapy for breast cancers expressing low HER2 levels doxorubicin, epirubicin, 2023 breast cancer that has relies on single-agent chemotherapy, but no therapies are liposomal doxorubicin) Note(s): FDA approved fam- progressed or recurred after approved specifically for low HER2–expressing tumors; Antimetabolites (eg, 5- trastuzumab deruxtecan- one or two lines of therapy fam-trastuzumab deruxtecan-nxki might provide a new fluorouracil, capecitabine, nxki to treat HER2-positive option for these patients. Deruxtecan inhibits the activity gemcitabine, methotrexate, breast cancer in December of topoisomerase I, an enzyme that relieves DNA pemetrexed) 2019 supercoiling, leading cells to cease their cell cycle and die because of replication-dependent, site-selective, DNA Immune checkpoint double-strand breaks. Fam-trastuzumab deruxtecan-nxki inhibitors (eg, purportedly binds to HER2 and triggers internalization of atezolizumab) the drug into the cells. This increases the likelihood that Microtubule inhibitors (eg, deruxtecan will target and kill malignant cells while eribulin, ixabepilone) minimizing toxicity on normal cells. In clinical trials, fam- Platinum agents (eg, trastuzumab deruxtecan-nxki is given intravenously at a carboplatin, cisplatin) dosage of 5.4 mg/kg once every 21 days until disease Poly adenosine progression or intolerable toxicity. diphosphate-ribose Developer(s): polymerase (PARP) Daiichi Sankyo Co, Ltd (Tokyo, Japan), in collaboration with inhibitors (eg, olaparib, AstraZeneca (Cambridge, United Kingdom) talazoparib) Taxanes (eg, docetaxel, nab-paclitaxel, paclitaxel) Vinca alkaloids (eg, vinorelbine)

Section 2. Cancer 42

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed Galinpepimut-S is a therapeutic cancer vaccine under Hypomethylating agents Overall survival FDA designation(s): Orphan acute myeloid leukemia study that targets the WT1 antigen to treat AML. (eg, azacitidine, decitabine) Progression-free Drug, Fast Track (AML) in complete remission Treatments for AML frequently achieve complete survival Clinical trial(s): Phase 3 after second-line induction remission, which is characterized by normalized blood Quality of life REGAL primary completion therapy, who are ineligible counts and no evidence of leukemic blasts in the bone December 2021 to receive an allogeneic marrow. However, even with subsequent therapy after stem cell transplant, and remission, AML frequently recurs. In particular, older whose leukemic cells patients ineligible for intensive consolidation therapy (eg, express the Wilms tumor allogeneic hematopoietic stem cell transplantation protein (WT1) antigen [HSCT]) experience relapse at a rate as high as 70% to 80%. WT1 is a protein overexpressed by a variety of malignancies, including AML. Galinpepimut-S is a multivalent WT1 peptide vaccine composed of 4 WT1- derived peptides designed to elicit CD4+ and CD8+ T-cell responses against WT1-expressing cancer cells. In clinical trials, galinpepimut-S is given in 3 phases over the course of 1 year: induction phase of 6 injections, 1 every 2 weeks; early booster phase of 6 injections, 1 every 4 weeks; and late booster phase of 6 injections, 1 every 6 weeks. Each galinpepimut-S administration is preceded by an injection of an immune stimulator (70 mg sargramostim). Developer(s): Sellas Life Sciences Group (New York, New York)

Section 2. Cancer 43

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed Idecabtagene vicleucel (ide-cel) is a chimeric antigen One or more of the Overall survival PDUFA date: March 27, 2021; and refractory multiple receptor (CAR) T-cell therapy. It is engineered to target B- following: Progression-free Priority Review myeloma (RRMM) that has cell maturation antigen (BCMA) using T cells isolated from Alkylating agents (eg, survival FDA designation(s): Orphan been treated with 3 or more a patient’s own blood sample. Patients whose disease has bendamustine, Quality of life Drug, Breakthrough Therapy lines of chemotherapy that progressed after 3 treatment lines have a very poor cyclophosphamide) Clinical trial(s): Phase 2 included a protease prognosis and no options. In this therapy, the collected T Anthracyclines (eg, KarMMa primary completion inhibitor, an cells are genetically modified with a lentiviral vector (ie, doxorubicin) November 2024, data immunomodulatory agent, transduction) encoding CARs with a unique anti-BCMA Glucocorticoids (eg, reported December 2019, and an anti-CD38 antibody single-chain variable fragment (ie, BB2121) fused to the dexamethasone) data presented May 2020; hinge and transmembrane domains of CD8α, the Immunomodulatory agents phase 3 KarMMa-3 primary costimulatory domain (ie, 4-1BB) of CD137, and the completion May 2022 signaling domains of CD3ζ. The BB2121 CAR-transduced T (eg, lenalidomide, cells that compose idecabtagene vicleucel are proliferated pomalidomide, and then reintroduced into the patient. The treatment thalidomide) purportedly targets malignant BCMA-expressing plasma Monoclonal antibodies (eg, cells in patients with multiple myeloma cells and daratumumab, promotes robust cellular activity against these cells to elotuzumab) treat the disease. BCMA has been proposed as a Proteasome inhibitors (eg, biomarker for targeting multiple myeloma because it is bortezomib, carfilzomib, highly expressed in malignant plasma cells. In clinical ixazomib) trials, idecabtagene vicleucel is given as a single Topoisomerase inhibitors 8 intravenous infusion at a dose ranging from 1.5 × 10 to (eg, etoposide) 4.5 × 108 anti-BCMA CAR T cells. Developer(s): bluebird bio, Inc (Cambridge, Massachusetts), in collaboration with Bristol Myers Squibb Co (New York, New York)

Section 2. Cancer 44

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have low- or Imetelstat, an oligonucleotide inhibitor of the RNA protein Hypomethylating agents Red blood cell FDA designation(s): Orphan intermediate-risk complex telomerase, is under study for treating MDS. (eg, azacitidine, decitabine) transfusion Drug, Fast Track myelodysplastic syndrome Lower-risk MDS that no longer responds to ESAs has few Lenalidomide dependence Clinical trial(s): Phase 2/3 (MDS), are transfusion treatment options, and available treatments have limited Luspatercept-aamt Overall survival iMerge primary completion dependent, and no longer efficacy. Telomerase is responsible for maintaining August 2022, data published respond to erythropoiesis- telomeres, structures at chromosome ends required for October 2020 stimulating agents (ESAs). chromosome stability. In the absence of telomerase Patients must not harbor a activity, telomeres shorten with each cell division, which deletion on the long arm of limits the number of times a cell can divide. Many cancers chromosome 5 and must overcome this limitation of cell proliferation by not have been previously overexpressing telomerase, which maintains telomere treated with length. Imetelstat is an oligonucleotide complementary to hypomethylating agents or the template region of the RNA component of telomerase lenalidomide. that purportedly acts as a direct, competitive inhibitor of telomerase activity. In clinical trials, imetelstat (7.5 mg/kg) is given intravenously once every 4 weeks. Developer(s): Geron Corp (Foster City, California)

Section 2. Cancer 45

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 years or Iomab-B (apamistamab-I-131) is an antibody-radiation One or more of the Overall survival FDA designation(s): Orphan older who have active, conjugate composed of the CD45-specific monoclonal following: Progression-free Drug relapsed, or refractory acute antibody apamistamab linked to the radioisotope iodine- Anthracyclines (eg, survival Clinical trial(s): Phase 3 myeloid leukemia (AML) 131. AML is the most common type of acute leukemia, daunorubicin, idarubicin) Quality of life SIERRA primary completion with leukemic cells and patients with relapsed or refractory AML have limited Antibody-drug conjugates December 2021, data expressing CD45 treatment options and poor outcomes. Iomab-B is under (eg, gemtuzumab presented December 2020 study for use as an induction and conditioning agent ozogamicin) before hematopoietic stem cell transplantation (HSCT) or Antimetabolites (eg, other cellular therapies. Apamistamab binds to CD45, a cytarabine, fludarabine) receptor purportedly involved in promoting AML cell proliferation, leading to Iomab-B cell internalization and BCL-2 inhibitors (eg, leukemic cell death through targeted radiation delivery. In venetoclax) clinical trials, Iomab-B is given as a component of a DNA synthesis inhibitors reduced-intensity conditioning regimen containing (eg, etoposide, fludarabine and low-dose total body irradiation before mitoxantrone) allogeneic HSCT. FLT3 inhibitors (eg, Developer(s): gilteritinib, sorafenib) Actinium Pharmaceuticals, Inc (New York, New York) Hypomethylating agents (eg, azacitidine, decitabine) IDH inhibitors (eg, enasidenib, ivosidenib)

Section 2. Cancer 46

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed or Ivosidenib (Tibsovo) is a small-molecule inhibitor of a Immunomodulatory agents Complete response FDA designation(s): Orphan refractory myelodysplastic mutated form of the enzyme isocitrate dehydrogenase 1 (eg, lenalidomide) rate Drug, Breakthrough Therapy syndrome (MDS) with a (IDH1), known to occur in about 3% of patients with MDS. Overall survival Clinical trial(s): Phase 1 susceptible IDH1 gene Limited treatment options exist, and there is no standard Quality of life primary completion mutation of care for MDS that is unresponsive to treatment with a December 2020; phase 2 hypomethylating agent. The mutant form of IDH1 causes primary completion January accumulation of the oncometabolite D-2-hydroxyglutarate 2022 and a decrease in the levels of IDH1’s normal metabolite, Note(s): FDA has approved α-ketoglutarate. These shifts purportedly have multiple ivosidenib to treat acute effects (eg, histone modification, DNA methylation) that myeloid leukemia (AML) with keep cells in the dedifferentiated state characteristic of a susceptible IDH1 gene MDS cells. Inhibiting the mutated form of IDH1 with mutation as detected by an ivosidenib purportedly causes differentiation of MDS cells, FDA-approved test reducing malignancy. Ivosidenib is taken daily as a 500-mg oral tablet. Developer(s): Agios Pharmaceuticals, Inc (Cambridge, Massachusetts)

Adults with primary KRT-232 is a small-molecule inhibitor of mouse double Hypomethylating agents Symptom control (eg, FDA designation(s): Orphan myelofibrosis or minute 2 homologue (MDM2) under study for treating (eg, azacitidine, decitabine) splenomegaly) Drug myelofibrosis arising from myelofibrosis. In myelofibrosis, a myeloproliferative Progression-free Clinical trial(s): Phase 2a/2b polycythemia vera or neoplasm, bone marrow stem cells develop abnormally. survival primary completion essential thrombocytopenia Two JAK inhibitors (ruxolitinib and fedratinib) have been Overall survival December 2023, data who have previously FDA approved to treat myelofibrosis; however, only about presented August 2020; received treatment with a 50% of patients respond to these therapies, and the phase 1/2 primary JAK inhibitor or in whom a therapies have not been shown to substantially limit completion October 2022 JAK inhibitor is inducing a disease progression. MDM2 is an E3 ubiquitin ligase that suboptimal response marks the tumor suppressor p53 for degradation by the proteasome. Upregulation of MDM2 in myeloproliferative neoplasms is thought to protect cells from p53-directed programmed cell death. KRT-232 purportedly interferes with MDM2-p53 binding, thereby blocking MDM2- mediated p53 degradation. In clinical trials, KRT-232 is taken by mouth once daily at a dosage of 120 or 240 mg on days 1 through 5 or 7 of a 21- or 28-day cycle. Developer(s): Kartos Therapeutics (Redwood City, California)

Section 2. Cancer 47

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Lifileucel (LN-144) is a T-cell therapy that uses cells One or more of the Overall survival Submission date: Biologics advanced or metastatic isolated from the patient’s own melanoma tumor. following: Progression-free License Application planned melanoma that has Lifileucel uses a personalized therapy strategy that relies Alkylating agents (eg, survival for 2021 progressed after one or on naturally occurring T cells, called tumor-infiltrating dacarbazine, Quality of life FDA designation(s): Orphan more lines of standard lymphocytes (TILs), that can penetrate cancerous tumors. temozolomide) Drug, Fast Track, systemic therapy TILs isolated from a patient’s tumor are grown in culture BRAF inhibitors (eg, Regenerative Medicine until reaching a count of billions of cells. Lifileucel is dabrafenib, vemurafenib) Advanced Therapy intended as a tumor-specific therapy to overcome the Immunotherapy (eg, Clinical trial(s): Phase 2 C- tumor’s immune-suppressive environment and promote ipilimumab, nivolumab, 144-01 primary completion its elimination. In clinical trials, lifileucel is given as an pembrolizumab) July 2020, data presented intravenous infusion followed by up to 6 doses of May 2020 interleukin-2 (IL-2) to support growth and activation of MEK inhibitors (eg, TILs. trametinib) Developer(s): Platinum-based agents (eg, carboplatin) Iovance Biotherapeutics, Inc (San Carlos, California), in collaboration with the National Institutes of Health’s Taxane agents (eg, National Cancer Institute (Bethesda, Maryland) paclitaxel)

Section 2. Cancer 48

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have Lifileucel (LN-145) is a T-cell therapy that uses cells One or more of the Overall survival Submission date: Biologics recurrent, metastatic, or isolated from the patient’s own cervical cancer. Lifileucel following: Disease-free survival License Application planned persistent cervical cancer uses a personalized therapy strategy that relies on Alkylating agents (eg, Quality of life for the second half of 2020 that is unsuitable for naturally occurring T cells, called tumor-infiltrating ifosfamide) FDA designation(s): surgical resection and/or lymphocytes (TILs), that can penetrate cancerous tumors. Angiogenesis inhibitors (eg, Breakthrough Therapy, Fast radiation therapy. Patients TILs isolated from a patient’s tumor are grown in culture bevacizumab) Track must have received at least until reaching a count of billions of cells. Lifileucel is Antimetabolites (eg, 5- Clinical trial(s): Phase 2 1 and no more than 3 prior intended as a tumor-specific therapy that can overcome fluorouracil, gemcitabine, innovaTIL-04 primary systemic therapy regimens. the tumor’s immune-suppressive environment and pemetrexed) completion December 2021, promote its elimination. In clinical trials, lifileucel is given data presented May 2019 as an intravenous infusion followed by up to 6 doses of DNA synthesis inhibitors interleukin-2 (IL-2) to support growth and activation of (eg, mitomycin-C) TILs. Immune checkpoint Developer(s): inhibitor (eg, pembrolizumab) Iovance Biotherapeutics, Inc (San Carlos, California) Taxanes (eg, albumin- bound paclitaxel, docetaxel) Topoisomerase inhibitors (eg, irinotecan)

Section 2. Cancer 49

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males who have 177Lu-PSMA-617 is a novel small-molecule radioligand Supportive care Overall survival Clinical trial(s): Phase 3 progressive prostate- therapy. It is made up of a high-affinity targeting ligand Progression-free VISION primary completion specific membrane antigen specific to PSMA that is chemically linked with a survival April 2021 177 177 (PSMA)–positive, metastatic, radionucleotide called lutetium-177 ( Lu). Lu-PSMA- Time to first castration-resistant prostate 617 is intended to deliver systemic and targeted radiation, symptomatic skeletal cancer (mCRPC) causing cell death to prostate cancer cells. PSMA protein event is highly expressed on the surface of most prostate cancer Quality of life cells but absent on most normal cells. Eligibility for treatment requires a positive result from a 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) scan. After 177Lu-PSMA-617 purportedly attaches to prostate cancer cells via binding to PSMA, the 177Lu component emits beta-particle radiation intended to induce cytotoxic DNA damage to the tumor cells. In clinical trials, 177Lu-PSMA-617 is given intravenously at a dosage of 7.4 GBq (± 10%) every 6 weeks for a maximum of 6 cycles. Developer(s): Novartis AG (Basel, Switzerland)

Section 2. Cancer 50

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have extensive- Lurbinectedin (Zepzelca) is a synthetic, marine-derived Chemoradiation therapy Overall survival Approval date: June 15, 2020 stage small cell lung cancer compound that selectively inhibits transactivated RNA Platinum-based agents (eg, Progression-free FDA designation(s): Orphan (SCLC) refractory to a single polymerase (Pol) II transcription. Patients with SCLC that carboplatin, cisplatin) survival Drug platinum-containing no longer responds to platinum chemotherapy have Topoisomerase inhibitors Quality of life Clinical trial(s): Phase 3 regimen limited treatment options and a poor prognosis. An FDA- (eg, etoposide, topotecan) ATLANTIS completed approved drug, lurbinectedin selectively inhibits RNA Pol II February 2020, data activity during the elongation phase of messenger RNA reported February 2021; (mRNA) synthesis. Although lurbinectedin interacts with phase 2 PM1183-B-005-14 RNA Pol II, it does not affect the activity of RNA Pol I, primary completion January mitochondrial RNA Pol, or basal transcription machinery. 2021, data presented June Lurbinectedin’s binding to RNA Pol II and inhibition of 2019, data published March mRNA synthesis purportedly induces cancer cell death by 2020 reducing the expression of cellular factors involved in Note(s): New Drug tumor progression. The recommended dosage in the FDA- Application filed under approved label is intravenous administration over 60 Accelerated Approval minutes of 3.2 mg/m2 every 21 days; the label also notes regulations to consider premedication with corticosteroids and serotonin antagonists. Developer(s): Pharma Mar SA (Madrid, Spain), in collaboration with Jazz Pharmaceuticals plc (Dublin, Ireland)

Section 2. Cancer 51

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults with newly diagnosed Magrolimab (Hu5F9-G4) is a CD47-specific monoclonal Azacitidine Overall survival FDA designation(s): Orphan intermediate-, high-, or very- antibody under study for treating patients with newly Decitabine Progression-free Drug, Fast Track, high-risk myelodysplastic diagnosed MDS. Patients with high-risk MDS treated with survival Breakthrough Therapy syndrome (MDS) standard-of-care azacitidine have a median time to Health-related quality Clinical trial(s): Phase 3 leukemic transformation or death of less than 2 years. A of life primary completion April protein, CD47 purportedly functions in an innate immune 2022 checkpoint pathway in which CD47 inhibits the phagocytic activity of macrophages, preventing the macrophages from ingesting and digesting CD47-expressing cells. High- risk MDS cells have been shown to express elevated CD47 levels, which may sensitize these cells to CD47 blockade with magrolimab. Additionally, preclinical studies have shown that use of magrolimab in combination with the chemotherapy drug azacitidine increased macrophage- induced phagocytosis of malignant cells to levels higher than that for either drug alone. Therefore, investigators are studying the combination of magrolimab and azacitidine for treating MDS. In clinical trials, patients receive intravenous magrolimab in combination with standard intravenous or subcutaneous azacitidine. Magrolimab is given at escalating doses during 28-day cycles 1 and 2, followed by 30 mg/kg every 2 weeks for subsequent cycles. Developer(s): Gilead Sciences, Inc (Foster City, California)

Section 2. Cancer 52

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have a recurrent MDNA55 is a cytokine that specifically targets the One or more of the Overall survival FDA designation(s): Orphan malignant glioma (eg, interleukin-4 receptor (IL-4R). A surface receptor, IL-4R is following: Progression-free Drug, Fast Track astrocytoma, glioblastoma reportedly overexpressed in different types of cancer Alkylating agents (eg, survival Clinical trial(s): Phase 3 trial multiforme [GBM]) stem cells, including those in GBM tumors. MDNA55 cyclophosphamide, Quality of life planned; phase 2 MDNA55- offers a novel approach for treating IL-4R-expressing temozolomide) 05 completed October 2019, tumors, because the brain cancer GBM does not respond Angiogenesis inhibitors (eg, data presented May 2020 well to standard therapy. MDNA55 is a genetically bevacizumab) engineered fusion protein composed of a circularly mTOR inhibitors (eg, permuted interleukin-4 molecule fused to the catalytic everolimus) domain of the bacterial Pseudomonas aeruginosa exotoxin A (PE) protein. The fusion protein functions as a molecular Platinum agents (eg, decoy by binding IL-4R and triggering receptor-mediated carboplatin, cisplatin) cell take-up (ie, endocytosis) to deliver the cytotoxic PE Vinca alkaloids (eg, payload into the cytoplasm. MDNA55 purportedly has vincristine) high specificity and affinity for IL-4R-expressing tumors to deliver cell-killing payloads to cancer stem cells and immunosuppressive cells of the tumor microenvironment. MDNA55 has the potential to not only kill the tumor cells but also “unblind” the immune system to cancer. MDNA55 is given as an infusion via convection-enhanced delivery (CED). Purportedly providing a safer, targeted delivery, CED uses a pressure gradient at the infusion catheter’s tip to push the therapeutic agent across the blood-brain barrier, through the brain’s interstitial spaces, and to the delivery site. In clinical trials, MDNA55 is infused at a single, unspecified dose. Developer(s): Medicenna Therapeutics Corp (Toronto, Ontario, Canada)

Section 2. Cancer 53

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have ocular Melphalan/Hepatic Delivery System (HDS) is a catheter- Cryoablation Overall survival Clinical trial(s): Phase 3 melanoma metastases in based system used to percutaneously deliver the Embolization Progression-free FOCUS primary completion the liver parenchyma bifunctional alkylating agent melphalan to the liver while (chemotherapy, survival May 2021, designed under protecting the patient’s body from the toxicity of high- immunotherapy, radiation) Quality of life Special Protocol Assessment dose chemotherapy. Blood exiting the liver is filtered Thermal ablation outside the body to remove melphalan before being returned to the patient. The procedure purportedly exposes liver metastases to high-dose chemotherapy while minimizing systemic exposure. It is intended to benefit patients with unresectable, hepatic-dominant ocular melanoma, who lack effective treatment options. In clinical trials, patients receive up to 6 rounds of melphalan infusion directly into the liver at a dose of 3 mg/kg using the HDS over 30 minutes followed by a 30-minute washout. Treatments are given 6 weeks apart with a potential delay of another 2 weeks before the next planned treatment to allow for recovery of melphalan- related toxicity, if needed. Developer(s): Delcath Systems, Inc (Queensbury, New York)

Section 2. Cancer 54

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 74 years Metformin is a biguanide drug (ie, a drug class that Active surveillance Disease-free survival Clinical trial(s): Phase 3 MA32 without diabetes mellitus prevents glucose production in the liver) often used to Overall survival primary completion who have localized breast treat type 2 diabetes mellitus (T2DM). Some researchers Quality of life February 2022 cancer that has been think the drug might benefit patients who have breast treated surgically, followed cancer, because retrospective studies of patients with by neoadjuvant or adjuvant diabetes taking metformin and window-of-opportunity chemotherapy studies in the neoadjuvant breast cancer setting have shown that metformin might have anticancer effects. Metformin purportedly exerts its anticancer effects by activating adenosine monophosphate (AMP)–activated protein kinase, which limits downstream components of the mTOR pathway. Additionally, metformin’s actions in reducing circulating insulin levels and improving insulin resistance in patients without diabetes might have anticancer effects because of insulin’s potential growth- stimulating activity. In clinical trials, metformin is being taken by mouth at a dosage of 850 mg twice daily for up to 5 years in the absence of disease progression. Developer(s): Canadian Cancer Trials Group (Kingston, Ontario, Canada)

Section 2. Cancer 55

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults with von Hippel– MK-6482 (formerly PT2977) is a small-molecule, hypoxia- Multikinase inhibitors (eg, Overall response rate FDA designation(s): Orphan Lindau (VHL) disease, based inducible factor-2 alpha (HIF-2α) inhibitor. It is intended to pazopanib, sunitinib; off- Overall survival Drug, Breakthrough Therapy on a germline alteration in treat VHL disease–associated clear cell renal cell label) Progression-free Clinical trial(s): Phase 2 6482- the VHL gene and at least carcinoma (ccRCC) and improve overall survival and Surgery survival 004 primary completion one measurable solid renal quality of life in the intended population. Currently, Time to surgery March 2022, data presented cell carcinoma surgery is the standard of care for patients with localized September 2020 disease. However, tumors can recur and repeated Quality of life surgeries may be needed. VHL disease is a rare genetic syndrome that occurs when the tumor suppressor protein VHL is inactivated, leading to accumulation of HIF proteins inside the tumor cells. MK-6482 purportedly inhibits HIF- 2α, which is responsible for driving the formation of blood vessels and tumor growth in renal cells. DNA testing for VHL gene mutation is needed to determine the patient’s eligibility before starting this treatment. In phase 2 clinical trials, MK-6482 is taken by mouth at a dosage of 120 mg once daily. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 56

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 78 years Motixafortide (BL-8040) is a high-affinity antagonist for the Stem cell transplantation Overall survival Clinical trial(s): Phase 3 who have newly diagnosed CXC chemokine receptor 4 (CXCR4). This receptor is after high-dose Progression-free GENESIS primary completion multiple myeloma (MM) and overexpressed in about 70% of cancers, including MM, chemotherapy with one or survival April 2019, results reported are eligible for autologous and is associated with disease severity. Motixafortide is more of the following: Quality of life October 2020 stem cell transplantation intended to mobilize hematopoietic stem cells (HSCs) for Alkylating agents (eg, (SCT) autologous (ie, self-donated) transplantation and delay bendamustine, MM progression after primary high-dose therapy. cyclophosphamide) Motixafortide is a biostable, synthetic, cyclic peptide with Anthracyclines (eg, 14 amino acid residues that binds CXCR4 with high doxorubicin) affinity. Expression of CXCR4 in CD34+ HSCs is directly Glucocorticoids (eg, involved in their retention in the bone marrow via binding dexamethasone) to the CXCL12 chemokine protein. However, in MM, CXCR4 expression is also involved in tumor progression, Immunomodulatory agents new blood vessel growth, metastasis, and cell survival. As (eg, lenalidomide, a CXCR4 antagonist, motixafortide purportedly leads to pomalidomide, the mobilization of CD34+ HSCs, MM cells, and immune thalidomide) cells into peripheral blood. Although mobilized CD34+ Proteasome inhibitors (eg, HSCs can be collected through apheresis for autologous bortezomib, carfilzomib, transplantation, mobilized MM cells are no longer ixazomib) protected in the bone marrow and are sensitive to Topoisomerase inhibitors maintenance therapy after transplantation. In clinical (eg, etoposide) trials, motixafortide is given as a single under-the-skin injection at a dosage of 1.25 mg/kg on day 1 in combination with granulocyte colony-stimulating factor (G-CSF) injected at a dosage of 10 µg/kg daily for 5 days. If initial treatment does not result in enough mobilized CD34+ HSCs needed for autologous transplantation (≥6 × 106 cells/kg), treatment can be extended up to 2 days for motixafortide and up to 8 days for G-CSF. Developer(s): BioLineRx, Ltd (Modi’in, Israel), in collaboration with Biokine Therapeutics, Ltd (Rehovot, Israel)

Section 2. Cancer 57

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have bacillus N-803 (Anktiva) is a novel interleukin-15 (IL-15) One or more of the Overall survival FDA designation(s): Fast Calmette-Guérin (BCG)– superagonist complex. NMIBC is unresponsive to following: Progression-free Track, Breakthrough Therapy unresponsive, high-grade, standard BCG treatment in about half of affected patients, Anthracyclines (eg, survival Clinical trial(s): Phase 2/3 non–muscle invasive whose disease then progresses. N-803 is intended to epirubicin, valrubicin) Quality of life QUILT-3.032 primary bladder cancer (NMIBC) provide an option after BCG treatment has failed. N-803 Antimetabolites (eg, completion January 2023, purportedly generates rapid and durable immune gemcitabine) preliminary data presented responses against NMIBC by simultaneously mobilizing DNA synthesis inhibitors May 2019, data reported both innate and adaptive immune cells to infiltrate the (eg, mitomycin-C) December 2020 tumor. N-803 combines the cytotoxic T-cell proliferation activity of cytokines IL-15 and IL-15α with the Taxanes (eg, docetaxel) immunoglobulin isotype G, subclass 1, Fc domain (IgG1 Fc) protein, which activates NK (natural killer) cell–specific, antibody-dependent, cell-mediated cytotoxicity. In clinical trials, N-803 is mixed with BCG and given as an intravesical (ie, within the bladder) instillation at an unspecified dose weekly for 6 consecutive weeks. At month 3, patients receive either a 3-week maintenance course or a 6-week reinduction course. Subsequently, patients receive 3-week maintenance treatment at 6, 9, 12, and 18 months. Developer(s): ImmunityBio (Miramar, Florida), in collaboration with AGC Biologics, Inc (Bothell, Washington)

Section 2. Cancer 58

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Nanoparticle albumin-bound sirolimus (nab-sirolimus; One or more of the Overall survival Submission date: Rolling advanced or metastatic Fyarro) is an mTOR inhibitor associated with human following: Progression-free New Drug Application perivascular epithelioid cell albumin nanoparticles through noncovalent hydrophobic Alkylating agents (eg, survival initiated June 25, 2020 tumor (PEComa) interactions. Nab-sirolimus has been developed to block dacarbazine, Quality of life FDA designation(s): Orphan the mTOR pathway, which is overactive in PEComas. This temozolomide, trabectedin) Drug, Fast Track, increased mTOR activity is caused by genetic mutations in Anthracyclines (eg, Breakthrough Therapy the TSC complex subunit 1 and/or 2 genes, TSC1 and/or doxorubicin, epirubicin, Clinical trial(s): Phase 2 TSC2. PEComa is a rare type of sarcoma originating from liposomal doxorubicin) AMPECT primary completion the soft tissues lining organs such as the intestines, lungs, Antimetabolites (eg, September 2020, data and stomach. PEComas are malignant in rare cases and gemcitabine, ifosfamide) presented May 2020 have potential to spread to other body parts. No approved treatments exist for PEComas, and standard Microtubule inhibitors (eg, sarcoma cytotoxic chemotherapies have minimal survival eribulin, vinorelbine) benefit. Nab-sirolimus purportedly enters proliferating mTOR inhibitors (eg, tumor cells via endocytosis and macropinocytosis to have everolimus, sirolimus, higher accumulation and better efficacy compared with temsirolimus) other mTOR inhibitors. Patient eligibility will be Multikinase inhibitors (eg, determined through an FDA-approved test of TSC1/2 gene imatinib, pazopanib, status. In clinical trials, nab-sirolimus is given by regorafenib, sorafenib, intravenous infusion at a weekly dosage of 100 mg/m2 in a sunitinib) 2-weeks-on, 1-week-off schedule until disease progression or intolerable toxicity. Developer(s): Aadi Bioscience, Inc (Pacific Palisades, California)

Section 2. Cancer 59

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have metastatic Napabucasin (BBI608) is a small-molecule inhibitor of the One or more of the Overall survival Clinical trial(s): Phase 3 colorectal cancer (CRC) that mitogenic signal transducer and activator of the following: Progression-free CanStem303C primary has been treated with a transcription 3 (STAT-3) pathway. Napabucasin’s novel Angiogenesis inhibitors (eg, survival completion February 2022; single systemic mechanism of action is intended to treat CRC that does bevacizumab, Quality of life phase 3 primary completion chemotherapy regimen not respond to second-line chemotherapy, purportedly by ramucirumab) November 2021 based on fluoropyrimidine targeting and killing cancer stem cells in tumors. Cancer Antimetabolites (eg, 5- and oxaliplatin stem cells are associated with treatment resistance, fluorouracil, capecitabine) metastasis, and poor prognosis. In clinical trials, EGFR antibodies (eg, napabucasin is taken by mouth at a dosage of 240 mg cetuximab, panitumumab) twice daily in combination with the multiagent cytotoxic chemotherapy regimen FOLFIRI (ie, leucovorin [folinic FOLFIRI acid], 5-fluorouracil, and irinotecan), with or without the FOLFOX (ie, leucovorin addition of bevacizumab, until disease progression or [folinic acid], 5-fluorouracil, intolerable toxicity. and oxaliplatin) Developer(s): Immune checkpoint Sumitomo Dainippon Pharma Oncology, Inc (Cambridge, inhibitors (eg, nivolumab, Massachusetts), a subsidiary of Sumitomo Dainippon pembrolizumab) for Pharma Co, Ltd (Osaka, Japan) patients with defects in mismatch repair or microsatellite instability Multikinase inhibitors (eg, regorafenib) Platinum agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)

Section 2. Cancer 60

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Nivolumab (Opdivo) and ipilimumab (Yervoy) are One or more of the Overall survival Approval date: October 2, advanced or metastatic monoclonal antibodies that target 2 receptors involved in following: Progression-free 2020 malignant pleural T-cell inhibition. Nivolumab targets the programmed cell Antimetabolites (eg, survival Clinical trial(s): Phase 3 mesothelioma (MPM) that death 1 (PD-1) protein and ipilimumab targets cytotoxic T pemetrexed) Quality of life CheckMate-743 primary has not been previously lymphocyte-associated protein 4 (CTLA-4). Front-line Platinum agents (eg, completion March 2020, treated with systemic therapy for MPM relies on platinum-based chemotherapy, carboplatin, cisplatin) data reported August 2020 therapy but effective options are needed because response rates are low and no second-line therapies exist. MPM cells overexpress the programmed cell death ligand 1 (PD-L1), a receptor that activates an immune checkpoint pathway by binding PD-1 and limiting the activation of cancer- specific T cells. CTLA binds to the receptors CD80 and CD86, which activate a different immune checkpoint pathway that also downregulates antitumor immune responses. Dual treatment with nivolumab and ipilimumab purportedly enhances cancer-specific T-cell responses by preventing the activation of immune checkpoints that promote immune tolerance. According to the FDA-approved label, the combination treatment is taken as nivolumab 360 mg every 3 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity or up to 2 years in patients without disease progression. Developer(s): Bristol Myers Squibb Co (New York, New York)

Section 2. Cancer 61

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 22 years or NovoTTF-100L is a device intended to treat solid tumors One or more of the Overall survival Clinical trial(s): Phase 3 older who have metastatic by exposing them to low-intensity, intermediate- following: Progression-free LUNAR primary completion non–small cell lung cancer frequency, alternating electric fields (ie, tumor-treating Immune checkpoint survival September 2023 (NSCLC) that has progressed fields [TTFs]). TTFs purportedly disrupt cell division inhibitors (eg, Quality of life after first-line, platinum- through effects on charged macromolecules and atezolizumab, nivolumab) based therapy organelles within cancer cells, potentially limiting tumor Taxanes (eg, docetaxel) growth. NovoTTF-100L is a battery-powered field generator coupled to an electrode array that is attached to the skin of the patient’s torso as a noninvasive device. The patient applies TTF therapy in the home setting 24 hours a day, 7 days a week. The therapy is intended for use in combination with standard systemic therapies for metastatic NSCLC. Developer(s): Novocure, Ltd (St Helier, Jersey, United Kingdom)

Adults who have metastatic NovoTTF-100M is a device intended to treat solid tumors Radiation therapy (eg, Overall survival Clinical trial(s): Phase 3 non–small cell lung cancer by exposing them to low-intensity, intermediate- stereotactic radiosurgery, Progression-free METIS primary completion (NSCLC) and newly frequency, alternating electric fields (ie, tumor-treating whole-brain radiotherapy) survival September 2022 diagnosed brain metastases fields [TTFs]). TTFs purportedly disrupt cell division In lieu of upfront radiation Quality of life that have been treated with through effects on charged macromolecules and therapy, systemic therapy stereotactic radiosurgery organelles within cancer cells, potentially limiting tumor with one of the following: growth. NovoTTF-100M is a battery-powered field ALK inhibitors (eg, alectinib, generator coupled to 4 electrically insulated electrode brigatinib, ceritinib) if ALK arrays attached to the skin of the patient’s head. In clinical rearrangement–positive trials, TTF therapy is given in the home setting 24 hours a EGFR inhibitors (eg, day, 7 days a week and is intended for use in combination osimertinib) if EGFR variant– with the best supportive treatment available until disease positive progression or intolerable toxicity. Immune checkpoint Developer(s): inhibitors (eg, nivolumab, Novocure, Ltd (St Helier, Jersey, United Kingdom) pembrolizumab) if programmed cell death ligand 1 (PD-L1)–positive

Section 2. Cancer 62

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 10 years or NY-ESO-1 SPEAR T cells (GSK3377794) are an autologous One or more of the Overall survival FDA designation(s): older and adults who have cell therapy engineered from T cells collected from a following: Progression-free Breakthrough Therapy locally advanced or patient’s peripheral blood. Patients with synovial sarcoma Alkylating agents (eg, survival Clinical trial(s): Phase 2 metastatic synovial sarcoma have limited treatment options, and NY-ESO-1 SPEAR T dacarbazine, Quality of life IGNYTE-ESO primary that has not been previously cells could represent a new option. In this therapy, T cells temozolomide) completion November 2022 treated or has progressed are genetically modified with a retroviral vector (ie, Anthracyclines (eg, or recurred after one line of transduction) encoding a T-cell receptor that recognizes a doxorubicin, epirubicin) chemotherapy specific antigen. The antigen is present in NY-ESO-1 (New Antimetabolites (eg, York esophageal squamous cell carcinoma-1), a protein gemcitabine, ifosfamide) with restricted expression in testis and ovaries that is reexpressed in up to 80% of synovial sarcomas. DNA synthesis inhibitors Successfully transduced cells are activated, grown in (eg, mitomycin-C) numbers in a laboratory, and then frozen until use. NY- Microtubule inhibitors (eg, ESO-1 SPEAR T cells purportedly strengthen the patient’s eribulin, vinorelbine) natural T-cell responses against cancer cells expressing Multikinase inhibitors (eg, NY-ESO-1. In clinical trials, after thawing, NY-ESO-1 SPEAR pazopanib, sorafenib) T cells are given as an intravenous infusion at an initial Tropomyosin receptor 9 9 dose ranging from 1 × 10 to 6 × 10 cells. Patients who kinase inhibitor (eg, have a confirmed response or stable disease for 3 or larotrectinib) more months might receive a second NY-ESO-1 SPEAR T- cell infusion. Developer(s): GlaxoSmithKline plc (Brentford, United Kingdom)

Section 2. Cancer 63

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have Ofranergene obadenovec (VB-111) is an adeno-associated One or more of the Overall survival FDA designation(s): Orphan recurrent, platinum- viral vector therapy intended for recurrent platinum- following: Progression-free Drug resistant ovarian cancer resistant ovarian cancer. Patients with recurrent platinum- Angiogenesis inhibitors (eg, survival Clinical trial(s): Phase 3 OVAL resistant ovarian cancer have a poor prognosis. bevacizumab) Quality of life primary completion Ofranergene obadenovec is intended to induce Anthracyclines (eg, December 2022, interim programmed cell death in endothelial cells that form new doxorubicin, pegylated data reported March 2020, blood vessels (ie, angiogenesis) in the tumor liposomal doxorubicin) interim data presented May microenvironment as well as induce cellular immune Taxanes (eg, docetaxel, 2020 responses against the tumor. Ofranergene obadenovec paclitaxel) purportedly targets the angiogenic endothelial cells in the tumor milieu and introduces a propriety angiogenesis- specific promoter that induces cell death. The therapy also purportedly recruits CD8+ T cells capable of inducing tumor-specific cellular immune responses. In clinical trials, ofranergene obadenovec is given intravenously at a dosage of 1 × 1013 viral particles every 2 months in combination with paclitaxel, which is given intravenously at a dosage of 80 mg/m2 weekly. Developer(s): VBL Therapeutics, Ltd (Tel Aviv, Israel), in collaboration with Gynecologic Oncology Group Foundation, Inc (Philadelphia, Pennsylvania)

Section 2. Cancer 64

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males who have Olaparib (Lynparza) is a small-molecule drug intended to Abiraterone alone Progression-free Clinical trial(s): Phase 3 metastatic, castration- inhibit poly adenosine diphosphate-ribose polymerase Docetaxel survival PROpel primary completion resistant prostate cancer (PARP), which functions in a DNA repair pathway. Olaparib Enzalutamide Overall survival April 2021 (mCRPC) that is being might provide a novel and potentially synergistic Quality of life Note(s): FDA approved treated with androgen mechanism of action when used with abiraterone to treat olaparib to treat ovarian deprivation therapy but has newly diagnosed mCRPC. Cancers are often deficient in a cancer in December 2014, to not yet been treated with DNA repair pathway, and when PARP is also inhibited the treat breast cancer in chemotherapy or a newer loss of 2 types of DNA repair results in cancer cell death in January 2018, to treat hormonal agent (ie, response to DNA damage. Preclinical studies have pancreatic cancer in abiraterone or indicated that cross-talk might exist between androgen December 2019, and to treat enzalutamide) at the mCRPC receptor signaling pathways and PARP. In phase 3 clinical previously treated prostate stage trials, olaparib is being studied in combination with the cancer in May 2020 hormone synthesis inhibitor abiraterone. Olaparib is taken by mouth at a dosage of 300 mg twice daily, in addition to abiraterone, until disease progression or intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, United Kingdom), in collaboration with Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 65

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 to 65 years Omidubicel (NiCord) is a donor (ie, allogeneic) stem cell Allogeneic bone marrow Bone marrow Submission date: Biologics who have a hematologic therapy derived from umbilical cord blood that has been transplantation engraftment rate License Application planned malignancy (ie, acute multiplied in a laboratory using proprietary nicotinamide Pooled unexpanded cord Neutrophil recovery for the second half of 2021 lymphoblastic leukemia (NAM) technology. Omidubicel is intended as a curative blood transplantation rate FDA designation(s): Orphan [ALL], acute myelogenous approach for high-risk blood cancers in patients who have Unexpanded cord blood Platelet recovery rate Drug, Breakthrough Therapy leukemia [AML], chronic no fully matched donor available. The therapy is intended transplantation Overall survival Clinical trial(s): Phase 3 myelogenous leukemia to efficiently and quickly restore blood and immune cells primary completion [CML], or myelodysplastic and improve resistance to infections and related December 2019, data syndrome [MDS]) complications. NAM purportedly prevents umbilical cord presented February 2021; blood cells from differentiating rapidly in culture, resulting phase 3 expanded access + – – in increased stem cells (CD34 CD38 Lin ). NAM works primary completion outside the genetic coding region in the DNA (ie, is December 2022 epigenetic) and purportedly increases the migration, bone marrow homing, and engraftment efficiency of allogeneic blood progenitor cells. In clinical trials, omidubicel is given as a single intravenous infusion at an unspecified dose. Developer(s): Gamida Cell, Ltd (Jerusalem, Israel), in collaboration with Be The Match BioTherapies, LLC (Minneapolis, Minnesota), a subsidiary of the National Marrow Donor Program/Be The Match (Minneapolis, Minnesota)

Section 2. Cancer 66

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 years or Onureg is a hypomethylating agent that FDA has Hypomethylating agents Overall survival Approval date: September 1, older with acute myeloid approved as an oral maintenance treatment for AML. (eg, azacitidine, decitabine) Progression-free 2020 leukemia (AML) who Treatments for AML frequently achieve complete survival Clinical trial(s): Phase 3 achieved complete remission, which is characterized by normalized blood Quality of life QUAZAR AML-001 primary remission or complete counts and no evidence of leukemic blasts in the bone completion July 2019, data remission with incomplete marrow. However, even with subsequent therapy after published December 2020 blood count recovery after remission, AML frequently recurs. In particular, older intensive induction patients ineligible for intensive consolidation therapy (eg, chemotherapy and who are allogeneic hematopoietic stem cell transplantation unable to complete [HSCT]) experience relapse at a rate as high as 70% to intensive curative therapy 80%. Novel, less-intensive therapies are sought. Approved by FDA, Onureg is a novel, orally bioavailable version of the well-established hypomethylating agent azacitidine. These drugs are chemical analogues of the nucleoside cytosine and are thought to exert their effects by inhibiting DNA methyltransferase after being incorporated into cellular DNA and by direct cytotoxic effect. According to the prescribing information, Onureg is taken by mouth once daily at 300 mg on days 1 through 14 of a 28-day treatment cycle. Developer(s): Bristol Myers Squibb Co (New York, New York)

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Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have Oraxol is a novel combination therapy composed of a One or more of the Overall survival PDUFA date: February 28, locally advanced or paclitaxel capsule and an encequidar tablet that is taken following: Progression-free 2021; Priority Review metastatic breast cancer for by mouth rather than given intravenously. Paclitaxel is a Anthracyclines (eg, survival FDA designation(s): Orphan whom treatment with taxane that inhibits cell division, but it is formulated only doxorubicin, liposomal Quality of life Drug intravenous paclitaxel has as an intravenous infusion containing additives that doxorubicin) Clinical trial(s): Phase 3 KX- been recommended increase the risk of neuropathy and hypersensitivity. Antimetabolites (eg, ORAX-001 primary These adverse reactions often prevent patients from capecitabine, gemcitabine) completion July 2020, data completing the chemotherapy regimen, thereby reducing Microtubule inhibitors (eg, reported December 2020 efficacy and adversely affecting health outcomes. eribulin, vinorelbine) Note(s): An FDA Complete Paclitaxel has been limited to intravenous administration Response Letter was issued because the drug is a substrate of P-glycoprotein (P-gp), Poly adenosine to Athenex in March 2021 an active transport protein on the gastrointestinal (GI) diphosphate-ribose indicating concerns for tract’s surface that is capable of pumping paclitaxel back polymerase (PARP) safety of patients and into the GI tract. This limits systemic exposure to inhibitors (eg, olaparib, uncertainty over primary paclitaxel taken by mouth. Encequidar is a P-gp inhibitor talazoparib) for BRCA1/2- end point results that prevents P-gp-mediated efflux of paclitaxel. As an mutated breast cancer orally administered taxane, oraxol has the potential to Taxanes (eg, docetaxel, decrease the burden of infusion clinic visits, paclitaxel) premedication, and potentially dangerous infusion- related reactions. In clinical trials, oraxol is given as an all- oral regimen of 205 mg/m2 paclitaxel plus 15 mg encequidar administered 3 days per week until disease progression or intolerable toxicity. Developer(s): Athenex Pharmaceuticals, Inc (Buffalo, New York)

Section 2. Cancer 68

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Pamrevlumab is a first-in-class monoclonal antibody One or more of the Overall survival FDA designation(s): Orphan unresectable locally specific for connective tissue growth factor (CTGF). It is following: Progression-free Drug, Fast Track advanced pancreatic cancer under study to treat unresectable LAPC, which is Antimetabolites (eg, survival Clinical trial(s): Phase 3 LAPIS (LAPC) associated with median survival of 6 to 10 months gemcitabine) Quality of life primary completion compared with about 23 months for patients with Taxanes (eg, nab-paclitaxel) September 2022; phase 1/2 resectable LAPC. CTGF promotes the growth of fibrous or primary completion connective tissue (ie, desmoplasia) associated with December 2021, data pancreatic tumors, which creates a microenvironment published August 2020 that promotes tumor growth, invasiveness, and resistance to chemotherapy. Therefore, pamrevlumab inhibition of CTGF may disrupt desmoplasia to slow cancer progression and/or enhance chemotherapy response, which could make nonresectable LAPC amenable to surgery. In clinical trials, pamrevlumab (35 mg/kg) is given intravenously in combination with gemcitabine and nab- paclitaxel chemotherapy. Developer(s): FibroGen, Inc (San Francisco, California)

Section 2. Cancer 69

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults with Gorlin-Goltz Patidegib (BBP-009) is a hedgehog pathway inhibitor Radiation therapy Overall survival FDA designation(s): Orphan syndrome, also known as intended to treat basal cell carcinomas and reduce Surgical resection Progression-free Drug, Breakthrough Therapy basal cell carcinoma nevus disease burden and symptoms in patients with BCCNS. Systemic chemotherapy survival Clinical trial(s): Phase 3 Pelle- syndrome (BCCNS), who Basal cell carcinoma is usually treated with surgery, (eg, vismodegib) Quality of life 926-301 primary completion have developed basal cell radiation, or chemotherapy (topical or systemic), all of Topical chemotherapy (eg, December 2020 carcinomas which have limited efficacy, can be hard to tolerate, and 5-fluorouracil, imiquimod) might not prevent new tumor growth. Patients with BCCNS harbor a mutation in the patched 1 gene, PTCH1, which encodes a negative regulator (PTC1) of the hedgehog pathway protein Smoothened (Smo). Without functional PTC1 to block Smo, the hedgehog pathway becomes active and causes basal cells to multiply uncontrollably into tumors. Patidegib is designed to inhibit this pathway and, in so doing, purportedly reduces tumor burden and BCCNS-associated symptoms in patients who cannot receive standard treatment or experience serious side effects. In clinical trials, patidegib is used as a 2% topical gel applied twice daily to the face for at least 12 months. Developer(s): PellePharm, Inc (San Francisco, California), a subsidiary of BridgeBio, Inc (Palo Alto, California), in collaboration with LEO Pharma A/S (Ballerup, Denmark)

Section 2. Cancer 70

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have malignant Pegargiminase (ADI-PEG 20) is a pegylated preparation of One or more of the Overall survival FDA designation(s): Orphan pleural mesothelioma the enzyme arginine deiminase, which catalyzes the following: Progression-free Drug (MPM) that has not been hydrolysis of arginine, depleting the supply of this Antimetabolites (eg, survival Clinical trial(s): Phase 2/3 treated with systemic essential amino acid from the bloodstream. Cells of many pemetrexed) Quality of life ATOMIC primary completion therapies and exhibits low tumor types cannot autonomously synthesize arginine Platinum agents (eg, October 2020 expression of the and so might be sensitive to arginine depletion. In cisplatin) argininosuccinate synthase particular, tumor cells that express low levels of ASS1 1 gene, ASS1 (involved in cellular arginine synthesis) might depend on exogenous arginine. This is thought to be the case in MPM, which lacks effective treatment options. In clinical trials, pegargiminase is given by intramuscular injection at a dosage of 36 mg/m2 weekly in combination with standard chemotherapy with cisplatin and pemetrexed until disease progression or intolerable toxicity. Developer(s): Polaris Group (San Diego, California)

Section 2. Cancer 71

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Female adults who have Pegloprastide (AVB-620) is a fluorescently labeled cell- Surgery without fluorescent Recurrence-free FDA designation(s): ductal carcinoma in situ or penetrating peptide (CPP) intended to help differentiate imaging of the primary survival Breakthrough Therapy primary invasive breast between malignant and nonmalignant tissue during tumor Repeat surgery Clinical trial(s): Phase 2/3 cancer who are undergoing primary surgery. Each year, about one-third of women Quality of life AVB-620-C-002 primary a lumpectomy or who undergo a lumpectomy require a repeat surgery to completion June 2020, data mastectomy as a primary remove additional malignant tissue. Pegloprastide’s reported August 2020 surgical treatment sequence is designed to be recognized and cleaved by a matrix metalloproteinase, an enzyme that is overexpressed in the surface of cancer cells. When cleaved, the CPP becomes active, allowing it to be delivered locally to malignant cells. Activated CPP also emits fluorescence at a specific wavelength. Using a multispectral imaging camera, surgeons measure the ratio of active CPP in cancer cells to that of inactive pegloprastide in surrounding tissue. Pegloprastide purportedly identifies cancer tissue in the margins of a surgically removed tumor, which could reduce repeat surgeries and improve patient outcomes. In clinical trials, pegloprastide is given as an intravenous infusion up to 24 hours before surgery at an unspecified dose. Developer(s): Avelas Biosciences, Inc (San Diego, California)

Section 2. Cancer 72

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have stage IV Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Approval date: June 29, 2020 colorectal cancer (CRC) that targets the programmed cell death 1 (PD-1) coinhibitory following: Progression-free FDA designation(s): is microsatellite instability– receptor expressed by activated T cells. Pembrolizumab is Angiogenesis inhibitors (eg, survival Breakthrough Therapy high (MSI-H) or mismatch intended to provide a targeted option for patients with bevacizumab) Quality of life Clinical trial(s): Phase 3 repair–deficient (dMMR) and MSI-H or dMMR colorectal cancers, which make up 15% to Antimetabolites (eg, 5- KEYNOTE-177 primary has not been previously 20% of nonhereditary cases and most hereditary cases. A fluorouracil, capecitabine) completion December 2021, treated hallmark of cancer is its ability to evade an immune EGFR antibodies (eg, data presented June 2020 response. Several types of cancer cells, including CRC cetuximab, panitumumab) Note(s): FDA has approved cells, activate an immune checkpoint pathway in T cells by pembrolizumab to treat overexpressing the programmed cell death ligand 1 (PD- FOLFIRI (ie, leucovorin many other cancers. See the L1), which binds to PD-1 and limits the activation of [folinic acid], 5-fluorouracil, FDA-approved labeling and cancer-specific T cells. Pembrolizumab purportedly and irinotecan) prescribing document for all prevents the interaction between PD-1 and PD-L1 to FOLFOX (ie, leucovorin approved indications. overcome CRC’s immune tolerance by enhancing cancer- [folinic acid], 5-fluorouracil, specific T-cell responses. Tumors with MSI-H or dMMR are and oxaliplatin) also purportedly more susceptible to pembrolizumab Platinum-based agents (eg, than are tumors with low MSI. The recommended dosage oxaliplatin) in the FDA-approved label is 200 mg given as an Topoisomerase inhibitors intravenous infusion once every 3 weeks for up to 24 (eg, irinotecan) months. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 73

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival PDUFA date: April 13, 2021; advanced or metastatic targets the programmed cell death 1 (PD-1) coinhibitory following: Progression-free Priority Review esophageal carcinoma or receptor expressed by activated T cells. Front-line therapy Anthracyclines (eg, survival Clinical trial(s): Phase 3 esophagogastric junction for esophageal carcinoma relies on platinum-based epirubicin) Quality of life KEYNOTE-590 primary (EGJ) carcinoma that is chemotherapy, but response rates are low and no Antimetabolites (eg, completion July 2020, data unsuitable for surgery and second-line therapies exist. Pembrolizumab is intended to capecitabine, 5-fluorouracil) presented September 2020 has not been previously provide an option for these patients. A hallmark of cancer HER2 antibodies (eg, Note(s): FDA has approved treated is its ability to evade an immune response. Several types trastuzumab) pembrolizumab to treat of cancer cells, including esophageal and EGJ carcinomas, Platinum agents (eg, many other cancers. See the activate an immune checkpoint pathway in T cells by FDA-approved labeling and overexpressing the programmed cell death ligand 1 (PD- carboplatin, cisplatin, oxaliplatin) prescribing document for all L1), which binds to PD-1 and limits the activation of approved indications. cancer-specific T cells. Pembrolizumab purportedly Taxanes (eg, docetaxel, prevents the interaction between PD-1 and PD-L1 to paclitaxel) overcome the immune tolerance of esophageal and EGJ carcinomas by enhancing cancer-specific T-cell responses. In clinical trials, pembrolizumab is given as an intravenous infusion at a dosage of 200 mg once every 3 weeks for up to 24 months. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 74

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Pemigatinib (Pemazyre) is a novel, highly potent, and Fluoropyrimidine-based Overall survival Approval date: April 17, 2020 advanced or metastatic selective small-molecule inhibitor of FGFR isoforms 1, 2, chemotherapy Progression-free FDA designation(s): Orphan cholangiocarcinoma and 3, which play an important role in cell proliferation, Pembrolizumab (for survival Drug, Breakthrough Therapy harboring gene mutations, survival, migration, and angiogenesis (ie, formation of new patients with microsatellite Quality of life Clinical trial(s): Phase 3 fusions, or translocations in blood vessels). The drug is approved by FDA. instability–high [MSI-H] or FIGHT-302 primary the fibroblast growth factor Cholangiocarcinoma is a rare cancer that forms in bile mismatch repair–deficient completion October 2023; receptor 2 gene, FGFR2, ducts, which carry fluid between the liver, the gallbladder, [dMMR] tumors) phase 2 FIGHT-202 primary whose disease has and the small intestine. About 20% of completion June 2021, data previously been treated with cholangiocarcinomas harbor an alteration in the FGFR2 published March 2020 at least one line of systemic gene, which typically involves a gene fusion or Note(s): This Accelerated therapy translocation that leads to constitutive FGFR2 activity. By Approval requires the targeting this aberrant FGFR signaling, pemigatinib conduct of a further clinical purportedly prevents the growth and spread of trial to verify and describe cholangiocarcinoma tumors, potentially improving pemigatinib’s clinical benefit outcomes of patients who have limited treatment options. Although pemigatinib specifically binds to FGFRs 1, 2, and 3, it is designed to avoid binding to similar signaling domains in the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR). Testing for FGFR2 gene alterations requires use of a genetic test (ie, a companion diagnostic), the FDA-approved FoundationOneCDx. The recommended dosage in the FDA-approved label is 13.5 mg taken by mouth in a 2-weeks-on, 1-week-off schedule until disease progression or intolerable toxicity. Developer(s): Incyte Corp (Wilmington, Delaware)

Section 2. Cancer 75

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have advanced Plinabulin is a marine fungus–derived microtubule Myelosuppressive Neutropenia Submission date: New Drug or metastatic cancer (eg, inhibitor. It is intended to prevent chemotherapy-induced chemotherapy with Thrombocytopenia Application planned for the breast cancer, non–small neutropenia (ie, loss of neutrophils, a type of white blood adjunctive long-lasting G- Infection incidence second quarter of 2021 cell lung cancer [NSCLC], cell involved in the body’s immune response), which CSF (eg, pegfilgrastim) Quality of life FDA designation(s): prostate cancer) that has occurs in most patients with cancer who are receiving Breakthrough Therapy progressed after at least myelosuppressive chemotherapy. Neutropenia renders Clinical trial(s): Phase 3 one previous line of patients susceptible to complications, including infection, Protective-1 primary treatment because the cytotoxic regimens they receive also deplete completion November 2020, blood-forming cells in the bone marrow. Unlike data published September granulocyte colony-stimulating factor (G-CSF), which 2020; phase 3 Protective-2 promotes growth of white blood progenitor cells to primary completion October restore neutrophils, plinabulin’s novel mechanism of 2020, data reported action (ie, targets microtubules differently from taxanes December 2020 and vinca alkaloids) purportedly facilitates the release of cytokines that protect neutrophils from programmed cell death (ie, apoptosis). In clinical trials, plinabulin is given as an intravenous infusion at a dose ranging from 5 to 40 mg/m2. Treatment with plinabulin continues until completion of systemic chemotherapy. Developer(s): BeyondSpring Pharmaceuticals, Inc (New York, New York)

Section 2. Cancer 76

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Male adults who have ProstAtak is a gene-mediated cytotoxic immunotherapy. It Radiation therapy with or Disease-free survival Clinical trial(s): Phase 3 localized prostate cancer consists of an adenovirus vector containing a herpes without ADT Overall survival PrTK03 primary completion that is deemed to be simplex virus thymidine kinase gene (ie, aglatimagene Quality of life June 2023, designed under intermediate or high risk besadenovec) that is injected into prostate tumors and Special Protocol Assessment; based on one factor and has leads infected cells to express thymidine kinase. After viral phase 2 ULYSSES primary been treated with radiation injection, a low dose of a synthetic guanosine analogue completion March 2021 (eg, valacyclovir) activated by thymidine kinase is given, potentially killing tumor cells expressing the transgene (ie, aglatimagene besadenovec). The intervention is intended to provide antitumor effects while preserving critical structures around the prostate. Release of tumor- associated antigens (TAAs) by dying tumor cells purportedly leads to an antitumor immune response. ProstAtak is given as 3 rounds of aglatimagene besadenovec (CAN-2409) delivered to the tumor with the help of trans-rectal ultrasound guided injections. This is followed by systemic valacyclovir administration in addition to standard radiation therapy with or without androgen deprivation therapy (ADT). Developer(s): Candel Therapeutics (Needham, Massachusetts)

Section 2. Cancer 77

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have a ProTmune is a next-generation allogeneic (ie, from a Standard HSCT Progression-free FDA designation(s): Orphan hematologic malignancy (ie, donor), off-the-shelf hematopoietic peripheral blood cell survival Drug, Fast Track acute lymphoblastic transplant (HPBCT). It is developed from donor-sourced, Overall survival Clinical trial(s): Phase 1/2 leukemia [ALL], acute mobilized, peripheral blood T cells that have been grown Quality of life PROTECT primary myeloid leukemia [AML], in numbers in culture in the presence of 2 small-molecule completion March 2020, chronic myelogenous stem cell modulators (ie, FT1050 and FT4145) that guide initial data reported March leukemia [CML], or cell differentiation. Many patients with hematologic 2018, expanded enrollment myelodysplastic syndrome malignancies seek curative therapy through May 2019 [MDS]) that will be treated hematopoietic stem cell transplantation (HSCT), but about with allogeneic 50% of patients undergoing HSCT die or experience hematopoietic peripheral disease recurrence within 2 years. The leading causes of blood cell transplantation nonrelapse (ie, treatment-related) death are graft-vs-host disease (GVHD) arising from the transplant or infection due to compromised immunity. ProTmune is intended to decrease GVHD incidence and severity while maintaining therapeutic activity against hematologic malignancies. Clinical trials do not specify ProTmune’s delivery route; however, it is likely given as an intravenous infusion. Developer(s): Fate Therapeutics, Inc (San Diego, California)

Section 2. Cancer 78

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have recurrent PVSRIPO is a Sabin type 1 strain of poliovirus genetically Fractionated external beam Overall survival FDA designation(s): Orphan malignant glioma (eg, engineered to not harm or kill normal cells. PVSRIPO uses radiation therapy Progression-free Drug, Breakthrough Therapy glioblastoma multiforme a novel oncolytic virus approach intended for patients One or more of the survival Clinical trial(s): Phase 2 [GBM], anaplastic whose cancer has recurred and who have limited options following: Quality of life Pro00077024 primary astrocytoma [AA]) that has after standard therapy. It selectively infects and replicates Alkylating agents (eg, completion August 2023 been treated with surgery, tumor cells that express the poliovirus receptor nectin-like carmustine, adjuvant radiation, and protein 5 (CD155), which is expressed in most types of cyclophosphamide, temozolomide solid-tumor cancers and in other immune cells, including lomustine, procarbazine, dendritic cells and macrophages. In tumor cells, PVSRIPO temozolomide) infection causes neuronal incompetence that results in Angiogenesis inhibitors (eg, cytotoxicity and death. In contrast, PVSRIPO infection of bevacizumab) immune cells facilitates induction of an antitumor immune response that does not kill or limit immune mTOR inhibitors (eg, function of dendritic cells and macrophages. Although everolimus) immune cells infected by PVSRIPO initiate a type I Platinum agents (eg, interferon-mediated response, this will not destroy the carboplatin, cisplatin) oncolytic virus. PVSRIPO purportedly targets and destroys Vinca alkaloids (eg, cells in brain tumors and activates tumor-specific immune vincristine) responses by stimulating dendritic cell activity and immune function. In clinical trials, PVSRIPO is given as a single injection into the tumor at a dose ranging from 7 × 106 to 7 × 109 plaque-forming units. Developer(s): Istari Oncology, Inc (Research Triangle Park, North Carolina), in collaboration with the Preston Robert Tisch Brain Tumor Center at Duke University (Durham, North Carolina)

Section 2. Cancer 79

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have metastatic Racemetyrosine (SM-88) is a modified dysfunctional One or more of the Overall survival FDA designation(s): Orphan pancreatic cancer previously tyrosine derivative under study as a third-line treatment following: Progression-free Drug treated with 2 lines of for pancreatic cancer. Pancreatic cancer has no FDA- Antimetabolites (eg, 5- survival Clinical trial(s): Phase 2/3 systemic therapy approved treatment options. The 5-year overall survival fluorouracil, capecitabine, Quality of life Tyme-88-Panc primary rate for patients with advanced disease is less than 3%; gemcitabine) completion December 2021, median survival is about 3 months. Racemetyrosine Chemoprotectant (eg, data presented April 2019, purportedly inhibits protein synthesis in cancer cells, leucovorin) data presented January 2021 including the synthesis of the protein MUC1, which leads DNA synthesis inhibitor (eg, to increased cellular oxidative stress and exposure to the irinotecan) body’s immune system. In clinical trials, racemetyrosine is given orally at a dosage of 920 mg daily with 3 EGFR inhibitor (eg, conditioning agents (methoxsalen 10 mg, phenytoin 50 erlotinib) mg, and sirolimus 0.5 mg [MPS]), which are thought to Platinum-based agents (eg, potentiate the effects of racemetyrosine, with sirolimus oxaliplatin) increasing its uptake or methoxsalen and phenytoin increasing levels of reactive oxygen species. Developer(s): Tyme Technologies, Inc (New York, New York), in collaboration with Eagle Pharmaceuticals, Inc (Woodcliff Lake, New Jersey)

Section 2. Cancer 80

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Relatlimab (BMS-986016) is a novel human One or more of the Overall survival Clinical trial(s): Phase 2/3 older and adults who have immunoglobulin isotype G, subclass 4 (IgG4) monoclonal following: Progression-free primary completion May melanoma that is unsuitable antibody against lymphocyte-activator gene-3 (LAG-3). Alkylating agents (eg, survival 2021 for surgery or is metastatic LAG-3 is a coinhibitor receptor primarily expressed on dacarbazine, Quality of life and has not been previously exhausted tumor-infiltrating lymphocytes (TILs). temozolomide) treated with systemic Relatlimab is intended to enhance activity of immune BRAF inhibitors (eg, therapy checkpoint inhibitors by stimulating TILs. As an adjunct to dabrafenib, encorafenib, a checkpoint inhibitor, relatlimab might also increase vemurafenib) treatment-related costs. Relatlimab’s binding to LAG-3 Immune checkpoint prevents inhibitory T-cell responses of TILs via interaction inhibitors (eg, ipilimumab, with major histocompatibility complex molecule class II nivolumab, (MHC-II) on dendritic cells and melanoma cells. Relatlimab pembrolizumab) purportedly promotes innate immune responses and FAS- mediated programmed cell death (ie, apoptosis) in MEK inhibitors (eg, melanoma cells expressing high MHC-II. Relatlimab also binimetinib, cobimetinib, synergizes with programmed cell death 1 (PD-1) immune trametinib) checkpoint inhibitors that might encourage melanoma- Platinum agents (eg, specific immune responses. In clinical trials, relatlimab is carboplatin) given intravenously at a dose of 160 mg in combination Taxane agents (eg, with intravenous nivolumab at a dose of 480 mg, on day 1 paclitaxel) of each 28-day cycle until disease progression or intolerable toxicity. Developer(s): Bristol Myers Squibb Co (New York, New York)

Section 2. Cancer 81

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males with androgen- Relugolix (Orgovyx) is a selective, gonadotropin-releasing ADT Overall survival Approval date: December 18, sensitive advanced prostate hormone (GnRH) receptor antagonist. It binds to and Time to castration 2020 cancer who require at least blocks the GnRH receptor in the anterior pituitary gland, resistance Clinical trial(s): Phase 3 1 year of continuous which is responsible for downstream secretion of Quality of life HERO primary completion androgen deprivation testosterone. However, patients who receive ADT for October 2019, data therapy (ADT) sustained testosterone suppression are at an increased published June 2020, data risk of hormone flares, which lead to poor clinical reported September 2020 outcomes and quality of life. Approved by FDA, relugolix might improve outcomes by preventing flares and improve quality of life by reducing the number of clinic visits that are needed for standard ADT. The FDA- approved label recommends taking relugolix by mouth at a dosage of 120 mg once daily, after a single loading dose of 360 mg. Developer(s): Myovant Sciences, Ltd (Basel, Switzerland)

Adults with very-low- to Roxadustat (FG-4592) is a hypoxia-inducible factor (HIF) Hypomethylating agents Red blood cell Clinical trial(s): Phase 3 intermediate-risk prolyl hydroxylase inhibitor under development to treat (eg, azacitidine, decitabine) transfusion primary completion April myelodysplastic syndrome anemia associated with MDS. Roxadustat is intended to Lenalidomide dependence 2021, preliminary data (MDS) who required 2 to 4 restore production of normal red blood cells, thus Luspatercept-aamt Overall survival presented December 2020 red blood cell units over the obviating the need for repeat red blood cell transfusions Note(s): A New Drug preceding 8 weeks and the accompanying iron chelation therapy. Roxadustat Application has been purportedly promotes red blood cell formation (ie, submitted to FDA for use of erythropoiesis) by stabilizing HIF, a transcription factor roxadustat in treating that is normally targeted for degradation by a prolyl patients with anemia hydroxylase inhibited by roxadustat. HIF accumulation resulting from chronic stimulates expression of genes involved in erythropoietin kidney disease production and iron transport, which promote erythropoiesis. In clinical trials, roxadustat (2.5. mg/kg) is taken by mouth 3 times per week. Developer(s): FibroGen, Inc (San Francisco, California), in collaboration with AstraZeneca (Cambridge, United Kingdom)

Section 2. Cancer 82

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 79 years RRx-001 is a novel checkpoint inhibitor in the innate One or more of the Overall survival FDA designation(s): Orphan who have extensive-stage immune system. SCLC usually responds to first-line following: Progression-free Drug small cell lung cancer (SCLC) platinum doublet chemotherapy but eventually develops Alkylating agents (eg, survival Clinical trial(s): Phase 3 that has progressed after 2 resistance. RRx-001 is intended to overcome the disease’s cyclophosphamide, Quality of life REPLATINUM primary or more lines systemic resistance to platinum-based chemotherapy and might temozolomide) completion November 2020 therapy including prior improve health outcomes of patients with limited Antimetabolites (eg, platinum doublet treatment options. SCLC cells activate an innate immune gemcitabine) chemotherapy checkpoint pathway in macrophages by overexpressing Antitumor antibiotics (eg, the protein CD47, which interacts with signal regulatory anthracyclines, protein-α (SIRPα) to prevent macrophage phagocytosis mitomycin-C) and render tumor cells less sensitive to innate immune surveillance. Through an unknown mechanism of action, Microtubule inhibitors (eg, RRx-001 decreases the expression of both CD47 on tumor paclitaxel, vinorelbine) cells and SIRPα on macrophages. By reducing expression of these innate immune checkpoint proteins, RRx-001 purportedly releases the brakes on phagocytosis, which may enhance cancer-specific macrophage responses and increase sensitivity to platinum-based therapy. In clinical trials, RRx-001 is given as an intravenous infusion at a dosage of 4 mg once weekly for 3 weeks, followed by up to 4 cycles of etoposide (100 mg/m2) plus carboplatin (AUC 5) or cisplatin (60 mg/m2). Developer(s): EpicentRx, Inc (La Jolla, California)

Section 2. Cancer 83

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Selinexor (Xpovio) is a first-in-class, reversible, potent, One or more of the Overall survival Submission date: New Drug older and adults who have selective inhibitor of the nuclear export protein XPO1 following: Progression-free Application planned for the advanced unresectable (also called CRM1). Selinexor’s novel mechanism of action Alkylating agents (eg, survival first quarter of 2021 dedifferentiated is intended to provide an option for patients with dacarbazine, Quality of life Clinical trial(s): Phase 2/3 liposarcoma (DDLS) and previously treated DDLS, who have a poor prognosis. temozolomide) SEAL primary completion have received at least 2 Selinexor’s binding to XPO1 purportedly restores nuclear Antimetabolites (eg, November 2020, data prior systemic therapies localization, or the accumulation of tumor suppressor gemcitabine) reported November 2020 proteins in the cell nucleus, thereby restoring and Antitumor antibiotics (eg, Note(s): FDA previously amplifying their tumor suppressor function. By restoring anthracyclines, approved selinexor for tumor suppressor function, selinexor purportedly mitomycin-C) treating multiple myeloma promotes cancer cell death while sparing normal cells (ie, Microtubule inhibitors (eg, (MM) and diffuse large B-cell selective apoptosis induction). In clinical trials, selinexor is lymphoma (DLBCL) taken by mouth at a dosage of 60 mg twice weekly until eribulin, vinorelbine) disease progression or intolerable toxicity. Multikinase inhibitors (eg, Developer(s): pazopanib, regorafenib) Karyopharm Therapeutics, Inc (Newton, Massachusetts) Tropomyosin receptor kinase inhibitor (eg, larotrectinib)

Section 2. Cancer 84

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Selpercatinib (Retevmo) is a novel, highly selective, ATP- One or more of the Overall survival Approval date: May 8, 2020 older and adults who have competitive small-molecule RET inhibitor. Selpercatinib is following: Progression-free FDA designation(s): locally advanced or intended to provide a targeted treatment option for Anthracyclines (eg, survival Breakthrough Therapy metastatic medullary patients with recurrent medullary thyroid cancer and a doxorubicin) Quality of life Clinical trial(s): Phase 3 thyroid cancer that harbors RET gene alteration. The receptor tyrosine kinase RET can Antimetabolite agents (eg, LIBRETTO-531 primary an alteration in a the be oncogenically activated by gene fusions or point 5-fluorouracil) completion May 2024; phase rearranged during rearrangements, and activating RET point rearrangements Tyrosine kinase inhibitors 1/2 LIBRETTO-001 primary transfection gene, RET, and affect about 60% of metastatic medullary thyroid cancers. (eg, cabozantinib, completion March 2022, has progressed after Unlike multikinase inhibitors that target specific vandetanib) data presented September treatment with cabozantinib alterations, selpercatinib has been designed to inhibit 2019, data published August and/or vandetanib diverse RET fusions, activating gene variants, and 2020, data presented acquired-resistance variants with nanomolar potency. September 2020 Selpercatinib targets and purportedly inhibits RET-variant tumor cells. Eligibility for the therapy requires testing for a RET gene alteration. The recommended dosage in the FDA-approved label is based on weight: 120 mg orally twice daily for patients who way less than 50 kg; 160 mg orally twice daily for patients who way 50 kg or greater. The dose is reduced in patients with severe hepatic impairment. Developer(s): Loxo Oncology, Inc (Stamford, Connecticut), a subsidiary of Eli Lilly and Co, Inc (Indianapolis, Indiana)

Section 2. Cancer 85

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or Selumetinib (Koselugo) is a selective small-molecule Pain management Progression-free Approval date: April 13, 2020 older who have inhibitor of a signaling pathway called ras (rat sarcoma), Radiation therapy survival FDA designation(s): Orphan neurofibromatosis type 1 which is often overactive in several types of cancers. The Systemic chemotherapy Quality of life Drug, Breakthrough Therapy (NF1) with symptomatic, drug is approved by FDA. About 50% of patients with NF1 (eg, carboplatin, vincristine) Clinical trial(s): Phase 1/2 inoperable plexiform develop PNs, benign tumors found in peripheral nerve Sprint 1 primary completion neurofibromas (PNs) sheaths that can cause substantial complications, January 2025, data published including airway, bladder, bowel and/or motor March 2020; phase 1/2 dysfunction, disfigurement, pain, and visual impairment. INSPECT primary completion Patients who have inoperable NF1-related PNs have no April 2021 approved treatment options. To block the ras pathway, Note(s): This Accelerated selumetinib specifically targets the mitogen-activated Approval requires the protein kinase kinases 1 and 2 (MEK1/2) to prevent conduct of a further clinical activation of the downstream extracellular signal-related trial to verify and describe kinase (ERK). ERK is associated with cell growth and selumetinib’s clinical benefit proliferation. Selumetinib purportedly prevents the uncontrolled proliferation of PNs and may contribute to their shrinkage. The recommended dosage in the FDA- approved label is 25 mg/m2 orally twice daily (about every 12 hours) until disease progression or intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, United Kingdom), in collaboration with Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 86

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Surufatinib (HMPL-012) is a novel, small-molecule, One or more of the Overall survival Submission date: New Drug advanced or metastatic tyrosine kinase inhibitor of vascular endothelial growth following: Progression-free Application rolling pancreatic or factor receptor (VEGFR), fibroblast growth factor receptor Alkylating agents (eg, survival submission initiated extrapancreatic (FGFR), and colony-stimulating factor-1 receptor (CSF-1R). temozolomide) Quality of life December 28, 2020 neuroendocrine tumors Those 3 tyrosine kinase receptors are associated with NET Antimetabolites (eg, FDA designation(s): Orphan (NETs) that have progressed development and immune evasion. NET is a rare type of capecitabine) Drug, Fast Track after 2 or more lines of cancer that originates from hormone-producing cells mTOR inhibitors (eg, Clinical trial(s): Phase 3 standard systemic therapy receiving signals from the nervous system. Most patients everolimus) SANET-ep primary with NET will develop recurrent disease and have limited completion March 2019, treatment options after failing 2 lines of therapy. Peptide receptor 68 data presented September Surufatinib has been designed to target NETs with radionuclide (eg, Ga- dotatate, 177Lu-dotatate) 2019, data presented aberrant signaling in the VEGFR, FGFR, and CSF-1R September 2020, data Somatostatin analogues pathways, which are involved in blood vessel formation, published September 2020; (eg, lanreotide, octreotide) cell proliferation, and inhibition of tumor-associated phase 3 SANET-p primary macrophages, respectively. Surufatinib-mediated completion March 2020, inhibition of these 3 pathways purportedly prevents the data presented September tumor from receiving the nutrients and oxygen it needs to 2020; phase 1/2 2015-012- grow rapidly and promotes the body’s immune response 00US1 primary completion against NETS, thus improving patient outcomes. In clinical September 2021, data trials, surufatinib is taken by mouth at a dosage of 300 mg presented May 2020 once daily until disease progression or intolerable toxicity. Developer(s): Hutchison China MediTech, Ltd (Kowloon, Hong Kong)

Adults who have newly Synthetic hypericin (SGX301) is a photosensitizing agent Chemotherapy Overall survival Submission date: Initiation diagnosed patch/plaque- for use with visible light to treat CTCL. Standard care for Ultraviolet A phototherapy Damage to tumor- of rolling New Drug phase cutaneous T-cell CTCL often requires photodynamic therapy with with psoralen adjacent tissue Application planned for first lymphoma (CTCL) that has ultraviolet light, which can damage surrounding tissue Ultraviolet B phototherapy Progression-free half of 2021 not been treated with and lead to skin burns, increased pigmentation, or survival FDA designation(s): Orphan systemic therapy secondary skin cancer. SGX301 purportedly clears CTCL Quality of life Drug, Fast Track lesions without increasing the patient’s risk of skin burns. Clinical trial(s): Phase 3 In clinical trials, SGX301 is applied topically to the CTCL FLASH primary completion lesion twice weekly (covered with an opaque bandage for December 2019, data 12 to 24 hours) followed by fluorescent light activation of reported April 2020, data the compound. reported October 2020 Developer(s): Soligenix, Inc (Princeton, New Jersey)

Section 2. Cancer 87

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults who Tabelecleucel (Tab-cel) is an off-the-shelf chimeric antigen One or more of the Progression-free Submission date: have received an allogeneic receptor (CAR) T-cell therapy. It is engineered to provide following: survival Completion of rolling hematopoietic cell specific immune responses against EBV using cytotoxic T Adrenocortical steroid (eg, Overall survival Biologics License Application transplant or solid organ lymphocytes (CTLs) from unrelated donors. Tabelecleucel prednisolone) Quality of life planned for the third quarter transplant and developed purportedly provides immunity against EBV-associated Alkylating agent (eg, of 2021 Epstein-Barr virus– cancers in patients who have received a hematopoietic cyclophosphamide, FDA designation(s): Orphan associated posttransplant cell transplant or organ transplant. EBV+PTLD can be hard dacarbazine) Drug, Breakthrough Therapy lymphoproliferative to treat with standard therapies, and treatment is Anthracyclines (eg, Clinical trial(s): Phase 3 disorder (EBV+PTLD) that associated with many comorbidities. In this therapy, CAR doxorubicin) MATCH primary completion does not respond to genes are delivered to the CTLs with an adenovirus vector November 2020; phase 3 rituximab called AdE1-LMPpoly, which targets specific regions of the Antitumor antibiotic (eg, bleomycin) ALLELE primary completion EBV nuclear antigen 1, latent membrane protein 1, and June 2022, interim data Vinca alkaloid (eg, latent membrane protein 2A. AdE1-LMPpoly also encodes reported November 2020 for a programmed cell death 1 (PD-1)–dominant negative vinblastine, vincristine) receptor to shield the CAR CTLs from being downregulated (ie, checkpoint inhibition). The EBV-specific CAR-transduced CTLs are proliferated and frozen until treatment and then thawed. In clinical trials, tabelecleucel is given as an intravenous infusion at a dose of 2 × 106 cells/kg on days 1, 8, and 15 of a 35-day cycle until maximal response or unacceptable toxicity. Developer(s): Atara Biotherapeutics, Inc (South San Francisco, California), in collaboration with Memorial Sloan Kettering Cancer Center (New York, New York)

Section 2. Cancer 88

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults with relapsed or Tazemetostat (Tazverik) is a first-in-class, small molecule Bendamustine plus CD20 Progression-free Approval date: June 18, 2020 refractory follicular that inhibits enhancer of zeste homolog 2 (EZH2). antibody (eg, survival FDA designation(s): Orphan lymphoma whose tumors Tazemetostat is intended to treat follicular lymphoma, an obinutuzumab, rituximab) Overall survival Drug, Fast Track are positive for a mutation indolent B-cell non-Hodgkin lymphoma. The disease CD20 monoclonal antibody Health-related quality Clinical trial(s): Phase 1/2 in the enhancer of the zeste typically responds well to initial chemoimmunotherapy, Ibritumomab tiuxetan of life primary completion May 2 polycomb repressive but if disease progresses within 24 months of diagnosis Lenalidomide plus CD20 2021, data published complex 2 subunit gene, and treatment, patients have limited effective options and antibody October 2020; phase 3 EZH2, and who have poor prognosis. EZH2 is an epigenetic regulator of gene PI3K inhibitor (eg, primary completion June received at least 2 prior expression that affects histone methylation. Methylation 2022 systemic therapies or have patterns promoted by EZH2 activity lead to cell copanlisib, idelalisib) Note(s): FDA has also no satisfactory treatment proliferation as well as growth and development of a approved tazemetostat to alternatives lymphoma (ie, lymphomagenesis). Therefore, treat metastatic or locally tazemetostat inhibition of EZH2 purportedly has advanced epithelioid therapeutic potential in follicular lymphoma. In particular, sarcoma not eligible for about 20% of follicular lymphomas harbor gain-of- complete resection function variants inEZH2, which may provide a biomarker for selection of patients likely to respond to tazemetostat. The FDA-approved label requires that eligible patients be identified for an EZH2 mutation by an FDA-approved genetic test. The recommended dosage in the FDA- approved label is 800 mg taken orally twice daily until disease progression or unacceptable toxicity. Developer(s): Epizyme, Inc (Cambridge, Massachusetts)

Section 2. Cancer 89

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Tedopi (OSE2101) is a therapeutic cancer vaccine One or more of the Overall survival FDA designation(s): Orphan advanced or metastatic designed to stimulate T-cell responses against NSCLC. following: Progression-free Drug non–small cell lung cancer Patients with NSCLC that do not respond to immune Angiogenesis inhibitors (eg, survival Clinical trial(s): Phase 3 (NSCLC) that expresses HLA- checkpoint inhibitors have limited treatment options and bevacizumab, Quality of life ATALANTE 1 primary A2 and has been previously a poor prognosis. Tedopi is based on a collection of neo- ramucirumab) completion December 2021, treated with an immune epitopes, which are short peptides derived from mutant Antimetabolites (eg, data reported September checkpoint inhibitor and versions of proteins expressed by genes mutated in gemcitabine, pemetrexed) 2020 platinum-based cancer cells, acting as antigens. Because neo-epitopes are Taxanes (eg, docetaxel) chemotherapy expressed only in the clonal cancer lineage, they are not recognized by the immune system as self-antigens and, therefore, might elicit a strong immune response against tumor cells expressing these antigens. Tedopi contains 9 neo-epitopes designed to elicit cytotoxic T-cell responses and an additional neo-epitope that initiates helper T-cell responses to further activate tumor-specific T-cell responses. In clinical trials, Tedopi is injected under the skin at a dosage of 5 mg once every 3 weeks for 6 cycles, then every 8 weeks for the remainder of the year, and finally every 12 weeks until disease progression or intolerable toxicity. Developer(s): OSE Immunotherapeutics SA (Nantes, France)

Section 2. Cancer 90

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have human Tesetaxel is being developed as the only oral form in the One or more of the Overall survival Submission date: New Drug epidermal growth factor taxane drug class (eg, docetaxel, nab-paclitaxel, following: Progression-free Application anticipated mid- receptor 2 (HER2)–negative, paclitaxel). Taxanes inhibit mitosis (ie, duplicative cell Anthracyclines (eg, survival 2021 hormone receptor (HR)– division) and are frequently used to treat breast cancer. doxorubicin, liposomal Quality of life Clinical trial(s): Phase 3 positive, locally advanced or However, available taxanes are formulated only as doxorubicin) CONTESSA primary metastatic breast cancer intravenous infusions and are frequently associated with Antimetabolites (eg, completion March 2023, top- previously treated with a hypersensitivity reactions because of additives needed as capecitabine, gemcitabine) line data presented taxane in the neoadjuvant part of the taxane infusion solution. These reactions can Microtubule inhibitors (eg, December 2020 or adjuvant setting prevent completion of a taxane regimen, potentially eribulin, vinorelbine) reducing efficacy. Breast cancer also develops resistance over time to these infused taxanes, but oral tesetaxel has Poly adenosine demonstrated anticancer activity in tumors that have diphosphate-ribose previously been exposed to other taxanes and developed polymerase (PARP) resistance. Thus, oral tesetaxel might provide a more inhibitors (eg, olaparib, convenient and comfortable administration route that talazoparib) for BRCA1/2- improves treatment adherence, as well as a treatment mutated breast cancer option when other taxanes become ineffective. In clinical Taxanes (eg, docetaxel, trials, tesetaxel (27 mg/m2 once every 21 days on day 1 of paclitaxel) each cycle) is being used in an all-oral regimen in combination with low-dose capecitabine until disease progression or intolerable toxicity. Developer(s): Odonate Therapeutics, Inc (San Diego, California)

Section 2. Cancer 91

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed or Tisagenlecleucel (Kymriah) is a chimeric antigen receptor Bendamustine plus CD20 Progression-free FDA designation(s): Orphan refractory follicular (CAR) T-cell therapy under study to treat follicular antibody (eg, survival Drug, Regenerative Medicine lymphoma lymphoma, an incurable, indolent B-cell non-Hodgkin obinutuzumab, rituximab) Overall survival Advanced Therapy lymphoma. Follicular lymphoma typically responds to CD20 monoclonal antibody Health-related quality Clinical trial(s): Phase 2 initial chemoimmunotherapy. However, for the subset of Ibritumomab tiuxetan of life ELARA primary completion patients whose disease has progressed on treatment with Lenalidomide plus CD20 November 2020, data multiple agents, limited treatment options are available monoclonal antibody presented December 2020 and prognosis is poor. To produce tisagenlecleucel, the Note(s): FDA has approved patient’s own (ie, autologous) T cells are genetically PI3K inhibitor (eg, copanlisib, idelalisib) tisagenlecleucel to treat modified to express a CAR fusion protein with a CD19- relapsed or refractory specific antigen recognition domain and a T-cell activation diffuse large B-cell domain. These genetically modified cells are grown in lymphoma (DLBCL) and number in a laboratory before infusion into the patient, relapsed or refractory acute where they purportedly induce a cytotoxic response to lymphoblastic leukemia (ALL) CD19-expressing lymphoma cells and normal B cells. In clinical trials, tisagenlecleucel is given as a single infusion at an unspecified dose. Developer(s): Novartis AG (Basel, Switzerland)

Section 2. Cancer 92

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years Uproleselan (GMI-1271) inhibits E-selectin, a One or more of the Overall survival FDA designation(s): Orphan who have relapsed or transmembrane glycoprotein that functions as a cell following: Progression-free Drug, Breakthrough refractory acute myeloid adhesion molecule. Uproleselan might provide a new Anthracyclines (eg, survival Therapy, Fast Track leukemia (AML) treatment option for a population of patients with daunorubicin, idarubicin) Quality of life Clinical trial(s): Phase 3 typically poor prognoses and outcomes. E-selectin retains Antibody-drug conjugate primary completion AML cells within the vascular niches of the bone marrow, (eg, gemtuzumab December 2020 where these cells are less susceptible to cytotoxic ozogamicin) chemotherapy. Uproleselan purportedly inhibits E- Antimetabolites (eg, selectin’s cell adhesion activity, mobilizing AML cells out of cladribine, clofarabine, bone marrow and into the bloodstream and rendering cytarabine, fludarabine) them more sensitive to chemotherapy. In clinical trials, uproleselan is given in combination with standard Cytokine (eg, granulocyte induction chemotherapy regimens (ie, mitoxantrone, colony-stimulating factor etoposide, and cytarabine [MEC]; or fludarabine, [G-CSF]) cytarabine [Ara-C], and idarubicin [FAI]). Uproleselan is DNA synthesis inhibitors given intravenously at a dose of 10 mg/kg. (eg, etoposide, Developer(s): mitoxantrone) GlycoMimetics, Inc (Rockville, Maryland) FLT3 inhibitor (eg, gilteritinib) Hypomethylating agents (eg, azacitidine, decitabine) IDH inhibitors (eg, enasidenib, ivosidenib) Multikinase inhibitor (eg, sorafenib)

Section 2. Cancer 93

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed or Venetoclax (Venclexta) is a first-in-class, potent, selective One or more of the Overall survival Clinical trial(s): Phase 3 refractory multiple myeloma inhibitor of the B-cell lymphoma-2 (BCL-2) protein. BCL-2 following: Progression-free CANOVA primary completion (RRMM) that has been prevents programmed cell death (ie, it is antiapoptotic). Alkylating agents (eg, survival June 2022 treated with 2 or more The translocation between chromosomes 11 and 14, bendamustine, Quality of life Note(s): FDA has approved therapies that included a abbreviated as t(11;14), is among the most common and cyclophosphamide) venetoclax to treat many protease inhibitor and an routinely tested genetic abnormalities in patients with Anthracyclines (eg, other cancers. See the FDA- immunomodulatory agent multiple myeloma (MM); about 15% to 20% of patients doxorubicin) approved labeling and and who harbor a with MM have it. Although this molecular subtype is Glucocorticoids (eg, prescribing document for all translocation between associated with poor prognosis with available treatments, dexamethasone) approved indications. chromosomes 11 and 14 t(11;14)-positive MM may be particularly sensitive to venetoclax because t(11;14)-positive MM cells purportedly Immunomodulatory agents depend on BCL-2 for survival. Therefore, BCL-2 inhibition (eg, lenalidomide, by venetoclax purportedly induces programmed cell pomalidomide) death of t(11;14)-positive MM cells. In clinical trials, Monoclonal antibodies (eg, venetoclax is taken by mouth at a dosage of 800 mg once daratumumab, daily in combination with dexamethasone taken by mouth elotuzumab) at a dosage of 20 mg once every week of each 28-day Proteasome inhibitors (eg, cycle until disease progression or intolerable toxicity. bortezomib, carfilzomib) Developer(s): Topoisomerase inhibitors AbbVie, Inc (North Chicago, Illinois), in collaboration with (eg, etoposide) Genentech, Inc (South San Francisco, California), a subsidiary of F Hoffman-La Roche AG (Basel, Switzerland)

Section 2. Cancer 94

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have mantle cell Venetoclax (Venclexta) plus ibrutinib (Imbruvica) is a Bendamustine with or Overall survival Clinical trial(s): Phase 3 lymphoma (MCL) and have combination therapy under study to treat relapsed or without rituximab Progression-free SYMPATICO primary received at least one prior refractory MCL. MCL is a rare B-cell non-Hodgkin Bortezomib with or without survival completion March 2022; treatment regimen that lymphoma that arises from the mantle zone of the lymph rituximab Health-related quality phase 2 primary completion failed to achieve a response node. Patients diagnosed with MCL typically respond to BTK inhibitors (eg, of life June 2017, data published intensive chemotherapy, but MCL invariably relapses, with acalabrutinib, ibrutinib) March 2018 increasingly shorter remission periods achieved with with or without rituximab Note(s): FDA has approved subsequent lines of therapy. Venetoclax and ibrutinib are Lenalidomide with or ibrutinib to treat MCL (as a 2 drugs that have demonstrated clinical activity against without rituximab monotherapy), chronic various B-cell lymphomas, including MCL, through lymphocytic leukemia R-CHOP (rituximab, nonoverlapping mechanisms. Venetoclax inhibits the pro- (CLL)/small lymphocytic cyclophosphamide apoptotic protein BCL-2. Ibrutinib is an inhibitor of Bruton lymphoma (SLL), hydroxydaunomycin tyrosine kinase (BTK), which plays a key role in the B-cell Waldenström [doxorubicin], vincristine receptor pathway involved in generating progrowth macroglobulinemia, [Oncovin], and prednisone) signals. Combined use of these drugs could improve MCL marginal zone lymphoma, treatment efficacy. In clinical trials, ibrutinib is taken by Venetoclax (off-label) and chronic graft-vs-host mouth at a dosage of 560 mg once daily and venetoclax is VR-CAP (bortezomib disease (GVHD). FDA has also taken by mouth at a final dosage of 400 mg once [Velcade], rituximab, approved venetoclax to treat daily. Venetoclax dosing may require a ramp-up period, cyclophosphamide, CLL/SLL and acute myeloid gradually increasing the dose from 20 to 400 mg to avoid doxorubicin, and leukemia (AML). the potential of toxicity due to tumor lysis syndrome. prednisone) Developer(s): Pharmacyclics, LLC (Sunnyvale, California), an AbbVie, Inc (North Chicago, Illinois), company

Section 2. Cancer 95

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have VGX-3100 is a DNA-based immunotherapy vaccine Colposcopy followed by Incidence of cervical Clinical trial(s): Phase 3 cervical high-grade containing plasmids that include expression cassettes for one of the following HSIL REVEAL 1 primary squamous intraepithelial HPV proteins E6 and E7. It is intended to offer a procedures to remove Incidence of cervical completion July 2020; phase lesion (HSIL) and confirmed nonsurgical approach to treat certain precancerous cervical lesions: cancer 3 REVEAL 2 primary infection with human cervical lesions that are typically treated surgically. As a Carbon dioxide laser Incidence of infection completion April 2021 papillomavirus (HPV) type noninvasive intervention, VGX-3100’s optimized DNA is ablation with HPV-16 and/or 16 and/or 18 delivered into cells, where it is translated into the E6 and Cold knife cone biopsy HPV-18 E7 proteins that act as antigens to induce targeted T-cell Laser cone biopsy Quality of life and antibody responses. VGX-3100 purportedly uses this immune system response to clear HPV-16 and HPV-18 Loop electrosurgical infections and precancerous lesions, enabling patients to excision avoid the risks associated with surgery, such as loss of reproductive health and negative psychosocial impacts. In clinical trials, VGX-3100 is given as an intramuscular injection followed by electroporation with the Cellectra- 5PSP device on day 0, week 4, and week 12 to introduce the plasmid DNA into cells. Developer(s): Inovio Pharmaceuticals, Inc (Plymouth Meeting, Pennsylvania)

Section 2. Cancer 96

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have untreated, Zanidatamab (ZW25), a bispecific antibody targeting 2 Chemotherapy (eg, Overall survival FDA designation(s): Orphan unresectable, locally different epitopes on HER2, is under study for treating fluoropyrimidine plus Progression-free Drug, Fast Track advanced, recurrent, or HER2-overexpressing GEA. Standard therapy for HER2- cisplatin or oxaliplatin) plus survival Clinical trial(s): Phase 2 metastatic overexpressing GEA includes a HER2-targeting anti-HER2 therapy (eg, Quality of life primary completion gastroesophageal monoclonal antibody (trastuzumab) used in combination trastuzumab) February 2022 adenocarcinoma (GEA) with chemotherapy. However, median overall survival overexpressing human with these regimens remains limited to about 14 months. epidermal growth factor A bispecific antibody, zanidatamab is intended to improve receptor 2 (HER2) existing HER2-targeted therapy through multiple mechanisms of action, including dual HER2 signal blockade; increased antibody binding, receptor clustering, and removal of HER2 from the cell surface relative to trastuzumab; and potent effector function. To determine eligibility for treatment, patients are tested for tumor HER2 overexpression using immunohistochemistry or in situ hybridization methods. In clinical trials, zanidatamab is given intravenously in combination with standard-of- care chemotherapy at unspecified dose levels and schedules. Developer(s): Zymeworks, Inc (Vancouver, British Columbia, Canada)

Section 2. Cancer 97

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have advanced Zolbetuximab (formerly IMAB362) is a claudin 18.2– Two or more of the Overall survival FDA designation(s): Orphan unresectable or metastatic specific monoclonal antibody intended to treat gastric following: Progression-free Drug gastric adenocarcinomas cancer. Standard therapy for advanced gastric cancer Antimetabolites (eg, 5- survival Clinical trial(s): Phase 3 with moderate to strong includes combination chemotherapy with multiple fluorouracil, capecitabine) Quality of life GLOW primary completion claudin 18.2 expression and cytotoxic agents; however, median overall survival with Platinum-based agents (eg, June 2022; phase 3 negative human epidermal these regimens is about 12 months. Claudin 18.2 is carboplatin, oxaliplatin) SPOTLIGHT primary growth factor receptor 2 expressed in about 50% to 70% of gastric cancers. In completion February 2022 (HER2) expression normal epithelial cells, claudin 18.2 is concealed in tight junctions; however, loss of cellular polarity during transformation to gastric cancer causes its relocation to the cell surface, allowing targeting by zolbetuximab. Zolbetuximab’s binding to claudin 18.2 purportedly triggers antibody-dependent cytotoxicity and complement-dependent cytotoxicity, leading to cancer cell death. In clinical trials, patients receive intravenous zolbetuximab every 3 weeks in combination with multiagent systemic chemotherapy. Developer(s): Astellas Pharma, Inc (Tokyo, Japan)

Section 2. Cancer 98 Table 2.3. Cancer Topics Archived Since Last Status Report: 5 Topics

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults who are at risk of oral Dusquetide (SGX942) is intended to treat OM, which has One or more of the Duration of severe In December 2020, Soligenix mucositis (OM) during no effective treatments and is a common side effect of following: mucositis reported that the phase 3 chemoradiation therapy anticancer therapies (eg, chemotherapy, radiation). OM Analgesics (eg, lidocaine, Incidence of severe DOM-INNATE trial with cisplatin and image- affects about 80% of patients with oropharyngeal cancer. narcotics) mucositis (NCT03237325) did not meet modulated radiation Dusquetide is a novel, synthetic, water-soluble, 5-amino- Localized therapy (eg, Pain its primary end point of therapy for locally acid peptide with anti-inflammatory and anti-infective achieving a statistically low-level laser therapy, Cancer treatment advanced, nonmetastatic properties. It is a member of a drug class called innate significant reduction in the oral cryotherapy) adherence squamous cell carcinoma of defense regulators. Dusquetide targets the innate median duration of severe Supportive care (eg, oral the oral cavity or immune system and binds to an intracellular adaptor Incidence of bacterial OM. hygiene protocols) oropharynx protein, sequestosome-1. Also called p62, this protein has infection a pivotal function in signal transduction during activation Quality of life and control of the innate immune system. In clinical trials, dusquetide is given as a 4-minute intravenous infusion at a dosage of 1.5 mg/kg twice weekly, starting within 3 days after initiating radiation therapy and continuing through 2 weeks after completing radiation therapy. Developer(s): Soligenix, Inc (Princeton, New Jersey)

Section 2. Cancer 99

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have Eprenetapopt (APR-246) is a small-molecule anticancer Azacitidine Overall survival In December 2020, Aprea myelodysplastic syndrome drug. It purportedly restores and reactivates wild-type p53 Decitabine Progression-free survival announced that the phase 3 (MDS) with at least one conformation and function in myelodysplastic cells, Erythropoiesis- Quality of life study of eprenetapopt failed genetic variant in the tumor causing initiation of programmed cell death (ie, apoptosis) stimulating agents (eg, to meet the primary end protein p53 gene, TP53 in cancer cells. Triggering programmed cell death of darbepoetin alfa, epoetin point of improving complete myelodysplastic cells might restore proper bone marrow alfa, filgrastim) remission rate. function, including blood cell production and function. Luspatercept-aamt MDSs represent a spectrum of blood stem cell malignancies in which the bone marrow fails to produce enough healthy blood cells. About 30% to 40% of patients with MDS progress to acute myeloid leukemia (AML). Mutations in p53 occur in about 20% of patients with MDS and AML and are associated with treatment resistance and poor prognosis. The manufacturer asserts that eprenetapopt has synergistic effects in combination with chemotherapy, small-molecule inhibitors, and immuno- oncology checkpoint inhibitors. In clinical trials, eprenetapopt is given as an intravenous infusion at an unspecified dose in combination with azacitidine. Developer(s): Aprea Therapeutics AB (Boston, Massachusetts)

Section 2. Cancer 100

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have bacillus Pembrolizumab (Keytruda) is an FDA-approved BCG monotherapy Overall survival FDA approved Calmette-Guérin (BCG)– monoclonal antibody that targets the programmed cell Cystectomy Progression-free survival pembrolizumab to unresponsive, high-risk, death 1 (PD-1) coinhibitory receptor expressed by Intravesical Quality of life treat NMIBC on January 8, non–muscle invasive activated T cells. About half of patients with NMIBC will chemotherapy with one 2020. Because it has been bladder cancer (NMIBC) with have recurrent disease after BCG induction therapy, and or more of the following: clinically available for more carcinoma in situ (CIS) with the disease in these patients is more likely to advance. than 1 year, it is no longer Anthracyclines (eg, or without papillary tumors Pembrolizumab might provide a treatment option. A within the time scope for the epirubicin, valrubicin) and who are ineligible for or hallmark of cancer is its ability to evade an immune PCORI Health Care Horizon have elected not to undergo response. Several types of cancer cells, including NMIBC, Antimetabolites (eg, Scanning System. The time cystectomy activate an immune checkpoint pathway in T cells by gemcitabine) scope is defined as 3 years overexpressing the programmed cell death ligand 1 (PD- DNA synthesis inhibitors before an intervention L1), which binds to PD-1 and limits the activation of (eg, mitomycin-C) becomes clinically available cancer-specific T cells. Pembrolizumab purportedly Taxanes (eg, docetaxel) outside of the research prevents the interaction between PD-1 and PD-L1 to setting to 1 year after an release the brake on the immune checkpoint pathway. intervention becomes Pembrolizumab in combination with BCG may overcome clinically available. NMIBC’s immune tolerance by enhancing cancer-specific T-cell responses. An oncologist prescribes pembrolizumab. The recommended regimen in the FDA- approved label is an intravenous infusion of 200 mg once every 3 weeks until disease progression or unacceptable toxicity or up to 24 months without disease progression, in combination with BCG induction therapy given as an intravesical instillation at a weekly dose of 50 mg for 6 consecutive weeks. Subsequently, patients receive a 3- week maintenance course of BCG at months 3, 6, 9, 12, 18, 24, 30, and 36. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 101

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adult females who have Robotic-assisted nipple-sparing mastectomy using the da Open surgical Patient satisfaction A systematic review invasive breast cancer or Vinci system has been pioneered by a few European mastectomy Tissue necrosis (nipple- evaluating the current use of ductal carcinoma in situ and investigators as an alternative to open surgery. Compared areola complex) robotic-assisted breast are undergoing total with open surgery, da Vinci robotic-assisted mastectomy Local tumor recurrence surgery and reconstruction mastectomy with immediate purportedly facilitates the performance of technically indicated a lack of short- and Distant tumor recurrence breast reconstruction challenging laparoscopic procedures, enhances cosmesis, long-term data comparing reduces length of stay, and improves patient satisfaction. Overall survival the safety, complication risk, In clinical trials, surgeons performing the surgery avoid Disease-free survival and cost of robotic-assisted the nipple-areola tissue by removing the target breast Quality of life surgery with traditional open cancer tissue through a small incision under the arm (ie, surgery. The lack of updates axillary access). After the robotically assisted steps, a for European trials and the surgeon manually reconstructs the breast using a absence of US trials conventional breast implant and standard subcutaneous addressing the evidence gap and cutaneous suturing techniques. needed to gain FDA Developer(s): approval likely moves European Institute of Oncology (Milan, Italy) and Gustave robotic-assisted breast Roussy Cancer Centre (Villejuif, France) surgery out of the time scope for the PCORI Health Care Horizon Scanning System. The time scope is defined as 3 years before an intervention becomes clinically available outside of the research setting to 1 year after an intervention becomes clinically available.

Section 2. Cancer 102

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Children aged 16 years or Tazemetostat (Tazverik) is a first-in-class, small molecule One or more of the Overall survival FDA approved tazemetostat older and adults who have that inhibits enhancer of zeste homolog 2 (EZH2). following: Progression-free survival to treat epithelioid sarcoma locally advanced or Tazemetostat is intended to treat epithelioid sarcoma, a Alkylating agents (eg, Quality of life on January 23, 2020. metastatic epithelioid rare and aggressive type of soft tissue sarcoma. Most dacarbazine, Because it has been clinically sarcoma ineligible for epithelioid sarcoma cases exhibit increased EZH2 activity temozolomide, available for more than 1 complete resection that results in many genes being turned off, in particular trabectedin) year, it is no longer within those involved in differentiation and cell cycle arrest. Anthracyclines (eg, the time scope for the PCORI Approved by FDA, tazemetostat purportedly improves doxorubicin, epirubicin, Health Care Horizon health outcomes in patients with limited treatment liposomal doxorubicin) Scanning System. The time options by restoring antitumorigenic gene expression that scope is defined as 3 years Antimetabolites (eg, prevents epithelioid sarcoma cells from proliferating. The before an intervention gemcitabine, ifosfamide) recommended dosage in the FDA-approved label is 800 becomes clinically available mg taken by mouth twice daily until disease progression Microtubule inhibitors outside of the research or intolerable toxicity. (eg, eribulin, vinorelbine) setting to 1 year after an Developer(s): mTOR inhibitors (eg, intervention becomes everolimus, sirolimus, Epizyme, Inc (Cambridge, Massachusetts) clinically available. temsirolimus) Multikinase inhibitors (eg, imatinib, pazopanib, regorafenib, sorafenib, sunitinib)

Section 2. Cancer 103 Section 3. Cardiovascular Diseases: 17 Topics

Table 3.1. Currently Monitored Cardiovascular Diseases Topics: 17 Topics

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 21 to 90 years CardiAMP cell therapy is a regenerative medicine that Baroreflex activation NYHA HF functional Clinical trial(s): Phase 3 who have New York Heart transplants a patient’s own bone marrow–derived therapy (ie, Barostim neo class CardiAMP primary Association (NYHA) mononuclear cells into damaged heart muscle. It is implant) Exercise tolerance completion December 2021, functional class II or III heart intended to improve heart function and exercise capacity Cardiac contractility HF-related initial data published failure (HF) with chronic through 2 mechanisms: direct and indirect regeneration. modulation (ie, Optimizer hospitalizations October 2020 ischemic left ventricular In direct regeneration, the transplanted cells purportedly implant) Survival Note(s): BioCardia dysfunction secondary to travel to injured heart muscle (ie, myocardium) and announced in August 2020 Guideline-directed optimal Quality of life myocardial infarction and transform into new functional heart cells. In indirect drug therapy (eg, that its phase 3 trial, which ventricular ejection fraction regeneration, the transplanted cells purportedly secrete angiotensin-converting had been interrupted by the between 20% and 40% that stimulatory cytokines to instruct resident stem cells to enzyme [ACE] inhibitors, effects of the COVID-19 is stable and being treated regenerate heart tissue. Clinicians first collect about 15 cc diuretics, hydralazine, pandemic, had begun to with guideline-directed of bone marrow and send it to a partner laboratory for ivabradine, continue enrollment, and 77 medical and device therapy proprietary molecular analysis to estimate a candidate’s sacubitril/valsartan) of 250 planned subjects had likelihood of successful cell therapy. If test results are been enrolled positive, patients return to the cardiac catheterization laboratory after 3 or more days to undergo the procedure. Clinicians collect about 60 cc of bone marrow from the patient to concentrate a sufficient dose of autologous cells at the point of care and inject the prepared cell product into the myocardium using a proprietary needle-injection catheter. Patients are discharged the same or next day. Developer(s): BioCardia, Inc (San Carlos, California)

Section 3. Cardiovascular Diseases 104

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 21 to 80 years CardiAMP cell therapy is a regenerative medicine that Enhanced external Angina incidence Clinical trial(s): Phase 3 who have Canadian transplants a patient’s own bone marrow–derived counterpulsation Coronary adverse CardiAMP CMI primary Cardiovascular Society class mononuclear cells into damaged heart muscle to improve Guideline-directed drug events completion December 2022 III or IV chronic refractory heart function and exercise capacity. The developer therapy (eg, aspirin, beta- Exercise tolerance angina from obstructive asserts that improving heart function could also reduce blockers, calcium channel Survival coronary artery disease that angina incidence in patients who are not candidates for blockers, nitrates, Quality of life is unsuitable for conventional revascularization procedures for ischemic ranolazine) conventional coronary artery disease. CardiAMP therapy purportedly revascularization improves heart function through 2 mechanisms: direct and indirect regeneration. In direct regeneration, the transplanted cells purportedly travel to injured heart muscle (ie, myocardium) and transform into new functional heart cells. In indirect regeneration, the transplanted cells purportedly secrete stimulatory cytokines to instruct resident stem cells to regenerate heart tissue. Clinicians first collect about 15 cc of bone marrow and send it to a partner laboratory for proprietary molecular analysis to estimate a candidate’s likelihood of successful cell therapy. If test results are positive, patients return to the cardiac catheterization laboratory after 3 or more days to undergo the procedure. Clinicians collect about 60 cc of bone marrow from the patient to concentrate a sufficient dose of autologous (ie, self-donated) cells at the point of care and inject the prepared cell product into the myocardium using a proprietary needle-injection catheter. Patients are discharged the same or next day. Developer(s): BioCardia, Inc (San Carlos, California)

Section 3. Cardiovascular Diseases 105

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 45 years or Dalcetrapib is an inhibitor of cholesteryl ester transfer Guideline-directed optimal Major adverse Clinical trial(s): Phase 3 Dal- older who have a confirmed protein (CETP), a plasma protein responsible for lipid drug therapy (eg, cardiovascular events GenE primary completion AA polymorphism at the transport. Dalcetrapib was originally intended to raise angiotensin-converting (MACE), including January 2021 rs1967309 location in the high-density lipoprotein levels by modulating CETP enzyme [ACE] inhibitors, cardiovascular death, adenylate cyclase type 9 activity. It is also intended to lower cardiovascular risk by aspirin, beta-blockers, myocardial infarction, gene, ADCY9, and who were helping lower levels of harmful low-density lipoproteins. calcium channel blockers, and stroke recently hospitalized for However, although dalcetrapib failed to reduce statins) acute coronary syndrome cardiovascular events in large phase 3 trials, patients Proprotein convertase treated with dalcetrapib who carried the AA subtilisin kexin type 9 polymorphism at the rs1967309 location of the ADCY9 (PCSK9) inhibitors gene showed a 39% drop in cardiovascular adverse events. DalCor licensed dalcetrapib and the AA allele genetic marker from Roche for use in a genetically defined subpopulation that has an increased cardiovascular risk. Roche is developing a companion diagnostic genetic test to identify potential candidates for dalcetrapib therapy in a phase 3 trial, which is also testing the drug. Dalcetrapib is taken by mouth at a dosage of 600 mg once daily. Developer(s): DalCor Pharmaceuticals (Montreal, Québec, Canada), in collaboration with F Hoffmann-La Roche, Ltd (Basel, Switzerland)

Section 3. Cardiovascular Diseases 106

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 40 years or InterAtrial shunt device (IASD) is intended to relieve HF Cardiac contractility NYHA functional class FDA designation(s): older who have symptoms by reducing elevated left atrial pressure. A modulation (ie, Optimizer Exercise tolerance Breakthrough Device symptomatic New York common feature of HF, elevated left atrial pressure implant) HF-related Clinical trial(s): Unphased Heart Association (NYHA) causes a backup of blood in the lungs, leading to Guideline-directed optimal hospitalization pivotal REDUCELAPHF-II class III or ambulatory class pulmonary congestion and breathing difficulty. IASD drug therapy (eg, Survival primary completion August IV heart failure (HF), left implantation would disrupt management for patients angiotensin-converting 2021; unphased Quality of life ventricular ejection fraction with HF with preserved left ventricular ejection fraction enzyme [ACE] inhibitors, REDUCELAPHF-I primary greater than 40%, and (ie, greater than 40%), which relies on drug therapy diuretics, hydralazine, completion December 2016, elevated left atrial pressure prescribed in an outpatient office setting. IASD ivabradine, data published October despite stable guideline- implantation might also compete with implantation of the sacubitril/valsartan) 2018; REDUCELAPHF-III directed optimal drug recently introduced Optimizer electronic implant in a European postmarket therapy subset of patients with left ventricular ejection fraction observational primary between 40% and 45%. To implant the IASD, a physician completion July 2021; inserts a specialized catheter into the femoral vein at the unphased REDUCELAPHF-IV groin and threads it up into the right atrium to create an continued access protocol opening in the septum, the wall separating the heart’s left primary completion January and right atrial chambers. The stent-like scaffold is 2022 designed to keep the transseptal puncture open. This new opening purportedly lowers left atrial pressure and helps reduce pulmonary congestion by allowing blood to cross into the low-pressure right atrium. Developer(s): Corvia Medical, Inc (Tewksbury, Massachusetts)

Section 3. Cardiovascular Diseases 107

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 21 to 80 years Ologo (CLBS14) is an autologous CD34+ cell therapy Enhanced external Angina incidence FDA designation(s): who have Canadian intended to reduce angina by stimulating growth of new counterpulsation Exercise capacity Regenerative Medicine Cardiovascular Society class microvasculature (ie, angiogenesis) in ischemic Guideline-directed optimal Major adverse Advanced Therapy III or IV chronic refractory myocardial tissue. CLBS14 is intended to improve medical drug therapy (eg, aspirin, cardiovascular events Clinical trial(s): Phase 3 angina and obstructive therapy for patients with drug-resistant angina for whom beta-blockers, calcium (MACE) RENEW completed coronary disease unsuited conventional revascularization is ineffective or unsuitable. channel blockers, nitrates, Survival November 2015, pivotal data for conventional During the proprietary process, patients receive ranolazine) published August 2016 Quality of life revascularization granulocyte colony-stimulating factor (G-CSF; 5 mg/kg Note(s): Caladrius reported subcutaneous injection) for about 4 days to mobilize their in an August 2020 SEC + own CD34 cells before plasma exchange (ie, apheresis) quarterly report that, after on day 5 to collect cells from peripheral blood. Clinicians working closely with FDA, it ship peripheral blood to a processing laboratory to isolate finalized design of a + CD34 cells and prepare the cell therapy product for confirmatory phase 3 trial transport back to the treating facility. After about 3 to 4 that will be considered for days, clinicians administer the cell product into ischemic the registration of CLBS14. heart muscle via catheter-based injection into the heart. The study design includes a Developer(s): 6-month primary end point, Caladrius Biosciences, Inc (Basking Ridge, New Jersey), and the Biologics License which acquired exclusive worldwide license from Shire plc Application is expected to (Dublin, Ireland), now part of Takeda Pharmaceutical Co, receive a 6-month review Ltd (Osaka, Japan) once submitted. The trial preparatory work is complete; however, the company will not start enrollment until it has sufficient capital dedicated to this program to fund the trial uninterrupted through completion.

Section 3. Cardiovascular Diseases 108

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 85 years Omecamtiv mecarbil (AMG 423) is a cardiac myosin Guideline-directed optimal NYHA HF functional FDA designation(s): Fast who have chronic heart activator intended to increase the duration of cardiac drug therapy (eg, class Track failure (HF); New York Heart muscle contractility and improve cardiac muscle angiotensin-converting Improved exercise Clinical trial(s): Phase 3 Association (NYHA) performance. The mechanism of action purportedly enzyme [ACE] inhibitors, tolerance GALACTIC-HF completed functional class II to IV; left improves cardiac muscle performance without increasing diuretics, hydralazine, HF-related September 2020, designed ventricular ejection fraction cellular calcium concentrations that can occur with other ivabradine, hospitalization under Special Protocol of 35% or less despite common HF drugs, thereby avoiding risk of increasing sacubitril/valsartan) Survival Assessment, data reported maximally tolerated, heart rate, blood pressure, and arrhythmias. In clinical October 2020, data Quality of life guideline-directed medical trials, omecamtiv mecarbil is taken by mouth at 25 to 50 published November 2020, therapy; and elevated levels mg twice daily. data presented December of B-type natriuretic peptide Developer(s): 2020; phase 3 METEORIC-HF (BNP) or N-terminal pro B- Cytokinetics, Inc (South San Francisco, California) primary completion October type natriuretic peptide Amgen, Inc (Thousand Oaks, California), which plans to 2021 (NTproBNP) terminate its omecamtiv mecarbil development collaboration with Cytokinetics in May 2021

Section 3. Cardiovascular Diseases 109

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult candidates for heart Organ Care System (OCS) is intended to maintain a donor Conventional cold storage Graft organ survival Submission date: Premarket transplantation organ in a warm, functioning state outside the body for Overall survival Approval (PMA) application an extended period, to optimize donor organ health and Quality of life April 14, 2014 allow for continuous clinical evaluation before Clinical trial(s): Unphased transplantation. The OCS Heart is optimized for EXPAND Heart completed preserving donor hearts. Many donor hearts are never March 2019, preliminary data transplanted because their condition degrades quickly published April 2019; after harvesting; thus, fewer patients receive the heart unphased HEART EXPAND transplant they need. OCS Heart would represent a continued access protocol substantial change to pretransplant procedures for primary completion potential donor organ assessment, procurement, and December 2021; unphased transport compared with static cold storage, which is the Donors After Circulatory current standard. OCS Heart purportedly could increase Death primary completion the number of heart transplantations, enabling longer- August 2021; unphased distance transport and giving clinicians more clinical data Donor After Circulatory to better assess donor organ suitability. The Death Heart continued manufacturer has developed similar technology to access protocol primary preserve lung and liver grafts. The OCS device comprises completion December 2021; 2 principal components: a portable battery-powered unphased observational console and an organ-specific perfusion kit that function clinical use cohort primary together as an integrated system. The system perfuses completion December 2021 donor organs with a proprietary blood-based solution to Note(s): On March 1, replenish oxygen and essential nutrients. When TransMedics announced that physicians harvest the donor heart, they place it in the FDA had rescheduled a perfusion module and revive it to a beating state. The Circulatory Systems Device self-contained perfusion module maintains the proper Advisory Panel meeting for temperature and humidity, protects the organ from April 6, 2021, to review the external contaminants, and allows sterile ultrasound OCS Heart PMA. The meeting assessment of heart function and sterile blood sampling was postponed twice in 2020 for laboratory analysis. A wireless monitor allows due to the impacts related to clinicians to assess the organ’s status and control system the COVID-19 pandemic. FDA functions. approved OCS Lung for Developer(s): standard-criteria lung TransMedics, Inc (Andover, Massachusetts) preservation in March 2018 and for expanded-criteria lung preservation in June 2019.

Section 3. Cardiovascular Diseases 110

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 45 to 99 years Placental expanded cells to treat peripheral artery Guideline-directed optimal Wound healing in the FDA designation(s): Fast who have critical limb disease (PLX-PAD) are mesenchymal-like adherent drug therapy (eg, treated leg Track, Expanded Access ischemia and ischemic stromal cells derived from full-term human placentas and angiotensin-converting Ischemic pain Program (EAP), EAP Cost lesions and minor tissue cultured in a proprietary bioreactor. PLX-PAD cells enzyme [ACE] inhibitors, Major amputation Recovery loss up to the ankle level purportedly release cytokines, chemokines, and growth aspirin, cilostazol, Clinical trial(s): Phase 3 PACE (Rutherford category 5) and factors to promote new blood vessel growth (ie, clopidogrel, statins) primary completion March who are deemed unsuitable angiogenesis) and increase circulation in ischemic tissue, Proprotein convertase 2021 for peripheral artery induce muscle tissue regeneration, and modulate subtilisin kexin type 9 Note(s): On December 9, revascularization by any inflammation to reduce connective tissue deposition and (PCSK9) inhibitors 2020, the PACE Data conventional method scarring. The cell product is given by intramuscular Monitoring Committee injection to the affected leg. recommended terminating Developer(s): the trial, noting that a low Pluristem Therapeutics, Inc (Haifa, Israel) amputation incidence in the placebo group decreased statistical power, making the trial unlikely to meet its primary end point

Section 3. Cardiovascular Diseases 111

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 90 years Pressure-controlled intermittent coronary sinus occlusion Standard percutaneous Change in size/volume FDA designation(s): who have ST-segment (PiCSO) is a system that consists of a proprietary catheter, coronary intervention (ie, of myocardial infarct Breakthrough Device elevation myocardial console, and monitor intended to be used to preserve at- balloon angioplasty with (ie, dead heart muscle) Clinical trial(s): Unphased infarction (STEMI) risk heart muscle during an acute heart attack. PiCSO is stenting) Heart function randomized PiCSO-AMI-I intended to be used as an adjunct to the standard primary completion percutaneous coronary intervention for STEMI, balloon December 2021; phase 2 angioplasty plus stenting. It could disrupt current nonrandomized OxAMI- management by adding procedural steps and capital PICSO primary completion equipment. During a percutaneous coronary intervention October 2020, data procedure, PiCSO therapy is initiated after blood flow has published June 2018; been restored. Physicians insert the PiCSO balloon unphased postmarket catheter in the femoral vein at the groin and advance it registry PiCSO-AMI-IV into the coronary sinus vein in the heart using standard primary completion catheter-based techniques. Using a proprietary algorithm February 2023; phase 2 that continuously monitors coronary sinus pressure PICSO-ViPER primary changes, a computerized PiCSO console inflates and completion August 2022 deflates the balloon to intermittently block the coronary sinus. This process purportedly redistributes blood to areas of oxygen-starved heart muscle, improves the removal of free radicals and other harmful agents that are released when circulation is restricted, and increases expression of vascular endothelial growth factor (VEGF) in heart muscle. The PiCSO protocol adds an estimated 20 to 30 minutes, on average, to the standard catheter- based intervention for heart attack. Developer(s): Miracor Medical SA (Awans, Belgium)

Section 3. Cardiovascular Diseases 112

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have New York Rexlemestrocel-L (Revascor) is a regenerative cellular LVAD implantation alone Mucosal and GI FDA designation(s): Orphan Heart Association (NYHA) therapy made from human bone marrow–derived, bleeding Drug, Regenerative Medicine functional class IIIB or IV donated (ie, allogeneic) adult mesenchymal stem cells. Functional capacity Advanced Therapy heart failure (HF) that has Patients who have end-stage HF and require LVAD Treatment-related Clinical trial(s): Phase 2 been unresponsive to implantation face a high risk of serious GI bleeding and adverse events completed August 2019, optimal medical repeated hospitalizations. A phase 2 trial of patients who Survival data published March 2019 management and who are received an LVAD found that adding rexlemestrocel-L Quality of life Note(s): Future confirmatory at risk of gastrointestinal significantly reduced the incidence of major GI bleeding phase 3 is planned (no date (GI) bleeding after by about 76% compared with a control group, although it stated) to support a future implantation of a left did not increase the rate of successfully weaning patients Biologics License Application ventricular assist device from LVAD therapy (the trial’s primary outcome). For for end-stage HF in patients (LVAD) patients with end-stage HF requiring an LVAD, with an LVAD implant rexlemestrocel-L given immediately after LVAD implantation is intended to reduce the risk of GI bleeding and related hospitalization. Rexlemestrocel-L purportedly releases a range of factors that induce functional recovery of damaged heart tissue by activating multiple pathways to induce new blood vessel growth, reduce inflammation, reduce fibrosis and scar tissue formation, and regenerate heart muscle. Rexlemestrocel-L is isolated from bone mononuclear cells with antistromal precursor antigen (STRO)-3 antibodies, grown in numbers in a laboratory, and cryopreserved until it is given to the patient. The product is intended as an off-the-shelf therapy given as a single injection of 25 million to 150 million cells into the endocardium using standard cardiac catheterization techniques. Developer(s): Mesoblast, Ltd (Melbourne, Australia)

Section 3. Cardiovascular Diseases 113

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 18 to 80 years Rexlemestrocel-L (Revascor) is a regenerative cellular Guideline-directed optimal NYHA HF functional Clinical trial(s): Phase 3 who have chronic (at least therapy made from human bone marrow–derived, drug therapy (eg, ACE class DREAM HF-1 completed May 6-month duration) ischemic donated (ie, allogeneic) adult mesenchymal precursor inhibitors, diuretics, Exercise tolerance 2020, data reported January or nonischemic New York cells. Standard medical therapy for HF attempts to slow hydralazine, ivabradine, HF-related 2021 Heart Association (NYHA) disease progression and relieve symptoms. sacubitril/valsartan) hospitalizations Note(s): FDA granted functional class II or III heart Rexlemestrocel-L purportedly releases a range of factors Survival rexlemestrocel-L Orphan failure (HF) while being that induce functional recovery within damaged heart Drug designation in June Quality of life treated with maximally tissue by activating multiple pathways to induce new 2019 for preventing mucosal tolerated doses of a beta- blood vessel growth, reduce inflammation, reduce bleeding after implantation blocker, an angiotensin- fibrosis and scar tissue formation, and regenerate heart of a left ventricular assist converting enzyme (ACE) muscle. Rexlemestrocel-L is isolated from bone device (LVAD) in adults with inhibitor or angiotensin- mononuclear cells with antistromal precursor antigen end-stage HF receptor blocker (ARB), (STRO)-3 antibodies, grown in numbers in a laboratory, and/or an aldosterone and cryopreserved until it is given to the patient. The antagonist, plus a diuretic product is intended to be an off-the-shelf therapy given as a single injection of 25 million to 150 million cells delivered into the endocardium using standard cardiac catheterization techniques. Developer(s): Mesoblast, Ltd (Melbourne, Australia)

Section 3. Cardiovascular Diseases 114

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have sustained Stereotactic body radiotherapy (SBRT) is an established No comparators exist VT episode incidence Clinical trial(s): Phase 1/2 ventricular tachycardia (VT) treatment for several solid-tumor cancers (eg, breast, Survival ENCORE-VT primary refractory to or unsuitable prostate, liver, kidney). The therapy is designed to deliver Quality of life completion July 2018, for conventional catheter high-dose radiation noninvasively to precise targets in the preliminary data published ablation of arrhythmias or body while avoiding damage to healthy adjacent tissue. January 2019, additional additional medical Investigators have begun evaluating whether SBRT could data presented November management and offer a noninvasive therapeutic alternative for VT, a 2019; unphased RAVENTA documented, recurrent VT potentially fatal irregular heartbeat, that has not primary completion June episodes despite an existing responded to conventional treatments. Although FDA has 2023; phase 1/2 STRA-MI-VT implantable cardioverter- cleared several radiation therapy systems for SBRT to primary completion defibrillator (ICD) treat tumors, SBRT for VT would be an off-label use. SBRT September 2022; phase 1/2 for refractory VT would represent a dramatic shift in SABR for refractory VT arrhythmia treatment that would require substantial primary completion collaboration among clinicians in different clinical service December 2022; unphased lines (eg, interventional cardiology, radiation physics) who STAR VTM primary do not typically collaborate. To receive an SBRT-for-VT completion December 2023; procedure, patients undergo detailed unphased proton therapy electrocardiographic imaging studies that combine primary completion July cardiac electrical mapping with anatomic imaging, which 2022 purportedly allows physicians to pinpoint the VT source Note(s): As a procedure, and possible arrhythmia trajectory. In an early study, rather than a drug or physicians delivered a total dose of 25 gy in a single medical device, SBRT for VT fraction (ie, session) without sedation or anesthesia, with would not be subject to FDA an average treatment time of less than 15 minutes. VT approval or clearance. US episodes may occur within the first 6 weeks after investigators typically treatment due to radiation-induced inflammation; perform the procedure off- however, VT episodes are expected to decline label using radiotherapy substantially after radiation-associated inflammation systems that have FDA resolves. SBRT typically uses photon-based radiation, clearance to perform SBRT although proton-based radiation is also being evaluated. for solid-tumor cancers. Developer(s): Mayo Clinic (Rochester, Minnesota) University of California at Los Angeles (Los Angeles, California) Varian Medical Systems, Inc (Palo Alto, California) Washington University School of Medicine in St Louis (St Louis, Missouri)

Section 3. Cardiovascular Diseases 115

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 20 to 80 years Symplicity Spyral is a catheter-based device intended to Guideline-directed optimal Blood pressure Clinical trial(s): SPYRAL HTN- who have 24-hour average ablate the sympathetic nerves that line the main renal antihypertensive drug Cardiovascular OFF MED pivotal primary ambulatory systolic blood arteries connecting the kidneys to the aorta. Deactivating therapy with one or more adverse events completion January 2020, pressure of at least 140 mm the renal sympathetic nerves purportedly can help agents (eg, angiotensin- Survival data published March 2020; Hg and less than 170 mm reduce difficult-to-manage high blood pressure (ie, converting enzyme [ACE] SPYRAL HTN-ON MED Quality of life Hg hypertension). An interventional procedure would shift inhibitors, angiotensin- primary completion October care from standard office-based medical management for receptor blockers [ARBs], 2021, preliminary data most patients with uncontrolled high blood pressure. A calcium channel blockers, published May 2018, post physician inserts the helical ablation catheter into the thiazide diuretics) hoc data published August femoral artery in the groin and advances it into the left 2020; SPYRAL DYSTAL and right renal arteries, alternately, to deliver primary completion March radiofrequency energy in a spiral pattern, about 1 minute 2021 per application, to one or more sections of each artery. The physician removes the catheter using standard interventional techniques after treating both renal arteries. Developer(s): Medtronic plc (Dublin, Ireland)

Section 3. Cardiovascular Diseases 116

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have pulmonary Therapeutic Intra-Vascular Ultrasound (TIVUS) System is Atrial septostomy (for drug- Exercise capacity FDA designation(s): arterial hypertension (PAH) intended to treat PAH by destroying (ie, ablating) the resistant PAH) PAH worsening Breakthrough Device nerves in the pulmonary arteries in a process called Guideline-directed medical Survival Clinical trial(s): Unphased pulmonary artery denervation. As an interventional therapy (eg, ambrisentan, Quality of life single-arm TROPHY II procedure to treat PAH, TIVUS would disrupt standard riociguat, tadalafil, primary completion July PAH treatment, which relies primarily on medical treprostinil) 2021; unphased single-arm management (ie, drugs). Studies have suggested that Lung transplantation (for TROPHY1-US primary baroreceptors and sympathetic nerve fibers near the advanced, drug-resistant completion April 2019, branching (ie, bifurcation) of the main pulmonary artery PAH) preliminary data published might contribute to the elevated blood pressure seen in April 2020; unphased single- PAH. Therefore, ablating the nerves embedded in the arm TROPHY1 primary main, left, and right pulmonary arteries might reduce completion October 2018, high blood pressure in the pulmonary arteries and lungs preliminary data published in patients with PAH. To perform pulmonary artery April 2020; unphased denervation, a physician inserts a proprietary catheter TROPHY PAH pivotal primary into the jugular vein in the neck and advances it into the completion January 2023 right heart to access the main pulmonary artery and its left and right branches. The system delivers high- intensity, unfocused ultrasonic energy through the arterial walls to ablate and deactivate the pulmonary arterial nerves. Developer(s): SoniVie, Ltd (Rosh Haayin, Israel)

Section 3. Cardiovascular Diseases 117

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Vitaria is an implant intended to treat HF by electrically Cardiac contractility NYHA HF functional FDA designation(s): symptomatic New York stimulating the vagus nerve in the neck. This approach, modulation (ie, Optimizer class Breakthrough Device Heart Association (NYHA) called autonomic regulation therapy, purportedly treats implant) Exercise tolerance Clinical trial(s): Unphased functional class III heart HF by correcting an imbalance in the autonomic nervous Guideline-directed optimal HF-related ANTHEM-HFrEF pivotal failure (HF), or NYHA class II system caused by overactive sympathetic nerves and drug therapy (eg, hospitalizations primary completion HF with an HF-related underactive parasympathetic nerves. Vagal nerve angiotensin-converting Survival December 2021, data hospitalization in the past 6 stimulation (VNS) could disrupt standard-of-care drug enzyme [ACE] inhibitors, presented March 2020 Quality of life months, and whose heart is therapy for many patients with HF. VNS therapy could diuretics, hydralazine, in normal sinus rhythm with also compete with the recently introduced Optimizer ivabradine, left ventricular ejection implantable device for treating some subsets of patients sacubitril/valsartan) fraction of 35% or less with HF. To deploy the device, a surgeon places a despite stable, guideline- pacemaker-like stimulator under the skin in the right directed optimal drug chest and tunnels the stimulator’s electrode lead under therapy the skin to the right vagus nerve in the neck. Device implantation is typically performed as an outpatient procedure that takes about 1 hour to perform with the patient under general anesthesia. Developer(s): LivaNova plc (London, United Kingdom)

Section 3. Cardiovascular Diseases 118

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 99 years V-Wave interatrial shunt is intended to relieve HF Baroreflex activation NYHA functional class FDA designation(s): who have New York Heart symptoms by reducing elevated left atrial pressure, a therapy (ie, Barostim neo Exercise tolerance Breakthrough Device Association (NYHA) class III common feature of HF. This elevated left atrial pressure implant) HF-related Clinical trial(s): Unphased or ambulatory class IV heart causes a backup of blood in the lungs, leading to Cardiac contractility hospitalization randomized RELIEVE-HF failure (HF) despite pulmonary congestion and breathing difficulty. V-Wave modulation (ie, Optimizer Survival primary completion October guideline-directed optimal device implantation would disrupt patient management implant) 2021; unphased single-arm Quality of life drug therapy and regardless for HF, which traditionally relies on office-based drug Guideline-directed optimal primary completion of left ventricular ejection therapy. V-Wave implantation might also compete with drug therapy (eg, December 2021 fraction implantation of 2 recently introduced electronic devices angiotensin-converting for HF: the Barostim neo and Optimizer implants. To enzyme [ACE] inhibitors, implant the V-Wave shunt, a physician inserts a diuretics, hydralazine, specialized catheter into the femoral vein at the groin and ivabradine, threads it up into the heart’s right atrium to create an sacubitril/valsartan) opening in the septum, the wall separating the left and right atrial chambers. The stent-like scaffold is designed to keep the transseptal puncture open. This new opening purportedly lowers left atrial pressure and helps reduce pulmonary congestion by allowing blood to cross into the low-pressure right atrium. Developer(s): V-Wave, Ltd (Caesarea, Israel, and Agoura Hills, California)

Section 3. Cardiovascular Diseases 119

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 18 years or Wireless Stimulation Endocardially for Cardiac Conventional biventricular NYHA HF functional FDA designation(s): older who have heart failure Resynchronization Therapy (WiSE-CRT) is a system that pacing/CRT with epicardial class Breakthrough Device (HF) and New York Heart purportedly improves on conventional CRT devices. It left ventricular lead Exercise tolerance Clinical trial(s): IDE pivotal Association (NYHA) class I or replaces epicardial left ventricular pacing stimulation Guideline-directed optimal HF-related (SOLVE CRT) primary IIa guideline indication for from an electrode lead placed within the heart’s coronary drug therapy (eg, hospitalizations completion June 2021; CT conventional cardiac sinus vein along the left ventricular wall with endocardial angiotensin-converting Survival Guided WiSE-CRT primary resynchronization therapy left ventricular pacing from a wireless electrode enzyme [ACE] inhibitors, completion December 2020; Quality of life (CRT) and whose disease implanted inside the left ventricle. A conventional diuretics, hydralazine, WiCS-LV postmarket registry has not responded to CRT pacemaker implanted under the skin in the chest senses ivabradine, primary completion or was previously and paces the right ventricle with a conventional right sacubitril/valsartan) September 2019, data untreatable (ie, had an atrial lead and a right ventricular lead. A wireless published March 2020 implanted CRT system electrode (2.7 × 16.3 mm) anchored in the left ventricular turned off due to electrode wall paces the left ventricle. A wireless transmitter placed lead failure or relative under the skin in the chest senses the right ventricular contraindications to an pacing and sends ultrasound energy to the implant to implanted lead) generate endocardial left ventricular pacing synchronized with right-sided pacing. A battery pack placed under the skin along the patient’s ribs and under the arm powers the wireless transmitter via a thin cable tunneled under the skin. Developer(s): EBR Systems, Inc (Sunnyvale, California)

Section 3. Cardiovascular Diseases 120 Section 4. Mental and Behavioral Health: 18 Topics

Table 4.1. Mental and Behavioral Health Topics Added Since Last Status Report: 1 Topic

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults aged 22 years or NightWare is a medical device intended to treat Alpha-1 adrenergic Anxiety and depression Approval date: November older who have nightmare nightmares associated with nightmare disorder or PTSD. antagonists (eg, prazosin; symptoms 10, 2020 disorder or nightmares It purportedly decreases nightmare frequency and off-label) Daytime sleepiness FDA designation(s): associated with intensity and increases sleep quality. PTSD is a chronic Alpha-2 adrenergic Nightmare frequency Breakthrough Therapy posttraumatic stress anxiety disorder caused by experiencing or witnessing a agonists (eg, clonidine; Nightmare intensity Clinical trial(s): Unphased disorder (PTSD) traumatic event. About 70% of patients with PTSD off-label) primary completion July experience regular nightmares. Nightmares due to PTSD Nighttime wakening Antihistamines (eg, frequency 2021; unphased primary or nightmare disorder can significantly disrupt patients’ hydroxyzine; off-label) completion May 2021; energy levels, emotional and physical health, and overall Quality of life Cognitive behavioral unphased primary quality of life. NightWare is an artificial intelligence (AI) interventions (eg, image completion February 2021; platform that is downloaded as a smart device application rehearsal therapy [IRT]) unphased completed August and used through a smart watch. It monitors a person’s 2019, data reported biometric patterns to identify elevated heart rate and November 2020 body movement data indicative of nightmares. When such signs are detected, the smart watch delivers a gentle vibration alert to arouse the patient out of the nightmare without waking. The platform uses an AI algorithm that purportedly learns the patient’s sleep patterns and better predicts each new episode. NightWare is FDA cleared for use at nighttime through a person’s smart watch. Developer(s): NightWare (Minneapolis, Minnesota)

Section 4. Mental and Behavioral Health 121 Table 4.2. Currently Monitored Mental and Behavioral Health Topics: 17 Topics

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years BXCL501 is dexmedetomidine in a proprietary sublingual Antipsychotics (eg, Agitation symptoms Submission date: New Drug who are acutely agitated (ie, under the tongue) film form. It is a selective alpha-2a olanzapine [intramuscular], and severity (eg, Application planned for the and have been clinically receptor agonist, intended to rapidly reduce acute ziprasidone excitement, hostility, first quarter of 2021 diagnosed with bipolar I or II agitation in patients who have bipolar disorder or [intramuscular], off-label uncooperativeness) FDA designation(s): Fast disorder, schizophrenia, schizophrenia. Acute agitation symptoms include haloperidol Rate of infliction of Track schizoaffective disorder, or excessive verbal or motor activity, irritability, [intramuscular]) harm to self or others Clinical trial(s): Phase 3 schizophreniform disorder uncooperativeness, and threatening or aggressive Benzodiazepines (eg, off- SERENITY I completed May behaviors toward the self or others. In bipolar disorder label lorazepam 2020, top-line data reported such symptoms are usually associated with manic or [intramuscular]) July 2020; phase 3 SERENITY hypomanic phases whereas they are more likely to occur Physical restraint II completed May 2020, top- at any time in schizophrenia. Few treatment options exist, line data reported July 2020; and BXCL501 might offer a safer alternative compared phase 1b completed July with intramuscular antipsychotics that can cause 2019, data reported July movement disorder side effects and off-label use of 2019 benzodiazepines that can cause respiratory depression. Dexmedetomidine is FDA approved for patient sedation during medical procedures and in the intensive care unit (ICU) related to intubation for mechanical ventilation. It purportedly activates alpha-2a receptors in the central nervous system, which might inhibit norepinephrine release and increase inhibitory gamma-aminobutyric acid (GABA) neuron activity. To treat acute agitation, BXCL501 purportedly produces calming but not sedative effects within 20 minutes and maintains its intended effects for 4 to 6 hours. In clinical trials, patients take a single dose of BXCL501 at a dose of 120 or 180 µg. Developer(s): BioXcel Therapeutics, Inc (New Haven, Connecticut), in collaboration with Cognitive Research Corporation (St Petersburg, Florida)

Section 4. Mental and Behavioral Health 122

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 65 years Dextromethadone (REL-1017), a single isomer of racemic Antidepressants (eg, Depressive symptoms FDA designation(s): Fast who have major depressive methadone, is an N-methyl-D-aspartate (NMDA) receptor monoamine oxidase and severity Track disorder (MDD) that has not antagonist intended to rapidly improve depressive inhibitors [MAOIs], selective Quality of life Clinical trial(s): Phase 3 responded to 1 to 3 prior symptoms in patients with treatment-resistant MDD. It serotonin reuptake RELIANCE-II planned; phase antidepressant regimens might change the paradigm of care and improve patient inhibitors [SSRIs], serotonin 3 RELIANCE-I primary health outcomes by improving depressive symptoms in a and norepinephrine completion June 2022; phase short, 7-day course of treatment. It might also have fewer reuptake inhibitors [SNRIs], 2 completed August 2019, side effects than does NMDA receptor antagonist tricyclic antidepressants top-line data reported ketamine, which is often used off-label. Overactivation of [TCAs]) October 2019 NMDA receptors has been associated with depression Brain stimulation (eg, deep and neuropathic pain. It is thought that the blocking brain stimulation [DBS], action of dextromethadone at NMDA receptors might electroconvulsive therapy reduce depressive symptoms. The manufacturer purports [ECT], transcranial that, unlike methadone, dextromethadone demonstrates magnetic stimulation virtually no opioid receptor activity and no ketamine-like [TMS], vagal nerve toxicities at its therapeutic dose. In a phase 2 clinical trial, stimulation [VNS]) dextromethadone was taken in powder form in juice at a Esketamine loading dose of 75 or 100 mg on day 1 followed by either Ketamine (off-label) 25 or 50 mg daily on days 2 through 7. Psychotherapy (eg, Developer(s): cognitive behavioral Relmada Therapeutics, Inc (New York, New York) therapy [CBT])

Section 4. Mental and Behavioral Health 123

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 8 to 12 years EndeavorRx is a video game digital therapy intended to Behavior therapy (eg, ADHD symptoms and Clearance date: June 15, who have inattentive or improve attention and related cognitive control processes applied behavior analysis severity 2020 combined-type attention- in children with ADHD. It is a novel intervention that might [ABA], cognitive behavioral Attentional functioning Clinical trial(s): Unphased deficit/hyperactivity provide a nondrug alternative for treating ADHD. A therapy [CBT]) Executive functioning STARS-ADHD completed disorder (ADHD) behavioral disorder, ADHD is characterized by inattention, External trigeminal nerve Spatial working August 2017, data published hyperactivity, and impulsivity that in children can lead to stimulation (eTNS) memory February 2020; unphased difficulty functioning at school, at home, and socially. Nonstimulant medications STARS-ADHD2 completed EndeavorRx is an action video game using proprietary (eg, atomoxetine, clonidine, February 2018; unphased selective stimulus management technology that guanfacine) STARS-Adjunct completed purportedly targets and activates the frontoparietal Stimulant medications (eg, September 2019, data network in the brain, a network thought to play an dexmethylphenidate, presented October 2020, important role in cognitive function and attention, to lisdexamfetamine, additional data presented improve attention and related cognitive control processes methylphenidate) October 2020, additional in children with ADHD. Users are given tasks such as data presented October interference management and sensory motor navigation. 2020; pooled data presented An embedded algorithm adapts to each user’s October 2020; unphased performance to provide challenging but tolerable game primary completion January play. Progress is indicated by earning rewards and 2020; unphased CAVES unlocking new environments. EndeavorRx is an completed May 2015, data application that can be downloaded on smart devices and published January 2018 used at home. It has been studied alone and in combination with stimulant medication. In clinical trials, EndeavorRx was used by the patient at home on a smart tablet for 25 minutes (5 sessions of 5 minutes) 5 times a week for 4 weeks. FDA clearance documentation states, “EndeavorRx should be considered for use as part of a therapeutic program that may include: clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder.” EndeavorRx is available in 3-month treatment periods. Developer(s): Akili Interactive Labs, Inc (Boston, Massachusetts)

Section 4. Mental and Behavioral Health 124

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years External trigeminal nerve stimulation (eTNS) is electrical Psychotherapy (eg, PTSD severity and Clinical trial(s): Phase 1 who have posttraumatic stimulation delivered through a patch placed on the cognitive behavioral symptoms completed January 2012, stress disorder (PTSD) patient’s forehead to activate the trigeminal nerve. It therapy [CBT], eye Depression severity data published April 2016; might reduce symptoms and severity of PTSD, a chronic movement desensitization and symptoms unphased pivotal primary anxiety disorder caused by experiencing or witnessing a and reprocessing [EMDR] Functional capacity completion September 2020 traumatic event. Common symptoms include therapy, prolonged Quality of life Note(s): FDA approved eTNS reexperiencing (eg, flashbacks, nightmares), avoidance exposure therapy [PET]) in April 2019 for pediatric (eg, avoiding triggering places or thoughts), increased Selective serotonin attention-deficit/ arousal or reactivity (eg, startling easily, irritability), and reuptake inhibitors (SSRIs; hyperactivity disorder impaired cognition and mood (eg, distorted thoughts, eg, paroxetine, sertraline) (ADHD) negative emotions). By activating the trigeminal nerve, eTNS purportedly activates areas of the brain that regulate mood, anxiety, and sleep (ie, brainstem, thalamus, and cortex) to decrease PTSD symptoms. The eTNS system is a cell phone–sized electrical pulse generator that delivers mild electrical signals via 2 wires connected to a small single-use electric patch that adheres to the forehead. In clinical trials, patients wear the eTNS system for 8 hours each night as an adjunct to pharmacotherapy for up to 8 weeks. Developer(s): Neurosigma (Los Angeles, California), in collaboration with University of California (Los Angeles, California)

Section 4. Mental and Behavioral Health 125

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 5 to 60 years Full-spectrum microbiota therapy (FSM; FIN-211, Dietary modifications and Autism symptoms and FDA designation(s): Fast who have autism spectrum previously CP-101) is an oral route of stool nutritional counseling severity Track disorder (ASD) with transplantation. The therapy introduces key strains of Fecal microbiota Aberrant behavior Clinical trial(s): Phase 2 gastrointestinal (GI) purportedly beneficial bacteria to increase microbial transplantation by other Social responsiveness SPROUT primary completion symptoms biodiversity within the gut using gut bacteria collected means GI symptoms May 2020; phase 2 MTT-ASD from healthy human donors. About half of individuals primary completion October with ASD have chronic GI symptoms, such as constipation, 2022; phase 2 primary diarrhea, and abdominal pain. This treatment is intended completion June 2022; phase to improve both GI symptoms and core symptoms in 1/2 completed April 2016, individuals with ASD. Research has found that individuals data published January 2017, with ASD are more likely to have an abnormal gut follow-up data published microbiome compared with healthy controls, which might April 2019 affect neurologic health in addition to GI symptoms. One course of FSM therapy purportedly improves autism symptoms for as long as 2 years. The oral capsules are made by processing feces until only bacteria remain, then encapsulating the bacteria concentrate inside a 3-layer gelatin capsule. In trials, a capsule of gut bacteria from healthy human donors is taken by mouth daily for 8 weeks. In one trial, patients also receive the antibiotic vancomycin and a bowel cleanse before FSM therapy. Developer(s): Finch Therapeutics (Somerville, Massachusetts), in collaboration with Arizona State University (Tempe, Arizona)

Section 4. Mental and Behavioral Health 126

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 65 years Ketamine (NRX-100)/cyclurad (NRX-101) is a sequential Antiepileptics (eg, Suicidal ideation FDA designation(s): who have severe bipolar drug plan that includes a single infusion of ketamine carbamazepine, Attempted suicide Breakthrough Therapy, Fast depression with acute (NRX-100) followed by an oral, fixed dose of 2 FDA- lamotrigine) Completed suicide Track suicidal ideation and approved drugs (NRX-101). The 2 drugs in NRX-101 are Antipsychotics (eg, Depression symptoms Clinical trial(s): NRX-100/ behavior lurasidone, a serotonin 2A (5-HT ) receptor antagonist, 2A clozapine, lurasidone) and severity NRX-101: Pivotal phase 2 and D-cycloserine (DCS), an N-methyl-D-aspartate (NMDA) STABIL-B completed Evidence-based Time to relapse receptor modulator. This combination therapy psychotherapy (eg, November 2018, data purportedly extends ketamine’s antidepressant and cognitive behavioral reported May 2019; NRX- antisuicidal effects and is intended to provide both rapid- therapy [CBT], dialectical 101: phase 2/3 primary onset and sustained treatment effects. The therapy can behavior therapy [DBT], completion December 2020; be given in the outpatient setting after a single dose of problem solving therapy phase 2/3 primary ketamine in a clinical setting. Lurasidone, alone or in [PST]) completion March 2022, combination with lithium or valproate, is an FDA- Lithium designed under Special approved treatment for depressive episodes in bipolar Protocol Assessment; phase Ketamine (off-label) depression. DCS, an agent used in tuberculosis therapy, 2/3 primary completion acts as a partial or full agonist (ie, activator) of NMDA Supportive care (eg, crisis August 2021, designed receptors. Studies of its use as a cognitive enhancer with response plans, under Special Protocol other psychosocial interventions have had mixed results hospitalization, postacute Assessment; NRX-100: phase in various psychiatric disorders. In trials, one 40-minute care) 3 primary completion June intravenous infusion of ketamine (0.5 mg/kg) is given, 2021 followed by administration of NRX-101 twice daily, adjusted to a combined dosage of 950/66 mg daily for 6 weeks. Patient observation is required after ketamine infusion. Developer(s): NeuroRx, Inc (Wilmington, Delaware)

Section 4. Mental and Behavioral Health 127

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have severe 3,4-Methylenedioxymethamphetamine (MDMA)–assisted Psychotherapy (eg, PTSD symptoms and FDA designation(s): posttraumatic stress psychotherapy involves treatment with MDMA during an cognitive behavioral severity Breakthrough Therapy disorder (PTSD) 8-hour standardized nondirective psychotherapy session therapy [CBT], eye Depression symptoms Clinical trial(s): Phase 3 performed by a therapist team. In the context of therapy, movement desensitization and severity MAPP1 completed August MDMA administration is intended to reduce avoidance and reprocessing [EMDR] Quality of life 2020; phase 3 MAPP2 and hyperarousal, purportedly leading to a desirable therapy, prolonged primary completion psychological state that enhances the therapeutic process exposure therapy [PET]) November 2021; phase 2 for patients with severe PTSD, which has limited effective Selective serotonin completed September 2010; treatment options. MDMA, known by the street names reuptake inhibitors (SSRIs; phase 2 completed February Ecstasy and Molly, is a psychedelic compound that is eg, paroxetine, sertraline) 2011; phase 2 completed known to release serotonin, norepinephrine, and November 2016; phase 2 dopamine in the brain and to indirectly increase oxytocin completed April 2017; phase and cortisol levels. MDMA is intended to reduce anxiety 2 completed February 2017; and emotional distress and increase prosocial behaviors, phase 2 completed including communication, compassion, and introspection. September 2017, phase 2 According to the Diagnostic and Statistical Manual of Mental pooled data published May Disorders, Fifth Edition (DSM-5), PTSD’s 4 main symptom 2019, phase 2 pooled long- categories are arousal and reactivity, avoidance of term data published June triggers, negative thoughts and feelings, and intrusive 2020, additional phase 2 thoughts and nightmares. In trials, a flexible dose of data published February MDMA is taken by mouth once a month for 3 months, 2020; phase 2 open-label during an 8-hour psychotherapy session. An initial dose primary completion August (80 to 120 mg) is taken, followed by a supplemental half- 2021 dose (40 or 60 mg) 1.5 to 2.0 hours after the initial dose during each session. The sessions are preceded by preparatory sessions and interspersed with 12 weeks of integrative psychotherapy sessions. A Risk Evaluation and Mitigation Strategy is planned. Developer(s): Multidisciplinary Association for Psychedelic Studies (Santa Cruz, California)

Section 4. Mental and Behavioral Health 128

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 65 years Nitrous oxide is an N-methyl-D-aspartate (NMDA) receptor Psychotherapy (eg, PTSD symptoms and Clinical trial(s): Phase 2 who fulfill Diagnostic and antagonist being investigated to treat PTSD in veterans. It cognitive behavioral severity completed April 2020, data Statistical Manual of Mental might improve patient health outcomes and improve therapy [CBT], eye Quality of life published June 2020; phase Disorders, Fifth Edition (DSM- quality of life by rapidly improving symptoms of PTSD movement desensitization 2 primary completion 5) criteria for posttraumatic compared with standard-of-care therapies. PTSD is a and reprocessing [EMDR] September 2023 stress disorder (PTSD) that chronic anxiety disorder caused by experiencing or therapy, prolonged Note(s): Nitrous oxide is an is combat related witnessing a traumatic event. Common symptoms include exposure therapy [PET]) FDA-approved medical gas reexperiencing (eg, flashbacks, nightmares), avoidance Repetitive transcranial and is used for anesthesia (eg, avoiding triggering places or thoughts), increased magnetic stimulation and pain relief in surgical arousal or reactivity (eg, startling easily, irritability), and (rTMS; off-label) and dental procedures impaired cognition and mood (eg, distorted thoughts, Selective serotonin negative emotions). Combat veterans are at an increased reuptake inhibitors (SSRIs; risk for developing PTSD, and there is an unmet need for eg, paroxetine, sertraline) rapid, effective therapies. Nitrous oxide is a colorless, odorless gas. When inhaled, it purportedly reduces symptoms of PTSD within 1 day with lasting effects for at least 1 week. Its action of blocking NMDA receptors purportedly blocks binding of overactive excitatory signaling (ie, with glutamate) thought to contribute to an exaggerated stress response in the body and intrusive thoughts of PTSD. Thus, nitrous oxide purportedly rapidly reduces the mechanisms contributing to PTSD symptoms. In clinical trials, patients inhale 50% nitrous oxide in combination with 50% oxygen for 1 hour, one time. Developer(s): Stanford University (Stanford, California), in collaboration with Department of Veterans Affairs’ (VA’s) Office of Research and Development (Washington, DC)

Section 4. Mental and Behavioral Health 129

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 65 years Oxytocin is a naturally occurring hormone in the brain Antidepressants (eg, Social cognition Clinical trial(s): Phase 4 who have schizophrenia that is known for its association with social bonding. Given selective serotonin Negative primary completion May intranasally, it purportedly improves social cognition in reuptake inhibitors [SSRIs], schizophrenia 2022; unphased completed patients with schizophrenia. Studies have shown that serotonin and symptoms August 2012, data published patients with schizophrenia have lower oxytocin levels, norepinephrine reuptake Quality of life July 2013; phase 2 CIDAR-3 which has been associated with impaired trust, empathy, inhibitors [SNRIs]) completed July 2014, data and ability to interpret mental states. Current Antipsychotics (oral and published January 2017; antipsychotic drugs have been used successfully to treat injectable) phase 2 completed the positive symptoms of patients with schizophrenia but Combination therapy November 2015, data have minimal effects on negative symptoms and cognitive published April 2016; phase Electroconvulsive therapy deficits. Increasing oxytocin levels might reduce negative 2 completed March 2017 symptoms and normalize social dysfunction associated Mood stabilizers with schizophrenia. It is being studied as both a Psychotherapy (eg, standalone and adjunct treatment. In the most recently cognitive behavioral completed clinical trial, oxytocin was used in combination therapy [CBT]) with risperidone. In this study, oxytocin was given intranasally at a dose of three 4-IU puffs per nostril for a total dose of 24 IU. Other trials used doses of 24 to 80 IU/day, for 1 to 6 weeks, and a dose-range study evaluated doses of 6 to 84 IU. Trials have studied single- dose treatments as well as daily treatment for up to 4 weeks. An ongoing clinical trial is evaluating intranasal oxytocin to improve outcomes of social cognitive skill training when administered just before training sessions. Developer(s): Emory University (Atlanta, Georgia), in collaboration with Atlanta Veterans Affairs’ (VA’s) Health Care System (Atlanta, Georgia) University of California (Los Angeles, California)

Section 4. Mental and Behavioral Health 130

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 65 years PH94B is a synthetic neurosteroid nasal spray under study Benzodiazepines (eg, Social anxiety FDA designation(s): Fast with social anxiety disorder as a rapid-onset treatment of SAD. Unlike current FDA- alprazolam, clonazepam; symptoms and severity Track (SAD) approved therapies for SAD that require daily dosing, off-label) Quality of life Clinical trial(s): Phase 3 PH94B is intended for as-needed use. SAD, also known as Beta-blocker (ie, planned; phase 3 completed social phobia, is a mental health condition in which social propranolol; off-label) March 2015, data published interactions cause anxiety, fear, self-consciousness, and GABA analogue (ie, August 2016; phase 2 embarrassment. It often leads to avoidance of social pregabalin; off-label) completed March 2011, data situations, which can produce feelings of isolation and Monoamine oxidase published June 2014 depression and decrease overall quality of life. Given in a inhibitors (MAOIs; eg, nasal spray, PH94B purportedly binds to nasal phenelzine; off-label) chemosensory receptors to activate neural circuits in the brain that suppress fear and anxiety. Specifically, it is Selective serotonin purported to trigger a subset of neurons in the main reuptake inhibitors (SSRIs; olfactory bulbs that stimulate inhibitory GABAergic ie, paroxetine, sertraline) neurons in the limbic amygdala to decrease the release of Serotonin and norepinephrine and facilitate fear extinction activity of the norepinephrine reuptake limbic-hypothalamic parasympathetic system. In clinical inhibitors (SNRIs; ie, trials, PH94B is taken one time intranasally at a dose of venlafaxine) 1.6 µg (two 0.4-µg sprays in each nostril) 15 minutes before laboratory-simulated public speaking and social interaction challenges, with 2 repeat challenges, each spaced 1 week apart. Developer(s): VistaGen Therapeutics, Inc (South San Francisco, California), in collaboration and with licensed marketing rights from Pherin Pharmaceuticals, Inc (Los Altos, California)

Section 4. Mental and Behavioral Health 131

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Pimavanserin (Nuplazid) is a selective serotonin inverse Antidepressants (eg, Negative symptoms Clinical trial(s): Phase 3 schizophrenia with agonist (ie, inverse activator) and antagonist targeting selective serotonin and symptom severity ADVANCE-2 (negative

predominant negative serotonin 2A (5-HT2A) receptors. It is intended to be used reuptake inhibitors [SSRIs]; of schizophrenia symptoms) primary symptoms as an adjunct to antipsychotic medication to treat off-label) Quality of life completion March 2023; negative symptoms of schizophrenia. Pimavanserin might Atypical antipsychotics (ie, phase 2 ADVANCE (negative improve patient health outcomes and quality of life, cariprazine, risperidone) symptoms) completed because no FDA-approved treatments exist specifically for Psychosocial interventions October 2019, top-line data negative symptoms of schizophrenia. These negative (eg, arts therapy, cognitive reported November 2019; symptoms include loss of interest, lack of expression, behavioral therapy [CBT]) phase 3 ENHANCE-1 emotional withdrawal, and cognitive impairment. (positive and negative Although positive symptoms of schizophrenia (eg, symptoms) completed June hallucinations, distorted thinking) are typically seen as 2019, top-line data reported more urgent to treat, negative symptoms more commonly July 2019; phase 3 extension impact patients’ ability to live independently, hold jobs, study (positive and negative

and maintain relationships. It is thought that 5-HT2A symptoms) primary receptors play an important role in psychosis, completion March 2024 schizophrenia, depression, and other neuropsychiatric Note(s): In April 2016, FDA disorders. Although the exact mechanism of action is approved pimavanserin to unknown, pimavanserin purportedly exerts its effects by treat hallucinations and acting on 5-HT2A receptors in the brain. Pimavanserin, FDA delusions associated with approved to treat hallucinations and delusions associated Parkinson disease psychosis with Parkinson disease, carries a warning for cardiac QT . FDA responded to safety interval prolongation. In clinical trials, pimavanserin is concerns over the use of taken by mouth at a dosage of 10, 20, or 34 mg once daily pimavanserin in patients as an adjunct to the patient’s current antipsychotic with hallucinations and medication. delusions associated with Developer(s): Parkinson disease in Acadia Pharmaceuticals, Inc (San Diego, California) September 2018.

Section 4. Mental and Behavioral Health 132

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 21 to 65 years Psilocybin is a psychoactive ingredient found in some Antidepressants (eg, Depression symptoms FDA designation(s): who have moderate to mushroom species. Synthetic psilocybin, when used in selective serotonin and severity Breakthrough Therapy severe major depressive combination with support from session facilitators, might reuptake inhibitors [SSRIs], Quality of life Clinical trial(s): Phase 2 disorder (MDD) improve patient health outcomes and disrupt the serotonin and PSIL201 primary completion paradigm of depression treatment. Recent research has norepinephrine reuptake February 2021; phase 2 found a link between mental health disorders and inhibitors [SNRIs]) PSIL201-LTFU primary hyperconnected, dysfunctional, neural networks in the Psychotherapy (eg, completion October 2022 brain. Psilocybin purportedly disrupts dysfunctional cognitive behavioral networks and helps restore healthier connectivity in the therapy [CBT]) brain, thus improving depression symptoms. Psilocybin is thought to exert its effects primarily through its metabolite, psilocin, which demonstrates agonist (ie, activator) or partial agonist activity at serotonin 2A (5-

HT2A) receptors. It produces marked changes in sensory perception, emotion, thought, and sense of self. In clinical trials, participants take synthetic psilocybin orally at a dose of 25 mg. Participants meet with session facilitators before dosing, undergo a session with facilitators and monitoring for 8 hours after dosing, and undergo 3 integration sessions after dosing to discuss intervention experiences with facilitators. Developer(s): Usona Institute (Madison, Wisconsin)

Section 4. Mental and Behavioral Health 133

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 13 to 65 years SEP-363856 is a psychotropic medication intended to treat Antipsychotics (first and Schizophrenia FDA designation(s): who have schizophrenia schizophrenia through a different mechanism from second generation) symptoms (positive Breakthrough Therapy currently approved antipsychotics by not binding to Psychotherapy (eg, and negative) and Clinical trial(s): Phase 3 dopamine 2 (D2) or serotonin 2A (5-HT2A) receptors. cognitive behavioral severity DIAMOND 1 primary Although the exact way it works is unknown, SEP-363856 therapy [CBT]) Frequency and completion September 2021; is thought to activate trace amine-associated receptor 1 duration of psychotic phase 3 DIAMOND 2 primary (TAAR1) and the serotonin 1A (5-HT1A) receptor. Many episodes completion October 2021; options for treating schizophrenia address either the Social functioning phase 3 DIAMOND 4 primary positive or negative symptoms of schizophrenia. This drug Quality of life completion March 2022; is intended to improve both positive and negative phase 3 DIAMOND 3 primary symptoms without the serious side effects of currently completion November 2022; available antipsychotics. In clinical trials, flexibly dosed phase 2 completed July SEP-363856 was given orally at a dosage of 25, 50, 75, or 2018, data published April 100 mg once daily for up to 52 weeks. 2020; phase 2 completed Developer(s): January 2019, data Sunovion (Marlborough, Massachusetts), a subsidiary of presented May 2020, data Sumitomo Dainippon Pharma (Osaka, Japan) presented September 2020

Section 4. Mental and Behavioral Health 134

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 to 55 years Sodium benzoate (NaBen) is a prescription-strength Antidepressants (eg, Schizophrenia FDA designation(s): Orphan who have a confirmed formulation of the sodium salt used as a common food selective serotonin symptoms (positive Drug, Breakthrough Therapy diagnosis of schizophrenia preservative. Sodium benzoate is a D-amino acid oxidase reuptake inhibitors [SSRIs], and negative) Clinical trial(s): Phase 2b/3 according to criteria of the (DAAO) inhibitor intended to treat schizophrenia’s positive serotonin and Efficacy of primary completion June Diagnostic and Statistical and negative symptoms. Existing drugs for treating norepinephrine reuptake antipsychotics 2021; phase 2b/3 primary Manual of Mental Disorders, schizophrenia have limited efficacy in reducing both inhibitors [SNRIs]) Quality of life completion June 2021; phase Fourth or Fifth Edition (DSM-IV positive and negative symptoms, and many are associated Antipsychotics (oral and 2b/3 primary completion or DSM-5), and are clinically with serious side effects. A key dysfunction related to injectable) June 2021 stable with residual schizophrenia is the reduced function of the N-methyl-D- Combination therapy symptoms; and adults aged aspartate (NMDA) receptor in the brain. NaBen addresses Mood stabilizers 18 to 55 years who have this by inhibiting DAAO metabolism to increase DAAO treatment-refractory activity, leading to production of more D-serine, which Psychotherapy (eg, schizophrenia increases NMDA activity in the hypothalamus. In ongoing cognitive behavioral phase 2b trials for patients with clinically stable therapy [CBT]) schizophrenia, 500-mg NaBen oral tablets are given twice daily at a total dosage of 1000 mg/day for 6 to 8 weeks. Participants’ current antipsychotic medication regimens remain unchanged for at least 8 weeks before study screening and during the study. In an ongoing phase 2b trial for patients with treatment-refractory schizophrenia, two 500-mg NaBen oral tablets are given twice daily, for a total dose of 2000 mg/day, or one 500-mg NaBen oral tablet is given twice daily, for a total dose of 1000 mg/day, for 8 weeks. Participants’ clozapine regimens remained unchanged for at least 3 months before study screening and during the study. After the 6 to 8 weeks of treatment, phase 3 open-label extension studies will continue for a randomly selected sample of these participants. Developer(s): SyneuRx International Corp (New Taipei City, Taiwan)

Section 4. Mental and Behavioral Health 135

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 54 years Synthetic psilocybin, being developed as COMP360, is Antidepressants (eg, Depression symptoms FDA designation(s): who have treatment- meant to mimic psilocybin, a psychoactive ingredient monoamine oxidase and severity Breakthrough Therapy resistant depression found in some species of mushroom. When used in inhibitors [MAOIs], selective Quality of life Clinical trial(s): Phase 2 combination with psychological support from trained serotonin reuptake COMP001 primary therapists, it might improve patient health outcomes and inhibitors [SSRIs], serotonin completion May 2021; phase disrupt the paradigm of depression treatment. Recent and norepinephrine 2 open-label primary research has found a link between mental health reuptake inhibitors [SNRIs], completion January 2021; disorders and hyperconnected, dysfunctional, neural tricyclic antidepressants unphased long-term follow- networks in the brain. Psilocybin purportedly disrupts [TCAs]) up COMP004 primary those dysfunctional networks and helps restore healthier Brain stimulation (eg, deep completion May 2022 connectivity in the brain, thus improving depression brain stimulation [DBS], symptoms. Psilocybin is thought to exert its effects electroconvulsive therapy primarily through its metabolite, psilocin, which [ECT], transcranial demonstrates agonist (ie, activator) or partial agonist magnetic stimulation activity at serotonin 2A (5-HT2A) receptors. It produces [TMS], vagal nerve marked changes in sensory perception, emotion, thought, stimulation [VNS]) and sense of self. In clinical trials, synthetic psilocybin is Ketamine (off-label) taken by mouth at a dose of 1, 10, or 25 mg before the Psychotherapy (eg, patient receives one-on-one psychological support from cognitive behavioral an assisting therapist throughout a session of unspecified therapy [CBT]) duration. The number or frequency of treatment sessions a patient might receive is unspecified. Developer(s): Compass Pathways (London, United Kingdom)

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Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 70 years Zonisamide (Zonegran) is a sulfonamide anticonvulsant Pharmacotherapy (eg, Alcohol consumption Clinical trial(s): Phase 3 who have alcohol use demonstrated to modulate gamma-aminobutyric acamprosate, disulfiram, Alcohol cravings primary completion disorder (AUD) acidergic (GABAergic) and glutamatergic naltrexone) Alcohol withdrawal February 2021; phase 3 neurotransmission. Approved medications to treat AUD Psychotherapy (eg, symptoms terminated October 2018, have shown limited effectiveness; only one-third of data reported June 2020 cognitive behavioral Relapse patients achieve full remission with available therapies. therapy [CBT]) Zonisamide is intended to reduce alcohol consumption in Health outcomes patients with heavy drinking behaviors or AUD. Treatment associated with with zonisamide might also ameliorate the symptoms of abstinence alcohol withdrawal syndrome. Its exact mechanism of Quality of life action is unknown, but zonisamide purportedly reduces GABAergic and glutamatergic neurotransmission in the brain, which is signaling involved with alcohol’s effect on the brain. In clinical trials, zonisamide is taken by mouth at doses of up to 500 mg daily. Developer(s): Boston University (Boston, Massachusetts), in collaboration with McLean Hospital (Belmont, Massachusetts) and University of Houston (Houston, Texas) Department of Veterans Affairs’ (VA’s) Office of Research and Development (Washington, DC)

Section 4. Mental and Behavioral Health 137

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years Zuranolone (SAGE-217) is a positive allosteric modulator Antidepressants (eg, Depression symptoms FDA designation(s):

who have major depressive of gamma-aminobutyric acid receptor A (GABAA) intended selective serotonin and severity Breakthrough Therapy disorder (MDD) to treat MDD. It purportedly yields benefits in about half reuptake inhibitors [SSRIs], Quality of life Clinical trial(s): Phase 2 the time of standard drug therapies (ie, 2 weeks or sooner serotonin and completed November 2017, vs 4 to 6 weeks); the manufacturer asserts that norepinephrine reuptake data published September zuranolone might improve symptoms within a few days. inhibitors [SNRIs]) 2019; phase 3 MOUNTAIN Reduced brain concentrations of the inhibitory Psychotherapy (eg, (MDD-301) completed March neurotransmitter GABA, as well as alterations in the cognitive behavioral 2020, top-line data reported subunit composition of GABAA (ie, deficits in GABAergic therapy [CBT]) December 2019; phase 3 transmission), are thought to contribute to MDD. WATERFALL (MDD-301B) Zuranolone purportedly works by amplifying GABAA primary completion May receptor activity. Investigators postulate that competing 2021; phase 3 SHORELINE standard-of-care antidepressants might similarly, but (MDD-303) primary more slowly, reduce GABAergic deficits due to completion November 2021, downstream effects. The manufacturer states that interim top-line data zuranolone is given orally once daily (dose unspecified), reported October 2020; for a target treatment length of 2 weeks. phase 3 open-label Developer(s): REDWOOD (MDD-302) Sage Therapeutics, Inc (Cambridge, Massachusetts), in primary completion collaboration with Biogen (Geneva, Switzerland) December 2021 Note(s): Sage Therapeutics released trial updates in May 2020: the REDWOOD study remains suspended as Sage focuses resources

Section 4. Mental and Behavioral Health 138 Section 5. Rare Diseases: 141 Topics

Table 5.1. Rare Diseases Topics Added Since Last Status Report: 20 Topics

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults diagnosed with CIVI030 is an intravenous form of iloprost. CIVI030 is Combined autologous Rate of symptomatic FDA designation(s): Orphan systemic sclerosis and under investigation to prevent the digital ischemic hematopoietic stem cell Raynaud phenomenon Drug history of Raynaud episodes experienced by people with systemic sclerosis, a transplantation (HSCT) Skin inflammation and Clinical trial(s): Phase 3 phenomenon rare, incurable, autoimmune, connective tissue disease. and high-dose scarring (AURORA) primary More than 90% of patients with systemic sclerosis immunosuppressive Survival completion June 2021 experience Raynaud phenomenon, a reversible therapy Quality of life vasospasm in response to cold temperatures or stress Low-dose that causes decreased blood flow to the fingers and other immunosuppressive extremities (eg, ears, toes). Ischemia caused by decreased therapy blood flow can lead to formation of ischemic ulcers that Peripheral vasodilators are prone to infection and tissue death. CIVI030 (eg, cilostazol, purportedly acts as a potent vasodilator and platelet moxisylyte, naftidrofuryl, inhibitor with anti-inflammatory and antiscarring effects, nifedipine, pentoxifylline) which may reduce the rate of symptomatic digital Symptom-based ischemic episodes of the disease. In clinical trials, CIVI030 palliative is given at a dosage of 0.5 to 2.0 ng/kg/min over 6 hours pharmacotherapy (eg, for 5 consecutive days. angiotensin-converting Developer(s): enzyme [ACE] inhibitors, Civi Biopharma (Chevy Chase, Maryland) nonsteroidal anti- inflammatory drugs [NSAIDs])

Section 5. Rare Diseases 139

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Patients aged 12 years or Dupilumab (Dupixent) is an anti-interleukin-4 receptor Dietary modification Dysphagia symptoms FDA designation(s): Orphan older with biopsy-confirmed monoclonal antibody under development to treat Proton pump inhibitors Quality of life Drug, Breakthrough Therapy eosinophilic esophagitis eosinophilic esophagitis. A rare disease of the digestive Systemic corticosteroids Clinical trial(s): Phase 3 system, eosinophilic esophagitis is caused by heavy Topical corticosteroids primary completion accumulation of eosinophils (ie, inflammation-promoting September 2021, white blood cells) in the esophagus and is characterized preliminary data reported by vomiting, pain in the stomach or chest, difficulty October 2020; phase 3 EoE swallowing, and failure to thrive. No FDA-approved KIDS (ages 1 to 11 years) treatments for eosinophilic esophagitis are available. primary completion June Standard treatment focuses on reducing symptoms by 2022 lessening esophageal inflammation using corticosteroids Note(s): Dupilumab or stomach acid reducers. Dupilumab could disrupt (Dupixent) was previously treatment by offering the first disease-modifying agent for FDA approved to treat eosinophilic esophagitis. Dupilumab purportedly inhibits moderate-to-severe atopic the signaling of the interleukin-4 (IL-4) and IL-13 cytokines dermatitis and moderate to by binding to the IL-4Rα subunit shared by the IL-4 and IL- severe asthma under certain 13 receptor complexes. By blocking IL-4Rα, dupilumab conditions purportedly inhibits IL-4 and IL-13 cytokine-induced inflammatory responses. In phase 3 trials for eosinophilic esophagitis, dupilumab is given as an injection under the skin at a dosage of 300 mg once weekly. Developer(s): Regeneron Pharmaceuticals, Inc (Tarrytown, New York), in collaboration with Sanofi (Paris, France)

Section 5. Rare Diseases 140

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Children aged 3 to 10 years Ibutamoren (LUM-201) is an oral, small-molecule drug Recombinant human Achievement of growth FDA designation(s): Orphan with a diagnosis of growth under development to treat growth hormone deficiency in growth hormone targets Drug hormone deficiency and children. In this rare disease, the pituitary gland fails to injections Adverse effects Clinical trial(s): Phase 2 normal thyroid function who produce enough growth hormone to promote normal Quality of life OraGrowtH210 primary are treatment-naïve growth and development. Standard treatment involves completion December 2021 daily injections under the skin of a recombinant growth hormone. Some studies suggest that more than half of patients have difficulty keeping up with growth hormone replacement therapy because of the discomfort and inconvenience of daily injections. A daily pill that replaces injections might improve treatment adherence and outcomes. Ibutamoren purportedly mimics the normal growth hormone secretion pattern by increasing the amplitude of endogenous (ie, internal) pulsatile growth hormone secretion. Ibutamoren is intended for use only in children with a functional, but reduced-capacity, hypothalamic-pituitary-growth hormone axis. Patients might require pituitary function testing to identify those likely to benefit from ibutamoren. In a phase 2 trial, it is given orally as a tablet at a dose of 0.8, 1.6, or 3.2 mg/kg, once daily. Developer(s): Lumos Pharma, Inc (Austin, Texas)

Section 5. Rare Diseases 141

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults with a diagnosis of Imsidolimab (ANB019) is an anti-interleukin-36 receptor Apremilast Improvement in Clinical FDA designation(s): Orphan active generalized pustular (anti-IL-36R) monoclonal antibody under investigation to Corticosteroids Global Impression (CGI) Drug psoriasis (GPP) treat GPP. A chronic, life-threatening inflammatory High-dose cyclosporine scale Clinical trial(s): Phase 2 disease, GPP is characterized by the development of Infliximab Reduction of body primary completion October pustules in large areas of the skin, along with fever, surface area covered by 2020, top-line data reported Methotrexate extreme tiredness, muscle weakness, an increased erythema and pustules October 2020 Oral retinoids number of white blood cells, and systemic inflammation. Rapid reduction of skin Patients with severe GPP can die from cardiopulmonary pustules failure, exhaustion, and/or infection that follows pustular flares. No therapies are FDA approved for treating GPP, and off-label use of immunosuppressant therapy (eg, cyclosporine, methotrexate, and retinoids) is associated with limited efficacy and substantial toxicity. GPP is associated with uncontrolled signaling by the IL-36 receptor. Imsidolimab purportedly inhibits IL-36R’s binding to all 3 IL-36 cytokines, potentially modifying the IL-36R-driven inflammatory process underlying the disease. In clinical trials, Imsidolimab is injected under the skin at an unspecified dose every 4 weeks. Developer(s): AnaptysBio (San Diego, California)

Section 5. Rare Diseases 142

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Patients aged 12 years or Leniolisib (CDZ173) is an oral, small-molecule Standard supportive Infection rate from Submission date: Biologics older who have phosphoinositide 3-kinase delta (PI3Kδ) inhibitor intended therapies (eg, baseline License Application planned documented activated to treat APDS. APDS is a primary immunodeficiency prophylactic antibiotic Infection severity for first half of 2022 phosphoinositide 3-kinase caused by gain-of-function variants in as the genes PIK3CD therapy, immunoglobulin Lung function FDA designation(s): Orphan delta syndrome (APDS; also and PIK3R1. Patients experience recurrent infections (eg, replacement therapy Survival Drug known as PASLI) with an ear, respiratory) beginning in childhood and develop [IRT], hematopoietic Quality of life Clinical trial(s): Phase 2/3 associated genetic PI3K progressive respiratory damage (ie, bronchiectasis), stem cell transplantation primary completion June delta mutation leading to difficulty breathing. No cure for APDS exists [HSCT]) 2021; phase 2/3 long-term and no treatments have been FDA approved. Leniolisib extension primary purportedly selectively inhibits the catalytic subunit of completion September 2026 PI3Kδ, the hyperactive protein responsible for driving the clinical manifestations of APDS. In clinical trials, leniolisib is given at a dose of 140 mg per day. Developer(s): Pharming Group NV (Leiden, the Netherlands), which licensed rights from Novartis AG (Switzerland)

Section 5. Rare Diseases 143

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Children aged 12 months to Maralixibat (LUM001) is an inhibitor of apical sodium- Cholestyramine Pruritus relief Submission date: New Drug 18 years with Alagille dependent bile acid transporter (ASBT) in development Rifampin Need for biliary diversion Application completed syndrome and moderate to for treating several rare liver diseases involving bile acid Ursodeoxycholic acid surgery February 1, 2021 severe itching (ie, pruritus) accumulation, including Alagille syndrome. The disease is (UDCA) Quality of life FDA designation(s): Orphan characterized by an abnormally low number of bile ducts, Drug, Breakthrough which may also be narrow and malformed. This results in Therapy, Rare Pediatric bile buildup in the liver, causing liver scarring and Disease impairing the liver’s ability to remove waste from the Clinical trial(s): Phase 2 bloodstream. The resulting liver dysfunction can reduce ICONIC completed May normal growth and development (failure to thrive), 2020, data presented requiring special nutritional and vitamin supplementation. November 2020 Alagille syndrome may also affect the heart, kidneys, bones, and eyes. Maralixibat purportedly prevents ASBT from recycling bile acid in the small intestine back into the liver. So, more bile is excreted in the feces, preventing buildup in the liver. Thus, more bile is excreted in feces, reducing bile levels in the liver and bloodstream. In phase 2 clinical trials, maralixibat is given as an oral solution at a dosage of 400 μg/kg once or twice daily. Developer(s): Mirum Pharmaceuticals, Inc (Foster City, California)

Section 5. Rare Diseases 144

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Males aged 12 to 74 years Marstacimab (PF-06741086) is a monoclonal antibody Emicizumab (hemophilia Bleeding episodes FDA designation(s): Orphan who have hemophilia A or B under development to treat hemophilia A or B in patients A) Thromboses (ie, blood Drug, Fast Track with or without inhibitors to with or without inhibitors to clotting factor replacement Factor VIII replacement clots) Clinical trial(s): Phase 3 BASIS clotting factor replacement therapy. As a weekly injectable therapy, marstacimab (human plasma derived Other treatment-related primary completion August therapy could disrupt standard patient management of regular or recombinant, porcine adverse events 2023 intravenous infusions of replacement clotting factors. recombinant; hemophilia Quality of life Marstacimab is a human monoclonal immunoglobulin A) isotype G, subclass 1 (IgG1) that targets and purportedly Factor IX replacement neutralizes the Kunitz 2 domain of tissue factor pathway (human plasma derived inhibitor (TFPI) to increase blood-clotting activity. TFPI is or recombinant; an anticlotting protein that inhibits early phases of the hemophilia B) clot-promoting response by inactivating the activated factor VII-tissue factor complex and activated factor X. By blocking TFPI, marstacimab purportedly allows increased factor Xa production that results in sufficient thrombin generation to improve blood-clotting capacity despite deficiencies in factor VIII in hemophilia A or factor IX in hemophilia B. In a phase 3 trial, marstacimab is given as an injection under the skin at a 300-mg initial dose followed by 150- to 300-mg weekly injections. Developer(s): Pfizer, Inc (New York, New York)

Section 5. Rare Diseases 145

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults with cystic fibrosis MRT5005 is an RNA therapeutic intended to treat CF. The CFTR modulator triple Respiratory function FDA designation(s): Orphan (CF) and 2 class I or II CF- drug is designed to deliver lipid nanoparticle therapy (ie, Survival Drug, Fast Track, Rare causing mutations in the encapsulated messenger RNA encoding a fully functional elexacaftor/tezacaftor/ Quality of life Pediatric Disease CFTR gene cystic fibrosis transmembrane conductance regulator ivacaftor [Trikafta] and Clinical trial(s): Phase 1/2 (CFTR) protein to the lungs. Available disease-modifying ivacaftor) RESTORE-CF primary CF therapies target certain genetic mutations that may be CFTR modulator dual completion October 2021 present in up to 90% of patients with CF. Thus, novel therapy (ie, disease-modifying treatments applicable to the entire lumacaftor/ivacaftor, population with CF are sought. MRT5005 is being tezacaftor/ivacaftor) developed to treat all patients with CF, regardless of the CFTR modulator underlying genetic mutation, including those with limited monotherapy (ie, or no CFTR protein. MRT5005 is delivered to the lung ivacaftor) epithelial cells by nebulization. Developer(s): Translate Bio (Lexington, Massachusetts)

Section 5. Rare Diseases 146

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Children aged 21 days or Oleogel-S10 (Filsuvez), formerly known as AP101, is a Supportive care for pain Change in wound size Submission date: Rolling older and adults with topical gel consisting of 10% birch bark extract and 90% and infection risk Infection frequency New Drug Application inherited epidermolysis sunflower oil. It is intended to quicken wound healing as a Time to wound closure planned for the first quarter bullosa (EB) subtypes symptomatic treatment in patients who have EB, which of 2021 Quality of life junctional EB, dystrophic EB, might improve patient health outcomes and improve FDA designation(s): Orphan or Kindler syndrome and quality of life. EB is a chronic skin condition characterized Drug, Fast Track, Rare with an EB target wound by fragile skin that blisters easily. Complications can Pediatric Disease include skin infection, sepsis, fusion of fingers, joint Clinical trial(s): Phase 3 EASE changes, eating difficulties, and increased risk of cancer. primary completion June There is no cure for EB and there are no FDA-approved 2020, top-line data reported treatments. Oleogel-S10 purportedly shortens wound October 2020 healing time by accelerating restoration of the epithelium (the tissue of the skin). Its active ingredient, birch bark, purportedly exerts bimodal pro- and anti-inflammatory effects and enhances migration and differentiation of certain cells found in the outer skin (ie, keratinocytes) to promote wound healing. In clinical trials, Oleogel-S10 is applied topically to EB wounds at an unknown frequency, in addition to standard-of-care wound dressings, for up to 24 months. Developer(s): Amryt Pharma plc (London, United Kingdom)

Section 5. Rare Diseases 147

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Children aged 16 to 18 years Omaveloxolone (RTA 408) is a small-molecule activator of Supportive care of organ Ambulatory and motor FDA designation(s): Orphan and adults aged up to 40 the nuclear factor erythroid 2–related factor 2 (Nrf2) complications function Drug years with Friedreich ataxia transcription factor intended to treat FRDA. It might (antiarrhythmic agents Neurological atrophy Clinical trial(s): Phase 2 (FRDA) and a modified improve patient health outcomes and quality of life for a and anticardiac failure Survival MOXIe primary completion Friedreich Ataxia Rating disorder that has no cure or approved treatments. FRDA medication; dietary Quality of life October 2019, data Scale (FARS) score between is a rare, inherited, neurodegenerative disorder best modification, oral published October 2020

20 and 80 (inclusive) characterized by loss of coordination and muscle hypoglycemic Note(s): In November 2020, strength, along with heart disease. It is caused by a therapeutics, and/or Reata Pharmaceuticals variant in the frataxin gene, FXN, that results in deficient insulin) announced that FDA had mitochondrial frataxin protein, causing mitochondrial Supportive care of proposed additional impairment in iron metabolism, especially in the spinal physical complications exploratory analyses of the cord and heart. Typically, motor symptoms emerge in (physical therapy, MOXIe phase 2 data, and childhood or young adulthood, and patients must use prostheses, orthopedic Reata will consider wheelchairs 10 to 20 years after symptom onset. Death interventions, walking conducting a second pivotal typically occurs for patients with FRDA in their late 30s, aids, wheelchairs, and trial usually related to heart disease. Omaveloxolone speech therapy) activation of Nrf2 purportedly promotes molecular pathways that restore mitochondrial function, reduce oxidative stress, and inhibit the proinflammatory signaling associated with FRDA. In clinical trials, omaveloxolone is taken by mouth at a dose ranging from 2.5 to 300 mg, once daily for 2 to 24 weeks, depending on the dose. Developer(s): Reata Pharmaceuticals, Inc (Irving, Texas)

Section 5. Rare Diseases 148

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Males aged 6 years or older Pamrevlumab, formerly known as FG-3019, is an anti– Corticosteroids (eg, Disease progression FDA designation(s): Orphan who have genetically connective tissue growth factor (anti-CTGF) monoclonal deflazacort, prednisone) Muscle strength (eg, Drug confirmed Duchenne antibody. Pamrevlumab is intended to treat DMD, an Exon-skipping therapies performance of upper Clinical trial(s): Phase 3 muscular dystrophy (DMD) inherited, X chromosome–linked genetic disorder caused (eg, eteplirsen, limb [PUL]) LELANTOS primary by variants in the human dystrophin gene, DMD. In golodirsen) Survival completion August 2022; patients with DMD, the absence of wild-type dystrophin Quality of life phase 3 primary completion protein causes progressive muscle fiber necrosis and January 2023; phase 2

eventual widespread muscle weakness. Although several primary completion March disease-modifying, exon-skipping therapies are available 2020, preliminary data to treat DMD, only a subset of patients with DMD presented June 2019 mutations are amenable to exon-skipping therapies, and these therapies require ongoing dosing. Pamrevlumab purportedly inhibits CTGF, a common factor in several fibrotic and proliferative disorders that is thought to contribute to tissue scarring (ie, fibrosis) and dysfunction. Fibrosis is pathologic feature of skeletal muscle in DMD, and elevated levels of CTGF have been observed in patients with DMD. Pamrevlumab may decrease muscle fibrosis in DMD, potentially improving muscle function. In clinical trials, pamrevlumab is given intravenously once every 2 weeks at a dose of 35 mg/kg, in addition to systemic corticosteroids, for up to 52 weeks. Developer(s): FibroGen, Inc (San Francisco, California)

Section 5. Rare Diseases 149

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Males aged 4 to 7 years who PF-06939926 is a gene therapy consisting of a Corticosteroids (eg, Ambulatory and gross FDA designation(s): Orphan have genetically confirmed recombinant adeno-associated virus serotype 9 (rAAV9) deflazacort, prednisone) motor function, as Drug, Fast Track, Rare Duchenne muscular vector containing a shortened version of the human Exon-skipping therapies measured by accepted Pediatric Disease dystrophy (DMD) dystrophin gene, DMD. It is intended to treat DMD, an (eg, eteplirsen, clinical ratings and scales Clinical trial(s): Phase 3 inherited, X chromosome–linked genetic disorder caused golodirsen) (eg, time to stand, 4-stair CIFFREO primary completion by variants in DMD. In patients with DMD, the absence of climb, 6-minute walk test September 2022 wild-type dystrophin protein causes progressive muscle [6MWT], North Star fiber necrosis and eventual widespread muscle weakness. Ambulatory Assessment Although several disease-modifying exon-skipping [NSAA]) therapies are available to treat DMD, only a subset of Disease progression patients with DMD mutations are amenable to exon- Muscle strength skipping therapies, and these therapies require ongoing Survival dosing. PF-06939926’s gene transfer approach purportedly induces durable dystrophin expression via a Quality of life single dose. The dystrophin gene is the largest known human gene. Its size precludes use of a full-length dystrophin transgene, and the PF-06939926 transgene consists of a functional, truncated dystrophin gene (ie, microdystrophin). In clinical trials, PF-06939926 is given as a single intravenous dose of 3 × 1014 vg/kg. Developer(s): Pfizer, Inc (New York, New York)

Section 5. Rare Diseases 150

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have Pridopidine is a selective sigma-1 receptor (S1R) agonist Edaravone Disability Clinical trial(s): Phase 2/3 amyotrophic lateral (ie, activator). Pridopidine is intended to treat ALS by Riluzole Disease progression HEALEY ALS regimen D sclerosis (ALS) slowing disease progression and loss of total functional Supportive care Functional capacity primary completion March capacity. ALS is a rare, neurodegenerative disorder 2022 Survival characterized by cell death in the brain and spinal cord that causes decline in motor function and, ultimately, paralysis. There is no cure, and average life expectancy is 2 to 5 years after symptom onset. S1R is thought to mediate cellular processes in motor neurons relevant to neurodegenerative diseases, such as calcium homeostasis, cytoskeleton dynamics, mitochondrial health, and neurotrophic factor release. In a mouse model of ALS, the S1R agonist pridopidine reduced toxic protein aggregates in motor neurons and lessened muscle fiber wasting. Initial clinical data also suggest that S1R is a promising target for ALS therapy, indicating that S1R activation may enhance bulbar function (brain function responsible for actions including speech, swallowing, and salivation) in patients with ALS. Pridopidine’s neuroprotective effects might slow ALS disease progression and thus extend life expectancy. In clinical trials, pridopidine is taken by mouth at a dosage of 45 mg twice daily. Developer(s): Prilenia Therapeutics (Naarden, the Netherlands)

Section 5. Rare Diseases 151

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults aged 21 years or Pridopidine is a selective sigma-1 receptor (S1R) agonist Symptomatic care (eg, Disease progression FDA designation(s): Orphan older who have genetically (ie, activator). Pridopidine is intended to treat HD by antipsychotics for chorea Motor and ambulatory Drug confirmed Huntington slowing disease progression and loss of total functional or agitation [off-label], function Clinical trial(s): Phase 3 disease (HD) and capacity. HD is an inherited, neurodegenerative disease physical therapy, speech Cognitive function PROOF-HD primary experienced adult onset of characterized by progressive movement disorder (ie, therapy, tetrabenazine to Survival completion March 2023; symptoms chorea), cognitive and functional decline, and behavioral treat chorea) phase 2 OPEN-HART Quality of life and mood changes. Symptoms typically begin around age completed January 2018, 40 and result in death about 20 years after onset. S1R is data published September thought to mediate cellular processes relevant to 2017, additional data neurodegenerative diseases, such as calcium published June 2020; phase homeostasis, cytoskeleton dynamics, mitochondrial 2 Open PRIDE-HD health, and neurotrophic factor release. Pridopidine terminated January 2018, purportedly positively acts on S1R-regulated pathways to data published December protect against injury to axons and neurons, enhance 2020; phase 2 PRIDE-HD brain-derived neurotrophic factor (BDNF) secretion, completed August 2016, restore mitochondrial function, and restore spine data published December impairments. Thus, it purportedly slows HD disease 2018 progression by exerting neuroprotective effects. In clinical Note(s): According to the trials, pridopidine is taken by mouth at a dosage of 45 mg clinical trial record, the Open twice daily. PRIDE-HD trial was Developer(s): terminated early because it Prilenia Therapeutics (Naarden, the Netherlands) “served its purpose in providing considerable safety data”

Section 5. Rare Diseases 152

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Children with primary Tadekinig alfa is a recombinant interleukin-18 binding Allogeneic (donor) stem Organ damage FDA designation(s): Orphan hemophagocytic protein (r-hIL-18BP) under development to treat primary cell transplantation Systemic inflammation Drug, Breakthrough lymphohistiocytosis (HLH) HLH. A rare, inherited, autoinflammatory disease, primary Chemotherapy (eg, flares Therapy, Rare Pediatric caused by a mutation in the HLH often has a poor prognosis due to systemic etoposide) Survival Disease NLRC4 gene or by inflammation that can severely damage organs. Donor Emapalumab-izsg Quality of life Clinical trial(s): Phase 3 chromosome X–linked stem cell transplantation intended to restore a healthy Immunosuppressant pivotal primary completion inhibitor of apoptosis (XIAP) immune system is potentially curative. However, stem cell therapy (eg, December 2020; phase 3 deficiency transplants carry a high complication risk, and difficulty corticosteroids, extension primary finding a suitable donor-recipient match can restrict cyclosporine) completion June 2021 availability. Other available treatments for HLH are Note(s): The Breakthrough intended to reduce systemic inflammation and Therapy designation for progressive organ damage by suppressing the immune tadekinig alfa covers a system, but they often have suboptimal results. Thus, new subgroup of HLH known as effective disease-modifying therapies are needed. monogenic, IL-18 associated Tadekinig alfa purportedly has a high affinity for IL-18, a autoinflammatory key inflammatory cytokine that is elevated in patients with conditions with ongoing HLH. High levels of free IL-18 (ie, unbound by endogenous systemic inflammation IL-18BP) promote prolonged systemic inflammation that can damage tissue and organs. Administration of tadekinig alfa purportedly restores the IL-18/IL-18BP balance, thus removing free IL-18 and reducing inflammation. Candidates for tadekinig alfa therapy might require a companion diagnostic test to detect circulating levels of free IL-18. In clinical trials, tadekinig alfa is given as an injection under the skin at an unspecified dose. Developer(s): AB2 Bio, Ltd (Lausanne, Switzerland)

Section 5. Rare Diseases 153

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Children aged 6 to 16 years Tideglusib (AMO-02) is a small-molecule inhibitor of Supportive care (eg, Symptom severity FDA Designation(s): Orphan with congenital myotonic glycogen synthase kinase type 3 beta (GSK3ß) under study assistive devices, cataract Overall survival Drug, Fast Track, Rare dystrophy type 1 (DM1) to treat congenital DM1. A rare genetic multisystem removal, hormone Quality of life Pediatric Disease disorder, DM1 is characterized by hypotonic and severe replacement therapy, Clinical trial(s): Phase 2/3 generalized weakness at birth, respiratory insufficiency, pain management, primary completion and shortened lifespan. No treatments have been treatment of February 2022 approved by FDA for DM1, and treatment is limited to hypothyroidism) supportive care. DM1 is caused by expansion of a trinucleotide repeat in the 3 untranslated region of the DM1 protein kinase gene, DMPK. The dysfunctional messenger RNA (mRNA) generated by this DMPK variant leads to the misregulation of a number of proteins including an increase in the level of active GSK3ß. Preclinical studies of the GSK3ß inhibitor tideglusib have indicated that reduction of GSK3ß activity leads to reductions in the levels of pathogenic DMPK mRNA and, therefore, may be of therapeutic benefit to patients with DM1. In clinical trials, tideglusib is administered orally at a weight-adjusted dose between 400 and 1000 mg, once daily. Developer(s): AMO Pharma (London, United Kingdom)

Section 5. Rare Diseases 154

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Patients aged 7 years or Vatiquinone is a small-molecule inhibitor of lipoxygenase Supportive care Ambulatory and motor FDA designation(s): Orphan older with Friedreich ataxia enzymes under study for treating patients with FRDA. A function Drug, Fast Track (FRDA) rare, inherited, neurodegenerative disorder, FRDA is best Disability Clinical trial(s): Phase 2/3 characterized by loss of coordination/muscle strength and Disease progression primary completion July heart disease. It is caused by a variant in the FXN gene Survival 2023 that results in a deficiency in the mitochondrial protein frataxin, causing impairment in mitochondrial iron Quality of life metabolism. Motor symptoms usually emerge in childhood or young adulthood, patients typically require wheelchair use 10 to 20 years after symptom onset, and death occurs in the late 30s, usually related to heart disease. Researchers have hypothesized that iron- dependent programmed cell death called ferroptosis, which is different from normal programmed cell death (ie, apoptosis), may contribute to pathogenic neuroinflammation and oxidative stress in FRDA. Vatiquinone inhibits 15-lipoxygenase, an enzyme that regulates the formation of lipid hydroperoxides that promote ferroptosis. Therefore, vatiquinone represents a rational therapeutic approach to treating the altered metabolic state that contributes to FRDA. In clinical trials, vatiquinone is administered orally 3 times daily at an age- and weight-based dose. Developer(s): PTC Therapeutics, Inc (South Plainfield, New Jersey)

Section 5. Rare Diseases 155

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Patients aged up to 18 years Vatiquinone is a small-molecule inhibitor of lipoxygenase Antiepileptics (eg, Monthly convulsive FDA designation(s): Orphan with mitochondrial disease– enzymes under study for treating patients who have clobazam, stiripentol, seizure frequency (MCSF) Drug, Pediatric Rare Disease related epilepsy who have mitochondrial disease–related epilepsy. Epilepsy is a topiramate, valproate) Convulsive seizure Clinical trial(s): Phase 2/3 uncontrolled epilepsy common symptom of genetic mitochondrial diseases, and Ketogenic diet duration primary completion despite ongoing treatment mitochondrial disease–related epilepsy frequently does Seizure-free interval September 2021 with at least 2 antiepileptic not respond to antiepileptic drugs. Researchers have Survival drugs hypothesized that iron-dependent programmed cell death called ferroptosis, which is different from normal Quality of life programmed cell death (ie, apoptosis), might contribute to mitochondrial disease–related epilepsy. Vatiquinone inhibits 15-lipoxygenase, an enzyme that regulates the formation of lipid hydroperoxides that promote ferroptosis. Therefore, vatiquinone represents a rational therapeutic approach to treating the altered metabolic state that leads to mitochondrial disease–related epilepsy. In clinical trials, vatiquinone (15 mg/kg) is administered orally 3 times daily. Developer(s): PTC Therapeutics, Inc (South Plainfield, New Jersey)

Section 5. Rare Diseases 156

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults aged up to 80 years Vixarelimab (KPL-716) is an oncostatin M receptor beta Antihistamines (eg, Anxiety and depression FDA designation(s): who have moderate to (OSMRβ)–specific monoclonal antibody under study to diphenhydramine, symptoms and severity Breakthrough Therapy severe itching associated treat itching (ie, pruritus) associated with prurigo hydroxyzine; off-label) Itch frequency and Clinical trial(s): Phase 2 with prurigo nodularis with nodularis. A chronic skin disease, prurigo nodularis is Anti IL-4Rα monoclonal severity primary completion at least 10 nodules on the characterized by hard lumps (ie, nodules) that form on the antibody (eg, dupilumab; Sleep quality February 2022; phase 2a body skin, causing intense itching, which often leads patients to off-label) Quality of life data presented May 2020; scratch the areas until they bleed. Current therapies often Immunosuppressants phase 2 completed June do not provide adequate symptomatic relief. The disease’s (eg, cyclosporine, 2020 cause is unknown, although some patients have methotrexate; off-label) underlying skin conditions or allergies that are thought to Over-the-counter lotions contribute to its development. Prurigo nodularis can be (eg, containing calamine, highly disruptive to patients’ daily lives because it can camphor, menthol, negatively affect sleep quality, mental health, pramoxine concentration, body image, and confidence. Vixarelimab hydrochloride) purportedly inhibits OSMRβ-mediated signaling by interleukin-31 and oncostatin M, 2 cytokines implicated in Phototherapy (ie, causing itching, inflammation, and fibrosis in prurigo narrow-band ultraviolet nodularis. In clinical trials, vixarelimab is injected under B, psoralen plus the skin at a dosage of 120, 360, or 540 mg once monthly. ultraviolet A; off-label) Developer(s): Topical capsaicin (off- label) Kiniksa Pharmaceuticals (Lexington, Massachusetts) Topical corticosteroids (eg, betamethasone, clobetasol; off-label)

Section 5. Rare Diseases 157

Potential patient Intervention description Potential Patient-oriented Regulatory information population Developer(s)/manufacturer(s) comparators outcome measures

Adults with a diagnosis of Ziritaxestat (GLPG1690) is a small-molecule inhibitor of Combined autologous Disease progression FDA designation(s): Orphan systemic sclerosis with autotaxin under investigation to treat systemic sclerosis, a hematopoietic stem cell Skin fibrosis and Drug diffuse cutaneous rare, incurable, autoimmune, connective tissue disease. transplantation (HSCT) inflammation Clinical trial(s): Phase 2a involvement Conventional immunosuppressive therapy has limited and high-dose Survival (NOVESA) completed June efficacy in preventing systemic sclerosis progression or immunosuppressive Quality of life 2020, top-line data reported reducing death rates. The disease is marked by therapy September 2020 vasculopathy, skin thickening due to collagen Low-dose accumulation, autoantibody formation, and inflammation, immunosuppressive which leads to scarring in skin and internal organs. therapy Patients with limited cutaneous systemic sclerosis have Symptom-based fairly high survival rates but are at increased risk of palliative pulmonary arterial hypertension. Patients with diffuse pharmacotherapy (eg, cutaneous systemic sclerosis have a more aggressive angiotensin-converting clinical course and may develop visceral complications enzyme [ACE] inhibitors, that can be life threatening. Ziritaxestat purportedly nonsteroidal anti- inhibits the main enzyme responsible for producing inflammatory drugs lysophosphatidic acid (LPA), a profibrotic and [NSAIDs]) proinflammatory lipid. In clinical trials, ziritaxestat is given orally at an unspecified dosage. Developer(s): Galapagos (Mechelen, Belgium)

Section 5. Rare Diseases 158 Table 5.2. Currently Monitored Rare Diseases Topics: 114

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 months or ABO-101 is a recombinant adeno-associated viral vector Supportive care Cognitive and motor FDA designation(s): Orphan older and adults who have carrying a wild-type copy of the N-acetyl-alpha-D- function, as measured Drug, Rare Pediatric Disease, Sanfilippo syndrome type B glucosaminidase gene, NAGLU. The therapy is intended for by validated clinical Fast Track (also called Sanfilippo syndrome type B, a childhood-onset, ratings and scales Clinical trial(s): Phase 1/2 mucopolysaccharidosis type progressive, inherited metabolic disorder caused by a NAGLU enzyme activity Transpher B primary III B [MPSIIIB]) mutation in NAGLU. Sanfilippo syndrome type B (about Heparan sulfate levels completion October 2022, 30% of all Sanfilippo syndrome cases) has no cure, and data presented May 2020; patients typically do not survive beyond their 20s. unphased long-term follow- Treatment consists of supportive care. Patients with the up primary completion June disorder cannot break down the polysaccharide heparan 2026 sulfate, a process normally mediated by the NAGLU enzyme. Buildup of heparan sulfate in cells of the central nervous system causes degeneration that manifests as behavioral problems, sleeplessness, loss of speech and cognitive skills, mental retardation, heart problems, seizures, and loss of mobility. In patients with this syndrome, ABO-101 purportedly restores NAGLU function, blocks central nervous system degeneration, and reduces disease-related symptoms. In clinical trials, ABO-101 is given intravenously via a peripheral-limb vein, at a low dose (2 × 1013 vg/kg) or high dose (5 × 1013 vg/kg), once. Developer(s): Abeona Therapeutics, Inc (Dallas, Texas)

Section 5. Rare Diseases 159

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 months or ABO-102 is a recombinant adeno-associated viral vector Bone marrow Age-related FDA designation(s): Orphan older and adults who have carrying a wild-type copy of the N-sulfoglucosamine transplantation developmental scores Drug, Fast Track, Rare Sanfilippo syndrome type A sulfohydrolase gene, SGSH. ABO-102 is intended to treat Supportive care Behavior, as measured Pediatric Disease, (also called Sanfilippo syndrome type A, a childhood-onset, by accepted clinical Regenerative Medicine mucopolysaccharidosis type progressive, inherited metabolic disorder caused by a ratings and scales Advanced Therapy III A [MPSIIIA]) and a mutation in SGSH. Patients with the disorder cannot break Brain, liver, and spleen Clinical trial(s): Phase 1/2 minimum cognitive down the polysaccharide heparan sulfate, a process volume Transpher A primary developmental quotient normally mediated by the SGSH-encoded enzyme Cognitive and motor completion December 2022, (DQ) of 60 or above, or heparan-N-sulfamidase. Buildup of heparan sulfate in function, as measured data presented May 2020; children or adults (age cells of the central nervous system causes degeneration by accepted clinical phase 1/2 ABT-003 primary unspecified) who have that manifests as behavioral problems, sleeplessness, loss ratings and scales completion December 2023; middle- or advanced-phase of speech and cognitive skills, mental retardation, heart unphased long-term follow- Heparan sulfate levels MPSIIIA and a DQ below 60 problems, seizures, and loss of mobility. No cure exists for up primary completion Sanfilippo syndrome type A (about 60% of all Sanfilippo Sleep quality and December 2025 syndrome cases), and patients typically do not survive duration past their 20s. Treatment consists of supportive care. In Sulfamidase enzyme these patients, ABO-102 purportedly restores sulfamidase activity enzyme function, blocks central nervous system Quality of life degeneration, and reduces disease-related symptoms. In clinical trials, ABO-102 is given intravenously via a peripheral-limb vein, at a low dose (0.5 × 1013 vg/kg), middle dose (1.0 × 1013 vg/kg), or high dose (3.0 × 1013 vg/kg), once. Developer(s): Abeona Therapeutics, Inc (Dallas, Texas)

Section 5. Rare Diseases 160

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults who Adrabetadex (VTS-270, cyclodextrin, 2-hydroxypropyl-β- Glucosylceramide synthase Disability Clinical trial(s): Pivotal phase have genetically confirmed cyclodextrin) is intended to treat neurologic inhibitor (ie, miglustat; off- Disease progression 2/3 primary completion Niemann-Pick disease type manifestations of Niemann-Pick disease type C (NPC) by label) Disease symptoms and September 2021; phase 3 C1 (NPC-1) or type C2 (NPC- regulating intracellular cholesterol in NPC-1-deficient cells. Supportive treatment (eg, severity open-label primary 2) with neurologic NPC is a rare, neurodegenerative, lysosomal storage completion May 2021; phase bowel regimen, Survival manifestations disorder caused by mutations in the NPC intracellular bronchoalveolar lavage, 2/3 open-label extension Quality of life cholesterol transporter 1 or 2 genes, NPC1 or NPC2. Lack bronchodilation therapy, primary completion of the encoded NPC1 or NPC2 protein disrupts gastrostomy tube, physical December 2021 intracellular cholesterol and other lipid trafficking, leading therapy) Note(s): In July 2020, to excessive lipid accumulation in tissues including the Mallinckrodt announced brain, liver, and spleen. This results in a range of adrabetadex will be available symptoms and complications, including enlarged liver and through an Expanded Access spleen; eye, liver, and lung disease; feeding difficulties; Program (EAP) while it hearing loss; motor impairment (including cataplexy and determines the feasibility of dystonia); and cognitive deterioration. About one-third of a regulatory filing after patients also develop seizures. The disease is most often receiving feedback from FDA diagnosed at about 10 years of age, and most patients die that current data are before 20 years of age. Adrabetadex purportedly insufficient to demonstrate promotes cholesterol transport, restores normal efficacy cholesterol metabolism and regulation, and slows disease progression in patients with NPC-1. It is injected directly into spinal fluid to better target the neurologic manifestations of NPC-1. In clinical trials of patients younger than 4 years of age, adrabetadex is infused into the spinal canal via lumbar puncture at a dose of 200 mg initially, with dose escalation of 100 mg every 2 weeks up to a maximum tolerable dose of 900 mg for up to 3 years. In clinical trials of children and adults aged 4 years or older, adrabetadex is infused into the spinal canal at a dose of 900, 1200, or 1800 mg every 2 weeks for up to 3 years. Developer(s): Mallinckrodt plc (Surrey, United Kingdom), which acquired developer Sucampo Pharmaceuticals (Rockville, Maryland), which, in turn, acquired original developer Vtesse, Inc (Gaithersburg, Maryland)

Section 5. Rare Diseases 161

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults undergoing surgery ADX-2191 is an intravitreal form of 0.8% methotrexate Supportive care Vision loss FDA designation(s): Orphan for recurrent retinal that is intended to prevent PVR. A rare inflammatory Surgery Retinal detachment Drug, Fast Track detachment due to disorder of the retina, PVR occurs secondary to ocular recurrence rate Clinical trial(s): Phase 3 proliferative surgery or trauma and can lead to severe retinal scarring Quality of life GUARD primary completion vitreoretinopathy (PVR) or and blindness. Additionally, PVR is the leading cause of December 2022 retinal detachment caused retinal detachment recurrence after surgical repair of by open globe injury retinal detachment. No FDA-approved treatments are available for preventing PVR. ADX-2191 purportedly downregulates retinal cell proliferation and activity, which could reduce retinal scarring and prevent blindness due to PVR. ADX-2191 is given as an intravitreal injection 13 times over 16 weeks upon completion of posterior (pars plana) vitrectomy. Developer(s): Aldeyra Therapeutics, Inc (Lexington, Massachusetts)

Adults who have Guillain- ANX005 is a humanized monoclonal antibody that targets Plasma therapy (eg, plasma GBS disability score FDA designation(s): Orphan Barré syndrome (GBS) a protein called complement component 1q exchange or Muscle weakness Drug, Fast Track (C1q) to inhibit the initiation of the classic complement immunoglobulin therapy) Quality of life Clinical trial(s): Phase 2/3 cascade. C1q is thought to be involved in the GBS disease Supportive care (eg, primary completion March process. GBS is a rare, acute autoimmune disease in intubation, mechanical 2023 which the body’s immune system mistakenly attacks part ventilation, physical of its peripheral nervous system. Preceding infection can therapy) trigger GBS, resulting in rapid progressive weakness in the limbs that can end in widespread peripheral nerve damage and paralysis within 4 weeks. ANX005 purportedly relieves GBS symptoms by inhibiting C1q activity, thereby preventing immune cell recruitment and inflammation via the soluble activation products C3a and C5a (anaphylatoxins), complement cleavage products deposited on cell membranes, and damage caused by activation of the membrane attack complex (MAC). In clinical studies, ANX005 is given intravenously at a dose of 75 mg/kg. Developer(s): Annexon Biosciences (San Francisco, California)

Section 5. Rare Diseases 162

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 2 to 21 years Apitegromab, formerly known as SRK-015, is an Manual chest Breathing (ie, FDA designation(s): Orphan with genetically confirmed antimyostatin monoclonal antibody intended to treat physiotherapy for ventilator) support Drug, Rare Pediatric Disease spinal muscular atrophy SMA, a neuromuscular disorder caused by a genetic ineffective cough (eg, Nutritional support Clinical trial(s): Phase 2 (SMA) type II or III defect in a gene called the survival of motor neuron 1, Cough Assist or VitalCough) Motor function, as TOPAZ primary completion telomeric, or SMN1. This defect results in loss of the gene’s Noninvasive positive measured by accepted January 2021, interim data encoded SMN protein, which is critical for motor neuron pressure ventilation clinical ratings and reported October 2020 function and transmission of signals from the brain to SMN-upregulating therapy scales skeletal muscles. Patients with SMA experience motor (eg, nusinersen, Muscle strength, as neuron loss, resulting in progressive muscle weakness onasemnogene measured by accepted and eventual paralysis. By selectively inhibiting the activity abeparvovec-xioi) clinical ratings and of myostatin, which normally prevents excessive muscle scales growth, apitegromab purportedly increases muscle mass, strength, and function in patients with SMA. FDA Developmental approved 2 SMN-upregulating therapies (ie, Spinraza, milestone achievement Zolgensma), which restore SMN expression and prevent Survival disease progression in patients with SMA, but these Hospitalization rates therapies may be cost prohibitive for patients. Apitegromab may be used either alone or in conjunction with these SMN-upregulating therapies. In clinical trials, patients receive 2 mg/kg (cohorts 1, 2, and half of 3) or 20 mg/kg (other half of cohort 3) of apitegromab, intravenously, once every 4 weeks for up to 12 months. Developer(s): Scholar Rock (Cambridge, Massachusetts)

Section 5. Rare Diseases 163

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Arimoclomol (BRX-345) is a small-molecule amine Edaravone Disability FDA designation(s): Orphan amyotrophic lateral intended to treat ALS by helping regulate proteins Riluzole Disease progression Drug, Fast Track sclerosis (ALS) involved with the disease. ALS is a rare and fatal Supportive care Functional capacity Clinical trial(s): Phase 3 neurodegenerative disease in which the death of nerve Survival ORARIALS-01 completed cells (ie, neurons) in the brain and spinal cord leads to a December 2020; phase 3 loss of voluntary muscle function, wasting of muscle ORARIALS-2 open-label mass, and eventual death. Although the exact cause of extension primary the disease is unknown, it is thought to be caused by completion July 2022; phase accumulations of abnormal proteins in neural cells. FDA- 2/3 (patients with SOD1 approved drugs to treat the disease (eg, edaravone, mutation) completed riluzole) can decrease symptom severity but do not November 2016, data prevent disease progression. Arimoclomol is intended to published February 2018 reduce abnormal protein accumulation and help deconstruct abnormal proteins, slowing disease progression and improving patient quality of life by prolonging motor function. Arimoclomol purportedly increases the activity of heat shock factor 1, a transcription factor that promotes expression of heat shock proteins (HSPs). These proteins are thought to regulate normal protein folding and deconstruct abnormal proteins. In clinical trials, patients take arimoclomol by mouth. One recent trial reported giving a dosage of 200 mg 3 times daily for up to 12 months. The dosage in the ongoing phase 3 trial is unspecified. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)

Section 5. Rare Diseases 164

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults aged 2 Arimoclomol (BRX-345) is a small-molecule drug intended Glucosylceramide synthase Disability PDUFA date: June 17, 2021; to 18 years who have to treat NPC by amplifying production of reparative heat inhibitor (ie, miglustat; off- Disease progression Priority Review Niemann-Pick disease type shock proteins (HSPs) to slow disease progression. NPC is label) Disease symptoms and FDA designation(s): Orphan C (NPC) a rare, neurodegenerative, lysosomal storage disorder Supportive treatment (eg, severity Drug, Fast Track, caused by mutations in the NPC intracellular cholesterol bowel regimen, Survival Breakthrough Therapy, Rare transporter 1 or 2 genes, NPC1 or NPC2. Lack of the bronchoalveolar lavage, Pediatric Disease Quality of life encoded NPC1 or NPC2 protein disrupts intracellular bronchodilation therapy, Clinical trial(s): Phase 2/3 cholesterol and other lipid trafficking, leading to excessive gastrostomy tube, physical primary completion June lipid accumulation in tissues, including the brain, liver, and therapy) 2018, data reported January spleen. This results in symptoms and complications, 2019, interim open-label including enlarged liver and spleen; eye, liver, and lung extension data reported disease; feeding difficulties; hearing loss; motor January 2020 impairment (including cataplexy and dystonia); and cognitive deterioration. About one-third of patients also experience seizures. The disease is most often diagnosed in patients at about 10 years of age, and most patients die before reaching their 20s. Arimoclomol purportedly amplifies the production of reparative HSPs, which are thought to rescue misfolded proteins, clear abnormal protein collections, and improve liposome function in NPC. The drug can purportedly cross the blood-brain barrier, thereby having a therapeutic effect in the brain as well as in the rest of the body. In clinical trials, it is given orally at a dosage of 150 to 600 mg (based on patient weight) 3 times daily. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)

Section 5. Rare Diseases 165

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 45 years or Arimoclomol (BRX-345) is a small-molecule drug intended Immunosuppressants (eg, Disease progression FDA designation(s): Orphan older who have sporadic to treat sIBM by increasing the production of reparative azathioprine, Functional capacity Drug, Fast Track inclusion body myositis heat shock proteins (HSPs) in damaged muscle cells. A methotrexate, prednisone) Survival Clinical trial(s): Pivotal phase (sIBM) degenerative muscle disease of unknown cause, sIBM Supportive care Quality of life 2/3 primary completion develops most often after 50 years of age and causes February 2021; phase 2/3 progressive loss of muscle strength and volume over 10 to completed September 2012, 15 years. No cure or treatment is available. Patients data published March 2016; progress to severe disability, requiring the use of a phase 3 open-label wheelchair and help with daily activities. Complications, extension primary including aspiration pneumonia, increase the risk of completion May 2022 death. Investigators suspect that sIBM-induced muscle degeneration might be caused by the accumulation of abnormal and misfolded proteins in muscle cells. Arimoclomol purportedly increases the activity of heat shock factor 1, a transcription factor that promotes HSP expression in cells experiencing stress or toxicity. HSPs protect against the accumulation of misfolded proteins and other toxic waste products by restoring functional protein shapes and degrading abnormal protein aggregates. In clinical trials, arimoclomol is given orally at a dosage of 400 mg (two 200-mg pills) 3 times daily, for a daily dose of 1200 mg. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)

Section 5. Rare Diseases 166

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years ARO-AAT is an RNA interference (RNAi) therapeutic Liver transplantation Rate of liver fibrosis FDA designation(s): Orphan who have alpha-1 intended for liver disease associated with AAT deficiency, (reserved for end-stage Liver function Drug, Fast Track antitrypsin (AAT) deficiency a rare inherited disease affecting mostly the lungs and liver disease) Quality of life Clinical trial(s): Phase 2/3 and biopsy-confirmed liver liver. AAT deficiency is caused by genetic variants in the Supportive care to prevent SEQUOIA primary fibrosis serpin family A member 1 gene, SERPINA1, which codes for or reduce the completion May 2023; phase AAT protein production. In AAT deficiency caused by complications of chronic 2 primary completion certain genetic variants, misfolded copies of the AAT liver disease (CLD; eg, November 2021, interim protein cannot be secreted normally into the blood, so ascites, portal vein data reported September they build up in and injure the liver. No approved disease- hypertension, 2020 modifying therapies are available for AAT deficiency– gastrointestinal related liver damage; treatment consists mainly of hemorrhage) supportive care. ARO-AAT is intended to block AAT protein production by degrading AAT-encoding messenger RNA (mRNA). Preclinical testing suggests ARO-AAT might prevent accumulation of liver disease–associated AAT variants (eg, Z-AAT), which might halt progression of, and possibly reverse, liver fibrosis. In a phase 2/3 trial, ARO- AAT is administered as an injection under the skin (dose not specified) at day 1, 29, 133, and every 84 days thereafter, with a minimum of 6 doses and maximum of 9. Developer(s): Arrowhead Pharmaceuticals, Inc (Pasadena, California), in collaboration with Takeda Pharmaceuticals (Osaka, Japan)

Section 5. Rare Diseases 167

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 55 years AT-007 is a small-molecule inhibitor of the enzyme aldose Lifestyle modification (eg, Cognitive decline from Submission date: New Drug who have classic reductase. Galactosemia is a rare genetic disease that avoidance of dairy products baseline Application planned for third galactosemia confirmed by affects patients’ ability to metabolize galactose, a simple and other sources of Cataract formation quarter of 2021 evidence of absent or sugar found in foods and produced during normal galactose) from baseline FDA designation(s): Orphan significantly decreased metabolism. Elevated circulating galactose is converted by Sepsis incidence from Drug galactose-1 phosphate aldose reductase into galactitol, a toxic metabolite that baseline Clinical trial(s): Phase 1/2 uridyl transferase (GALT) causes long-term complications, including central nervous ACTION-Galactosemia enzyme activity system damage (eg, convulsions, irritability, lethargy, pivotal primary completion developmental delays) and cataracts. Galactosemia has December 2019, data no cure or approved treatments. AT-007 purportedly presented July 2020 penetrates tissues, including the central nervous system, to inhibit aldose reductase, thereby reducing toxic galactitol levels and limiting disease complications. In clinical trials, AT-007 was taken by mouth once daily at a dose of up to 20 mg/kg. Developer(s): Applied Therapeutics, Inc (New York, New York)

Section 5. Rare Diseases 168

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Male children aged 5 to 18 Ataluren (Translarna) is a small-molecule drug intended to Corticosteroids (eg, Ambulatory and gross FDA designation(s): Orphan years who have Duchenne treat DMD by restoring dystrophin protein function. DMD deflazacort, prednisone) motor function, as Drug muscular dystrophy (DMD) is an inherited, neuromuscular disorder caused by a measured by accepted Clinical trial(s): Phase 3 and harbor a nonsense mutation in the dystrophin gene, DMD, that encodes clinical ratings and primary completion dystrophin mutation dystrophin, a protein that helps promote muscle function. scales (eg, time to September 2023; phase 3 Insufficient dystrophin protein in patients with DMD stand, 4-stair climb, 6- primary completion causes progressive muscle fiber necrosis and eventual minute walk test December 2021; unphased widespread muscle weakness. No cure exists, and first- [6MWT], North Star STRIDE registry primary line corticosteroid treatment (eg, deflazacort) manages Ambulatory completion May 2025, data symptoms but does not prevent disease progression and Assessment [NSAA]) reported June 2020, data has significant side effects. FDA approved 2 gene Disease progression published January 2020; therapies for patients who have a specific mutation in Muscle strength phase 3 ACT DMD DMD (ie, in exon 51 or exon 53), but patients who have Survival completed August 2015, other DMD mutations are ineligible for these therapies. In data published July 2017; Quality of life about 10% to 15% of patients with DMD, the DMD gene phase 3 extension study harbors what is called a nonsense mutation, which completed June 2018, data encodes a premature stop signal (ie, stop codon) in the published August 2018; messenger RNA (mRNA) encoding dystrophin, preventing phase 2 completed October the production of full-length functional dystrophin 2020, data presented protein. Ataluren purportedly promotes premature stop February 2021 codon read-through by the cell’s translational machinery, Note(s): The manufacturer producing full-length dystrophin. Its exact mechanism of initially submitted a New action is unknown. Therefore, by restoring dystrophin Drug Application to FDA in function, ataluren might prevent or delay disease March 2017. In October progression. In clinical trials, patients receive an oral 2017, FDA issued a Complete suspension of ataluren 3 times daily for up to 144 weeks. Response Letter stating that In the morning and afternoon, patients receive a dose of data from additional trials 10 mg/kg and in the evening a dose of 20 mg/kg, for a were needed. Ataluren has total of 40 mg/kg/day. been approved to treat Developer(s): children who have DMD in PTC Therapeutics, Inc (South Plainfield, New Jersey) Brazil, the European Union, Iceland, Liechtenstein, and Norway.

Section 5. Rare Diseases 169

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have newly Avacopan (CCX168) is a small-molecule anti-inflammatory Prednisone with Remission PDUFA date: July 7, 2021 diagnosed or relapsed drug. It purportedly binds and inhibits the complement cyclophosphamide Response time FDA designation(s): Orphan antineutrophil cytoplasmic anaphylatoxin C5a from triggering inflammatory reactions followed by azathioprine Estimated glomerular Drug antibody (ANCA)–associated through C5 receptors, which are associated with AAV Prednisone with rituximab filtration rate (eGFR) Clinical trial(s): Phase 3 vasculitis (AAV) requiring pathogenesis. Patients with AAV have limited treatment followed by azathioprine Vasculitis Damage ADVOCATE completed treatment with options and increased risk of death from inflammatory Index November 2019, top-line cyclophosphamide or vascular complications arising in various organs (often the Quality of life data reported November rituximab kidneys). Avacopan is intended to reduce inflammation, 2019, data presented vascular tissue damage, and subsequent organ failure November 2020 that occurs in many patients with poorly managed AAV. AAV is caused by autoantibodies called antineutrophil cytoplasmic antibodies that increase vascular adhesion molecules and contribute to alternative complement pathway (including C5) activation and formation of immune complexes in blood vessels. These inflammatory effects trigger the homing and inflammatory processes of granulocytes (particularly neutrophils), causing tissue damage in areas of high cell and complex accumulation. Avacopan is intended to inhibit C5 activity and its role in downstream inflammatory effects. In clinical trials, avacopan is given orally at an unspecified dosage in combination with rituximab or in combination with cyclophosphamide followed by azathioprine. Developer(s): ChemoCentryx, Inc (Mountain View, California), in collaboration with Vifor Fresenius Medical Care Renal Pharma (St Gallen, Switzerland)

Section 5. Rare Diseases 170

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 to 60 years Bardoxolone methyl (bardoxolone) is an anti- Angiotensin-converting Preserved kidney Submission date: New Drug with a genetically confirmed inflammatory drug in development to treat Alport enzyme (ACE) inhibitors or function Application planned for the diagnosis of Alport syndrome, a rare, inherited disease. In Alport syndrome, angiotensin-receptor Quality of life first quarter of 2021 syndrome and estimated mutations in genes encoding for type IV collagen change blockers (ARBs) to lower FDA designation(s): Orphan glomerular filtration rate the structure and function of the glomerular basement urine proteins Drug (eGFR) between 30 and 90 membrane, the kidneys’ filtration system. These Diet (low salt, potassium, Clinical trial(s): Phase 2/3 2 mL/min/1.73 m mutations cause mitochondrial dysfunction and chronic and fluids) CARDINAL completed inflammation, leading to scarring and fibrosis of the Diuretics (to prevent fluid October 2020, data reported kidneys’ blood vessels that ends in kidney failure. No FDA- overload) November 2020 approved therapies exist for Alport syndrome. Kidney Kidney transplantation transplantation is potentially curative but is typically (reserved for end-stage limited in availability. Disease management focuses on renal disease [ESRD]) slowing the rate of kidney damage through diet, limiting fluid overload, and controlling high blood pressure to prevent overworking the damaged kidneys. Bardoxolone purportedly could preserve kidney function and reduce the need for kidney transplantation. Bardoxolone is an activator of the Keap1/Nrf2 regulatory pathway, which helps resolve inflammation by normalizing mitochondrial function, restoring the oxidation-reduction balance, and suppressing cytokine production. In clinical trials, bardoxolone is taken as oral capsules at doses of 5 to 30 mg, once daily. Developer(s): Reata Pharmaceuticals, Inc (Plano, Texas)

Section 5. Rare Diseases 171

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Benralizumab (Fasenra) is a monoclonal antibody that Corticosteroids Annualized rate of HES FDA designation(s): Orphan older and adults who have targets the interleukin-5 (IL-5) α chain (IL-5α) receptor Cytotoxic drugs (eg, flares from baseline Drug hypereosinophilic syndrome expressed on the surface of eosinophils. The receptor’s cyclophosphamide, Fatigue score from Clinical trial(s): Phase 3 (HES) ligand is IL-5, a cytokine responsible for promoting the hydroxyurea, vincristine) baseline NATRON primary completion activation and inflammatory responses of eosinophils (ie, Imatinib Overall survival August 2022 inflammation-promoting white blood cells). HES is a group Quality of life Note(s): In November 2017, of rare inflammatory disorders characterized by the FDA approved benralizumab chronic overproduction of eosinophils. These eosinophils to treat severe asthma of the infiltrate tissues and can damage organs, such as the eosinophilic subtype (ie, heart and lungs, which can negatively affect quality of life characterized by and increase risk of death. Treatment options are limited. inflammation from high Benralizumab purportedly binds the IL-5α receptor and levels of eosinophils). attracts natural killer (NK) cells that induce rapid and near- Approval does not include complete eosinophil depletion via programmed cell death treatment of other (ie, apoptosis). In clinical trials, benralizumab was injected eosinophilic conditions. under the skin at a dosage of 30 mg every 4 weeks. Developer(s): AstraZeneca plc (Cambridge, United Kingdom)

Section 5. Rare Diseases 172

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 months or Beremagene geperpavec (B-VEC) is a herpes simplex virus Supportive care to Wound healing FDA designation(s): Orphan older and adults who have 1 (HSV-1) vector–based gene therapy intended for chronic minimize and manage skin Quality of life Drug, Fast Track, Rare dystrophic epidermolysis or recurring wounds in patients with DEB. This rare, wounds Pediatric Disease, bullosa (DEB) and have at debilitating connective tissue disorder has no approved Regenerative Medicine least one wound between treatments. Patients with DEB carry a genetic variant in a Advanced Therapy 10 and 20 cm2 in size gene called collagen type VII alpha 1 chain, COL7A1. This Clinical trial(s): Phase 3 GEM- variant prevents cells from producing type VII collagen, 3 primary completion August causing severe, painful, and/or itchy epidermal wounds 2021; phase 2 GEM-1 that can affect a patient’s longevity and quality of life. primary completion Beremagene geperpavec is a recombinant, replication- February 2020, data incompetent, HSV-1 vector that contains a full-length copy presented May 2020 of the human COL7A1 gene to correct the expression of type VII collagen. By restoring type VII collagen production in keratinocytes, beremagene geperpavec purportedly anchors the skin’s dermal and epidermal layers to prevent blistering and promote wound healing without heavy scarring. In clinical trials, beremagene geperpavec is applied topically over a skin wound on days 1 through 5 and again on days 30, 60, and 90. Developer(s): Krystal Biotech, Inc (Pittsburgh, Pennsylvania)

Section 5. Rare Diseases 173

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults aged up Betibeglogene autotemcel (formerly LentiGlobin) is a gene Allogeneic stem cell Transfusion need Submission date: Rolling to 50 years who have therapy intended for β-thalassemia, an inherited blood transplantation (SCT) status Biologics License Application transfusion-dependent β- disorder caused by a mutation in the hemoglobin subunit Luspatercept-aamt Organ function initiated, with expected thalassemia, also known as beta gene, HBB. This mutation causes ineffective red Repeated blood Level of iron overload completion in mid-2021 β-thalassemia major, with a blood cell production, leading to severe anemia. Standard transfusions Quality of life FDA designation(s): Orphan β0/β0 genotype (ie, no β- of care involves use of frequent blood transfusions and Drug, Breakthrough Therapy + 0 globin expression) or a β /β supportive care. Betibeglogene autotemcel might provide Clinical trial(s): Phase 3 genotype (ie, little β-globin a one-time functional cure for β-thalassemia. The gene NORTHSTAR-2 primary + expression) therapy consists of bone marrow–derived CD34 completion February 2022, hematopoietic stem cells (HSCs) harvested from the interim data reported patient and treated with a lentivirus vector that stably December 2019, data inserts a functional copy of the HBB gene into the cells. presented December 2020; The cells are then multiplied in culture to facilitate uptake. phase 3 NORTHSTAR-3 This autologous HSC therapy does not require primary completion June immunosuppressive therapy. In clinical trials, 2022, preliminary data betibeglogene autotemcel is given as a single intravenous reported December 2019, infusion, at an unspecified dose, after patients are treated data presented December with busulfan to destroy β-thalassemia-causing blood 2020 cells. Note(s): On February 16, Developer(s): 2021, bluebird bio bluebird bio, Inc (Cambridge, Massachusetts) temporarily suspended phase 1/2 and phase 3 trials of betibeglogene autotemcel to treat sickle cell disease to investigate potential unexpected serious adverse reactions. Two previously treated patients reportedly developed acute myeloid leukemia (AML) and myelodysplastic syndrome, respectively. The company has also temporarily suspended marketing of betibeglogene autotemcel to treat β-thalassemia in the European Union while the AML case is evaluated.

Section 5. Rare Diseases 174

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 2 to 50 years Betibeglogene autotemcel (formerly LentiGlobin) is a gene Blood transfusions Frequency of VOCs FDA designation(s): Orphan who have severe sickle cell therapy. It consists of patient-derived hematopoietic stem Crizanlizumab-tmca and hospitalizations Drug, Regenerative Medicine disease (SCD) cells transduced with a functional copy of the human Hematopoietic stem cell Number of blood Advanced Therapy, Fast hemoglobin subunit beta gene, HBB, which are then transplantation (HSCT) transfusions required Track reintroduced to the patient. In SCD, sickled red blood cells Hydroxyurea Quality of life Clinical trial(s): Phase 3 are more susceptible to oxidative damage, inappropriate single-arm primary Pharmaceutical-grade adhesion, and vascular obstruction, leading to vaso- completion November 2023; l-glutamine occlusive crises (VOCs) that cause severe pain, requiring phase 1/2 primary hospitalization. VOC complications can include circulating Voxelotor completion September 2022, blood clots, stroke, organ failure, or early death. interim data presented June Betibeglogene autotemcel has a unique amino acid 2020, data presented substitution in the HBB gene that promotes antisickling of December 2020 red blood cells. By replacing dysfunctional human HBB Note(s): On February 16, genes, betibeglogene autotemcel might address SCD’s 2021, bluebird bio underlying cause rather than just reduce symptoms. temporarily suspended Betibeglogene autotemcel is given by intravenous infusion phase 1/2 and phase 3 trials as a single dose after myeloablative conditioning with of betibeglogene autotemcel busulfan. to treat sickle cell disease to Developer(s): investigate potential bluebird bio, Inc (Cambridge, Massachusetts) unexpected serious adverse reactions. Two previously treated patients reportedly developed acute myeloid leukemia (AML) and myelodysplastic syndrome, respectively. The company has also temporarily suspended marketing of betibeglogene autotemcel to treat β-thalassemia in the European Union while the AML case is evaluated.

Section 5. Rare Diseases 175

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Male children aged 10 years BIIB112 (NSR-RPGR) is a recombinant adeno-associated Supportive care Best corrected visual Clinical trial(s): Phase 2/3 or older and adults who viral vector that delivers a codon-optimized form of RPGR- Vitamin and nutritional acuity (BCVA) XIRIUS completed November have retina specialist– ORF 15. This gene encodes a full-length functional protein supplementation Retinal sensitivity 2020, preliminary data confirmed chromosome X– intended to treat XLRP. No effective treatments are Peripheral vision presented May 2019, data linked retinitis pigmentosa approved for this rare condition, and BIIB112 could published February 2020 Recovery time (XLRP) and variants of the become the first retinal gene therapy to delay XLRP or retinitis pigmentosa GTPase reverse vision loss. XLRP is the most common form of RP Quality of life regulator-open reading caused by variants in the eye-specific form of the RPGR frame 15 gene, RPGR-ORF 15 gene, RPGR-ORF 15. BIIB112 is intended to express a full- length RPGR-ORF 15 protein in retinal cells that will restore the function of cones and rods. In clinical trials, a single dose is given via subretinal injection into the eye. Developer(s): Biogen (Cambridge, Massachusetts)

Section 5. Rare Diseases 176

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Females aged 5 to 45 years Blarcamesine (ANAVEX2-73) is a small-molecule sigma-1 Supportive care (eg, Behavioral symptom FDA designation(s): Orphan who have genetically receptor activator intended to treat Rett syndrome, a rare, anticonvulsants, assistive severity, as measured Drug, Fast Track, Rare confirmed Rett syndrome postnatal, progressive neurologic disorder. Rett syndrome devices, noninvasive by accepted clinical Pediatric Disease is caused by a mutation in the methyl CpG binding protein ventilation, nutritional ratings and scales Clinical trial(s): Phase 2/3 2 gene, MECP2. Located on the X chromosome, MECP2 support, oxygen treatment, Seizure frequency EXCELLENCE primary encodes the MeCP2 protein that normally mediates gene physical and occupational Sleep quality and completion June 2021; phase expression in neuronal and glial cells. Loss of MeCP2 therapy, speech/language duration 2 completed October 2020, function results in nerve cell dysfunction, which is thought therapy) top-line data reported to be reversible. Patients with Rett syndrome develop December 2020; phase 2 normally until 6 to 18 months of age and subsequently AVATAR primary completion experience developmental delays and regression of January 2021 previously learned motor and verbal skills. The disease eventually causes additional symptoms, such as repeated hand movements, impaired gait, slowed head growth, disordered breathing, and seizures. Symptom severity varies by patient and depends on the individual’s specific MECP2 mutation and the amount of mutant MeCP2 protein expression. No cure exists, and treatment consists of supportive care to manage symptoms. By activating the cellular sigma-1 receptor, blarcamesine purportedly reduces protein misfolding, inflammation, oxidative stress, and mitochondrial dysfunction, all of which might contribute to the symptoms of Rett syndrome and other neurodegenerative disorders (eg, Alzheimer’s disease). By promoting normal nerve cell function, blarcamesine might reduce disease symptoms. In clinical trials, patients take or caregivers give a liquid solution containing 5 mg of blarcamesine by mouth once daily for up to 48 weeks. Developer(s): Anavex Life Sciences Corp (New York, New York)

Section 5. Rare Diseases 177

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 45 years BPN14770 is a small-molecule, allosteric inhibitor of Behavior-stabilizing Aggression symptoms FDA designation(s): Orphan who have genetically phosphodiesterase type 4D (PDE4D). BPN14770 is under medications (eg, alpha-2 and severity Drug confirmed fragile X study to treat patients who have fragile X syndrome, a agonists, anticonvulsants, Anxiety symptoms and Clinical trial(s): Phase 2 syndrome rare, X chromosome–linked neurodevelopmental antidepressants, beta- severity primary completion July disorder. In patients with fragile X syndrome, loss of blockers) Hyperactivity 2020, top-line results function in the protein Fmrp leads to the development of symptoms and severity reported November 2020 autism-like symptoms, including anxiety, irritability, Irritability symptoms aggression, hyperactivity, and restricted and repetitive and severity behaviors. Animal models of fragile X syndrome have suggested that one molecular mechanism underlying the Repetitive behavior syndrome is dysregulation of cyclic adenosine symptoms and severity monophosphate (cAMP), a signaling molecule that plays a key role in synaptic function. Therefore, researchers have hypothesized that BPN14770 inhibition of PDE4D, which promotes cAMP degradation, could improve symptoms of fragile X syndrome, possibly by enhancing memory formation. In clinical trials, BPN14770 is administered orally, twice daily at a dose of 25 mg. Developer(s): Tetra Therapeutics (Grand Rapids, Michigan), acquired by Shionogi & Co, Ltd (Osaka, Japan)

Section 5. Rare Diseases 178

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have biopsy- Budesonide (Nefecon) is a synthetic corticosteroid Corticosteroids Proteinuria change FDA designation(s): Orphan proven immunoglobulin intended to treat IgA nephropathy. A kidney disease, IgA Immunosuppressants (eg, from baseline Drug isotype A (IgA) nephropathy nephropathy occurs when an antibody subtype called IgA azathioprine, Occurrence of ESRD Clinical trial(s): Phase 3 (Berger disease) and an accumulates in the kidneys and causes local inflammation cyclophosphamide, Change in eGFR from Nefigard primary completion estimated glomerular that can gradually affect kidney function. The disease can mycophenolate) baseline December 2020, top-line filtration rate (eGFR) cause end-stage renal disease (ESRD) within 10 to 20 Change in quality of results reported November between 45 and 90 years in up to 40% of affected patients. No treatments are life from baseline 2020; phase 3 open-label mL/min/1.73 m2 (stage 2 to approved for IgA nephropathy. The standard of care (ie, extension primary 3A chronic kidney disease) high-dose systemic corticosteroids) is controversial completion March 2024 and medically controlled because of the increased risks of adverse events and blood pressure serious infections, high blood pressure, weight gain, diabetes mellitus, and osteoporosis. Budesonide is intended to avert these systemic side effects. Treatment is targeted to the Peyer patches of the small intestine, where IgA complexes are thought to originate, via the manufacturer’s proprietary TARGIT technology. Drug tolerability is purportedly optimized by the drug’s low bioavailability (about 90% is inactivated in the liver before reaching the circulation) compared with corticosteroids. In clinical trials, budesonide is taken by mouth at a dosage of 16 mg once daily for 9 months. Developer(s): Calliditas Therapeutics AB (Stockholm, Sweden)

Section 5. Rare Diseases 179

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 10 years or CAP-1002 is a cell-based therapy intended for DMD, an Corticosteroids (eg, Ambulatory and gross FDA designation(s): Orphan older who have genetically inherited, X chromosome–linked genetic disorder caused deflazacort, prednisone) motor function, as Drug, Rare Pediatric Disease, confirmed Duchenne by rearrangements or deletions in the dystrophin gene, measured by accepted Regenerative Medicine muscular dystrophy (DMD), DMD. DMD encodes the dystrophin protein, which helps clinical ratings and Advanced Therapy are either ambulatory or promote muscle function. The absence of wild-type scales (eg, time to Clinical trial(s): Phase 2 nonambulatory, and are dystrophin protein causes progressive muscle fiber stand, 4-stair climb; 6- HOPE-2 completed March receiving stable doses of necrosis and eventual widespread muscle weakness. No minute walk test 2020, data presented systemic glucocorticoids cure for DMD exists, and first-line corticosteroid [6MWT], North Star October 2020; phase 1/2 treatment addresses symptoms but does not prevent Ambulatory HOPE completed September disease progression and has significant side effects. FDA Assessment [NSAA]) 2017, data published January approved 2 gene therapies for patients who have a Cardiac function 2019 specific mutation in DMD (ie, in exon 51 or exon 53); Disease progression however, patients who have other DMD mutations are Muscle strength ineligible for these therapies. CAP-1002 contains cardiosphere-derived cells (CDCs) from donor heart Survival tissue. The CDCs in CAP-1002 purportedly secrete growth Quality of life factors and exosomes that promote cellular regeneration and improve muscle function in patients with DMD. In clinical trials, a solution of CAP-1002 containing 150 million CDCs is given intravenously once every 3 months, 4 times. Developer(s): Capricor Therapeutics, Inc (Beverly Hills, California), in collaboration with Lonza (Basel, Switzerland)

Section 5. Rare Diseases 180

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 7 to 18 years Carbetocin (LV-101) is an analogue of the hormone Cognitive behavioral Hyperphagia FDA designation(s): Fast who have Prader-Willi oxytocin intended to treat nutritional phase 3 therapy (CBT) symptoms and severity Track syndrome (PWS) with hyperphagia in children with PWS. Hyperphagia is Diazoxide (off-label) Rate of comorbidities Clinical trial(s): Phase 3 nutritional phase 3 abnormally increased appetite without feelings of satiety Diet and food intake (eg, cardiovascular CARE-PWS primary hyperphagia (ie, fullness after eating). PWS is a genetic condition with a control disease, diabetes completion May 2020, data loss of function in genes on chromosome 15 that results Exercise mellitus, obesity) reported August 2020 in slowed development, intellectual disability, behavioral Quality of life Note(s): Phase 3 enrollment problems, and various physical manifestations. A hallmark Glucagon-like peptide 1 (GLP-1) receptor agonist paused in April 2020 symptom is hyperphagia, which begins in childhood and because of issues related to often results in morbid obesity if food intake is not (eg, exenatide or liraglutide; off-label) the COVID-19 pandemic, not restricted. The exact cause of the increased appetite in a suspension of institutional this population is unknown but might be linked to review board (IRB) approval oxytocin dysregulation in the hypothalamus area of the brain. Patients have been found to have fewer oxytocin- producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin is thought to play a role in regulating eating behaviors, social interactions, and emotional reactivity. Oxytocin supplementation for treating PWS has been researched but is not FDA approved. Carbetocin, a longer-acting analogue of oxytocin with an improved oxytocin receptor selectivity profile, purportedly helps suppress appetite. The developer additionally purports it might reduce obsessive- compulsive symptoms and anxiety. In clinical trials, carbetocin (dose unspecified) is given as a nasal spray 3 times daily before meals. Developer(s): Levo Therapeutics, Inc (Skokie, Illinois), which acquired exclusive worldwide license from Ferring Pharmaceuticals (Parsippany, New Jersey)

Section 5. Rare Diseases 181

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients who have Casimersen (Amondys 45) is a phosphorodiamidate Corticosteroids (eg, Ambulatory and gross Approval date: February 25, Duchenne muscular morpholino oligomer (PMO; DNA analogue). Casimersen deflazacort, prednisone) motor function, as 2021 dystrophy (DMD) with a is FDA approved to treat DMD, an inherited, X measured by accepted FDA designation(s): Orphan confirmed variant in the chromosome–linked genetic disorder caused by clinical ratings and Drug dystrophin gene, DMD, that rearrangements or deletions in the DMD gene. DMD scales (eg, time to Clinical trial(s): Phase 3 is amenable to exon 45 encodes the dystrophin protein, which is involved in stand, 4-stair climb; 6- ESSENCE primary skipping muscle function, and the absence of wild-type dystrophin minute walk test completion May 2022, top- protein causes progressive muscle fiber necrosis and [6MWT], North Star line data reported March eventual widespread muscle weakness. Casimersen Ambulatory 2019; phase 3 open-label purportedly binds exon 45 of dystrophin pre-messenger Assessment [NSAA]) extension primary RNA (mRNA; ie, precursor RNA composed of introns and Disease progression completion August 2026 exons) and promotes skipping of exon 45 during mRNA Muscle strength processing. This allows for synthesis of an internally Survival truncated, but functional, dystrophin protein. Casimersen treatment is intended to promote skeletal muscle Quality of life function and prevent or delay disease progression in patients with DMD who have DMD exon 45 variants. Casimersen is given intravenously at a dosage of 30 mg/kg once weekly. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 182

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years Cilofexor (GS-9674) is a selective, nonsteroidal farnesoid X Endoscopy (ie, Liver fibrosis FDA designation(s): Orphan who have large duct primary receptor (FXR) agonist (ie, activator) being developed to cholangioscopy) with or progression Drug sclerosing cholangitis (PSC) treat PSC. In PSC, the bile ducts narrow severely for without stents to widen Need for liver Clinical trial(s): Phase 3 and stage F0 to F3 liver reasons not clearly understood, preventing bile acid from narrowed bile ducts transplantation PRIMIS primary completion fibrosis leaving the liver and causing progressive inflammation Liver transplantation Quality of life August 2023; phase 2 and scarring (ie, fibrosis) of liver tissue. Most care is (reserved for advanced completed May 2020, data supportive and targets symptom relief. Liver liver disease) published January 2019 transplantation is potentially curative but generally Long-term antibiotics (to reserved for patients with end-stage liver disease. treat and prevent frequent Additionally, PSC reportedly recurs often after liver infections caused by transplantation (in up to 45% of patients in some reports). blocked bile ducts) Cilofexor purportedly works by multiple mechanisms to Supportive care to reduce regulate bile acid synthesis and excretion. FXR itching (eg, bile acid downregulation by cilofexor in the intestine purportedly sequestrants, leads to release of a hormone that downregulates the antihistamines, rate-limiting enzyme in bile acid synthesis in the liver. ursodeoxycholic acid Additionally, direct activation of FXR in liver cells (ie, [UDCA]) hepatocytes) increases the expression of transporters responsible for moving bile acid out of the liver while inhibiting bile acid synthesis and uptake by liver cells. In a phase 3 trial, cilofexor is taken as an oral tablet of 100 mg once daily for 12 weeks and up to 2 years in an extension phase. Developer(s): Gilead Sciences, Inc (Foster City, California)

Section 5. Rare Diseases 183

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 12 years or Concizumab is a humanized immunoglobulin isotype G, Emicizumab-kxwh Bleeding episodes FDA designation(s): Orphan older who have hemophilia subclass 4 (IgG4) monoclonal antibody under (hemophilia A) Treatment-related Drug, Breakthrough Therapy A or hemophilia B with or development for treating hemophilia A and B. Factor VIII replacement complications Clinical trial(s): Phase 3 without inhibitors to clotting Concizumab therapy would replace regular intravenous (human plasma derived or Survival Explorer8 primary factor replacement therapy infusions of clotting factors with daily under-the-skin recombinant, porcine Quality of life completion May 2022; phase injections. Concizumab is designed to impede the activity recombinant; hemophilia A) 3 Explorer7 primary of tissue factor pathway inhibitor (TFPI), which plays a key Factor IX replacement completion November 2021 role in blocking initiation of the tissue factor–induced (human plasma derived or Note(s): Phase 2 and phase 3 coagulation process through a negative feedback loop recombinant; hemophilia B) trials (Explorer5, Explorer7, involving clotting factors VIIa and Xa. By blocking TFPI, and Explorer8) halted March concizumab purportedly allows increased factor Xa 16, 2020, to investigate 3 production that results in sufficient thrombin generation nonfatal thrombotic events to improve blood-clotting capacity despite deficiencies in in trial patients. On August factor VIII in hemophilia A or factor IX in hemophilia B. In 13, 2020, the developer phase 3 trials, concizumab (0.25 mg/kg) is given as a daily announced FDA had subcutaneous injection. removed the clinical hold, Developer(s): and trials resumed. Novo Nordisk (Bagsvaerd, Denmark)

Section 5. Rare Diseases 184

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Infants who have CUTX-101 is an injectable form of copper histidinate Parenteral copper salt Growth from baseline Submission date: initiation biochemically or genetically intended to supplement blood and brain copper levels in injections (off-label) Developmental of rolling New Drug confirmed Menkes disease patients with Menkes disease. This rare, chromosome X– Supportive care milestones Application planned for third linked pediatric disease is caused by mutations in the Overall survival quarter of 2021 copper transporter ATP7A, leading to reduced copper FDA designation(s): Orphan levels in the blood and brain, as well as abnormal levels of Drug, Fast Track, Rare catecholamines. Patients with Menkes disease present Pediatric Disease, clinically with failure to thrive, severe neurological Breakthrough Therapy symptoms (eg, seizures), and connective tissue problems. Clinical trial(s): Phase 3 No treatments are approved for Menkes disease, and primary completion August many patients die before 3 years of age. Patient care is 2020, top-line data reported generally managed with off-label administration of August 2020 parenteral formulations of copper salts. CUTX-101 is intended to cross the blood-brain barrier as well as bypass the limitations of oral copper absorption, which is impaired in patients with Menkes disease. The manufacturer also purports that, because of the physiological pH of the drug, injections with CUTX-101 are better tolerated than are off-label parenteral copper options. In clinical trials, CUTX-101 is given as a subcutaneous injection at an unspecified dose. Developer(s): Sentynl Therapeutics (Solena Beach, California)

Section 5. Rare Diseases 185

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or Debcoemagene autoficel (D-Fi; formerly FCX-007) is a cell- Supportive care for pain Change in wound size FDA designation(s): Orphan older and adults who have based gene therapy. It consists of patient-derived dermal and infection risk Time to wound closure Drug, Fast Track, Rare recessive dystrophic fibroblasts (ie, skin cells) treated to produce a functional Pediatric Disease, epidermolysis bullosa copy of a gene called collagen type VII alpha 1 chain, or Regenerative Medicine (RDEB) COL7A1. The cell therapy is delivered by injection into the Advanced Therapy patient’s skin lesions to promote wound healing. RDEB is a Clinical trial(s): Phase 3 FCX- rare genetic disease caused by mutations in the collagen 007 primary completion COL7A1 protein, which is needed for maintaining proper April 2022; phase 1/2 FI-FCX- skin integrity. Loss of COL7A1 expression in RDEB leads to 007 primary completion May widespread blistering, resulting in severe scarring, vision 2020, interim data presented loss, disfigurement, and other serious medical problems. January 2020 Debcoemagene autoficel is intended to prevent blistering and promote wound healing without heavy scarring by delivering transduced COL7A1-expressing fibroblasts into poorly healing lesions. The therapy is thought to form anchoring fibrils that hold the layers of skin together to prevent RDEB-caused wounds. In clinical trials, debcoemagene autoficel was injected directly at an unspecified dose into the papillary dermis of blisters and wounds. Developer(s): Castle Creek Biosciences, Inc (Exton, Pennsylvania)

Section 5. Rare Diseases 186

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 4 years or Diazoxide choline controlled release (DCCR) is an Cognitive behavioral Hyperphagia FDA designation(s): Orphan older and adults who have investigational, proprietary crystalline salt formulation of therapy (CBT) symptoms and severity Drug, Fast Track Prader-Willi syndrome (PWS) diazoxide, a potassium channel activator that inhibits Diet and food intake Rate of comorbidities Clinical trial(s): Phase 3 with hyperphagia insulin secretion. It is intended to treat hyperphagia (ie, control (eg, cardiovascular DESTINY C601 completed abnormally increased appetite) in patients with PWS. PWS Exercise disease, diabetes May 2020, data reported is a rare genetic disease (affecting about 8000-11 000 US Glucagon-like peptide 1 mellitus, obesity) September 2020, data patients) caused by lack of expression of several genes on (GLP-1) receptor agonist Survival presented November 2020; chromosome 15. It is often managed with off-label (eg, exenatide or liraglutide; Quality of life phase 3 C602 open-label diazoxide (Proglycem), which is approved to treat low off-label) extension primary blood glucose. However, patients with PWS require a completion April 2021; lower dose of diazoxide than the current formulation, phase 3 C603 open-label which often causes high blood glucose as a side effect. primary completion March DCCR purportedly blocks the production and release of 2023 the appetite stimulatory neuropeptides Y and agouti- related protein and blocks fatty acid production. DCCR might also augment the action of gamma-aminobutyric acid (GABA) receptors, which are thought to be disrupted in patients with PWS, who experience behavioral problems such as aggression. Thus, DCCR might address overeating and behavioral PWS symptoms and decrease body fat and circulating fat levels. In clinical trials, DCCR is given as an oral tablet at a dosage of 75 to 450 mg (depending on body weight) once daily. Developer(s): Soleno Therapeutics, Inc (Redwood City, California)

Section 5. Rare Diseases 187

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 to 17 years Eculizumab (Soliris) is a recombinant humanized Acetylcholinesterase Disease severity FDA designation(s): Orphan who have refractory monoclonal antibody intended to treat gMG in children. It inhibitors (eg, Functional activity level Drug generalized myasthenia purportedly blocks the complement system activation pyridostigmine) Quality of life Clinical trial(s): Phase 3 gravis (gMG) and positive that contributes to gMG’s inflammation and destruction of Corticosteroids (eg, primary completion June test results for anti- the muscle membrane at the neuromuscular junction. prednisone) 2021 acetylcholine receptor (anti- Eculizumab is FDA approved for use in adults and was the Nonsteroidal Note(s): In October 2017, AchR) antibodies first complement inhibitor approved for gMG. In gMG, a immunosuppressive agents FDA approved eculizumab to progressive, autoimmune neuromuscular disorder, the (eg, cyclosporine, treat adults who have gMG body develops at the neuromuscular junction antibodies methotrexate, and test positive for anti- against AchRs, which are necessary to turn nerve signals mycophenolate mofetil, AchR antibodies. Eculizumab into muscle movements. The disorder manifests as tacrolimus) is also FDA approved (and muscle weakness that often begins in the eyes and eyelids Thymus gland removal available only under a Risk and generalizes to more areas of the body, including the Evaluation and Mitigation head, neck, trunk, limbs, and chest. No cure is available Strategy) to treat paroxysmal for gMG, and some patients do not respond to standard nocturnal hemoglobinuria to immunosuppressive therapies. Eculizumab purportedly reduce hemolysis, atypical binds with high affinity to the complement protein C5 (a hemolytic uremic syndrome soluble component of the innate immune system). to inhibit complement- Activation of the complement pathway causes mediated thrombotic inflammation and muscle membrane destruction at the microangiopathy, and neuromuscular junction, contributing to gMG pathology relapsing neuromyelitis and symptoms. When eculizumab binds to C5, this optica. activation is thought to be reduced. In clinical trials, patients receive eculizumab intravenously, at a weight- based biweekly dose of 300, 600, 900, or 1200 mg, for up to 4 years. Developer(s): Alexion Pharmaceuticals, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 188

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Efgartigimod (ARGX-113) is an immunoglobulin isotype G, Acetylcholinesterase Muscle weakness Submission date: Biologics myasthenia gravis with subclass 1, Fc domain (IgG1 Fc) antibody fragment under inhibitor (ie, symptoms and severity License Application January generalized muscle study for treating gMG. In patients with gMG, a pyridostigmine) Functional activity level 8, 2021 weakness (ie, generalized progressive, autoimmune neuromuscular disorder, the Corticosteroids (eg, Quality of life Clinical trial(s): Phase 3 myasthenia gravis [gMG]); body develops IgG antibodies against proteins expressed prednisolone) ADAPT completed April meet criteria for Myasthenia at the neuromuscular junction (eg, acetylcholine receptor, Intravenous 2020, data presented Gravis Foundation of muscle-specific kinase). This impairs the ability of muscle immunoglobulin (IVIG) October 2020; phase 3 America (MGFA) class II, III, cells to receive proper signals from nerve cells to produce Nonsteroidal ADAPT+ primary completion IVa, or IVb; and are receiving motor movements. No cure is available for gMG, and immunosuppressant drugs June 2023; phase 2 standard-of-care treatment patients often do not respond to standard-of-care (eg, azathioprine, completed October 2017, for gMG therapies and may experience side effects of treatment. cyclosporine, data reported December Efgartigimod purportedly competes with IgG for binding mycophenolate mofetil) 2017; phase 3 ADAPTsc to the neonatal Fc receptor (FcRn) to block FcRn-mediated primary completion Thymus gland removal rescue of IgG from recycling through lysosomal September 2021 degradation. Thus, efgartigimod purportedly decreases levels of IgG antibodies (including pathogenic IgG autoantibodies) without impacting levels of IgM antibodies, IgA antibodies, or albumin. In clinical trials, which began before the developer submitted for FDA regulatory approval, efgartigimod was and is now given intravenously at a dosage of 10 mg/kg once weekly for at least 8 weeks and up to 3 years. The developer has since begun an additional clinical trial comparing its intravenous form with a subcutaneous form, at unknown doses and frequencies, for 12 weeks. Developer(s): argenx BVBA (Zwijnaarde, Belgium)

Section 5. Rare Diseases 189

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years Elafibranor is a first-in-class dual agonist (ie, activator) of Obeticholic acid Overall survival FDA designation(s): Orphan who have primary biliary peroxisome proliferator-activated receptor (PPAR) alpha Rate of progression to Drug, Breakthrough Therapy cholangitis (PBC) and have (PPARα) and PPAR delta (PPARδ) intended to treat PBC. An liver failure Clinical trial(s): Phase 2 had an inadequate response autoimmune disease, PBC damages the liver’s bile ducts, Symptom relief (eg, completed October 2018, to ursodeoxycholic acid causing bile to accumulate in the liver and leading to diarrhea due to fat data published January 2021; (UDCA) treatment irreversible liver scarring and, potentially, liver failure. malabsorption, fatigue, phase 3 ELATIVE primary Elafibranor is intended to provide a safer alternative to itching) completion September 2023 obeticholic acid (Ocaliva) for treating PBC in patients for Quality of life whom initial therapy with UDCA is inadequate. Elafibranor purportedly reduces bile acid synthesis, improves bile detoxification in the bile duct, and acts as an anti- inflammatory agent. Further, elafibranor might reduce itching (ie, pruritus), a major symptom of PBC that existing treatments do not address. In a phase 2 clinical trial, elafibranor is taken in 80- or 120-mg tablets twice daily for 12 weeks. Developer(s): GENFIT Corp (Loos, France)

Section 5. Rare Diseases 190

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 12 years or Elamipretide is a peptide compound designed to treat Supportive care directed at Exercise tolerance FDA designation(s): Orphan older who have genetically mitochondrial dysfunction disorders by restoring cellular relieving individual Fatigue Drug, Fast Track, Rare confirmed Barth syndrome energy production. Barth syndrome is a chromosome X– symptoms (eg, bacterial Quality of life Pediatric Disease and a baseline body weight linked mitochondrial disorder characterized by infection, heart failure) Clinical trial(s): Phase 2/3 of more than 30 kg with degeneration of heart muscle (ie, dilated cardiomyopathy) TAZPOWER primary estimated glomerular and skeletal muscle (ie, myopathy), recurrent infections completion April 2021, filtration rate (eGFR) greater due to neutropenia (ie, low white cells), and short stature. preliminary data reported than 90 mL/min/1.73 m2 or Barth syndrome is managed primarily with supportive April 2019, additional data body weight of more than care because no pharmacologic therapies have yet presented November 2019 40 kg and eGFR greater than demonstrated clinical benefits. In Barth syndrome, 60 but less than 90 mutations in the tafazzin gene, TAZ, result in production of mL/min/1.73 m2 dysfunctional tafazzin protein. This protein ensures adequate levels of functional cardiolipin, a lipid required for normal mitochondrial structure, function, and energy production. Tissues with the highest energy demands (eg, heart and skeletal muscle) are most affected. Elamipretide purportedly penetrates mitochondrial membranes to bond reversibly to cardiolipin, thereby normalizing the inner mitochondrial membrane structure and improving mitochondrial function. Elamipretide is thought to enhance energy generation through increased production of ATP, a critical component in energy transport, and to potentially lower levels of reactive oxygen species that can damage cardiolipin. In clinical trials for Barth syndrome, patients receive subcutaneous injections of elamipretide at a dosage of 40 mg once daily for 12 weeks. Developer(s): Stealth Biotherapeutics, Inc (Newton, Massachusetts)

Section 5. Rare Diseases 191

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged up to 17 years Elivaldogene autotemcel (Lenti-D) is a bone marrow– Hematopoietic stem cell CALD progression Submission date: Biologics who have active cerebral derived gene therapy product intended for transplantation (HSCT) Functional disability License Application planned adrenoleukodystrophy adrenoleukodystrophy (ALD). A rare, X chromosome– Lorenzo’s oil (4 parts Quality of life for the third quarter of 2021 (CALD) linked, inherited metabolic disorder, ALD is caused by glyceryl trioleate to 1 part FDA designation(s): Orphan mutations in the ATP binding cassette subfamily D glyceryl trierucate) Drug, Breakthrough Therapy member 1 gene, ABCD1. The disorder leads to Clinical trial(s): Phase 2/3 accumulation of abnormally high levels of unbranched, Starbeam primary saturated, very-long-chain fatty acids in patients’ brains completion May 2021, data and adrenal cortexes. CALD is the most severe form and presented August 2020; involves neurodegeneration, including the breakdown of phase 3 primary completion the protective myelin sheath of nerve cells in the brain. February 2024 Symptoms occur in early childhood and progress rapidly, causing severe loss of neurologic function and eventual death. CALD can be treated with bone marrow or stem cell transplants. However, fewer than 30% of patients find matching donors, and allogenic (ie, unrelated donor) transplants can have potentially fatal side effects. Elivaldogene autotemcel is intended to restore expression of the adrenoleukodystrophy protein gene, ALDP, which metabolizes very-long-chain fatty acids that are thought to contribute to CALD neurodegeneration. Elivaldogene autotemcel consists of patient-derived CD34+ stem cells that are harvested and treated with a lentivirus vector that stably inserts a functional copy of ALDP into the cells. The cells are then multiplied in culture to facilitate uptake. In clinical trials, elivaldogene autotemcel is given as a single intravenous infusion after myeloablative (ie, bone marrow destroying) conditioning with busulfan and cyclophosphamide. Developer(s): bluebird bio, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 192

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 16 years or Emixustat is a reversible antagonist of an enzyme called No FDA-approved Best corrected visual FDA designation(s): Orphan older and adults who have retinal pigment epithelium protein-65 (RPE-65). Emixustat treatments are available acuity (BCVA) Drug macular atrophy secondary is intended to inhibit the accumulation of a toxic retinal Disease progression Clinical trial(s): Phase 3 to Stargardt disease byproduct, A2E, that causes light-induced damage to the Quality of life SeaSTAR primary completion retina in Stargardt disease. Also called juvenile macular April 2022; phase 2a degeneration, Stargardt disease is a rare genetic disease completed December 2017, that causes gradual deterioration of photoreceptors data published June 2020 within the eyes leading to progressive vision loss starting during childhood and adolescence. Stargardt disease has no effective treatment and is caused by a genetic mutation of the ABCA4 gene, which causes the accumulation of toxic vitamin A byproducts such as A2E. RPE-65 is a key component of the visual cycle that recycles vitamin A derivatives in the eye, and emixustat inhibition of RPE-65 enzyme purportedly reduces the accumulation of A2E in the retina. In clinical trials, patients were given 10 mg emixustat hydrochloride orally once daily for 24 months. Developer(s): Kubota Vision, Inc (Seattle, Washington), a subsidiary of Kubota Pharmaceutical Holdings Co, Ltd (Tokyo, Japan)

Section 5. Rare Diseases 193

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males who have Etranacogene dezaparvovec (AMT-061, EtranaDez) gene Factor IX replacement Bleeding episodes FDA designation(s): Orphan moderate to severe therapy consists of adeno-associated viral serotype 5 therapy (human plasma Treatment-related Drug, Breakthrough Therapy congenital (ie, inherited) (AAV5) vector containing a codon-optimized human factor derived or recombinant) complications Clinical trial(s): Phase 3 hemophilia B and are IX Padua gene (AAV5-hFIXco-Padua). The adeno- Survival HOPE-B primary completion receiving factor IX associated viral vector delivers a copy of the Padua Quality of life September 2020, top-line prophylaxis with more than variant of the factor IX gene, F9 or FIX. It purportedly has data reported November 150 days’ exposure to factor an 8-fold increase in activity compared with wild-type (ie, 2020; single-arm phase 2 IX protein treatment not caused by any known genetic variant) factor IX to primary completion October provide sustained coagulation. As a single-treatment gene 2018, data published therapy, etranacogene dezaparvovec could eliminate the October 2019, further data need for repeated coagulation factor replacement. The presented December 2019 manufacturer asserts that nearly all patients screened in Note(s): In December 2020, clinical trials, potentially even patients with some FDA placed a clinical hold on preexisting antibodies to the AAV5 viral vector, are eligible all trials of etranacogene for therapy. In clinical trials, AMT-061 is given as a single dezaparvovec to treat 13 intravenous infusion at a dose of 2 × 10 gc/kg. hemophilia B, to investigate Developer(s): a potential adverse event uniQure NV (Amsterdam, the Netherlands) and CSL related to a hepatocellular Behring (King of Prussia, Pennsylvania) carcinoma diagnosis in one trial patient at high risk of liver cancer in the HOPE-B trial

Section 5. Rare Diseases 194

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 2 years or Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, Monthly convulsive Approval date: June 25, 2020 older who have Dravet amphetamine derivative intended as an adjunctive clobazam, stiripentol, seizure frequency FDA designation(s): Orphan syndrome therapy for Dravet syndrome. A rare, severe, infantile- topiramate, valproate) (MCSF) Drug, Fast Track onset form of epilepsy, Dravet syndrome is usually caused Ketogenic diet Convulsive seizure Clinical trial(s): Phase 3 by a variant in a gene called sodium voltage-gated Plant-derived CBD duration completed January 2019, channel alpha subunit 1, or SCN1A. Approved by FDA, Seizure-free interval data published December Fintepla is intended as an option for patients who have Functional capacity 2019; phase 3 primary prolonged seizures that are difficult to control with Quality of life completion July 2020; phase available antiepileptic drugs. Besides having seizures, 3 primary completion July patients typically experience cognitive impairment, 2020, pooled data published behavioral problems, muscle weakness, and sleep December 2019, top-line disorders. FDA has approved cannabidiol (CBD) to treat data reported September the disease, but it can cause liver impairment, especially 2020; phase 3 open-label when used in conjunction with certain antiepileptics; the extension primary drug also can cause sleepiness, sedation, and suicidal completion December 2020, behavior. In patients with Dravet syndrome, fenfluramine data presented December hydrochloride low-dose purportedly promotes serotonin 2018, data presented release and stabilizes nerve activity in the brain, which October 2019, data might decrease seizure frequency and duration. The presented October 2020; recommended dosage in the FDA-approved label is 0.1 phase 3 long-term follow-up mg/kg twice daily administered as an oral solution and primary completion April may be increased to a maximum of 26 mg total daily in 2023 patients not taking adjunctive stiripentol or a maximum of Note(s): Approval requires 17 mg total daily in patients taking adjunctive stiripentol both a Risk Evaluation and and clobazam. Mitigation Strategy and Developer(s): classification as a Schedule Zogenix, Inc (Emeryville, California) IV controlled substance until the US Drug Enforcement Agency (DEA) has made a final scheduling decision

Section 5. Rare Diseases 195

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 2 to 35 years Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, Frequency of seizures Submission date: who have Lennox-Gastaut amphetamine derivative intended as an adjunctive clobazam, stiripentol, that result in drops (ie, Supplemental New Drug syndrome that is being therapy for Lennox-Gastaut syndrome. The syndrome is a topiramate, valproate) where all or part of the Application planned for the treated with 1 to 4 rare, severe, infantile- or childhood-onset form of Ketogenic diet body droops) second quarter of 2021 antiepileptic drugs epilepsy. Fintepla might improve health outcomes in Plant-derived CBD Duration of seizures FDA designation(s): Orphan patients with Lennox-Gastaut syndrome, who often that result in drops Drug experience multiple types of seizures (eg, atonic, tonic, Seizure-free interval Clinical trial(s): Pivotal phase atypical absence, drop attacks) difficult to control with Functional capacity 3 primary completion FDA-approved antiepileptic drugs. In addition, patients Quality of life December 2020, data typically experience cognitive impairment, intellectual presented December 2020; disability, behavioral problems, delayed development, and phase 2 primary completion muscle weakness. FDA has approved cannabidiol (CBD) to September 2018, data treat the disease, but it might cause hepatic impairment, published August 2018; especially when used in conjunction with certain phase 3 long-term follow-up antiepileptics; the drug can also cause sleepiness, primary completion April sedation, and suicidal behavior. In patients with Lennox- 2023 Gastaut syndrome, fenfluramine hydrochloride low-dose purportedly promotes serotonin release and stabilizes nerve activity in the brain, which might decrease seizure frequency and duration. In clinical trials, patients take the drug by mouth at a dosage of 0.2 or 0.8 mg/kg daily (up to a maximum of 20 mg/day) for up to 52 weeks. The drug is intended to be taken daily on an ongoing basis. Developer(s): Zogenix, Inc (Emeryville, California)

Section 5. Rare Diseases 196

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 16 years or Fezagepras (PBI-4050; 3-pentylbenzeneacetic acid sodium Organ transplantation Change from baseline FDA designation(s): Orphan older and adults who have salt) is a novel, synthetic, medium-chain fatty acid Supportive care in skin pathology Drug, Rare Pediatric Disease Alström syndrome derivative, oral antifibrotic (ie, reduces scar tissue Change from baseline Clinical trial(s): Phase 2/3 formation). It is intended to treat Alström syndrome, a in fasting plasma primary completion May rare genetic syndrome. Alström syndrome is glucose 2020, preliminary data characterized by obesity in childhood or adolescence and Change from baseline presented April 2018; pivotal type 2 diabetes mellitus (T2DM), often with severe insulin in plasma insulin phase 3 planned resistance, dyslipidemia, high blood pressure, and severe Change from baseline life-threatening multiorgan fibrosis involving the bladder, in glycated hemoglobin kidney, liver, and heart. Progressive loss of vision and (HbA ) hearing, dilated cardiomyopathy, and short stature might 1c also occur. Fezagepras is intended to alleviate Change from baseline development of insulin resistance, dyslipidemia, and in blood glucose, as hypertension and severe multiorgan scarring. The drug measured by weekly 4- purportedly has stimulating activity toward the G-protein point profile coupled receptor 40 (GPR40) and inhibiting activity toward Change from baseline a related receptor, GPR84. This activity reduces fibrotic in liver stiffness activity in macrophages, fibroblasts, myofibroblasts, and epithelial cells. In clinical trials, fezagepras was given as four 200-mg capsules (800 mg total) once daily. Developer(s): Liminal Biosciences (Laval, Québec, Canada)

Adult males aged up to 65 Fidanacogene elaparvovec (PF-06838435) is an adeno- Factor IX replacement Bleeding episodes FDA designation(s): Orphan years who have moderate to associated viral vector gene therapy under development therapy (human plasma Treatment-related Drug, Breakthrough Therapy severe hemophilia B (factor to treat hemophilia B. As a single-treatment gene therapy, derived or recombinant) complications Clinical trial(s): Phase 3 IX activity of 2% or less) and fidanacogene elaparvovec could eliminate the need for Survival single-arm BENEGENE-2 have received routine factor repeated injections of coagulation factor replacement. Quality of life primary completion May IX replacement therapy for The therapy uses an adeno-associated viral vector to 2022 at least 6 months deliver a high-activity factor IX gene whose expression is driven by a liver-specific apolipoprotein E (Apo E) enhancer and human α1-antitrypsin (hAAT) promoter. In clinical trials, fidanacogene elaparvovec is given as a single intravenous infusion at an unspecified dose. Developer(s): Pfizer, Inc (New York, New York)

Section 5. Rare Diseases 197

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 12 years or Fitusiran (ALN-AT3) is an RNA interference (RNAi) Emicizumab-kxwh Bleeding episodes Clinical trial(s): Phase 3 older who have hemophilia therapeutic under development for hemophilia A and B. (hemophilia A) Treatment-related ATLAS-INH primary A or B Fitusiran purportedly reduces expression of antithrombin, Factor VIII replacement complications completion November 2020; an enzyme that inactivates several other enzymes in the (human plasma derived or Survival phase 3 ATLAS-A/B primary blood-clotting cascade. This inactivation promotes completion January 2021; recombinant, porcine Quality of life sufficient thrombin generation to restore hemostasis and recombinant; hemophilia A) phase 3 ATLAS-PPX primary prevent bleeding. Fitusiran therapy would replace regular Factor IX replacement completion June 2022; phase intravenous blood factor infusions with a monthly (human plasma derived or 2/3 ATLAS-PEDS primary subcutaneous injection. In clinical trials, fitusiran is recombinant; hemophilia B) completion June 2022; phase injected under the skin at a dosage of 80 mg once 3 ATLAS-OLE primary monthly for up to 20 months. completion January 2026; Developer(s): phase 2 OLE primary Alnylam Pharmaceuticals (Cambridge, Massachusetts), in completion February 2023, collaboration with Sanofi Genzyme (Cambridge, interim data presented June Massachusetts) 2020 Note(s): FDA lifted a clinical hold on fitusiran studies in December 2017

Infants and children aged Fosdenopterin (Nulibry) is a synthetic version of cyclic Anticonvulsants Ability to sit upright Approval date: February 26, up to 5 years who have pyranopterin monophosphate (cPMP). It is FDA approved Breathing (ie, ventilator) independently for at 2021 molybdenum cofactor to restore molybdenum cofactor (MoCo) levels and sulfite support least 30 seconds at 12 FDA designation(s): Orphan deficiency (MoCD) type A oxidase activity to enable clearance of sulfite from Supportive care months Drug, Breakthrough patients with MoCD type A. An ultra-rare genetic Bayley Scales of Infant Therapy, Rare Pediatric metabolic disorder, MoCD type A causes catastrophic and Development at 12 Disease irreversible neurologic damage within the first weeks of months Clinical trial(s): Phase 2 life. MoCD type A has no effective treatments. It is caused Pediatric Evaluation of primary completion by a mutation in the molybdenum cofactor synthesis 1 Disability Inventory December 2020; phase 2/3 gene, MOCS1, which turns guanosine triphosphate to (PEDI) at 12 months primary completion cPMP, an intermediate in the body’s production of MoCo. Survival at 12 months December 2021 MoCo is a key component of the sulfite oxidase enzyme, which clears the neurotoxic metabolic byproduct sulfite from the body. Fosdenopterin is given intravenously at a dosage of 80 to 320 μg/kg daily. Developer(s): Origin Biosciences (San Francisco, California), a subsidiary of BridgeBio Pharma (Palo Alto, California)

Section 5. Rare Diseases 198

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 13 to 22 years Gaboxadol (OV101) is a small-molecule derivative of Supportive care (eg, Aberrant behavior FDA designation(s): Orphan who have fragile X muscimol, a compound found in the mushroom Amanita anticonvulsants for incidence and severity Drug, Fast Track syndrome (FXS) muscaria. It is intended to treat FXS, a rare, noninherited, seizures and/or behavior Cognitive function Clinical trial(s): Phase 2 X chromosome–linked neurodevelopmental disorder. FXS stabilization, behavior- Quality of life ROCKET completed February is caused by mutations in the fragile X mental retardation stabilizing medications [eg, 2020, top-line data 1 gene, FMR1, responsible for encoding Fmr1 protein alpha2 agonists, presented October 2020 (Fmrp). Fmrp, which is expressed in neurons and glial antidepressants, beta- cells, is thought to promote synapse formation and blockers], educational adaptation (ie, synaptic plasticity) in the brain and is interventions, sensory thought to be important for learning, memory, and integration techniques) regulating RNA protein synthesis and transport in the brain. In patients with FXS, loss of Fmrp function leads to development of autism-like symptoms, including anxiety, irritability, aggression, hyperactivity, and restricted and repetitive behaviors. Some patients also experience seizures. Symptom severity varies by patient and is determined by gender and the number of CGG trinucleotide repeats that the patient harbors (ie, males with high numbers of CGG trinucleotide repeats typically exhibit the most severe symptoms). Gaboxadol is a

selective gamma-aminobutyric acid receptor A (GABAA) agonist (ie, activator) that purportedly restores the process of nerve inhibition and normalizes brain activity in patients with FXS. In clinical trials, patients receive an unspecified dose of gaboxadol 1, 2, or 3 times daily for up to 12 weeks. Developer(s): Ovid Therapeutics, Inc (New York, New York)

Section 5. Rare Diseases 199

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 2 to 21 years Ganaxolone (CCD-1042) is a positive allosteric modulator Antiepileptic drug Behavioral disturbance Submission date: New Drug

who have CDKL5 deficiency of gamma-aminobutyric acid receptor A (GABAA). It is combinations (eg, symptoms and severity Application planned for disorder (CDD) with a intended to treat seizures associated with CDD by benzodiazepines, Seizure duration midyear 2021 genetically confirmed restoring electrical balance to the seizing brain. CDD is a glutamate blockers, sodium Seizure frequency FDA designation(s): Orphan mutation in the cyclin- rare, chromosome X–linked genetic disorder channel blockers) Sleep quality Drug, Rare Pediatric Disease dependent kinase-like 5 characterized by early-onset seizures and severe Vagal nerve stimulation Quality of life Clinical trial(s): Phase 3 gene, CDKL5, with at least 16 neurodevelopmental impairment. CDD-related seizures (VNS) MARIGOLD primary primary-type seizures are difficult to control and often do not respond to completion July 2020, data occurring within 28 days current antiepileptic medications. Children with CDD often presented December 2020; that are refractory to 2 or cannot walk, talk, or feed themselves and often use phase 2 primary completion more antiseizure wheelchairs and depend heavily on caretakers for January 2018, data medications activities of daily living (ADLs). Ganaxolone purportedly presented December 2018 reduces seizures and anxiety in patients with CDD through positive allosteric modulation at synaptic and

extrasynaptic GABAA receptors. Through this mechanism, it purportedly blocks seizure propagation and elevates seizure threshold. Initial studies indicate that patients do not develop tolerance to ganalaxone’s anticonvulsant activity. In clinical trials, ganaxolone is taken by mouth 3 times daily in a liquid suspension (50 mg/mL) at a dosage of up to 1800 mg daily for 17 weeks, as an adjunct to the patient’s current antiepileptic drug regimen. Developer(s): Marinus Pharmaceuticals (Radnor, Pennsylvania)

Section 5. Rare Diseases 200

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males aged up to 64 Giroctocogene fitelparvovec (SB-525, PF-07055480) is a Emicizumab-kxwh Bleeding episodes FDA designation(s): Orphan years who have hemophilia recombinant adeno-associated virus serotype 6 (AAV6) Factor VIII replacement Factor VIII replacement Drug, Fast Track, A and residual factor VIII vector gene therapy in development to treat hemophilia (human plasma derived or use Regenerative Medicine levels of 1 IU/dL or lower A. It is intended to be a single treatment to reduce or recombinant, porcine Treatment-related Advanced Therapy despite stable factor VIII eliminate the need for repeated treatments with factor recombinant) adverse events Clinical trial(s): Phase 3 replacement therapy VIII replacement or emicizumab-kxwh to reduce bleeding Quality of life AFFINE primary completion risk. Giroctocogene fitelparvovec purportedly corrects the August 2022; phase 1/2 factor VIII deficiency that characterizes hemophilia A by primary completion July delivering a proprietary, synthetic, liver-specific promoter 2024, data reported module (FVIII transgene) that encodes the complementary December 2020 DNA for the B-domain-deleted human FVIII gene. In a phase 2 dose-finding trial, giroctocogene fitelparvovec is given as an intravenous infusion at a dose of 1 × 911 to 1 × 313 vg/kg, once. Developer(s): Pfizer, Inc (New York, New York), and Sangamo Therapeutics (Brisbane, California)

Section 5. Rare Diseases 201

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 6 years or older Givinostat is a small-molecule histone deacetylase (HDAC) Corticosteroids (eg, Ambulatory and gross FDA designation(s): Orphan who have Duchenne inhibitor intended to treat DMD, an inherited X deflazacort, prednisone) motor function, as Drug, Fast Track, Rare muscular dystrophy (DMD), chromosome–linked genetic disorder caused by measured by accepted Pediatric Disease are ambulatory, and are mutations or deletions in the dystrophin gene, DMD. DMD clinical ratings and Clinical trial(s): Phase 3 receiving a stable dose of encodes the dystrophin protein, which helps keep muscle scales (eg, time to primary completion March corticosteroids cells intact. The absence of wild-type dystrophin protein stand, 4-stair climb; 6- 2022; phase 2/3 long-term causes progressive muscle fiber necrosis and eventual minute walk test follow-up primary widespread muscle weakness. Patients with DMD also [6MWT], North Star completion December 2023 have increased HDAC levels that might be caused by Ambulatory dystrophin loss. HDAC overactivity prevents gene Assessment [NSAA]) expression, including that of genes responsible for muscle Disease progression cell regeneration and normal function, and it might trigger Muscle strength inflammation. No cure exists for DMD, and first-line Survival corticosteroid treatment (eg, deflazacort) manages symptoms but does not prevent disease progression and Quality of life has significant side effects. FDA approved 2 gene therapies for patients who have a specific mutation in DMD (ie, in exon 51 or exon 53), but patients who have other DMD mutations are ineligible for these therapies. In patients with DMD, givinostat purportedly blocks HDAC overactivity and improves muscle regeneration and function. In clinical trials, patients receive an unspecified, weight-dependent dose of an oral suspension of givinostat, at a concentration of 10 mg/mL, twice daily with food for up to 18 months. Developer(s): Italfarmaco SpA (Milan, Italy)

Section 5. Rare Diseases 202

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have sickle cell IMR-687 is a selective inhibitor of the enzyme Blood transfusion Frequency of vaso- FDA designation(s): Orphan disease (SCD) phosphodiesterase type 9 (PDE9) and is in development Crizanlizumab-tmca occlusive crises (VOCs) Drug, Fast Track, Rare to treat SCD. Donor stem cell transplantation is the only Hematopoietic stem cell and hospitalization Pediatric Disease potentially curative treatment for SCD but is not widely transplantation (HSCT) Number of blood Clinical trial(s): Phase 2 available because of the difficulty of finding a closely Hydroxyurea transfusions required randomized completed matched donor to increase the chance of success. IMR- August 2020, interim data Pharmaceutical-grade Quality of life 687 could represent a disease-modifying treatment that is presented June 2020, data l-glutamine more widely available. The oral drug purportedly prevents reported January 2021; destruction and increases levels of cyclic guanosine Voxelotor phase 2 extension primary monophosphate (cGMP). Higher cGMP levels in turn completion March 2025; increase production of fetal hemoglobin while reducing phase 2 primary completion the sickling of red blood cells and the stickiness of white December 2021 blood cells. IMR-687 purportedly does not reduce levels of certain white blood cells that can occur with hydroxyurea use, increasing infection risks. In a phase 2 trial, patients take IMR-687 at dose of either 50 or 100 mg, once daily for up to 24 weeks. Developer(s): Imara, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 203

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Inebilizumab (Uplizna) is a humanized monoclonal Azathioprine Attack rate Approval date: June 11, 2020 neuromyelitis optica or antibody intended to bind to CD19, which is expressed on Eculizumab plus Functional FDA designation(s): Orphan neuromyelitis optica a broad range of B cells. Inebilizumab is intended to bind immunosuppressants impairments (eg, Drug, Breakthrough Therapy spectrum disorder to and deplete autoreactive B cells involved in the Intravenous corticosteroids vision, mobility, bowel Clinical trial(s): Phase 2/3 N- (NMOSD), regardless of neurodegenerative disease course of NMOSD, for which Mycophenolate mofetil or bladder MOmentum completed aquaporin-4- no cure exists. NMOSD is a rare autoimmune disease that incontinence) change Plasmapheresis October 2018, pivotal study immunoglobulin isotype G affects myelin in the eyes, spinal cord, and other parts of from baseline data published October Rituximab (AQP4-IgG) antibody the body. Patients with NMOSD can have pain, paralysis, Hospitalizations 2019 presence, and who have vision loss, and bladder and bowel problems. Quality of life change had one relapse requiring Inebilizumab is approved by FDA; other approved from baseline rescue therapy in the treatments are immunosuppressants and/or add-on previous year therapies for those with positive aquaporin-4 (AQP4) antibodies. About 80% of patients test positive for autoantibodies to water channel protein AQP4, produced by B cells. Hepatitis B virus, quantitative serum immunoglobulins, and tuberculosis screening is required before the first dose. The recommended regimen and dosage in the FDA-approved label is to premedicate with a corticosteroid, an antihistamine, and an antipyretic, then to administer inebilizumab as an intravenous infusion over 90 minutes at a starting dose of 300 mg followed 2 weeks later by a second 300-mg intravenous infusion. Subsequent doses start 6 months from the first infusion and continue every 6 months. Patients must be monitored closely during the infusion and for at least 1 hour after completion of the infusion. Developer(s): Viela Bio (Gaithersburg, Maryland)

Section 5. Rare Diseases 204

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 to 60 years Leriglitazone (MIN-102) is a selective peroxisome Supportive care Ambulatory and motor FDA designation(s): Orphan who have genetically proliferator-activated receptor gamma (PPARγ) agonist (ie, function Drug, Rare Pediatric Disease confirmed Friedreich ataxia activator). It is intended to treat FRDA by restoring Survival Clinical trial(s): Phase 2 (FRDA) mitochondrial function and energy production to improve Quality of life FRAMES completed motor function. It might improve patient health outcomes September 2020, data and quality of life for a disorder that has no cure or reported December 2020 approved treatments. FRDA is a rare, inherited, neurodegenerative disorder best characterized by loss of coordination and muscle strength and heart disease. It is caused by a variant in the frataxin gene, FXN, that results in deficient mitochondrial frataxin protein. This deficiency causes mitochondrial impairment in iron metabolism, especially in the spinal cord and heart. Typically, motor symptoms emerge in childhood or young adulthood, and patients must use wheelchairs 10 to 20 years after symptom onset. Death typically occurs for patients with FRDA in their late 30s, usually related to heart disease. Leriglitazone purportedly crosses the blood-brain barrier to bind to PPARγ receptors in the central nervous system that modulate multiple genes involved in mitochondrial biogenesis, potentially restoring mitochondrial function and energy production to increase neuronal survival, decrease neurite degeneration, and improve motor function. In clinical trials, leriglitazone is administered once daily in an oral suspension at an unspecified dose for 48 weeks. Developer(s): Minoryx Therapeutics (Barcelona, Spain)

Section 5. Rare Diseases 205

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males aged up to 65 Leriglitazone (MIN-102) is a selective peroxisome Hematopoietic stem cell Ambulatory and motor FDA designation(s): Orphan years who have genetically proliferator-activated receptor gamma (PPARγ) agonist (ie, transplantation (HSCT) function Drug, Fast Track, Rare confirmed chromosome X– activator). It is intended to treat X-ALD by promoting Supportive care Cognitive function Pediatric Disease linked mitochondrial homeostasis and reducing inflammation Survival Clinical trial(s): Phase 2/3 adrenoleukodystrophy and neurodegeneration. It might improve patient health Quality of life ADVANCE primary (X-ALD) outcomes and quality of life for a disorder that has no completion June 2021, top-

cure or approved treatments. X-ALD is a rare, inherited, line data reported January neurodegenerative disorder characterized by 2021 accumulation of very-long-chain fatty acids (VLCFAs) that leads to central inflammatory demyelination in the brain, axonal degeneration in the spinal cord, and adrenal insufficiency. Two main phenotypes exist: adrenomyeloneuropathy (AMN), characterized by progressive motor dysfunction, and cerebral ALD (CALD), characterized by rapid neurodegeneration that leads to early death. Leriglitazone is intended to treat both forms. It purportedly crosses the blood-brain barrier to bind to PPARγ receptors in the central nervous system that modulate multiple genes involved in mitochondrial biogenesis, potentially restoring the lost energy balance, decreasing oxidative stress, and restoring mitochondrial function disrupted by accumulation of VLCFAs. Leriglitazone also purportedly promotes remyelination and neuronal survival, reduces macrophage/microglia activation to decrease neuroinflammation, and reduces monocyte adhesion to cells of the blood-brain barrier. In the phase 2/3 ADVANCE clinical trial, leriglitazone is given in an unspecified route at an unspecified dose and frequency for 96 weeks. In a phase 1 clinical trial, it was given orally daily at single doses of 30, 90, and 270 mg and multiple doses of 135 and 270 mg daily over 8 days. Developer(s): Minoryx Therapeutics (Barcelona, Spain)

Section 5. Rare Diseases 206

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who develop Liposomal cyclosporine A for inhalation (L-CsA-i) is an Immunosuppressants (eg, Disease progression FDA designation(s): Orphan bronchiolitis obliterans immunosuppressive treatment intended to reduce the azithromycin, Lung retransplantation Drug, Fast Track syndrome (BOS) after lung inflammatory disease burden of BOS, the most common mycophenolate, tacrolimus) Survival Clinical trial(s): Phase 3 transplantation cause of chronic lung allograft dysfunction after Supportive care (eg, Quality of life BOSTON-2 primary transplantation. No treatments are approved for BOS, and corticosteroids, oxygen) completion April 2023; no standardized treatment protocols are available. phase 3 BOSTON-1 primary Cyclosporine A is a potent immunosuppressive drug for completion April 2023; preventing transplant rejection, but systemic phase 3 BOSTON-3 open- administration has insufficient penetration into the lungs label extension primary to treat BOS and carries a risk of nephrotoxicity. L-CsA-i completion March 2024 uses a proprietary inhaled liposomal nanodelivery system to administer what researchers believe to be a sufficient concentration of cyclosporine A directly to the lung parenchyma, mediating immunosuppressive effects. L- CsA-i purportedly dampens key inflammatory T-cell activity in the lungs thought to contribute to the chronic inflammation and irreversible scarring caused by BOS, slowing or preventing disease progression. In clinical trials, the drug is inhaled using the PARI eFlow Nebulizer system at a dosage of 5 mg twice daily for 48 weeks for participants with a single-lung transplantation or 10 mg twice daily for 48 weeks for participants with a double- lung transplantation. Developer(s): Breath Therapeutics, a Zambon Group company (Cambridge, Massachusetts)

Section 5. Rare Diseases 207

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 to 80 years Lirentelimab (AK002) is a humanized monoclonal antibody Dietary modification Dysphagia symptoms FDA designation(s): Orphan who have active, biopsy- specific for Siglec-8 under study to treat eosinophilic Protein pump inhibitors Quality of life Drug confirmed eosinophilic esophagitis. A rare disease of the digestive system, Systemic corticosteroids Clinical trial(s): Phase 2/3 esophagitis that is eosinophilic esophagitis is caused by accumulation of Topical corticosteroids primary completion inadequately controlled by large numbers of eosinophils (ie, inflammation-promoting December 2021 standard-of-care treatment white blood cells) in the esophagus. The disease is (eg, proton pump inhibitors, characterized by vomiting, pain in the stomach or chest, corticosteroids, dietary difficulty swallowing, and failure to thrive. Mast cells and modification) eosinophils are thought to act as drivers of eosinophilic esophagitis pathology by contributing to a chronic inflammatory state. Siglec-8 is an inhibitory receptor expressed on the surface of both mast cells and eosinophils. Lirentelimab binding to Siglec-8 purportedly inhibits mast cells and antibody-dependent cellular cytotoxicity of eosinophils and, therefore, has the potential to inhibit the chronic inflammation underlying eosinophilic esophagitis. In clinical trials, lirentelimab (1 or 3 mg/kg) is given intravenously once monthly. Developer(s): Allakos (Redwood City, California)

Section 5. Rare Diseases 208

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 80 years Lirentelimab (AK002) is a humanized monoclonal antibody Azathioprine Abdominal symptoms FDA designation(s): Orphan with biopsy-confirmed specific for Siglec-8 under study to treat eosinophilic Corticosteroids (eg, pain, cramping, Drug eosinophilic gastritis or gastritis and eosinophilic duodenitis (formerly known as Dietary modification loss of appetite, Clinical trial(s): Phase 3 eosinophilic duodenitis eosinophilic gastroenteritis). Eosinophilic gastritis and bloating) Proton pump inhibitors primary completion whose disease is eosinophilic duodenitis are rare diseases of the digestive Quality of life December 2021; phase 3 inadequately controlled by system caused by accumulation of large numbers of extension primary standard-of-care therapies eosinophils (ie, inflammatory white blood cells) in the completion March 2023 (eg, proton pump inhibitors, lining of the stomach or small intestine. Both diseases are antihistamines, characterized by vomiting, stomach pain, weight loss, and corticosteroids, dietary diarrhea. Mast cells and eosinophils are thought to act as modification) drivers of eosinophilic gastritis and eosinophilic duodenitis pathology by contributing to a chronic inflammatory state. Siglec-8 is an inhibitory receptor expressed on the surface of both mast cells and eosinophils. Lirentelimab binding to Siglec-8 purportedly inhibits mast cells and antibody-dependent cellular cytotoxicity of eosinophils and, therefore, has the potential to inhibit the chronic inflammation underlying these conditions. In clinical trials, lirentelimab (1 or 3 mg/kg) is given intravenously once monthly. Developer(s): Allakos (Redwood City, California)

Section 5. Rare Diseases 209

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults with a Lonafarnib (Zokinvy) is an orally active inhibitor of Occupational and physical Changes in auditory Approval date: November genetic and clinical farnesyltransferase, an enzyme involved in the therapy function, dental 20, 2020 diagnosis of progeria modification of proteins through a process called Supportive care (statins, anomalies, and FDA designation(s): prenylation. Progeria is a rare and fatal genetic condition nonsteroidal anti- dermatologic changes Breakthrough Therapy, Rare of precocious aging that starts at birth or in early inflammatory drugs Changes in body Pediatric Disease childhood. It is caused by a point mutation in the lamin [NSAIDs], and bone health composition and Clinical trial(s): Phase 2 A/C gene, LMNA, which encodes the lamin A protein, drugs) cardiovascular primary completion October yielding progerin. Progerin is an abnormal protein that structure and function 2009, results published has been farnesylated. Researchers believe it cannot be Changes in skeletal 2012; phase 2 primary cleaved, resulting in tight association with and changes to abnormalities, joint completion July 2020; phase the nuclear envelope, affecting the form of the nuclear contracture and 1/2 primary completion envelope, and causing subsequent cellular damage. function, and growth December 2020 Progerin is thought to cause premature aging in patients Survival with progeria due to these disruptions in nucleus and cell stability. As a prenylation inhibitor, lonafarnib is intended Quality of life to block the production of progerin, thereby preventing progeria. According to the FDA-approved label, lonafarnib is taken at a starting dose of 115 mg/m2 twice daily and escalated to 150 mg/m2 after 4 months. Developer(s): Eiger BioPharmaceuticals (Palo Alto, California)

Section 5. Rare Diseases 210

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 65 years Losmapimod is a selective inhibitor of p38 alpha/beta Supportive care (eg, Ambulatory and gross FDA designation(s): Orphan who have genetically mitogen-activated protein kinase (p38 MAPKα/β) that is assistive devices, pain motor function, as Drug confirmed intended to treat FSHD1 by reducing overactive DUX4 control, physical therapy) measured by accepted Clinical trial(s): Phase 2 facioscapulohumeral gene expression in muscle cells and reducing clinical ratings and ReDUX4 completed January muscular dystrophy type 1 inflammation. It might improve patient health outcomes scales (eg, time to 2021, interim data presented (FSHD1) with 1 to 9 repeats by slowing disease progression and improving quality of stand, 4-stair climb; 6- October 2020; phase 2 open- in the D4Z4 region of life. FSHD is a form of muscular dystrophy characterized minute walk test label extension primary chromosome 4 by muscle weakness and atrophy that arises most often in [6MWT], North Star completion February 2024; the face, shoulder blades, and upper arms, but can also Ambulatory phase 2 primary completion affect other body parts. Symptoms typically emerge in Assessment [NSAA]) April 2021 adolescence. About 95% of cases are categorized as Disease progression FSHD1. FSHD1 is associated with a shortened D4Z4 Muscle strength macrosatellite repeat on chromosome 4, which leads to Survival overexpression of the DUX4 gene that is thought to contribute to muscle cell damage. Losmapimod inhibition Quality of life of p38 MAPKα/β purportedly modulates DUX4 gene expression and mediates inflammation to reduce muscle cell damage and death. In clinical trials, losmapimod is taken by mouth at a dosage of 15 mg twice daily for 48 to 52 weeks. Developer(s): Fulcrum Therapeutics, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 211

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients of any age who Lumasiran (Oxlumo, formerly ALN-GO1) is an RNA Diet management and fluid Change in urinary Approval date: November have primary hyperoxaluria interference (RNAi) therapeutic intended to reduce intake oxalate excretion from 24, 2020 type 1 (PH1) glycolate oxidase (GO) expression in PH1. A rare inherited Organ transplantation (ie, baseline FDA designation(s): Orphan disorder, PH1 is characterized by development of kidney isolated or combined liver Hospitalizations Drug, Breakthrough Therapy and bladder stones from the buildup of excessive oxalate. and kidney) Quality of life for Clinical trial(s): Phase 3 Lumasiran is intended to improve health outcomes in Renal dialysis patients and caregivers ILLUMINATE-A primary patients with PH1 by reducing illness from oxalate crystals Shockwave lithotripsy completion November 2019, accumulating in the kidneys and urinary tract. No data reported December pharmacologic treatments are available for PH1. 2019, data presented June Lumasiran purportedly lowers liver levels of GO, which 2020; phase 3 ILLUMINATE-B produces the substrate necessary for the subsequent primary completion June production of oxalate. Limiting the substrate necessary 2020, data presented for oxalate production is intended to limit its buildup. As October 2020; phase 3 recommended in the FDA-approved label, lumasiran is ILLUMINATE-C primary given an injection under the skin. Patients weighing more completion May 2021; phase than 20 kg start at 3 mg/kg per month for 3 months (3 1/2 completed January 2019, doses), followed by a maintenance dose of 3 mg/kg once data reported February 2019 every 3 months. Patients weighing up to 20 kg start at 6 mg/kg/month for 3 months with the maintenance dose split into 2 cohorts as follows: patients weighing between 10 kg and 20 kg take maintenance doses of 6 mg/kg once every 3 months; patients weighing less than 10 kg take maintenance doses of 3 mg/kg once monthly. Developer(s): Alnylam Pharmaceuticals (Cambridge, Massachusetts)

Section 5. Rare Diseases 212

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 months or LYS-SAF302 is a viral vector–based gene therapy intended Supportive care Developmental and FDA designation(s): Orphan older and adults who have for Sanfilippo syndrome type A, a childhood-onset, cognitive delays, as Drug, Fast Track, Rare genotypically confirmed progressive, inherited metabolic disorder caused by a measured by MPS Pediatric Disease Sanfilippo syndrome type A variant in the N-sulfoglucosamine sulfohydrolase gene, clinical ratings and Clinical trial(s): Phase 2/3 (also called SGSH. Patients with the disorder cannot break down the scales AAVance primary completion mucopolysaccharidosis type polysaccharide heparan sulfate, a process normally Independence, as March 2022, interim data III A [MPSIIIA]) mediated by the SGSH-encoded enzyme heparan-N- measured by MPS reported December 2020 sulfamidase. Buildup of heparan sulfate in central clinical ratings and Note(s): A clinical hold has nervous system cells causes degeneration that manifests scales been placed on the phase as behavioral problems, sleeplessness, loss of speech and Sleep duration 2/3 AAVance trial after cognitive skills, mental retardation, heart problems, Quality of life discussions with FDA and seizures, and loss of mobility. No cure exists for Sanfilippo while recent magnetic syndrome type A (about 60% of all Sanfilippo syndrome resonance imaging (MRI) cases), and patients typically do not survive past their 20s. findings in patients are Treatment consists of supportive care. LYS-SAF302 is a investigated recombinant adeno-associated viral vector carrying SGSH. LYS-SAF302 purportedly restores heparan-N-sulfamidase function, blocks central nervous system degeneration, and reduces disease-related symptoms. In clinical trials, LYS-SAF302 is injected once intracerebrally into both halves of the brain through image-guided tracks. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts), in collaboration with Lysogene SA (Paris, France)

Section 5. Rare Diseases 213

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 1 to 18 years Maralixibat (LUM001) is an inhibitor of apical sodium- Ursodeoxycholic acid Liver function FDA designation(s): Orphan who have progressive dependent bile acid transporter (ASBT). It purportedly (UDCA) Need for surgical Drug, Breakthrough familial intrahepatic prevents bile acids from accumulating in the liver of intervention Therapy, Rare Pediatric cholestasis (PFIC) patients with PFIC subtypes 1, 2, 3, and 4. A progressive Quality of life Disease disease, PFIC can require surgical intervention or liver Clinical trial(s): Phase 2 transplantation and has minimally effective therapy. PFIC INDIGO completed May is characterized by variants in key genes leading to 2020, data reported June decreased bile acid flow through the liver. Accumulation 2020; phase 3 MARCH-PFIC of bile acid in the liver can lead to jaundice, intense primary completion July itching, gallstones, abdominal pain, nausea, vomiting, and 2021; phase 3 extension liver damage, as well as a higher risk of hepatocellular primary completion carcinoma (HCC). Maralixibat purportedly prevents ASBT November 2022 from recycling bile acid in the small intestine back into the liver. So, more bile is excreted in the feces, preventing buildup in the liver. In phase 3 clinical trials, maralixibat is given as an oral solution at a dosage of up to 600 μg/kg twice daily for 26 weeks. Developer(s): Mirum Pharmaceuticals, Inc (Foster City, California)

Section 5. Rare Diseases 214

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Mavorixafor (X4P-001) is a CXC chemokine receptor 4 Granulocyte colony- Infection rate FDA designation(s): Orphan older and adults who have a (CXCR4) inhibitor. It purportedly prevents most leukocytes stimulating factor (G-CSF; Severity of infections Drug, Breakthrough clinical diagnosis of WHIM from homing to and localizing in the bone marrow. to prevent infection) Wart control Therapy, Fast Track, Rare (warts, Retention of leukocytes in the bone marrow is a Pediatric Disease Imiquimod (to treat warts) Hematologic and hypogammaglobulinemia, characteristic of WHIM syndrome, a rare primary Intravenous immunologic Clinical trial(s): Phase 2 infections, and immunodeficiency typically caused by gain-of-function immunoglobulin (IVIG; to parameters primary completion myelokathexis) syndrome mutations in the C-X-C motif chemokine receptor 4 gene, December 2022, data prevent infection) Quality of life CXCR4. The mutations associated with the syndrome published December 2020; cause dysfunction of the immune system, which increases phase 3 primary completion infection risk and other complications, including wart September 2021 emergence. No cure exists. Standard treatment involves antibiotic prophylaxis, immune stimulation, and treatment of infections and their consequences. Mavorixafor is intended to reduce infection risk. In a clinical trial, Mavorixafor is given orally once daily as four 100-mg capsules. Developer(s): X4 Pharmaceuticals (Cambridge, Massachusetts)

Section 5. Rare Diseases 215

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Mepolizumab (Nucala) is a monoclonal antibody specific Corticosteroids Annualized rate of HES Approval date: September older and adults who have for interleukin-5 (IL-5), a cytokine responsible for Cytotoxic drugs (eg, flares from baseline 25, 2020 hypereosinophilic syndrome promoting activation of eosinophils (ie, inflammation- cyclophosphamide, Fatigue score from FDA designation(s): Orphan (HES) promoting white blood cells) and inflammatory hydroxyurea, vincristine) baseline Drug, Fast Track responses. HES is a group of rare inflammatory disorders Imatinib Overall survival Clinical trial(s): Phase 3 characterized by the chronic overproduction of Quality of life completed December 2019; eosinophils. These eosinophils infiltrate tissues and can phase 3 completed August damage organs such as the heart and lungs, which can 2019, data reported negatively impact quality of life and increase risk of death. November 2019, data Treatment options are limited. Mepolizumab purportedly presented May 2020, data binds to IL-5 and prevents it from binding to the IL-5 published September 2020; receptor on the surface of eosinophils, which inhibits phase 3 completed inflammatory signaling and reduces eosinophil levels in September 2010, data circulation without completely depleting them from the published October 2012 body. According to the FDA-approved label, mepolizumab Note(s): FDA approved is administered as 3 separate 100-mg injections under the mepolizumab to treat severe skin every 4 weeks. asthma in November 2015, Developer(s): to treat eosinophilic GlaxoSmithKline plc (Brentford, United Kingdom) granulomatosis with polyangiitis (Churg-Strauss syndrome) in December 2017, for self-administration in June 2019, and for children aged 6 to 11 years with severe eosinophilic asthma in September 2019

Section 5. Rare Diseases 216

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have a Mitapivat (AG-348) is a small-molecule allosteric activator Supportive care, including Need for transfusions Submission date: New Drug genetically confirmed of the enzyme pyruvate kinase being developed to treat red blood cell transfusions Quality of life Application planned for the pyruvate kinase deficiency PKD. PKD arises from inherited mutations in the PKLR as needed for anemia second quarter of 2021 (PKD) with at least 2 mutant gene that lead to hemolytic anemia (ie, anemia caused by FDA designation(s): Orphan alleles in the pyruvate red blood cell destruction). No approved treatments exist Drug, Fast Track kinase L/R gene, PKLR for PKD; care is supportive, consisting mainly of red blood Clinical trial(s): Phase 3 cell transfusions as needed, based on the severity and ACTIVATE completed symptoms of anemia. This drug is intended to reduce the October 2020, data reported need for transfusions and provide the first disease- December 2020; phase 3 modifying treatment for PKD. Mitapivat purportedly ACTIVATE-T completed activates pyruvate kinase-R, the form of pyruvate kinase November 2020, data present in red blood cells, which helps convert glucose (ie, reported January 2021; sugar) into energy. Without sufficient pyruvate kinase-R phase 2 DRIVE-PK primary activity, red blood cells have a shortened lifespan due to completion May 2017, insufficient energy production. In phase 3 trials, mitapivat preliminary data published is taken by mouth at 20 or 50 mg twice daily. September 2019, further Developer(s): data reported December Agios Pharmaceuticals, Inc (Cambridge, Massachusetts) 2019

Patients of any age who MT1621 is an oral combination of the DNA building blocks Supportive care Motor function Submission date: New Drug have genetically confirmed deoxycytidine and deoxythymidine intended to address assessment from Application planned for the thymidine kinase 2 the underlying cause of TK2d. A rare disorder, TK2d is baseline first half of 2022 deficiency (TK2d) due to a caused by genetic mutations in mitochondrial DNA 6-minute walk test FDA designation(s): Orphan mutation in the thymidine leading to mitochondrial dysfunction, including (6MWT) change from Drug, Breakthrough Therapy kinase 2 gene, TK2 inadequate energy production by cells. TK2d causes baseline Clinical trial(s): Phase 2 progressive and severe muscle weakness that impairs Respiratory status pivotal primary completion movement, breathing, and eating and can be fatal. No change from baseline January 2022; phase 2 therapies are approved for TK2d. MT1621 purportedly Health care services completed May 2019, data provides cells an adequate balance of the nucleotide use reported October 2019; building blocks and restores cell function in patients with Survival phase 3 open-label primary TK2d. In clinical trials, up to 400 mg/kg daily of MT1621 is completion March 2025 taken by mouth as a dissolved solution. Quality of life Developer(s): Modis Therapeutics (Oakland, California), a subsidiary of Zogenix (Emeryville, California)

Section 5. Rare Diseases 217

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have generalized Nalbuphine (Haduvio) is a kappa opioid receptor agonist Antihistamines (eg, Anxiety and Clinical trial(s): Phase 2/3 prurigo nodularis covering (ie, activator) and mu opioid receptor antagonist being hydroxyzine, depression symptoms PRISM primary completion at least 2 separate areas of developed in an extended-release form to treat itch in diphenhydramine; off- and severity December 2021; phase 2/3 the body with at least 10 prurigo nodularis. Its novel mechanism of action might label) Itch frequency and completed August 2016, nodules and who alleviate disease severity and improve patient quality of Immunosuppressants (eg, severity data presented January experience severe itching life, because current therapies often do not provide methotrexate, Sleep quality 2021; phase 2/3 open-label adequate symptomatic relief. Prurigo nodularis is a extension completed cyclosporine; off-label) Quality of life chronic skin disease of unknown cause in which hard Monoclonal antibody (eg, September 2017 lumps (ie, nodules) form on the skin and cause intense dupilumab; off-label) Note(s): The developer itching that often leads patients to scratch the areas until Over-the-counter lotions announced in July 2020 they bleed. Scratching can cause more nodules to appear. (eg, containing calamine, plans to expand participant The disease can be highly disruptive to patients’ daily lives camphor, menthol, or enrollment in the phase 2/3 and can negatively affect sleep quality, mental health, pramoxine hydrochloride) PRISM trial after a concentration, and body image and confidence. recommendation from an Phototherapy (ie, narrow- Nalbuphine purportedly activates kappa opioid receptors independent data band ultraviolet B, psoralen in the body to relieve pain and itch sensation while monitoring committee. This plus ultraviolet A; off-label) blocking mu opioid receptors to mitigate side effects trial is anticipated to be including sedation, respiratory depression, constipation, Topical capsaicin (off-label) completed in the third and activation of neural pathways associated with Topical corticosteroids (eg, quarter of 2021, with top- euphoria and risk for dependence and/or abuse. In clinical betamethasone, clobetasol; line data expected in the trials, nalbuphine is taken by mouth at a dosage of 162 off-label) fourth quarter of 2021. mg twice daily. Developer(s): Trevi Therapeutics (New Haven, Connecticut)

Section 5. Rare Diseases 218

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or Narsoplimab (OMS721) is a fully human monoclonal Eculizumab Platelet count change FDA designation(s): Orphan older and adults who have antibody that binds an enzyme called mannan-binding Plasma therapy (ie, plasma from baseline Drug, Fast Track primary atypical hemolytic lectin-associated serine protease-2 (MASP-2), the effector infusion or plasmapheresis) Glomerular filtration Clinical trial(s): Phase 3 uremic syndrome (aHUS) enzyme of the lectin pathway in the complement system. rate from baseline primary completion An ultra-rare genetic disease, aHUS results in chronic TMA events from February 2020 uncontrolled complement activation, leading to baseline complement-mediated thrombotic microangiopathy Disease remission rate (TMA). TMA is characterized by the formation of blood clots in small blood vessels throughout the body that can progressively damage organs, including the kidneys, and carries a high risk of serious illness and death. Narsoplimab is intended to reduce the excessive complement-mediated inflammation and endothelial damage characteristic of aHUS while leaving other complement system functions intact. In clinical trials, narsoplimab was given as an intravenous infusion at an unspecified loading dose followed by daily under-the-skin injections. Developer(s): Omeros Corp (Seattle, Washington)

Section 5. Rare Diseases 219

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Narsoplimab (OMS721) is a fully human monoclonal Eculizumab (off-label) Inflammation PDUFA date: July 17, 2021; hematopoietic stem cell antibody that binds an enzyme called mannan-binding Rituximab with biomarkers from Priority Review transplantation (HSCT)– lectin-associated serine protease-2 (MASP-2). Narsoplimab plasmapheresis baseline FDA designation(s): Orphan associated thrombotic is being investigated to treat HSCT-TMA. About 10% to Supportive care (eg, Red blood cell Drug, Breakthrough Therapy microangiopathy (TMA) 25% of HSCTs lead to TMA and, in high-risk patients (eg, antibiotics, transfusion Clinical trial(s): Phase 2 patients with comorbid graft-vs-host disease [GVHD] antihypertensives, requirements from primary completion January whose TMA has not responded to modified erythropoietin, baseline 2020, data announced immunosuppressive therapy), the death rate is more than thrombopoietin) Platelet requirements October 2020 90%. No treatments are FDA approved for HSCT-TMA. from baseline TMA is characterized by formation of blood clots in small Survival blood vessels throughout the body that can progressively damage organs, including the kidneys, and carries a high risk of serious illness and death. In addition, TMA is characterized by excessive activation of the immune system’s complement system. MASP-2 is a key enzyme in the lectin pathway responsible for activating the complement system in response to tissue damage or microbial infection. By binding and inhibiting MASP-2, narsoplimab purportedly reduces excessive complement- mediated inflammation and endothelial damage characteristic of TMA while leaving other complement system functions intact. In clinical trials, narsoplimab has been given as an intravenous infusion at an unspecified loading dose followed by daily unspecified low, medium, or high doses as under-the-skin injections. Developer(s): Omeros Corp (Seattle, Washington)

Section 5. Rare Diseases 220

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Narsoplimab (OMS721) is a fully human monoclonal Corticosteroids Kidney function from FDA designation(s): Orphan immunoglobulin isotype A antibody that binds an enzyme called mannan-binding Immunosuppressants (eg, baseline Drug, Breakthrough Therapy (IgA) nephropathy lectin-associated serine protease-2 (MASP-2). Narsoplimab azathioprine, Urine protein excretion Clinical trial(s): Phase 3 is intended to reduce excessive complement-mediated cyclophosphamide, from baseline primary completion August inflammation and endothelial damage characteristic of mycophenolate) 2020 IgA nephropathy while leaving other immune system Supportive care functions intact. IgA nephropathy is a kidney disease that occurs when an antibody subtype called IgA accumulates in the kidneys and causes local inflammation that can gradually affect kidney function and cause end-stage renal disease (ESRD) within 10 to 20 years in up to 40% of affected patients. No treatments are approved for IgA nephropathy. The standard of care (ie, high-dose systemic corticosteroids) is controversial because of the increased risks of adverse events and serious infections, high blood pressure, weight gain, diabetes mellitus, and osteoporosis. MASP-2 is a key enzyme for activating the lectin pathway of the body’s complement system in response to tissue damage or microbial infection. Excessive complement activation is a trait of IgA nephropathy. Targeting the lectin pathway is intended to reduce excessive inflammation while leaving other key complement functions intact. In clinical trials, narsoplimab is given as an intravenous infusion at an unspecified loading dose followed by daily under-the-skin injections. Developer(s): Omeros Corp (Seattle, Washington)

Section 5. Rare Diseases 221

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults with severe itching Nemolizumab (CD14152) is a novel monoclonal antibody Antihistamines (eg, Itch frequency and FDA designation(s): (ie, prurigo) associated with that blocks signaling of interleukin-31 (IL-31) to treat diphenhydramine, severity Breakthrough Therapy moderate to severe prurigo itching (ie, pruritus) associated with prurigo nodularis. A hydroxyzine; off-label) Anxiety and Clinical trial(s): Phase 3 nodularis with at least 20 chronic skin disease, prurigo nodularis is characterized by Immunosuppressants (eg, depression symptoms primary completion October nodules on the body hard lumps (ie, nodules) that form on the skin, causing cyclosporine, and severity 2021; phase 3 primary intense itching, which often leads to patients scratching methotrexate; off-label) Sleep quality completion December 2021; the areas until they bleed. Current therapies often do not Monoclonal antibody (eg, Quality of life phase 3 primary completion provide adequate symptomatic relief. Scratching can dupilumab; off-label) January 2023; phase 2 cause more nodules to appear. The disease cause is Over-the-counter lotions completed September 2018, unknown, although some patients have underlying skin (eg, containing calamine, data published February conditions or allergies that are thought to contribute. camphor, menthol, 2020 Prurigo nodularis can be highly disruptive to patients’ pramoxine hydrochloride) daily lives because it can negatively affect sleep quality, mental health, concentration, and body image and Phototherapy (ie, narrow- confidence. Nemolizumab purportedly reduces itching by band ultraviolet B, psoralen blocking the binding of the inflammatory cytokine IL-31 to plus ultraviolet A; off-label) IL-31α receptors that are thought to play a key role in itch Topical capsaicin (off-label) signaling to the brain in prurigo nodularis. In phase 2 Topical corticosteroids (eg, clinical trials, nemolizumab was injected under the skin at betamethasone, clobetasol; a dosage of 0.5 mg/kg once every 4 weeks for a total of 3 off-label) doses. In phase 3 clinical trials, nemolizumab will be injected under the skin at a dose of 30 mg at an unspecified frequency. Developer(s): Galderma (Lausanne, Switzerland), which acquired worldwide license from Chugai Pharmaceutical Co, Ltd (Tokyo, Japan)

Section 5. Rare Diseases 222

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults with primary or Nipocalimab (M281) is a fully human monoclonal antibody Corticosteroids Hemoglobin response FDA designation(s): Orphan secondary warm directed against the FcRn protein. Nipocalimab Immunosuppressive drugs and range at steady Drug, Fast Track autoimmune hemolytic purportedly blocks FcRn-mediated recycling of Rituximab state Clinical trial(s): Phase 2/3 anemia (wAIHA) immunoglobulin isotype G (IgG), reducing circulating Splenectomy Daily corticosteroid primary completion June levels of antibodies, including autoantibodies implicated use 2021 in causing wAIHA disease. Patients with wAIHA have Hospitalizations autoantibodies that bind to red blood cells at 37°C with or Total score from the without complement activation. The disease is Functional Assessment characterized by the destruction of red blood cells, of Chronic Illness resulting in severe anemia, weakness, and fatigue. Up to Therapy—Fatigue 30% of patients with severe wAIHA disease are admitted (FACIT-F; quality of life) to an intensive care unit (ICU), and up to 8% of patients from baseline with wAIHA die prematurely. Spleen macrophages carry Fcγ receptors that bind the Fc region of warm reacting IgG that are already bound to erythrocytes. This leads to red blood cell destruction via phagocytosis or cell membrane removal that causes lysis. By blocking the activity of FcRn, nipocalimab is expected to lower the level of autoantibodies circulating in the bloodstream and thereby rapidly relieve the signs and symptoms of wAIHA. In clinical trials, nipocalimab is given as an intravenous infusion once every 4 weeks at an unspecified dose. Developer(s): Momenta Pharmaceuticals, Inc (Cambridge, Massachusetts), a subsidiary of Johnson & Johnson (New Brunswick, New Jersey)

Section 5. Rare Diseases 223

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have desmoid Nirogacestat is a novel, selective, small-molecule inhibitor One or more of the Progression-free FDA designation(s): Orphan tumors that cannot be of γ-secretase under study for treating desmoid tumors. following: survival Drug, Fast Track, managed by surgery or These are rare, benign, soft tissue tumors that can invade Anti-inflammatory agents Quality of life Breakthrough Therapy radiation therapy surrounding healthy tissue in joints, organs, and muscles. (eg, celecoxib, sulindac) Clinical trial(s): Phase 3 DeFi No therapies are approved for treating desmoid tumors, Hormone therapy (eg, primary completion March and patients have only palliative options to manage fulvestrant, tamoxifen) 2021 desmoid tumor–associated signs and symptoms, which Tyrosine kinase inhibitors include disfigurement, internal bleeding, range-of-motion (eg, imatinib, sorafenib) loss, severe pain, weakness, and even death. Desmoid tumors frequently exhibit aberrant signaling by the transmembrane receptor Notch, which is involved in the tumors’ proliferation, survival, migration, blood vessel formation, and drug resistance. Notch activity is regulated by γ-secretase, an integral membrane protein that cleaves Notch, releasing its intracellular domain and allowing it to translocate to the cell nucleus to direct gene expression. Nirogacestat-mediated inhibition of γ-secretase purportedly prevents Notch from activating pathways that contribute to desmoid tumor growth. In clinical trials, nirogacestat is taken by mouth at a dosage of 150 mg twice daily until disease progression or intolerable toxicity. Developer(s): SpringWorks Therapeutics, Inc (Stamford, Connecticut)

Section 5. Rare Diseases 224

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have new-onset Nomacopan (rVA576) is a recombinant small-protein Antimicrobial anti- Blister and hive FDA designation(s): Orphan or relapsing mild to severe inhibitor of complement component 5 (C5) and lipid inflammatories (eg, severity Drug bullous pemphigoid (BP) mediator leukotriene B4 (LTB4) under study to treat BP by dapsone, doxycycline) Itch severity Clinical trial(s): Phase 3 blocking their role in driving inflammation in the disorder. Corticosteroids (eg, Quality of life planned; phase 2 completed Nomacopan might improve patient health outcomes, systemic prednisolone, April 2020, top-line data compared with current therapies, by targeting specific topical clobetasol) reported May 2020 pathways with fewer side effects, and it might reduce Immunosuppressants (eg, health care costs of hospitalizations for BP exacerbations. azathioprine, BP is a rare, autoimmune skin disorder in which the methotrexate) immune system attacks proteins responsible for holding the layers of the skin together, resulting in abnormal breakdown of the skin. It is characterized by intense itching, blisters, and hives and can cause considerable distress and pain. It most frequently affects the elderly. Patients with BP have been found to have high levels of LTB4 and C5/C5 activation products, mediators of inflammation, in their skin. Nomacopan purportedly acts on complement C5 to prevent the release of C5a and formation of C5b-9, also known as the membrane attack complex (MAC). It purportedly inhibits LTB4 activity to prevent the exaggerated inflammatory response that contributes BP pathology and severity. In clinical trials, nomacopan is given daily as an injection under the skin at an unspecified dose. Developer(s): Akari Therapeutics (New York, New York; London, United Kingdom)

Section 5. Rare Diseases 225

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Nomacopan (rVA576) is a recombinant small-protein Allogeneic (ie, donor) Hemoglobin levels FDA designation(s): Orphan paroxysmal nocturnal inhibitor of the immune complement system under hematopoietic stem cell Red blood cell Drug, Fast Track hemoglobinuria (PNH) who development to treat PNH. Nomacopan could disrupt transplantation (HSCT) transfusion need Clinical trial(s): Phase 3 require regular blood patient management by replacing intravenous infusions Anticomplement therapy, Quality of life CAPSTONE completed transfusions (every 2 weeks to 2 months) of complement component 5 intravenous (eg, September 2020, interim (C5) inhibitors with daily subcutaneous injections patients eculizumab, ravulizumab- data reported January 2020, give themselves. Nomacopan binds to and inhibits the cwvz) further data reported cleavage of C5, a key protein responsible for activating the Oral anticoagulation (to December 2020; phase 3 complement system in response to tissue damage or prevent recurrent blood CONSERVE primary microbial infection. C5 cleavage releases the clots; eg, warfarin, completion June 2025 proinflammatory anaphylatoxin C5a and allows the rivaroxaban) Note(s): Fast Track formation of the C5b-9 membrane attack complex (MAC). designation applies only to Thus, nomacopan purportedly reduces the excessive use in patients with PNH complement-mediated inflammation characteristic of who have genetic variants PNH. The manufacturer also purports that nomacopan that cause resistance to independently inhibits the activity of leukotriene B4 eculizumab therapy (LTB4), a proinflammatory molecule that might contributed to the inflammatory state in PNH. In clinical trials, nomacopan is taken daily as an under-the-skin injection at an unspecified dose. Developer(s): Akari Therapeutics (New York, New York; London, United Kingdom)

Section 5. Rare Diseases 226

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 months to Odevixibat (A4250) inhibits the apical sodium-dependent Cholestyramine Liver function PDUFA date: July 20, 2021; 18 years who have bile acid transporter (ASBT), also known as the ileal bile Phenobarbital Need for surgical Priority Review genetically confirmed acid transporter. It is in development to treat PFIC, Rifampicin intervention FDA designation(s): Orphan progressive familial including PFIC subtypes 1, 2, 3, and 4 (preliminary focus Sodium 4-phenylbutyrate Quality of life Drug, Rare Pediatric Disease, intrahepatic cholestasis type on subtypes 1 and 2). In PFIC, inherited alterations in Fast Track UDCA 1 (PFIC1) or type 2 (PFIC2) genes that regulate bile acid flow cause a buildup of bile Clinical trial(s): Phase 3 acid in the liver, eventually leading to poor growth and randomized PEDFIC1 progressive liver disease. No drugs are FDA approved to completed July 2020, top-line treat patients who have PFIC, and off-label treatments (eg, data reported September cholestyramine, rifampicin, ursodeoxycholic acid [UDCA]) 2020; phase 3 single-arm are ineffective in some patients. Nonresponders may extension PEDFIC2 primary require surgical management (eg, biliary diversion, liver completion December 2021, transplantation) to address symptoms of bile acid data presented November accumulation and progressive liver damage. Odevixibat 2020 purportedly prevents ASBT from recycling bile acid in the small intestine back into the liver. So, more bile is excreted in the feces, preventing buildup in the liver. Odevixibat purportedly acts locally in the gut with minimal systemic exposure at therapeutic doses. In phase 3 clinical trials, odevixibat capsules are taken by mouth at 40 or 120 μg/kg once daily for 24 weeks. Developer(s): Albireo Pharma, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 227

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults who Olipudase alfa (GZ402665) is an enzyme replacement Blood transfusions Fatigue Submission date: Biologics have chronic visceral acid therapy consisting of recombinant human acid Hyperlipidemia drugs Lung function License Application planned sphingomyelinase deficiency sphingomyelinase intended to treat ASMD. ASMD is a Supplemental oxygen Pain for second half of 2021 (ASMD; also known as rare, genetic lysosomal storage disease in which the Supportive care (eg, Survival FDA designation(s): Orphan Niemann-Pick disease type enzyme acid sphingomyelinase, normally found in nutritional counseling, Drug, Breakthrough Therapy B [NPD-B]) or chronic lysosomes and responsible for metabolizing the lipid Quality of life occupational therapy, Clinical trial(s): Phase 2/3 neurovisceral ASMD (also sphingomyelin, is deficient or absent. This leads to an physical therapy) ASCEND primary completion known as Niemann-Pick accumulation of excess sphingomyelin in cells, which October 2019, data reported disease type A/B [NPD-A/B]) leads to cell death, organ enlargement, and malfunction January 2020; phase 2 of major organ systems. Olipudase alfa is intended to ASCEND-peds completed replace the deficient acid sphingomyelinase enzyme and December 2019, data purportedly breaks down sphingomyelin in lysosomes to reported January 2020; prevent excess accumulation of sphingomyelin. Initial phase 2 primary completion studies of olipudase alfa indicated that it did not affect September 2023, interim ASMD’s neurologic symptoms; therefore, studies of data published January 2018, olipudase alfa are currently limited to treating less-severe interim data published June forms of the disease (ie, chronic visceral ASMD [NPD-B], 2020 chronic neurovisceral ASMD [NPD-A/B]) characterized by reduced or absent neurologic involvement. In clinical trials, olipudase alfa is given intravenously at a dosage of up to 3 mg/kg once every 2 weeks for up to 9 years. Developer(s): Sanofi Genzyme (Cambridge, Massachusetts)

Section 5. Rare Diseases 228

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults aged up OTL-103 is a bone marrow–derived gene therapy product Hematopoietic stem cell Frequency of Submission date: Biologics to 65 years who have intended for WAS, a rare X chromosome–linked inherited transplantation (HSCT) immunoglobulin or License Application planned Wiskott-Aldrich syndrome primary immunodeficiency disorder caused by mutations Immunoglobulin infusion platelet infusions for 2022 (WAS) in a gene called WASP actin nucleation promoting factor, Platelet infusion Rate of FDA designation(s): Orphan or WAS. The WAS gene is a cytoskeleton regulator hospitalizations for Drug, Regenerative Medicine expressed only in blood-forming (ie, hematopoietic) cells. infection or bleeding Advanced Therapy, Rare WAS deficiency leads to eczema, petechiae, episodes Pediatric Disease thrombocytopenia, reduced blood clotting, and Clinical trial(s): Phase 1/2 susceptibility to infections. A bone marrow transplant TIGET-WAS primary from an allogeneic (ie, unmatched) donor can potentially completion October 2018, cure WAS. OTL-103 is intended to relieve WAS symptoms data published May 2019; by repopulating the bone marrow with WAS-expressing phase 2 primary completion hematopoietic stem cells to restore growth, replication, February 2022 and functional capacities that enable immune responses to infectious agents and injury. OTL-103 consists of patient-derived CD34+ hematopoietic stem cells that are harvested from the patient and treated with a lentivirus vector that stably inserts a functional copy of the WAS gene into the cells. The cells are then multiplied in culture to facilitate uptake and frozen until needed for use. In clinical trials, the transduced OTL-103 cell product is given as a single intravenous infusion of an unspecified number of cells after patients have received a myeloablative (ie, bone marrow destroying) conditioning regimen with busulfan, fludarabine, and anti-CD20 antibody. Developer(s): Orchard Therapeutics, Ltd (London, United Kingdom)

Section 5. Rare Diseases 229

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults who OTL-200, formerly known as GSK 2696274, is a gene Supportive care (eg, Gross motor function FDA designation(s): Orphan have genetically confirmed therapy intended for patients who have MLD. OTL-200 nutritional therapy; Neurocognitive Drug, Rare Pediatric Disease, metachromatic consists of autologous CD34+ hematopoietic stem cells occupational, physical, and function Regenerative Medicine leukodystrophy (MLD) transduced in the laboratory with a lentiviral vector speech therapy) Quality of life Advanced Therapy containing the arylsulfatase A gene, ARSA. MLD, a Clinical trial(s): Phase 1/2 progressive inherited lysosomal storage disorder, is primary completion April caused by variants in both alleles of ARSA. The gene 2018, interim data published normally encodes the enzyme arylsulfatase A, which July 2016, data presented breaks down sphingolipids. Lack of arylsulfatase A activity March 2019, data presented leads to sphingolipid accumulation in the brain, gall September 2019; phase 2 bladder, kidneys, liver, and spleen, which in turn causes primary completion August myelin loss on nerve fibers of the central nervous system. 2022, data presented Affected patients experience convulsions, motor October 2019; phase 3 open- disturbances, paralysis, personality changes, progressive label extension primary dementia, seizures, spasticity, and visual impairment. No completion January 2032 cure exists for MLD, and the disease is fatal; treatment consists of supportive care to manage symptoms. OTL- 200 purportedly repopulates the central nervous system with microglial cells that have restored arylsulfatase A function and, thus, might delay or halt disease progression. In clinical trials, patients first receive myeloablative conditioning with busulfan, and then an unspecified dose of fresh or cryopreserved OTL-200 is given intravenously, once. Developer(s): Orchard Therapeutics, Ltd (London, United Kingdom)

Section 5. Rare Diseases 230

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or Oxabact is a purportedly benign (ie, does not cause Alkali citrates (potassium or Change in blood FDA designation(s): Orphan older and adults with disease) bacterium under development to treat PH. A rare sodium citrate) oxalate concentration Drug, Rare Pediatric Disease primary hyperoxaluria (PH) inherited disease, PH is caused by mutations in 1 of 3 Hemodialysis Kidney function Clinical trial(s): Phase 3 and reduced renal function genes involved in glyoxylate metabolism, resulting in Hyperhydration Cardiac function ePHex primary completion (estimated glomerular overproduction of oxalate that accumulates in various Lumasiran (Oxlumo; Hemodialysis April 2021; phase 3 ePHEex- filtration rate [eGFR] < 90 organs. Most often, PH causes recurrent kidney stones injection) frequency OLE primary completion mL/min/1.73 m2) that can lead to end-stage renal disease (ESRD). A April 2023 standardized therapy could disrupt PH management and Organ transplantation Quality of life (for reduce the need for frequent dialysis to reduce oxalate (isolated or combined liver patients and accumulation, preserve kidney function, and postpone and kidney) caregivers) organ transplantation. Standard PH management relies Pyridoxine (vitamin B6) on high fluid intake to prevent oxalate crystal deposits, coupled with a diet that avoids high-oxalate foods and includes vitamins and minerals that inhibit calcium oxalate accumulation. In addition, frequent dialysis to remove excess oxalate from the blood is usually required because dietary changes are insufficient. Oxabact is isolated from Oxalobacter formigenes, an anaerobic bacterium that purportedly relies exclusively on oxalate for energy. Oxabact purportedly reroutes oxalate secretion from the kidneys to the gut, where it is degraded and eliminated, thereby reducing oxalate concentration in the kidneys and lowering the risk of kidney damage. In phase 3 trials, Oxabact is taken by mouth at an unspecified dose and formulation. Developer(s): OxThera AB (Stockholm, Sweden)

Section 5. Rare Diseases 231

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 14 years or Palovarotene is a selective retinoic acid receptor gamma Supportive care (eg, New HO formation FDA designation(s): Orphan older and adults who have (RARγ) agonist (ie, potentiator) being developed to treat assistive devices, Number of body Drug, Breakthrough fibrodysplasia ossificans FOP. A rare connective tissue disorder, FOP leads to the corticosteroids, regions with HO Therapy, Fast Track, Rare progressiva (FOP) abnormal growth of bone in muscles, tendons, and nonsteroidal anti- Flare rate Pediatric Disease ligaments, known as heterotopic ossification (HO). inflammatory drugs Range of motion, as Clinical trial(s): Phase 3 Palovarotene treatment is intended to prevent HO in [NSAIDs], occupational measured by accepted MOVE primary completion patients with FOP. HO flares can occur spontaneously or therapy) clinical ratings and January 2020, data reported after physical trauma (eg, injury, infection). Once formed, scales August 2020; phase 2 the heterotopic bone cannot be removed because tissue completed May 2016; phase Physical function, as disruption causes additional HO episodes. HO 2 long-term extension measured by accepted progressively interferes with normal body functions, primary completion October clinical ratings and including walking, bending, breathing, chewing, and 2021 scales swallowing. FOP is caused by a mutation in the activin A Note(s): Palovarotene is receptor type 1 gene, ACVR1, which encodes for the under partial clinical hold in ACVR1/ALK2 receptor. ALK2 normally regulates the bone patients younger than 14 morphogenetic protein (BMP) pathway, which is years of age responsible for cartilage regulation and bone development and growth. In patients with FOP, mutant ALK2 overactivates Smad 1/5/8, a group of 3 signal transduction proteins that, when activated, bind DNA and initiate the transcription of genes in the BMP2 pathway that promotes HO. Palovarotene purportedly binds to and activates RARγ, which promotes Smad destruction. In clinical trials, for preventive treatment, patients receive oral palovarotene 5 mg once daily for 24 months. For disease flares, patients receive oral palovarotene 20 mg once daily for 4 weeks, followed by 10 mg once daily for 8 weeks. Developer(s): Ipsen Group (Paris, France)

Section 5. Rare Diseases 232

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have a Pegcetacoplan (APL-2) is an immune complement system Allogeneic hematopoietic Hemoglobin levels PDUFA date: May 14, 2021; confirmed diagnosis of inhibitor under development to treat PNH. Pegcetacoplan stem cell transplantation Red blood cell Priority Review paroxysmal nocturnal could disrupt patient management by replacing (HSCT) transfusion need FDA designation(s): Orphan hemoglobinuria (PNH) intravenous infusions (every 2 weeks to 2 months) of Anticomplement therapy, Drug, Fast Track complement component 5 (C5) inhibitors with twice- intravenous (eg, Clinical trial(s): Phase 3 weekly subcutaneous injections patients give themselves. eculizumab, ravulizumab- PEGASUS completed August Pegcetacoplan is a synthetic cyclic peptide that targets the cwvz) 2020, data presented June complement component 3 (C3) pathway, which operates Oral anticoagulation (to 2020, top-line data reported earlier in the complement cascade than does C5. The C3 prevent recurrent blood December 2020; phase 3 protein helps regulate opsonization (ie, tagging cell clots; eg, warfarin, PRINCE primary completion surfaces for immune system targeting), inflammation, and rivaroxaban) January 2021; phase 3 formation of the membrane attack complex on cell extension primary surfaces, which pierces cell membranes, causing cells to completion August 2022 rupture and die. By targeting C3, pegcetacoplan purportedly offers broader inhibition of the complement cascade compared with existing complement inhibitors that target C5. In phase 3 clinical trials, patients give themselves pegcetacoplan 1080 mg as an under-the-skin injection twice weekly for up to 26 weeks. Developer(s): Apellis Pharmaceuticals (Waltham, Massachusetts)

Section 5. Rare Diseases 233

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or Pegzilarginase (AEB1102) is a modified version of the Low-arginine diet Mobility (eg, 2-minute FDA designation(s): Orphan older and adults who have human arginase 1 enzyme. It is intended to treat arginase Nitrogen-scavenging drugs walk test, Functional Drug, Breakthrough arginase 1 deficiency 1 deficiency, a rare, inherited metabolic disorder caused (eg, sodium phenylacetate, Mobility Assessment) Therapy, Rare Pediatric by mutations in the arginase 1 gene, ARG1. Lack of the sodium benzoate) Adaptive behavior (eg, Disease ARG1-encoded arginase enzyme, which is part of the Seizure medications (eg, Vineland Adaptive Clinical trial(s): Phase 3 cellular urea cycle, leads to excessive nitrogen carbamazepine, Behavior Scale II) PEACE primary completion accumulation in the blood and cerebrospinal fluid. phenobarbital) March 2021; phase 2 Affected patients typically experience seizures, growth primary completion June impairment, and intellectual disability. According to the 2022, data presented May manufacturer, pegzilarginase is modified to increase 2020 enzyme activity and stability compared with native arginase. Pegzilarginase treatment purportedly restores arginase 1 activity, which might slow or halt the deficiency and disease progression. In clinical trials, patients receive intravenous infusions of an unspecified dose of pegzilarginase weekly, in conjunction with an individualized disease management regimen (eg, severe protein restriction, essential amino acid supplementation, nitrogen-scavenging drugs) for up to 150 weeks. Developer(s): Aeglea Biotherapeutics, Inc (Austin, Texas)

Section 5. Rare Diseases 234

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 10 years or Plerixafor (Mozobil) is a CXC chemokine receptor 4 Granulocyte colony- Infection rate FDA designation(s): Orphan older and adults aged up to (CXCR4) inhibitor. It purportedly prevents most leukocyte stimulating factor (G-CSF; Severity of infections Drug 75 years who have a clinical subsets from homing to and localizing in the bone to prevent infection) Wart control Clinical trial(s): Phase 2/3 diagnosis of WHIM (warts, marrow. Retention of leukocytes in the bone marrow is a Imiquimod (to treat warts) Hematologic and primary completion October hypogammaglobulinemia, characteristic of WHIM syndrome, a rare primary Intravenous immunologic 2020 infections, and immunodeficiency typically caused by gain-of-function immunoglobulin (IVIG; to parameters Note(s): In December 2008, myelokathexis) syndrome mutations in CXCR4. The mutations associated with the prevent infection) Quality of life FDA approved plerixafor for with a heterozygous syndrome cause dysfunction of the immune system, use in combination with G- mutation in the C-tail of the which increases infection risk and other complications, CSF to mobilize C-X-C motif chemokine including wart emergence. No cure exists. Standard hematopoietic stem cells receptor 4 gene, CXCR4, treatment involves antibiotic prophylaxis, immune (HSCs) to the peripheral documented neutropenia, stimulation, and treatment of infections and their blood for collection and and history of severe or consequences. Plerixafor is intended to reduce infection subsequent autologous recurrent infections risk. In a clinical trial, it is given by an injection of 0.02 to transplantation in patients 0.04 mg/kg daily for 6 months. with non-Hodgkin Developer(s): lymphoma and multiple National Institutes of Health’s National Institute of Allergy myeloma (MM) and Infectious Diseases (Bethesda, Maryland)

Section 5. Rare Diseases 235

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 24 months or PTC-AADC (previously known as GT-AADC, AGIL-AADC, and Dopamine agonists (eg, Motor function, as Submission date: Biologics older and adults who have AAV2-hAADC) is an adeno-associated virus serotype 2 bromocriptine, measured by accepted License Application planned genetically confirmed, vector containing a functional copy of the human dopa pramipexole, ropinirole, clinical ratings and for the first half of 2021 symptomatic aromatic decarboxylase gene, DDC. It is intended to treat patients rotigotine) scales FDA designation(s): Orphan l-amino acid decarboxylase who have AADCD, a childhood-onset, progressive, Monoamine oxidase Developmental delays Drug, Rare Pediatric Disease deficiency (AADCD) inherited neurometabolic disorder. AADCD is caused by a inhibitors (eg, selegiline, Dyskinesia Clinical trial(s): Phase 1/2 rearrangement in DDC that results in the loss of the gene’s tranylcypromine) Quality of life primary completion encoded enzyme, aromatic l-amino acid decarboxylase Vitamin B6 December 2020, data (AADC). This enzyme is critical for converting published December 2017; neurotransmitter precursors into dopamine, epinephrine, phase 2 MIND primary norepinephrine, or serotonin. Patients with AADCD completion January 2022; experience symptoms including severe developmental pooled data presented May delays, weak muscle tone, involuntary movements of the 2018, pooled data presented arms and legs, and seizures. Existing treatments only October 2019 (abstracts 207, manage symptoms and do not prevent disease 231) progression. Delivery of a functional copy of DDC by PTC- AADC treatment might enhance neurotransmitter production, restore motor function, and delay or prevent other disease symptoms. In clinical trials, PTC-AADC is given to the brain (ie, intracerebrally) into the bilateral putamen via stereotactic surgery, at a dose of 1.8 × 1011 or 2.4 × 1011 vg, once. Developer(s): PTC Therapeutics, Inc (South Plainfield, New Jersey)

Section 5. Rare Diseases 236

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or PTR-01 is a form of recombinant collagen type VII (rC7) Supportive care for pain Change in wound size FDA designation(s): Orphan older and adults who have intended to improve RDEB lesions and other symptoms and infection risk from baseline Drug, Fast Track recessive dystrophic and complications. It purportedly replaces defective Time to wound closure Clinical trial(s): Phase 2 epidermolysis bullosa collagen type VII with functional recombinant collagen at from baseline open-label primary (RDEB) skin lesion sites to promote healing. RDEB is a rare Quality of life completion June 2021; phase genetic disease caused by mutations in the collagen type 1/2 primary completion VII alpha 1 chain gene, COL7A1, and is characterized by November 2020, interim widespread blistering that leads to severe scarring. The data presented July 2020 scars can lead to vision loss, disfigurement, and other serious medical problems, such as poor nutrition and slowed growth from difficulty eating due to scarring in the mouth and esophagus. Individuals with RDEB are also at high risk of developing squamous cell carcinoma, an aggressive, often life-threatening form of skin cancer. No cure exists for RDEB, and treatment relies on preventing blister formation and managing symptoms. PTR-01 is purported to selectively anchor the skin and other tissues affected by an absence of collagen type VII, which promotes RDEB wound healing. In clinical trials, PTR-01 is given as an intravenous infusion at a dosage of 0.1 mg/kg every 2 weeks. Developer(s): Phoenix Tissue Repair (Boston, Massachusetts) an affiliate company of BridgeBio, Inc (Palo Alto, California)

Section 5. Rare Diseases 237

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have autosomal QR-1123 is an antisense oligonucleotide under study for Nutritional Best corrected visual FDA designation(s): Orphan dominant retinitis treating adRP caused by a variant, P23H, in the RHO gene. supplementation acuity (BCVA) Drug, Fast Track pigmentosa (adRP) caused A rare genetic disease, adRP causes progressive vision Supportive care Retinal sensitivity Clinical trial(s): Phase 1/2 by the P23H variant in the loss, typically leading to blindness by middle adulthood. In Peripheral vision AURORA primary completion rhodopsin gene, RHO adRP caused by the RHO P23H variant, the mutated Quality of life October 2021 rhodopsin protein is toxic to photoreceptor cells in the retina and leads to progressive photoreceptor loss. QR- 1123 is intended to bind and degrade mutated RHO messenger RNA (mRNA) specifically, inhibiting mutant rhodopsin expression without affecting wild-type rhodopsin. Inhibiting mutant rhodopsin expression could stop or reverse the vision loss associated with P23H adRP. In clinical trials, QR-1123 is given by injections into the eye (ie, intravitreal) once every 3 months at various dose levels. Developer(s): ProQR Therapeutics (Leiden, the Netherlands)

Section 5. Rare Diseases 238

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 70 years Reboxetine (AXS-12) is a selective norepinephrine Amphetamines Cataplexy attack FDA designation(s): Orphan who have narcolepsy with reuptake inhibitor intended to treat patients who have Antidepressants (eg, frequency Drug, Breakthrough Therapy excessive daytime EDS and cataplexy from narcolepsy, a chronic neurologic selective serotonin EDS symptoms and Clinical trial(s): Phase 3 sleepiness (EDS) and sleep disorder. Narcolepsy treatments typically address reuptake inhibitors [SSRIs], severity planned; phase 2 CONCERT cataplexy either EDS or cataplexy, whereas reboxetine purportedly tricyclic antidepressants Wakefulness completed November 2019, addresses both. Narcolepsy is caused by impaired [TCAs]) Quality of life top-line data reported production of hypocretin, an excitatory neuropeptide that Nonamphetamine December 2019 regulates the sleep-wake cycle. About 60% to 70% of stimulants (eg, armodafinil, Note(s): More than 40 patients with narcolepsy also experience cataplexy, a modafinil) countries outside of the disorder characterized by sudden, uncontrollable muscle Sodium oxybate United States have approved weakness or paralysis that occurs during the daytime and Solriamfetol reboxetine to treat major is often triggered by a strong emotion, such as crying, depressive disorder (MDD) excitement, or laughter. Reboxetine purportedly promotes wakefulness and increases the activity of the excitatory neurotransmitter norepinephrine. In clinical trials, patients receive an unspecified dose of reboxetine by mouth twice daily for 3 weeks. Developer(s): Axsome Therapeutics, Inc (New York, New York), which licensed clinical and nonclinical data and intellectual property rights from Pfizer, Inc (New York, New York)

Section 5. Rare Diseases 239

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults aged up Recombinant ADAMTS13 (TAK-755) is a genetically Plasma infusions Acute TTP episodes FDA designation(s): Fast to 70 years who have a engineered version of the ADAMTS13 enzyme under Anemia Track confirmed diagnosis of development to treat hereditary TTP. In hereditary TTP, Quality of life Clinical trial(s): Phase 3 hereditary thrombotic genetic variants of the ADAMTS13 gene cause insufficient randomized primary thrombocytopenic purpura levels and activity of the ADAMTS13 protein (ie, von completion February 2023; (TTP) Willebrand factor–cleaving protease), an enzyme that phase 3 nonrandomized helps regulate blood clotting. ADAMTS13 deficiency primary completion August results in dysregulated clotting in the small blood vessels, 2026 low platelet counts, and anemia from blood cell loss. Therapy consisting of repeated plasma infusions to restore ADAMTS13 levels is the only effective option for acute or prophylactic treatment, but the treatment carries a risk of transfusion-related reactions (eg, acute lung injury) and is burdensome. In a phase 3 clinical trial, recombinant ADAMTS13 is given as periodic intravenous infusions for acute treatment and subsequent prophylaxis (dosage and frequency unspecified). Developer(s): Shire plc (Dublin, Ireland), part of Takeda Pharmaceutical Co, Ltd (Osaka, Japan)

Section 5. Rare Diseases 240

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 40 to 80 years RG6354 (formerly PRM-151) is a recombinant form of the Nintedanib Respiratory function FDA designation(s): Orphan who have idiopathic innate immunity protein pentraxin-2. It is active at sites of Pirfenidone Exercise capacity Drug, Breakthrough Therapy pulmonary fibrosis (IPF) tissue damage and has demonstrated broad antifibrotic Survival Clinical trial(s): Phase 2 activity in preclinical models. Unlike available therapies for Quality of life completed May 2017, data IPF that slow only the rate of disease progression, RG6354 published June 2018, data is an agonist (ie, activator) that purportedly reverses IPF published May 2019; phase disease course. RG6354 purportedly turns off the 3 primary completion proliferation pathway mediated by proinflammatory and February 2023 profibrotic macrophages that leads to scarring (ie, fibrosis), and it helps activate the healing resolution pathway by directing the differentiation of monocytes into proresolution macrophages. In clinical trials, RG6354 was given as an intravenous infusion of 10 mg/kg over 60 minutes on days 1, 3, and 5, then once every 4 weeks. Developer(s): F Hoffman-La Roche AG (Basel, Switzerland), which acquired developer Promedior, Inc (Lexington, Massachusetts) in February 2020

Section 5. Rare Diseases 241

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 4 months to 17 RGX-121 is a recombinant, adeno-associated viral vector Enzyme replacement Cognitive, behavioral, FDA designation(s): Orphan years who have Hunter (ie, AAV9) carrying the human iduronate-2-sulfatase gene, therapy (ie, recombinant and adaptive function Drug, Fast Track, Rare syndrome (also called IDS. RGX-121 is intended to treat Hunter syndrome, a idursulfase) Quality of life Pediatric Disease mucopolysaccharidosis type childhood-onset, progressive, inherited metabolic Supportive care Clinical trial(s): Phase 1/2 II [MPSII]) disorder caused by a mutation in IDS. Patients with the RGX-121-101 primary disorder cannot break down the polysaccharides completion May 2021, dermatan sulfate and heparan sulfate, which is normally interim data reported mediated by the IDS-encoded enzyme iduronate-2- December 2020; phase 1/2 sulfatase. Buildup of dermatan sulfate and heparan RGX-121-1102 primary sulfate in cells of the central nervous system causes completion November 2021; degeneration that manifests as behavioral problems, unphased long-term follow- sleeplessness, loss of speech and cognitive skills, mental up primary completion retardation, heart problems, seizures, and loss of September 2025 mobility. No cure exists for Hunter syndrome, and standard-of-care treatment consists of weekly enzyme replacement infusions. RGX-121 is a gene therapy intended to deliver a functional copy of the IDS gene to the central nervous system. It purportedly restores iduronate 2-sulfatase function, blocks central nervous system degeneration, and reduces disease-related symptoms with a single injection, thereby eliminating the need for weekly enzyme replacement therapy. In clinical trials, RGX-121 is injected into the cerebrospinal fluid (ie, intracisternally) at a dose of 1.3 × 1010 or 6.5 × 1010 gc/g of brain mass, once. Developer(s): Regenxbio, Inc (Rockville, Maryland)

Section 5. Rare Diseases 242

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 80 years Rilzabrutinib (PRN1008) is a small-molecule, reversible, Glucocorticoids (ie, Complete remission FDA designation(s): Orphan who have newly diagnosed, selective, covalent inhibitor of Bruton tyrosine kinase prednisone) Morbidity Drug chronic, or relapsing (BTK). It is intended as an ongoing therapy to reduce the Immunosuppressants (eg, Death Clinical trial(s): Pivotal phase moderate to severe number of skin lesions in moderate to severe PV and PF. azathioprine, Pain 3 PEGASUS primary pemphigus vulgaris (PV) or Complications with current treatments can be life cyclophosphamide, completion December 2021; Quality of life pemphigus foliaceus (PF) threatening, and rilzabrutinib might induce complete mycophenolate) phase 2 BELIEVE-PV disease remission and reduce steroid and Monoclonal antibody (ie, completed January 2020, immunosuppressant use. Pemphigus is an autoimmune rituximab) part A data reported blistering skin disorder that most often occurs in middle- October 2019, part B data aged adults. PV and PF are the 2 most common types. PV reported June 2020 usually begins with painful blisters in the mouth that spread to the skin and genitals. PF usually causes itchy (more so than painful) blisters on the chest, back, and shoulders. Rilzabrutinib purportedly reversibly, selectively inhibits BTK, an enzyme involved downstream of the B-cell receptor that is thought to contribute to inflammation and autoimmunity. The drug’s exact mechanism of action in treating pemphigus is unknown. Rilzabrutinib is based on the developer’s proprietary Tailored Covalency platform, which purportedly produces prolonged, reversible action at the target site while being eliminated rapidly from the body. In phase 3 clinical trials, rilzabrutinib is taken by mouth twice daily at a dose of 400 mg. Developer(s): Principia Biopharma, Inc, a unit of Sanofi Company (South San Francisco, California)

Section 5. Rare Diseases 243

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 years or Rivipansel (GMI-1070) is a synthetic molecule that is Analgesia (eg, Opioid use FDA designation(s): Orphan older and adults who have similar in structure to a carbohydrate. It is a panselectin acetaminophen, morphine, Frequency of VOCs Drug, Fast Track, Rare sickle cell disease (SCD) and inhibitor that targets inflammatory and adhesion nonsteroidal anti- Hospital stay Pediatric Disease are experiencing a vaso- processes that might contribute to VOC. Rivipansel is inflammatory drugs Rehospitalizations Clinical trial(s): Phase 3 occlusive crisis (VOC) intended to reduce the duration of VOC and hospital [NSAIDs]) within 3 days of RESET completed May 2019, stays. In SCD, sickled red blood cells are more susceptible Crizanlizumab-tmca discharge designed under Special to oxidative damage, inappropriate adhesion, and Hydration Protocol Assessment, pivotal vascular obstruction, leading to VOCs that cause severe Quality of life Hydroxyurea data reported August 2019; pain, requiring hospitalization. VOC complications can phase 3 extension Voxelotor include circulating blood clots, stroke, organ failure, or terminated November 2019 early death. In clinical trials, rivipansel is given by Note(s): The phase 3 RESET intravenous infusion every 12 hours for up to 15 doses. trial failed to meet primary For patients older than 12 years and heavier than 40 kg, and key secondary end the first dose is 1680 mg and subsequent doses are 840 points; post hoc subgroup mg. For patients aged 6 to 12 years or weighing less than analyses reported June 2020 40 kg, the first dose is 40 mg/kg up to 1680 mg and (see JSCDH abstract page 26) subsequent doses are 20 mg/kg up to 840 mg every 12 and December 2020 showed hours. positive results. The Developer(s): company is discussing with GlycoMimetics, Inc (Rockville, Maryland) FDA the possible regulatory path forward for rivipansel.

Section 5. Rare Diseases 244

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults with diagnosed Rozanolixizumab is a humanized monoclonal antibody Corticosteroids Clinically meaningful FDA designation(s): Orphan primary immune that targets the human FcRn receptor. It has been Intravenous immune platelet response Drug thrombocytopenia (ITP) that designed to block the interaction of FcRn and globulin (IVIG; eg, anti-RhD Change in Immune Clinical trial(s): Phase 3 has lasted for at least 3 immunoglobulin isotype G (IgG), inhibiting IgG recycling immune globulin ) Thrombocytopenic primary completion July months and promoting the removal of IgG autoantibodies thought Rituximab Purpura Patient 2022; phase 2 completed to play a role in development of ITP. A rare acquired Splenectomy Assessment February 2019, data autoimmune disorder, ITP is characterized by the Questionnaire (ITP- presented November 2019 presence of pathogenic IgG autoantibodies that target PAQ) symptom score and destroy platelets and megakaryocytes (platelet Time to first rescue precursors). Patients experience increasing propensity for therapy bleeding episodes, debilitating fatigue, and impaired Quality of life quality of life. Rozanolixizumab might reduce the presence of circulating autoantibodies involved in ITP disease, increasing patient platelet levels and improving outcomes. In clinical trials, rozanolixizumab is given as a subcutaneous injection at fixed doses across body weight tiers, which are then adjusted according to platelet count values or medical needs. Developer(s): UCB SA (Brussels, Belgium)

Section 5. Rare Diseases 245

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 to 50 years RT001 is a stabilized, polyunsaturated fatty acid (ie, Supportive care Ambulatory and motor FDA designation(s): Orphan who have Friedreich ataxia deuterated linoleic acid) intended to treat FRDA by function Drug (FRDA); biallelic pathogenic stabilizing mitochondrial and cellular membranes. It might Disability Clinical trial(s): Phase 3 variants in the frataxin gene, improve patient health outcomes and quality of life for a Disease progression primary completion FXN; and are ambulatory disorder that has no cure or approved treatments. FRDA Survival February 2021 (with or without assistive is a rare, inherited, neurodegenerative disorder best devices) characterized by loss of coordination and muscle strength Quality of life and heart disease. It is caused by a variant in FXN that encodes deficient mitochondrial frataxin protein, causing mitochondrial impairment in iron metabolism. Typically, motor symptoms emerge in childhood or young adulthood, patients must use wheelchairs 10 to 20 years after symptom onset, and death occurs in the late 30s, usually related to heart disease. Lipid peroxidation, the free-radical damage of polyunsaturated fats in mitochondrial and cellular membranes, is thought to be a primary source of cell death in certain neurodegenerative diseases. RT001 purportedly incorporates into mitochondrial and cellular membranes to stabilize them and potentially restore cell health. In clinical trials, RT001 is taken by mouth either as 3 capsules twice daily for a total daily dose of 5.76 g or 3 capsules 3 times daily for a total daily dose of 8.64 g. Developer(s): Retrotope, Inc (Los Altos, California)

Section 5. Rare Diseases 246

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 18 months to RT001 is a stabilized, polyunsaturated fatty acid (ie, Supportive care Ambulatory and motor FDA designation(s): Orphan 10 years who have infantile deuterated linoleic acid) intended to treat INAD by function Drug neuroaxonal dystrophy stabilizing mitochondrial and cell membranes. It might Cognitive function Clinical trial(s): Pivotal phase (INAD), are homozygous for improve health outcomes and quality of life for patients Developmental delay 2/3 primary completion PLA2G6 gene deficiency, and with a disease that has no cure or approved treatments. or regression August 2020 have impairment in at least INAD, a subtype of PLA2G6-associated Seizure frequency 2 assessed categories at neurodegeneration, or Seitelberger disease, is an ultra- baseline rare, inherited, neurodegenerative disease that affects the Survival central nervous system, autonomic nervous system, and Quality of life peripheral nerves. Symptoms of developmental delays and regression typically start at about 6 to 18 months of age and progress to include muscle weakness, motor impairment, cranial nerve dysfunction, seizures, and cognitive decline. Life expectancy ranges from early childhood to early adulthood. INAD is thought to occur due to loss-of-function variants in the PLA2G6 gene that contribute to abnormal phospholipid metabolism and nerve cell damage and death. RT001 purportedly incorporates into mitochondrial and cellular membranes to stabilize them and restore cell health. In clinical trials, RT001 is taken by mouth as four 960-mg capsules daily for a total daily dose of 3.84 g. Developer(s): Retrotope, Inc (Los Altos, California)

Section 5. Rare Diseases 247

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Infants and children who RVT-802 is an allogeneic (ie, unmatched) donor thymus– Hematopoietic stem cell T-cell proliferation Submission date: FDA have primary immune derived, cell-based therapy intended to restore immune transplantation (HSCT) Survival accepted Rolling Biologics deficiency from congenital function in patients with primary immune deficiencies Supportive care License Application (BLA) athymia (ie, lack of a from congenital athymia, which includes complete June 2019; Priority Review thymus), which includes DiGeorge genetic anomaly, CHARGE syndrome, and FDA designation(s): Orphan complete DiGeorge genetic FOXN1 deficiency. Patients with congenital athymia have a Drug, Rare Pediatric Disease, anomaly; coloboma, heart high risk of death (often by 24 months of age) due to Breakthrough Therapy, defects, atresia choanae, chromosomal mutations that disrupt T-cell production. Regenerative Medicine retarded growth and The absence of functional mature T cells or B cells Advanced Therapy development, genital severely compromises immunity. RVT-802 is intended to Clinical trial(s): Phase 2 hypoplasia, and ear restore the patient’s ability to produce naïve T cells with a completed April 2009; phase abnormalities and deafness broad T-cell receptor repertoire, conferring effective 2 completed November 2010 (CHARGE) syndrome; and immune responses. Isolated thymocytes are cultured in a Note(s): FDA declined to Forkhead Box N1 (FOXN1) manufacturing facility for 14 to 21 days. In clinical trials, approve RVT-802 because of deficiency RVT-802 is given by placing a cultured thymus slice into a manufacturing concerns on small hole in the quadriceps muscle, which is then pulled December 5, 2019. over the slice using an insoluble stitch. The dose is 4 to 18 Sumitomo Dainippon is g/m2 of thymus tissue per patient body weight in preparing a BLA kilograms. resubmission. Developer(s): Sumitovant Biopharma, Inc (New York, New York), a subsidiary of Sumitomo Dainippon Pharma Co (Osaka, Japan)

Section 5. Rare Diseases 248

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or Ryplazim is a form of plasminogen derived from plasma. Fresh frozen plasma Number and size of PDUFA date: March 5, 2021 older and adults with Ryplazim is under study to treat patients who have C- Plasminogen eye drops lesions FDA designation(s): Orphan congenital plasminogen PLGD, a rare genetic disease. C-PLGD is caused by loss-of- Surgical removal of lesions Rate of surgical Drug, Rare Pediatric Disease, deficiency (C-PLGD) function variants in the plasminogen gene, PLG. Activated management of Fast Track plasminogen (ie, plasmin) has multiple functions in the lesions Clinical trial(s): Phase 2/3 body, including the lysis of fibrin clots and clearance of complete, data published extravasated fibrin (ie, fibrin that has been let or forced March 2018 out of blood vessels). Loss of plasminogen results in the accumulation of fibrin-rich lesions on mucous membranes, which may impair organ function and impact quality of life if left untreated. In particular, patients with C-PLGD may develop recurrent lesions on the conjunctiva of the eye that can lead to vision loss. Ryplazim is an enzyme replacement therapy intended to restore functional levels of plasminogen. In clinical trials, Ryplazim was given intravenously every 2 to 4 days at a dose of 6.6 mg/kg. Developer(s): Liminal BioSciences (Laval, Québec, Canada)

Section 5. Rare Diseases 249

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years Seladelpar (MBX-8025) is an orally administered Obeticholic acid Overall survival FDA designation(s): Orphan who have primary biliary peroxisome proliferator-activated receptor delta (PPARδ) Rate of progression to Drug, Breakthrough Therapy cholangitis (PBC) that agonist (ie, activator) in development for treating PBC. An liver failure Clinical trial(s): Phase 3 responded inadequately to autoimmune disease, PBC damages the liver’s bile ducts, Symptom relief (eg, ENHANCE primary ursodeoxycholic acid (UDCA) causing bile to accumulate in the liver and leading to diarrhea due to fat completion December 2020, treatment or who could not irreversible liver scarring and potential liver failure. malabsorption, fatigue, data presented November tolerate it Seladelpar is intended to provide a safer alternative to itching) 2020; phase 3 primary obeticholic acid (Ocaliva) for treating PBC in patients for Quality of life completion December 2024 whom initial therapy with UDCA is inadequate or who Note(s): On November 25, cannot tolerate it. Seladelpar purportedly has 2019, CymaBay Therapeutics anticholestatic and anti-inflammatory effects that might suspended clinical trials for reduce itching (ie, pruritus), inflammation, and destruction all indications and halted of the intrahepatic bile ducts. In a phase 3 clinical trial, seladelpar development seladelpar is taken as a 5- or 10-mg tablet once daily for after identifying abnormal 52 weeks. liver findings in some trials. Developer(s): However, the company CymaBay Therapeutics (Newark, California) affirmed in a July 23, 2020, news release it would resume development of seladelpar because FDA had lifted all clinical holds on seladelpar trials.

Section 5. Rare Diseases 250

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 8 years or Sepofarsen (QR-110) is a first-in-class investigational RNA- Supportive care Visual acuity FDA designation(s): Orphan older and adults who have based oligonucleotide that targets homozygous or Mobility course Drug, Fast Track, Rare Leber congenital amaurosis compound heterozygous mutations due to aberrant Full-field light Pediatric Disease type 10 (LCA10) splicing of centrosome protein 290 (CEP290) messenger sensitivity Clinical trial(s): Phase 2/3 RNA (mRNA). This aberration causes LCA10, the leading Quality of life ILLUMINATE primary genetic cause of childhood blindness. Sepofarsen is completion December 2021 intended to restore vision in these patients. Sepofarsen purportedly repairs the RNA defect by binding to the mutated pre-mRNA sequence and causing normal pre- mRNA splicing, restoring normal (ie, wild-type) CEP290 protein production and reversing LCA10 disease symptoms. In clinical trials, sepofarsen is given through injections into the eye at doses of 40 μg (with an 80-μg loading dose) or 80 μg (with a 160-μg loading dose) at the start of the trial, at 3 months, and every 6 months thereafter. Developer(s): ProQR Therapeutics (Leiden, the Netherlands)

Section 5. Rare Diseases 251

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 years or Setmelanotide (RM-493) is a selective melanocortin-4 Lifestyle modifications (eg, Hunger symptoms and Approval date: November older and adults who have (MC4) receptor agonist (ie, activator) peptide intended to diet, exercise) severity 27, 2020 proopiomelanocortin treat patients with POMC deficiency obesity. This is a rare, Psychotherapy (eg, Rate of comorbidities FDA designation(s): Orphan (POMC) deficiency genetic recessive, genetic disorder in which patients are often cognitive behavioral (eg, cardiovascular Drug, Breakthrough obesity severely obese by 1 year of age, remain obese for life, and therapy [CBT]) disease, diabetes Therapy, Rare Pediatric experience a variety of obesity-related complications. mellitus, obesity) Disease Setmelanotide might improve patient quality of life and Weight Clinical trial(s): Phase 2/3 health outcomes by reducing insatiable hunger, obesity, Quality of life completed July 2020, top-line and obesity-related complications. POMC deficiency data reported August 2019, obesity is caused by variants in the proopiomelanocortin additional data (body mass gene, POMC, that result in insufficient production of index [BMI] and adrenocorticotropic hormone (ACTH), alpha melanocyte- cardiovascular) reported stimulating hormone (α-MSH), and beta melanocyte- November 2019; phase 2/3 stimulating hormone (β-MSH). Normally, α-MSH and β- primary completion May MSH bind to MC4 receptors in the brain and help 2021; phase 2/3 long-term suppress appetite. A lack of α-MSH and β-MSH in patients extension primary with POMC deficiency is thought to lead to excessive completion March 2023 hunger and obesity. Setmelanotide purportedly activates MC4 receptors in the paraventricular nucleus and lateral hypothalamic nuclei areas in the brain to suppress appetite. Setmelanotide also purportedly increases resting energy expenditure. Setmelanotide might require patients to take a companion diagnostic test to determine genetic eligibility. According to the FDA-approved label, setmelanotide is given as an injection under the skin. Patients aged 12 years or older take a 2-mg daily dose that can be increased to 3 mg daily for more weight loss or reduced to 1 mg, if not tolerated, and gradually increased to 2 mg again if tolerated. Patients aged 6 to 12 years start a 1 mg daily dose that is gradually increased to 2 mg daily and can be increased to 3 mg daily for more weight loss. If not tolerated, the starting dose is 0.5 mg, gradually increased to 1 mg and up to 2 mg, if tolerated, for more weight loss. Developer(s): Rhythm Pharmaceuticals, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 252

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 4 to 17 years SGT-001 is an adeno-associated viral vector (ie, AAV9) Corticosteroids (eg, Ambulatory and gross FDA designation(s): Orphan who have genetically containing a synthetic version of the dystrophin gene, deflazacort, prednisone) motor function, as Drug, Fast Track, Rare confirmed Duchenne DMD. It is intended to treat DMD, an inherited, X measured by accepted Pediatric Disease muscular dystrophy (DMD), chromosome–linked genetic disorder caused by clinical ratings and Clinical trial(s): Phase 1/2 are on a stable dose of rearrangements or deletions in the DMD gene. DMD scales (eg, time to IGNITE DMD primary corticosteroids, and have encodes the dystrophin protein, which helps keep muscle stand, 4-stair climb; 6- completion April 2022, levels of anti-AAV9 cells intact. The absence of wild-type dystrophin protein minute walk test interim data presented May antibodies below a specified causes progressive muscle fiber necrosis and eventual [6MWT], North Star 2020 threshold widespread muscle weakness. No cure exists for DMD. Ambulatory Note(s): Solid Biosciences First-line corticosteroid treatment manages symptoms but Assessment [NSAA]) announced in October 2020 does not prevent disease progression and has significant Disease progression that a hold placed on the side effects. FDA approved 2 gene therapies for patients Muscle strength IGNITE trial by FDA in who have a specific mutation in DMD (ie, in exon 51 or Survival November 2019 had been exon 53), but patients who have other DMD mutations are lifted ineligible for these therapies. The synthetic DMD gene in Quality of life SGT-001 encodes for microdystrophin, a truncated but functional protein surrogate for dystrophin, because the large size of the dystrophin protein prohibits delivery by viral vectors. In patients with DMD, SGT-001 treatment might restore skeletal muscle function and prevent or delay disease progression, independent of the patient’s mutation status. In clinical trials, SGT-001 is given intravenously at 1 of 3 unspecified doses, once. Developer(s): Solid Biosciences, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 253

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have end-stage SNF472 is a selective calcification inhibitor under Supportive care to manage Chronic wound FDA designation(s): Orphan renal disease (ESRD) who development to treat CUA, also called calciphylaxis. A rare pain, treat ulcerated severity Drug are receiving maintenance disease, CUA is characterized by calcium buildup and wounds, and adjust Pain Clinical trial(s): Phase 3 hemodialysis in a health scarring of small blood vessels in skin and fat tissue that medications to reduce Quality of life CALCIPHYX primary care facility for at least 2 can cause blood clots and painful skin ulcers, which can calcium concentration or completion March 2022; weeks and with a clinical develop potentially fatal infections. CUA occurs primarily, accumulation phase 2 CaLIPSO completed diagnosis of calcific uremic but not exclusively, in patients with advanced kidney September 2019, data arteriolopathy (CUA) and at disease. A disease-modifying treatment that could slow or published November 2019, least one ulcerated CUA skin halt the abnormal calcium accumulation in blood vessels data presented June 2020 lesion causing CUA could disrupt disease management, which focuses on pain relief and chronic wound care. SNF472 purportedly slows the development and progression of abnormal calcium deposits by binding to the growth sites of hydroxyapatite (HAP) crystals, the main component of abnormal calcification deposits. Blocking HAP crystal formation in blood vessels purportedly prevents vessels from becoming narrowed and stiff through calcification. This process, in turn, would prevent the reduced blood flow that can promote chronic wound development in skin and fat tissue. In clinical trials, SNF472 was given 3 times weekly by infusion via a hemodialysis machine during patient hemodialysis procedures. Developer(s): Sanifit (Palma, Spain; San Diego, California)

Section 5. Rare Diseases 254

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 80 years Sodium phenylbutyrate-taurursodiol (PB-TURSO), also Edaravone Disability FDA designation(s): Orphan who have amyotrophic referred to as AMX0035, is a combined form of a fatty acid Riluzole Disease progression Drug lateral sclerosis (ALS) with (phenylbutyrate) and bile acid (taurursodiol) intended to Supportive care Functional capacity Clinical trial(s): Phase 2/3 symptom onset in the past treat ALS. It purportedly slows disease progression and Survival CENTAUR completed 18 months prolongs time to death. ALS is a rare, neurodegenerative November 2019, data disorder characterized by cell death in the brain and published September 2020, spinal cord that causes decline in motor function and, additional data published ultimately, paralysis. There is no cure, and life expectancy October 2020; phase 2 is 2 to 5 years after symptom onset. PB-TURSO CENTAUR-OLE open-label purportedly reduces nerve cell death by reducing extension primary endoplasmic reticulum stress and mitochondrial completion January 2021, dysfunction. More specifically, phenylbutyrate purportedly data published October upregulates protective heat shock proteins and 2020 taurursodiol purportedly reduces mitochondrial membrane permeability and decreases the likelihood of programmed cell death. In clinical trials, PB-TURSO is taken by mouth at a fixed dose of sodium phenylbutyrate 3 g and taurursodiol 1 g once daily for the first 3 weeks then twice daily for up to 35 months. Developer(s): Amylyx Pharmaceuticals, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 255

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 to 17 years Soticlestat (TAK-935/OV935) is a first-in-class inhibitor of Amphetamine derivative Monthly convulsive FDA designation(s): Orphan who have a clinical the enzyme cholesterol 24-hydroxylase (CH24H). (ie, fenfluramine) seizure frequency Drug diagnosis of Dravet Soticlestat is intended to treat seizures associated with Antiepileptics (eg, (MCSF) Clinical trial(s): Phase 3 syndrome, have seizures Dravet syndrome by decreasing seizure susceptibility and clobazam, stiripentol, Convulsive seizure planned; phase 2 ELEKTRA refractory to at least 2 improving seizure control. It might improve health topiramate, valproate) duration completed June 2020, data antiepileptic drugs in the outcomes for patients with this disorder, which is often Ketogenic diet Seizure-free interval presented December 2020 past, and are currently refractory to current treatment options. Dravet syndrome Plant-derived CBD Survival taking 1 to 4 antiepileptic is a rare seizure disorder characterized by frequent drugs seizures and developmental delays that begins in infancy Quality of life or early childhood. It is most commonly caused by a variation in the SCN1A gene, which affects sodium ion channel signaling in the brain and causes neurons to be susceptible to creating and transmitting the overactive electric signaling of seizures. Soticlestat purportedly inhibits the activity of CH24H from converting cholesterol to 24S-hydroxycholesterol (24HC), thus decreasing levels of 24HC, which is thought to play a role in seizure activity and neurotoxicity by overactivating excitatory glutamatergic signaling in the brain. By reducing 24HC levels, soticlestat might improve excitatory-inhibitory balance of receptors involved in glutamatergic signaling and seizure propagation. In clinical trials, soticlestat is taken by mouth at an unspecified dose for up to 20 weeks. Developer(s): Takeda Pharmaceutical, Inc (Tokyo, Japan), in collaboration with Ovid Therapeutics, Inc (New York, New York)

Section 5. Rare Diseases 256

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 3 months to 7 SRP-9001 is an adeno-associated viral vector gene Corticosteroids (eg, Ambulatory and gross FDA designation(s): Orphan years with Duchenne therapy. It is under development to treat DMD, an deflazacort) motor function, as Drug, Fast Track, Rare muscular dystrophy (DMD) inherited, X chromosome–linked genetic disorder caused Exon-skipping therapies measured by accepted Pediatric Disease and documented dystrophin by mutations or deletions in the dystrophin gene, DMD. In (eg, eteplirsen, golodirsen) clinical ratings and Clinical trial(s): Phase 1/2 gene mutation patients with DMD, the absence of wild-type dystrophin scales (eg, time to primary completion April protein causes progressive muscle fiber necrosis and stand, 4-stair climb; 6- 2023, data published June eventual widespread muscle weakness. While several minute walk test 2020, long-term data disease-modifying exon-skipping therapies are available [6MWT], North Star presented September 2020; for treating DMD, only a subset of patients with DMD Ambulatory phase 2 primary completion mutations are amenable to exon-skipping therapies, and Assessment [NSAA]) December 2020, top-line these therapies require ongoing dosing. SRP-9001’s gene Disease progression data presented January 2021 transfer approach purportedly induces durable Muscle strength dystrophin expression via a single dose. The dystrophin Survival gene is the largest known human gene. Because its size precludes use of a full-length dystrophin transgene, the Quality of life SRP-9001 transgene consists of a functional truncated dystrophin gene (ie, microdystrophin) under control of a cardiac and skeletal muscle–specific promoter. In clinical trials, SRP-9001 is given as a single intravenous dose of 2 × 1014 vg/kg. Developer(s): Sarepta Therapeutics (Cambridge, Massachusetts)

Section 5. Rare Diseases 257

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 4 to 15 years SRP-9003, previously known as MYO-101, is a Exercise Ambulatory and gross FDA designation(s): Orphan who have genetically recombinant, adeno-associated viral vector carrying the Physical therapy motor function, as Drug, Rare Pediatric Disease confirmed, early human sarcoglycan beta gene, SGCB. SRP-9003 is intended Supportive care measured by accepted Clinical trial(s): Phase 1/2 symptomatic limb-girdle to treat LGMD2E (also called β-sarcoglycanopathy), a clinical ratings and IRB17-00253 primary muscular dystrophy type 2E progressive, inherited neuromuscular disorder caused by scales (eg, time to completion February 2023, (LGMD2E) a mutation in SGCB. The gene normally encodes the stand, 4-stair climb; 6- data reported September protein β-sarcoglycan, which is part of a complex involved minute walk test 2020 in muscle function, regulation, and repair. Without β- [6MWT], North Star sarcoglycan function, these patients develop weakness Ambulatory and atrophy of muscles connected to the limb girdles (ie, Assessment [NSAA]) bony structures in the shoulder and pelvis). Early Disease progression symptoms include difficulty running, jumping, and Muscle strength climbing stairs, but as the disease progresses, patients Survival typically depend on wheelchairs and develop more severe symptoms, such as scoliosis, joint contractures, Quality of life respiratory impairment, and heart problems. SRP-9003 purportedly restores β-sarcoglycan production in muscle cells to improve disease-related symptoms or to prevent symptoms from occurring before disease onset. In clinical trials, patients receive SRP-9003 intravenously at a dose of 5 × 1013 or 2 × 1014 vg/kg, once. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 258

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 7 years or SRP-9004, formerly known as MYO-102, is a recombinant, Exercise Ambulatory and gross FDA designation(s): Orphan older and adults who have adeno-associated viral vector carrying the human Physical therapy motor function, as Drug genetically confirmed, early sarcoglycan alpha gene, SGCA. It is intended to treat Supportive care measured by accepted Clinical trial(s): Phase 1/2 symptomatic limb-girdle LGMD2D (also called α-sarcoglycanopathy), a progressive, clinical ratings and completed March 2019 muscular dystrophy type 2D inherited neuromuscular disorder caused by a mutation scales (eg, time to (LGMD2D) in the SGCA gene. The gene normally encodes the protein stand, 4-stair climb; 6- α-sarcoglycan, which is part of a complex involved in minute walk test muscle function, regulation, and repair. Without α- [6MWT], North Star sarcoglycan function, these patients develop weakness Ambulatory and atrophy of muscles connected to the limb girdles Assessment [NSAA]) (bony structures in the shoulder and the pelvis). Early Disease progression symptoms include difficulty running, jumping, and Muscle strength climbing stairs, and as the disease progresses, patients Survival typically depend on a wheelchair and develop more severe symptoms, such as scoliosis, joint contractures, Quality of life respiratory impairment, and heart problems. SRP-9004 purportedly restores α-sarcoglycan production in muscle cells to improve disease-related symptoms or to prevent symptoms from occurring before disease onset. In clinical trials, patients receive a single intravenous infusion of SRP-9004 at a dose of 1 × 1012 or 3 × 1012 vg/kg. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts), which acquired original developer Myonexus Therapeutics (New Albany, Ohio)

Section 5. Rare Diseases 259

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have primary Sutimlimab (BIVV009) is a humanized monoclonal Plasmapheresis Hemoglobin level PDUFA date: November 13, cold agglutinin disease antibody that purportedly selectively inhibits the C1 Rituximab with or without Number of blood 2020; Priority Review (CAD) complex of the complement system. Sutimlimab is fludarabine transfusions required FDA designation(s): Orphan thought to prevent classical complement activation Number of acute Drug, Breakthrough Therapy without affecting the alternative or lectin pathways. A rare hemolytic crises Clinical trial(s): Phase 3 autoimmune hemolytic anemia, CAD is characterized by Change in Functional Cardinal primary completion overactivation of the classical complement pathway in Assessment of Chronic September 2021, interim response to triggers (eg, cold temperatures or viral Illness Therapy— data reported November infections). This overactivation leads to erythrocyte Fatigue scale score 2019, data presented June engulfment by phagocytes (ie, opsonization), (FACIT-F; quality of life) 2020 (abstract S333), data extravascular destruction, and anemia, which can cause from baseline presented December 2020; severe fatigue, acute hemolytic crisis, and poor quality of phase 3 Cadenza primary life. CAD also puts patients at increased risk of blood clot completion December 2021 formation and early death. No treatments are approved Note(s): FDA issued a for CAD. In a clinical trial, sutimlimab was given Complete Response Letter to intravenously at a dose of 6.5 g to patients weighing less Sanofi in November 2020, than 75 kg and a dose of 7.5 g to patients weighing 75 kg identifying deficiencies or more, on days 0 and 7, followed by biweekly infusions. found during a prelicense Developer(s): inspection of a third-party Sanofi Genzyme (Cambridge, Massachusetts) manufacturing facility

Section 5. Rare Diseases 260

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have congenital Tildacerfont (SPR001) is a small-molecule antagonist of Glucocorticoids (eg, Disease progression FDA designation(s): Orphan adrenal hyperplasia (CAH) the corticotropin-releasing factor type 1 (CRF1) receptor. It dexamethasone, Measures of disease Drug due to 21-hydroxylase might help reduce symptoms associated with adrenal hydrocortisone, severity (eg, serum Clinical trial(s): Phase 2 deficiency enlargement and excessive androgen production and prednisone) levels of 17- primary completion reduce chronic treatment with high-dose steroids. CAH is hydroxyprogesterone, December 2021; phase 2 a group of genetic disorders characterized by abnormal androstenedione, and completed May 2019, data hormone production in the adrenal gland. Accounting for ACTH) reported March 2019; phase about 95% of cases, CAH due to 21-hydroxylase deficiency Symptom severity 2 completed September occurs when variations in the CYP21A2 gene cause a Quality of life 2019, data reported deficiency of 21-hydroxylase, an enzyme necessary for the September 2019 production of cortisol and aldosterone in the adrenal gland. The result is reduced or absent cortisol and aldosterone production, and, indirectly, elevated levels of adrenocorticotropic hormone (ACTH) that cause enlargement of the adrenal gland and increased production of adrenal androgens. Depending on severity, patients experience risk of adrenal crisis, salt-losing, growth failure, atypical genitalia, virilization, menstrual

dysfunction, and infertility. Tildacerfont’s binding to CRF1 receptors on the pituitary gland in the brain purportedly decreases the release of ACTH, which helps decrease adrenal enlargement and adrenal androgen production. In clinical trials, tildacerfont is taken by mouth at a dosage of 400 mg once daily for 12 weeks in addition to baseline glucocorticoid therapy. Developer(s): Spruce Biosciences (San Francisco, California)

Section 5. Rare Diseases 261

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males who have Timrepigene emparvovec (BIIB111) is an adeno-associated Low-vision aids (eg, Best corrected visual FDA designation(s): Orphan genetically confirmed virus serotype 2 (AAV2) vector that delivers a recombinant telescopic and magnifying acuity (BCVA) Drug, Regenerative Medicine choroideremia (CHM) human CHM-associated gene. The gene encodes Rab lenses) Color vision Advanced Therapy escort protein 1 (REP1) inside the eye to treat Supportive care Contrast sensitivity Clinical trial(s): Phase 3 STAR choroideremia, a rare, degenerative, chromosome X– Retinal sensitivity completed December 2020 linked genetic retinal disorder primarily affecting males, for which no treatment is available. Timrepigene emparvovec is intended to introduce a functional choroideremia gene, CHM, designed to enhance expression of REP1. This is thought to reduce accumulation of waste products in retinal cells and slow or stop vision decline. REP1’s enhanced expression might also slow or reverse early stages of cell death in damaged retinal cells, possibly improving visual acuity in some patients. In clinical trials, timrepigene emparvovec was given by injection into the subretinal space, which is between the retina’s outer layers, at a low (1 × 1010) or high (1 × 1011) vector dose. Developer(s): Biogen (Cambridge, Massachusetts)

Section 5. Rare Diseases 262

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have inherited Tofersen (BIIB067) is an antisense oligonucleotide Edaravone Disability Clinical trial(s): Phase 3 amyotrophic lateral intended to treat a variation in the SOD1 gene (in SOD1- Riluzole Disease progression VALOR primary completion sclerosis (ALS) and a ALS disease). It does this by lowering the level of Supportive care Functional capacity July 2021; phase 3 extension confirmed variation of the abnormal SOD1 protein encoded by the gene. Abnormal study primary completion Survival superoxide dismutase 1 SOD1 protein is thought to cause motor neuron death June 2023 gene, SOD1 and contribute to ALS disease course. ALS is a rare and fatal neurodegenerative disease in which the death of nerve cells (ie, neurons) in the brain and spinal cord leads to a loss of voluntary muscle function, wasting of muscle mass, and eventual death. Although the exact cause is unknown, neuronal accumulation of abnormally formed proteins, such as variant SOD1, might contribute to the death of those cells. About 2% of patients with ALS have a SOD1 gene alteration, and it is the second most common genetic cause of ALS. Misfolded SOD1 proteins have been found in higher concentrations in the cerebrospinal fluid of patients with SOD1-ALS and are thought to contribute to SOD1-ALS pathology. FDA-approved drugs to treat the disease (eg, riluzole, edaravone) decrease symptom severity in some patients but do not prevent neuronal injury and ALS progression. Tofersen is an artificially created piece of DNA purported to bind to SOD1 messenger RNA (mRNA) and inhibit the production of SOD1 protein. In a phase 1 trial, tofersen was injected into the spinal canal (ie, intrathecally) during a 12-hour infusion at a dose of 0.15, 0.50, 1.5, or 3.0 mg, once. The dose in phase 3 trials has not been announced. Developer(s): Biogen, Inc (Cambridge, Massachusetts), in collaboration with Ionis Pharmaceuticals (Carlsbad, California)

Section 5. Rare Diseases 263

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 25 year or older Tominersen (RG6042), formerly called RO7234292, ISIS Symptomatic care (eg, Disease progression FDA designation(s): Orphan who have genetically 443139, and IONIS-HTTRx, is an antisense oligonucleotide antipsychotics for chorea Motor and ambulatory Drug confirmed, symptomatic intended to treat HD. It purportedly treats HD by or agitation [off-label], function Clinical trial(s): Phase 3 Huntington disease (HD) preventing the production of the toxic, mutant, huntingtin physical therapy, speech Cognitive function GENERATION HD1 primary (HTT) protein that leads to neurodegeneration and therapy, tetrabenazine to Survival completion March 2022; disease progression. HD is an inherited (autosomal treat chorea) phase 3 open-label Quality of life dominant), progressive, neurodegenerative disease extension primary caused by mutations in the huntingtin gene, HTT. Mutant, completion June 2024; phase elongated HTT proteins are cleaved into smaller, 1/2 completed November neurotoxic fragments that accumulate in neurons, causing 2017, data published June neurodegeneration that manifests as uncontrolled 2019; phase 2 open-label movements (ie, chorea), cognitive decline, and mood extension completed changes. Symptoms typically begin in the fourth or fifth October 2019 decade of life, and typical life expectancy after symptom onset is about 20 years. There is no cure or disease- modifying treatment for HD. Tominersen purportedly reduces production of mutant HTT proteins by binding to the messenger RNA (mRNA) that encodes it to prevent harmful HTT accumulation in neurons that contribute to progressive neurodegeneration. It can potentially treat all patients with HD regardless of individual HTT mutation. In phase 3 clinical trials, tominersen is injected into the spinal cord (ie, intrathecally) once every 8 or 16 weeks for 25 months. Developer(s): F Hoffmann-La Roche, Ltd (Basel, Switzerland), which licensed rights from original developer Ionis Pharmaceuticals (Carlsbad, California)

Section 5. Rare Diseases 264

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Females aged 5 to 45 years Trofinetide (NNZ-2566) is a novel synthetic analogue of Supportive care (eg, Symptom frequency FDA designation(s): Orphan who have genetically the amino‐terminal tripeptide of insulinlike growth factor anticonvulsants; assistive and severity Drug, Fast Track, Rare confirmed Rett syndrome 1 (IGF-1) intended to treat Rett syndrome. A rare, devices; noninvasive Motor function Pediatric Disease postnatal, progressive neurologic disorder, Rett syndrome ventilation; nutritional Quality of life Clinical trial(s): Phase 3 is caused by a mutation in a gene called methyl CpG support; oxygen treatment; LAVENDER primary binding protein 2, MECP2. Located on the X chromosome, physical, occupational, and completion September 2021; MECP2 encodes the MeCP2 protein that normally speech/language therapy) phase 3 LILAC open-label mediates gene expression in neuronal and glial cells. Loss extension primary of MeCP2 function results in nerve cell dysfunction, which completion October 2022; is thought to be reversible. Patients with Rett syndrome phase 2 Rett-001 completed develop normally until 6 to 18 months of age and September 2014, data subsequently experience developmental delays and published November 2017; regression of previously learned motor and verbal skills. phase 2 Rett-002 completed The disease eventually causes additional symptoms, such January 2017, data published as repeated hand movements, impaired gait, slowed head April 2019 growth, disordered breathing, and seizures. Symptom severity varies by patient and depends on the individual’s specific MECP2 mutation and the amount of mutant MeCP2 protein expression. No cure exists, and treatment generally consists of supportive care for managing symptoms. Trofinetide, because of its homology with the amino-terminal tripeptide of IGF-1, which promotes neuronal and glial function, is intended to decrease symptom severity and disease progression in patients who have Rett syndrome. In clinical trials, patients receive trofinetide either by mouth or via a gastrostomy tube, at a dosage of 35, 50, 70, 100, or 200 mg/kg twice daily for 40 to 56 days. Developer(s): Acadia Pharmaceuticals, Inc (San Diego, California), in collaboration with Neuren Pharmaceuticals, Ltd (Camberwell, Australia), and Rettsyndrome.org (Cincinnati, Ohio)

Section 5. Rare Diseases 265

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 75 years Troriluzole (BHV-4157) is a third-generation, tripeptide- Physical and occupational Ataxia symptom Clinical trial(s): Phase 3 who have genetically prodrug conjugate of riluzole being developed to treat therapy severity primary completion confirmed spinocerebellar certain autosomal dominant (ie, inherited) types of SCA. A Supportive care Activities of daily living November 2021; phase 2/3 ataxia (SCA) type 1, 2, 3, 6, 7, progressive neurodegenerative disease, SCA is generally Use of assistive devices Daily functioning primary completion August 8, or 10 characterized by loss of balance and motor coordination, capacity 2017, preliminary post hoc abnormal speech, vision problems, and cognitive data released March 2019 Quality of life impairment. All autosomal dominant forms of SCA are caused by repeat expansions in genes normally involved in neuron function, and disruption of these genes causes progressive neuronal damage. In patients with SCA or other neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), damaged brain cells might be susceptible to further cellular injury mediated by overactivity of the excitatory neurotransmitter glutamate. Another drug, riluzole (Rilutek), is a sodium channel blocker and glutamate modulator approved by FDA for treating ALS. It purportedly reduces glutamate-mediated excitotoxicity and nerve cell deterioration by promoting the neurotransmitter’s reuptake into nerve cells. Troriluzole purportedly has the same mechanism of action as riluzole but has improved bioavailability and tolerability, which could reduce adverse events typically associated with riluzole treatment (eg, fatigue, weakness, dizziness, liver toxicity). Troriluzole treatment might decrease glutamate-mediated neuronal damage and improve disease symptoms in patients with SCA. In clinical trials, patients take troriluzole by mouth at a dosage of 200 mg once daily for 48 weeks. Developer(s): Biohaven Pharmaceuticals, Inc (New Haven, Connecticut)

Section 5. Rare Diseases 266

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 40 to 80 years Verdiperstat (BHV-3241) is a first-in-class, irreversible Supportive care (eg, Ambulatory and motor FDA designation(s): Orphan who have clinically inhibitor of the enzyme myeloperoxidase (MPO) intended assistive devices, function Drug, Fast Track diagnosed or suspected to treat MSA by reducing microglial activation and symptomatic treatment Independence Clinical trial(s): Phase 3 M- multiple system atrophy neuroinflammation. It might improve patient health with dopamine agonists Survival STAR primary completion (MSA) who can walk at least outcomes and quality of life by slowing disease [eg, amantadine, levodopa; Quality of life October 2021; phase 2 10 steps (assistive devices progression. MSA is a rare, neurodegenerative disorder off-label], physical therapy) completed September 2016 but not persons are characterized by progressive damage to neurons in the allowed) and have a life brain and scarring that contributes to impairments in expectancy of at least 3 motor movement and coordination and autonomic years dysfunction. Signs and symptoms of the disease include unstable vital signs, sweating, and difficulty controlling bowel and bladder function. The exact cause is unknown, but the disorder is associated with glial cell dysfunction and inflammation. The disorder most commonly emerges in middle adulthood and typically causes death 6 to 10 years after onset. Verdiperstat purportedly crosses the blood-brain barrier and works by inhibiting MPO, an enzyme thought to be a key contributor to pathologic oxidative stress and inflammation in the brain. In clinical trials, verdiperstat is taken by mouth at a dosage of 300 mg twice daily for 48 weeks. Developer(s): Biohaven Pharmaceuticals, Inc (New Haven, Connecticut)

Section 5. Rare Diseases 267

Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients of all ages who Vosoritide (BMN 111) is a recombinant C-type natriuretic Human growth hormone Health complications PDUFA date: August 20, 2021 have achondroplasia peptide analogue intended to treat achondroplasia by Limb-lengthening surgery Quality of life FDA designation(s): Orphan promoting long-bone growth. Achondroplasia, the most Drug common form of human dwarfism, is a genetic disorder Clinical trial(s): Phase 2 that results in irregular bone growth, short stature, and primary completion May serious health complications, including extra fluid in the 2021; phase 2 open-label brain and compression of the spinal cord. Less severe extension primary complications, but nonetheless limiting, include bowed completion September 2026; legs, recurrent ear infections, and sleep apnea. Vosoritide phase 2 completed October might lessen achondroplasia’s health impacts by allowing 2017; phase 2 primary normal conversion of cartilage into bone at growth plates completion October 2022, as a child ages. Achondroplasia results from a defect in height data reported the fibroblast growth factor receptor 3 gene, FGFR3. The November 2019; unphased defect promotes overactivity of negative regulators of primary completion October bone growth. Vosoritide purportedly interrupts 2024; pooled phase 2 and intracellular pathways that contribute to the overactivity. unphased data published In clinical trials, vosoritide is given as an injection under July 2019; phase 3 the skin at a dosage of 15 mg/kg daily. completed October 2019, Developer(s): data published September BioMarin Pharmaceutical, Inc (Novato, California) 2020; phase 3 primary completion October 2024, data reported December 2020; phase 2 primary completion December 2026

Section 5. Rare Diseases 268 Table 5.3. Rare Diseases Topics Archived Since Last Status Report: 7 Topics

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults aged up to 75 years Autologous mesenchymal stem cells secreting Edaravone Disease progression In November 2020, who have rapidly neurotrophic factors (MSC-NTF; NurOwn) is a bone Riluzole Disability BrainStorm Cell reported progressing amyotrophic marrow–derived therapy intended to treat ALS. A rare and Supportive care Quality of life that the phase 3 trial lateral sclerosis (ALS) fatal neurodegenerative disease, ALS is characterized by (NCT03280056) of NurOwn the death of nerve cells (ie, neurons) in the brain and failed to meet its primary spinal cord that leads to a loss of voluntary muscle and secondary end points of function, wasting of muscle mass, and eventual death. In improvement and change in patients with ALS, the presence of abnormal proteins in a functional rating scale the brain and spinal cord causes neuronal death and compared with placebo. contributes to disease progression. The exact cause of these aggregates is unknown. FDA-approved drugs to treat the disease (eg, riluzole, edaravone) decrease symptom severity in some patients but do not prevent neuronal injury and ALS progression. MSC-NTF grows the patient’s bone marrow cells in a proprietary culture media to differentiate mesenchymal stromal cells into astrocyte- like cells. The cultured cells purportedly secrete neurotrophic and growth factors, including glial-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF). These factors have immunomodulatory characteristics intended to protect neurons and glial cells from toxins and facilitate tissue repair. Thus, MSC-NTF could delay or prevent neuronal injury in patients with rapidly progressing ALS. In clinical trials, MSC-NTF is injected into the spinal cord (ie, intrathecally) at an unspecified dose every other month, 3 times. Developer(s): BrainStorm Cell Therapeutics (New York, New York)

Section 5. Rare Diseases 269

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have diffuse Lenabasum (JBT-101) is a novel synthetic anti- Combined autologous Disease progression In September 2020, Corbus cutaneous systemic inflammatory and antiscarring (ie, antifibrotic) medication hematopoietic stem cell Skin fibrosis and Pharmaceuticals reported sclerosis under investigation to treat systemic sclerosis, a rare, transplantation (HSCT) inflammation that the phase 3 RESOLVE-1 incurable, autoimmune, connective tissue disease. and high-dose Survival trial (NCT03398837) did not Conventional immunosuppressive therapy has limited immunosuppressive meet its primary end point Quality of life efficacy in preventing disease progression or reducing therapy of achieving a statistically death rates. The disease is marked by vasculopathy, skin Low-dose significant difference in thickening due to collagen accumulation, autoantibody immunosuppressive efficacy of lenabasum formation, and inflammation, which leads to scarring in therapy compared with placebo. skin and internal organs. Patients with limited cutaneous Symptom-based systemic sclerosis have fairly high survival rates but are at palliative increased risk of pulmonary arterial hypertension. pharmacotherapy (eg, Patients with diffuse cutaneous systemic sclerosis have angiotensin-converting worse survival rates. Preclinical studies suggest that enzyme [ACE] inhibitors, lenabasum preferentially activates specific immune cell nonsteroidal anti- cannabinoid receptors (ie, CB2). Lenabasum purportedly inflammatory drugs binds CB2 receptors and triggers inflammation resolution, [NSAIDs]) a multifaceted process that reduces immune-mediated inflammation and tissue injury to improve systemic sclerosis symptoms. In clinical trials, lenabasum is given orally at 5- or 20-mg doses twice daily. Developer(s): Corbus Pharmaceuticals Holdings, Inc (Norwood, Massachusetts)

Section 5. Rare Diseases 270

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Children aged 15 years or Lenadogene nolparvovec (Lumevoq) is a gene therapy. It Supportive care Visual acuity Phase 3 results from the older and adults who have is intended for LHON, a rare maternally inherited genetic Quality of life RESCUE trial failed to Leber hereditary optic disease of mitochondrial DNA that leads to irreversible provide evidence that neuropathy (LHON) caused vision loss. Lenadogene nolparvovec is intended to lenadogene nolparvovec by a mutation in the NADH restore vision loss and quality of life in patients with would have a beneficial dehydrogenase 4 gene, ND4 LHON caused by a mutation in the ND4 gene. Lenadogene effect on patient-oriented nolparvovec is an adeno-associated virus serotype 2 outcomes, suggesting that (AAV2) vector that delivers a functional copy of the ND4 lenadogene nolparvovec is gene into cells. The therapy uses a mitochondrial unlikely to cause disruption. targeting sequence that carries therapeutic messenger RNA (mRNA) transcribed from this transgene from the nucleus of treated cells directly to the mitochondria, where functional ND4 proteins are produced and incorporated, treating the deficiency. In clinical trials, lenadogene nolparvovec is given as a single intravitreal (ie, into the eye) injection at a dose of 9 × 1010 vg in 90 μL of balanced salt solution plus 0.001% Pluronic F68. Developer(s): Gensight Biologics, Inc (New York, New York)

Children aged 6 years or Nedosiran (DCR-PHXC) is an RNA interference (RNAi) Diet management and Change in urinary A similar drug (lumasiran) in older and adults who have therapy targeting lactate dehydrogenase under study for fluid intake oxalate excretion from the same class has been primary hyperoxaluria (PH) treating PH. An ultra-rare, life-threatening disorder, PH is Kidney dialysis baseline approved for this patient type 1, 2, or 3 caused by genetic mutations in the glyoxylate metabolism Lumasiran Hospitalizations population. Therefore, the pathway that lead to overproduction of oxalate. This subsequent approval of Organ transplantation Quality of life for patients causes kidney damage. Nedosiran is intended to inhibit nedosiran for a similar (ie, isolated or combined and caregivers expression of lactate dehydrogenase (LDH), a key enzyme indication would no longer liver and kidney) in the production of oxalate. The liver is responsible for be considered disruptive. most oxalate overproduction, and the nedosiran siRNA is Shockwave lithotripsy conjugated to N-acetylgalactosamine ligands that bind to receptors on hepatic cells, targeting the therapy to the liver. By inhibiting liver LDH, nedosiran might reduce oxalate levels and improve health outcomes in patients with PH. In clinical trials, nedosiran was given under the skin at unspecified monthly doses. Developer(s): Dicerna Pharmaceuticals, Inc (Lexington, Massachusetts)

Section 5. Rare Diseases 271

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have genetically PTX-022 (Qtorin) is an anhydrous gel containing the mTOR Botulin toxin (off-label) Palmoplantar In January 2021, Palvella confirmed pachyonychia inhibitor rapamycin under study as a topical treatment for Fluorouracil (off-label) keratoderma symptoms Therapeutics announced congenita (PC) patients with PC. An autosomal dominant, inherited Oral retinoids (off-label) Quality of life that PTX-022 failed to meet keratinizing disorder, PC is caused by genetic variants in its primary end point in the Phenytoin (off-label) keratins upregulated after tissue stress (ie, inducible phase 3 randomized keratins). The disorder primarily affects the skin and nails, withdrawal portion of the and patients with PC develop blisters and calluses on the VALO trial. soles of their feet and the palms of their hands (ie, palmoplantar keratoderma) that can cause substantial pain and limit mobility. No FDA-approved treatments exist for treating PC, and novel, effective treatments are sought. Preclinical research has demonstrated a role for mTOR in promoting translation of messenger RNAs (mRNAs) containing a terminal 5′ oligopyrimidine tract, which includes the mRNAs encoding the inducible keratins involved in the disease course of PC. By delivering rapamycin locally to affected skin cells on the feet and hands using a topical gel, PTX-022 purportedly reduces expression of mutated keratins in keratinocytes while avoiding the toxicity associated with systemic mTOR inhibitor exposure. In clinical trials, PTX-022 containing 3.9% rapamycin is applied topically at undefined frequency. Developer(s): Palvella Therapeutics (Wayne, Pennsylvania)

Section 5. Rare Diseases 272

Potential patient Intervention description Potential Patient-oriented Archive reason population Developer(s)/manufacturer(s) comparators outcome measures

Adults who have stage 2 or RGN-259 is a sterile, preservative-free eye drop form of Antibiotic eye drops Visual acuity According to the clinical trial 3 neurotrophic keratopathy thymosin beta 4 (Tβ4), a naturally occurring regenerative Bandage contact lenses Corneal sensitivity record (NCT02600429), the in at least one eye peptide. RGN-259 is intended to treat neurotrophic Cenegermin-bkbj eye Quality of life manufacturer, ReGenTree, keratitis (NK), a rare degenerative disease of the corneal drops has terminated the phase 3 epithelium that has no effective treatments. NK is study for business reasons. Surgery characterized by decreased corneal sensitivity and poor Thus, this intervention no corneal wound healing, which makes the cornea sensitive longer meets criteria for to injury and decreases reflex tear production. RGN-259 inclusion in the PCORI purportedly promotes cell migration and laminin-5 Health Care Horizon production, reducing both cell death and inflammation in Scanning System. the cornea. In clinical trials, RGN-259 ophthalmic solution is given as a direct instillation into the affected eye or eyes 5 times daily for 4 weeks. Developer(s): RegeneRx Biopharmaceuticals, Inc (Rockville, Maryland), in collaboration with ReGenTree, LLC (Princeton, New Jersey)

Adults who have moderate Teprotumumab-trbw (Tepezza) is an FDA-approved fully Corticosteroids Vision On January 21, 2020, FDA to severe active thyroid eye human monoclonal antibody specific for insulinlike Orbital decompression Light sensitivity granted teprotumumab-trbw disease (TED) growth factor 1 receptor (IGF-1R) intended to treat TED. surgery Quality of life approval to treat adults who TED is a rare autoimmune condition in which have TED. Because it has inflammation and increased volume of muscles and fatty been clinically available for tissues behind the eye cause the eyes to be pushed more than 1 year, it is no forward and bulge outward. IGF-1R plays a central role in longer within the time scope TED pathogenesis, promoting the structural changes for the PCORI Health Care driving the disease. Teprotumumab-trbw inhibition of IGF- Horizon Scanning System. 1R-mediated signaling might provide a noninvasive The time scope is defined as alternative to surgical treatment for patients with TED. 3 years before an The recommended dosage in the FDA-approved label is intervention becomes 10 mg/kg for the first dose and 20 mg/kg thereafter given clinically available outside of intravenously over 60 to 90 minutes, every 3 weeks over the research setting to 1 21 weeks for a total of 8 infusions. year after an intervention Developer(s): becomes clinically available. Horizon Therapeutics plc (Dublin, Ireland)

Section 5. Rare Diseases 273 Section 6. Potentially Disruptive Trends: 37 Trends

Table 6.1. Trends Added Since Last Status Report: 13 Trends

Title Description Threats Opportunities

Artificial intelligence Several AI algorithms are being developed to predict the onset of and Might lead to confounding of Might identify subtle markers of (AI) analysis of diagnose dementia associated with AD using language analysis. AD is known results due to cognitive decline cognitive decline, leading to earlier linguistic markers for to affect a person’s use of language in specific ways, such as replacing nouns from other neurological diagnosis and treatment early detection and with pronouns, using indirect language (circumlocutions), using simplified conditions, such as aphasia, stroke, Might decrease the need for diagnosis of dementia phrases, repeating words, misspelling common words, slower speech, and traumatic brain injuries, and invasive tests or scans associated with more pauses. Language impairment increases with the severity of cognitive depression Might be less expensive compared Alzheimer’s disease impairment. These AI models are trained to identify linguistic and acoustic Might lead to overdetection or with other diagnostic tests, (AD) markers that differentiate subjects with AD from healthy controls by overdiagnosis including other recent diagnostic analyzing data from a written or spoken picture-description task or a advances such as detecting sentence-reading task. The models in development differ in their intent. biomarkers using scans, spinal Some are designed to predict the development of AD years before fluid, and blood tests symptoms are severe enough to be identified by a typical diagnostic method Might allow accuracy to be and monitor the progression of AD, while others are designed to accurately improved over time with the diagnose AD without the need for additional scans or in-person testing. incorporation of newly identified Current AI models claim accuracy ranging from 70% to 95%. Algorithms are linguistic markers being developed by IBM (Armonk, New York), funded by Pfizer, Inc (New York, New York), Stevens Institute of Technology (Hoboken, New Jersey), and Panasonic Corp (Newark, New Jersey), in collaboration with the National Center for Geriatrics and Gerontology (Ōbu City, Japan) and Kaiser Permanente Washington Health Research Institute (Seattle, Washington).

Section 6. Potentially Disruptive Trends 274

Title Description Threats Opportunities

Artificial intelligence Radiotherapy is a treatment for patients with cancer that uses high doses of Might lead, due to algorithmic Might lead to better outcomes and (AI)–assisted radiation to kill tumor cells. Before radiation therapy can be offered, detection errors, to treatment of fewer side effects compared with radiotherapy plans to radiation oncologists plan a radiotherapy workflow to determine tumor and healthy tissue instead of cancer, conventionally planned radiation organ segmentation, dose optimization, outcome prediction, and quality treat cancer which could have health and/or therapy assurance. However, planning a workflow takes time and occasionally legal implications provides poor targeting that can damage nearby organs and tissue. AI Might enable radiation oncologists algorithms that aggregate patient and workflow data are being developed to Might be viewed by some radiation to plan a highly targeted improve the speed and precision of an often hours-long process to oncologists as a threat to their radiotherapy workflow in less time formulate a radiotherapy plan for patients with cancer. If an AI tool performs autonomy as clinicians than it would take conventionally as well as radiation oncologists in delineating tumor boundaries from without the aid of an AI platform images, their implementation has potential to improve clinical decision Might enable patients to receive making and the radiotherapy’s precision. The Mayo Clinic (Rochester, Minnesota), in collaboration with Google Health (Palo Alto, California), the radiotherapy sooner than with a University College London (United Kingdomand the University of Texas conventional radiation plan, and Southwestern (Dallas) are developing AI tools for identifying the contours patients might be less likely to around tumors, determining radiation dose, and developing a treatment plan delay subsequent chemotherapy for patients with cancer. treatment, if needed

Artificial intelligence Earlier detection and treatment of rare diseases might improve patient Might create disparities at centers Might reduce or eliminate the (AI) machine learning outcomes. However, manual searches of patient records and test results can with fewer resources to implement need for manual searching of to help diagnose rare take time and be inefficient, especially when symptoms or disease NLP review of patient records and patient records by specialists, diseases manifestations are shared across multiple conditions. AI methods that use genetic tests reducing workload on some health natural language processing (NLP) are being used more often to help Might create or expand disparities care staff improve rare disease diagnosis. NLP can scan published literature to identify for uninsured or underinsured Might improve patient outcomes if newly discovered associations between genetic variants and rare diseases. patients with less access to genetic rare diseases can be correctly NLP can also more quickly scan electronic health records for key terms (eg, testing diagnosed sooner and treatment, head size, heart defects) and match them with relevant genetic test results, Might increase risk of misdiagnosis if available, can be started earlier within hours compared with days in some cases. Rady Children’s Institute if NLP search strategies are too for Genomic Medicine (San Diego, California) experts used NLP to broad, too narrow, or otherwise automatically match phenotypes (physical features) with genetic diseases in misaligned a median of about 20 hours, altering treatment in 3 of 7 critically ill children. University of Iowa Stead Family Children’s Hospital (Iowa City) researchers completed NLP phenotype extraction for 100 patients in about 10 minutes compared with more than 34 hours manually. Developers offering AI-NLP platforms for rare disease diagnosis include Fabric Genomics, Inc (Oakland, California), Linguamatics (Marlborough, Massachusetts), and Emedgene (Tel Aviv, Israel).

Section 6. Potentially Disruptive Trends 275

Title Description Threats Opportunities

Artificial intelligence The inappropriate use of antibiotics has accelerated the problem of bacterial Might cause overreliance on AI Might reduce overall antibiotic use (AI) to select resistance to many of these agents. Researchers have been developing AI methods and diminish clinicians’ if the drugs that are most likely to appropriate antibiotics methods to improve the likelihood of selecting the most effective antibiotic analytical skills in selecting be effective are identified sooner as first-line treatment. Avoiding the use of antibiotics that are unlikely to appropriate antibiotics Might reduce treatment costs by effectively treat certain bacteria could reduce the spread of drug-resistant Might promote increased use of avoiding use of ineffective bacteria. Massachusetts Institute of Technology (Boston) researchers inappropriate antibiotics if AI antibiotics developed an algorithm that predicts whether first- or second-line training data set is flawed or Might slow the growth of antibiotics can effectively treat a urinary tract infection and recommends a incomplete antibiotic-resistant bacteria if the first-line agent when possible, reducing the risk of treatment failures. most effective agents are used Researchers in China have proposed that predictive accuracy of AI for sooner in the treatment course antibiotic selection could increase if more hospitals shared their clinical data to improve the training data set and if multiple biomarkers were included.

Artificial intelligence Voice analysis using AI is being investigated and used to help detect Might incorrectly diagnose or Might significantly improve patient (AI) voice analysis to symptoms of anxiety and depression. A recent study of children found that a overdiagnose children and adults health outcomes and quality of life, detect symptoms of machine learning analysis of audio data from a task was 80% accurate in with anxiety and depressive and decrease health care costs by anxiety and identifying anxiety and depression. The researchers stated that the most disorders, which can have allowing for earlier diagnosis and depression differentiating features for these disorders, compared with controls, are significant mental health treatment of anxiety and especially low-pitch voices, repeated speech patterns, and high-pitch consequences (ie, altered self- depression responses to surprising stimuli. Company Ellipsis Health (San Francisco, concept or self-esteem) and lead Might significantly improve long- California) recently launched an app called Rising Higher, which is a clinical to increased health care use and team health outcomes in children decision support tool for health care providers to detect anxiety and costs (eg, improved psychosocial depression symptoms with a machine learning algorithm. The app uses a Might pose cybersecurity and development, better school few minutes of natural speech to provide an immediate assessment and, confidentiality risks if this performance, fewer health thus, can be used during a patient encounter. Similarly, Clarigent Health technology is used through smart behavior risks in adolescence [eg, (Mason, Ohio) recently launched a clinical decision support tool using AI to device applications and on substance use]) analyze speech to identify patients at higher risk for suicide and other clinicians’ personal devices Might improve patient mental health issues. management if clinicians can more easily detect changes in anxiety and depression symptoms that will help guide their treatment plan

Section 6. Potentially Disruptive Trends 276

Title Description Threats Opportunities

Clustered regularly CRISPR-based assays can purportedly detect the presence or absence of Might increase the rate of Might help clinicians identify the interspaced short nucleic acids from infectious diseases within an hour in a highly specific way. misdiagnosis if CRISPR-based infectious agent the same day a palindromic repeats CRISPR-based assays employ a loop-mediated isothermal amplification assays inaccurately detect their patient is tested, which allows for (CRISPR)–based assays reaction to amplify nucleic acids in the sample. The products of this target nucleic acids immediate management to treat to diagnose infectious amplification reaction are exposed to an RNA-guided nuclease (eg, Cas12a, Might create disparities for the disease and prevent its spread diseases Cas13a) that becomes activated only in the presence of a specific nucleic patients who do not have access to Might save health systems time acid sequence. If activated, the nuclease cleaves a fluorophore-labeled health centers and laboratories and money because CRISPR-based reporter nucleic acid and, depending on the reporter technology used, that offer CRISPR-based testing assays are expected to cost less reporter cleavage is measured by fluorimeter or lateral flow assay. FDA has and deliver results faster granted Emergency Use Authorization to CRISPR-based assays developed by compared with polymerase chain Sherlock Biosciences (Cambridge, Massachusetts) and Mammoth reaction (PCR) or next-generation Biosciences (Brisbane, California) to diagnose COVID-19. Sherlock sequencing (NGS) assays Biosciences, in collaboration with the Broad Institute of MIT and Harvard (Cambridge, Massachusetts), is developing a CRISPR assay to diagnose malaria. Synthego (Redwood City, California) and Mammoth Biosciences are looking for collaborators to develop new CRISPR assays to diagnose additional bacterial infections (eg, Mycobacterium tuberculosis, Staphylococcus aureus) and viral infections (eg, dengue virus, Ebola virus, human papillomavirus, Zika virus). These tests are being developed for use in a point-of-care setting to identify the infectious agent responsible for a patient’s symptoms and help clinicians guide patient management.

KRAS G12C inhibitors The Kirsten rat sarcoma gene, KRAS, is among the most frequently Might increase cost of care relative Might address the unmet need of for treatment of solid mutated genes in cancer, occurring in about 40% of cancers. However, no to existing treatment options patients with KRAS G12C-positive drugs targeting KRAS are available. About 13% of lung cancers and about tumors Might require additional testing to tumors for targeted therapies, 1% to 3% of other cancers harbor a specific KRAS mutation, G12C, which potentially improving patient encodes a constitutively active KRas protein that initiates and maintains the determine whether patients are cancer phenotype. Recently, a class of drugs targeting KRAS harboring a eligible for KRAS G12C inhibitor outcomes G12C mutation has been developed. These inhibitors covalently bind a treatment Might improve understanding of cysteine residue in the switch II pocket of KRAS G12C while demonstrating the ability to pharmacologically minimal binding to nonmutated KRAS. Inhibitor binding to the switch II inhibit KRAS in a wide variety of pocket locks the KRas protein in an inactive state, inhibiting cancer- tumor types promoting signaling. Multiple developers have brought KRAS G12C inhibitors to clinical trials, including sotorasib (AMG510, Amgen, Thousand Oaks, California), adagrasib (MRTX849, Mirati Therapeutics, San Diego, California), and GDC-6036 (Genentech, South San Francisco, California).

Section 6. Potentially Disruptive Trends 277

Title Description Threats Opportunities

Lay counselor Lay counselors are individuals without professional mental health training Might pose health risks to patients Might significantly decrease intervention for who intend to provide mental health counseling. Researchers are if lay counselors are inadequately depressive symptoms and improve preventing and investigating whether lay counselors providing structured interventions, trained or counsel beyond their quality of life in older adults, who treating depressive such as cognitive behavioral therapy (CBT), can prevent and treat depressive intended scope are at an increased risk for symptoms in older symptoms in older adults. Older adults are at an increased risk for Might pose legal challenges depression adults depression because of reasons such as social isolation and immobility. considering lay counselors are not Might decrease health disparities Psychiatric medications often do not provide adequate relief or have currently credentialed to provide by allowing older adults who live in intolerable side effects. Also, homebound patients have difficulty accessing such services rural areas, are low-income, or are mental health services. A recent study showed that lay counselors were as homebound to access mental clinically effective as were professionally trained mental health counselors at health services more readily (ie, significantly lowering depression symptoms in older adults when structured increasing ease of access) behavioral therapy was administered via videoconferencing. Similarly, lay Might help mitigate the US’s counselors have been found to be effective at preventing major depression shortage of mental health in older adults living in low- and middle-income countries. providers and improve population health outcomes

Messenger RNA Technological advances and innovation in the area of mRNA vaccine Might have long-term Might decrease long-term costs of (mRNA) vaccines applications have led to the creation of multiple mRNA vaccine platforms consequences that are not seen care associated with treating against infectious against infectious diseases and cancers. These mRNA vaccines use lipid during development and testing certain infections and cancers diseases and cancers nanoparticles to deliver genetic information to human cells, to produce certain proteins that elicit an immune response. The mRNA is degraded by Might increase costs associated Might improve the understanding the body and does not alter human genes. For instance, the complexity of with vaccine storage due to the of mRNA-based technologies to HIV, as well as its genetic diversity, has been a major challenge and barrier mRNA vaccine’s special low- treat a wide array of infections and in the creation of an effective and preventive vaccine for HIV. Moderna temperature requirements diseases (Cambridge, Massachusetts) is working on 2 mRNA HIV vaccine candidates, mRNA-1644 and mRNA-1574, that are set to start phase 1 trials in 2021. VRC01 is another mRNA vaccine, in development by the University of Pennsylvania (Philadelphia), that protected humanized mice against HIV infection. Besides developing the HIV mRNA vaccines, Moderna has also announced development programs for a wide range of viruses, such as Chikungunya, Epstein-Barr, influenza, Nipah, and Zika. Moderna and BioNTech (Mainz, Germany) are each investigating mRNA cancer vaccines, including mRNA-4157 for head and neck squamous cell carcinoma and mRNA-5671 for cancers with KRAS mutations (Moderna) and BNT111 for people with advanced melanoma (BioNTech).

Section 6. Potentially Disruptive Trends 278

Title Description Threats Opportunities

Neuromodulation Currently, the therapeutic options for AD are limited and none slow the Might increase short-term costs if Might provide a convenient, using gamma progression of this disease in a clinically meaningful manner. not covered by insurance noninvasive treatment option for oscillations to improve Neuromodulation using gamma oscillations might provide a noninvasive Might increase disparities in access AD and MCI neurological function method to decrease the amyloid and tau deposits in the brain that are to care Might improve patient health in Alzheimer’s disease known to cause neurodegeneration. For example, transcranial alternating outcomes and quality of life (AD) current stimulation (tACS) is a device that multiple investigators are Might reduce cost of long-term evaluating for AD and mild cognitive impairment (MCI). The device consists care of a cap with electrodes that transmit gamma oscillations to the brain at a frequency of 40 Hz. Gamma oscillations of 40 Hz are thought to trigger the immune response of microglia in the brain to clear amyloid beta (Aβ) and tau protein deposits. In clinical trials, tACS sessions were administered daily or twice daily for 2 or 4 weeks for 1 hour each followed by 5 to 7 assessments, which included electroencephalography (EEG), cognitive testing, and an amyloid positron emission tomography (PET) scan. Another example, Gamma SENSE (sensory engaging nebulized scent experience stimulation system; Aging Brain Alzheimer’s Initiative at MIT, Cambridge, Massachusetts) is being evaluated for mild to moderate cognitive impairment and AD. On January 21, 2021, Cognito Therapeutics, Inc (Boston, Massachusetts), received Breakthrough Device designation from FDA for using light and sound brain stimulation to treat AD.

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Title Description Threats Opportunities

Novel immune Immune checkpoint inhibitors have changed the treatment landscape for a Might increase the cost of treating Might improve patient health checkpoint targeting number of cancers since the first immune checkpoint inhibitor, ipilimumab, various cancers, potentially outcomes by increasing response drugs as adjuncts to was approved in 2011. In particular, inhibitors of the programmed cell death exacerbating existing disparities rates to immune-based therapies existing 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint have based on socioeconomic status Might improve understanding of immunotherapies to been approved by FDA to treat many cancer types. Although treatment with Might increase the potential for mechanisms of resistance to treat various cancers existing checkpoint inhibitors improves patient outcomes overall, many immune-related adverse events immune-based therapies patients fail to respond to these therapies or develop resistance to the already observed with existing therapy after an initial response. Therefore, investigators are studying immune checkpoint therapies whether the adjunctive use of drugs targeting alternative immune Might increase the complexity of checkpoints can increase the effectiveness of existing checkpoint inhibitors. immune-based therapy, imposing Compounds targeting multiple alternative immune checkpoints have a substantial learning curve on entered clinical trials. The most advanced clinical program is for an antibody clinicians and patients regarding against the T-cell immunoreceptor with Ig and ITIM domains (TIGIT), immunotherapy treatment options tiragolumab. Tiragolumab in combination with the PD-L1 inhibitor atezolizumab is under study in phase 3 trials to treat locally advanced or metastatic non–small cell lung cancer (NSCLC) and small cell lung cancer. Additionally, lymphocyte activator gene 3 (LAG-3) inhibitor trials are ongoing for relatlimab in combination with the PD-1 inhibitor nivolumab in melanoma; eftilagimod alpha (IMP321) in combination with the PD-1 inhibitor pembrolizumab in NSCLC and head and neck cancer; and LAG525 in combination with the PD-1 inhibitor spartalizumab in triple-negative breast cancer (TNBC). Additional novel checkpoint targeting compounds in development include the anti B7-H3 antibody enoblituzumab and the VISTA/PD-L1 antagonist CA-170.

Section 6. Potentially Disruptive Trends 280

Title Description Threats Opportunities

Personalized Genetic instability of cancer cells frequently generates somatic mutations Might increase costs related to the Might improve patient health neoantigen vaccines to that generate novel antigens (ie, neoantigens) with the potential to production of personalized cancer outcomes, particularly by treat various cancers differentiate tumors from normal tissue. Because neoantigens were not therapies increasing the efficacy of other present during the generation of immune diversity, they should be free from Might cause a delay in treatment immune-based treatment immune tolerance and, therefore, may elicit a robust immune response. related to the time needed to modalities Personalized neoantigen vaccines are intended to generate an anticancer produce the personalized cancer Might increase understanding of immune response using neoantigens that have occurred in a specific therapy the mechanisms behind immune- patient’s tumor. Generally, production of a personalized neoantigen involves Might lead to an increase in based treatment of cancer 3 steps: (1) identification of neoantigen-generating somatic mutations by immune-related adverse events nucleic acid sequencing of a tumor biopsy sample; (2) selection of Might exacerbate existing health neoantigens based on their predicted immunogenicity; and (3) production of disparities based on the vaccine itself. Neoantigen vaccines based on multiple formats are in socioeconomic status development, including liposome-encapsulated messenger RNA (mRNA) vaccines, dendritic cell vaccines, and synthetic long peptide vaccines. Multiple personalized neoantigen vaccine candidates are in clinical trials, including a phase 2 trial of the mRNA vaccine mRNA-4157 in combination with the immune checkpoint inhibitor pembrolizumab for treating melanoma sponsored by Moderna (Cambridge, Massachusetts); a phase 2 trial of the mRNA vaccine BNT122/RO7198457 for treating melanoma and a phase 2 trial of the same vaccine to treat colorectal cancer sponsored by BioNTech (Mainz, Germany) and Roche (Basel, Switzerland); a phase 1/2 trial of the peptide vaccine GRANITE in combination with immune checkpoint inhibitors for treating solid various tumors sponsored by Gristone Oncology (Emeryville, California); and a phase 1/2 trial of the peptide vaccine GEN-009 in combination with immune checkpoint inhibitors for treating various solid tumors sponsored by Genocea (Cambridge, Massachusetts).

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Title Description Threats Opportunities

Prostate-specific Conventional methods used to image prostate cancer cells include Might increase the risk of Might promote earlier disease membrane antigen computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, misdiagnosis, because binding detection, which is essential for (PSMA)–targeted and bone scans. However, these imaging methods are limited in detecting may occur with other types of effective disease management positron emission prostate cancer lesions. PET drugs such as F18 fluciclovine and C 11 choline cancer Might reduce costs of imaging for tomography (PET) are approved for prostate cancer imaging but only for patients with Might increase logistical issues prostate cancer staging and imaging agents to suspected cancer recurrence. Prostate cancer cells have elevated levels of because of a waiting period disease spread diagnose prostate PSMA, thereby making PSMA a suitable target for novel imaging agents. On between giving the agent to the cancer December 1, 2020, FDA approved one such imaging agent, Ga 68 PSMA-11, patient and performing the to detect PSMA-positive prostate cancer. The approval was granted to the imaging study University of California at Los Angeles and San Francisco. PyL (also known as 18F-DCFPyL) is another PSMA-targeted PET imaging agent that enables visualization of lesions to diagnose recurrent or metastatic prostate cancer. Pivotal data from the phase 3 CONDOR study (NCT03739684) showed that PyL can better detect metastatic lesions with high correct localization rate and positive prediction value. The CONDOR study’s sponsor is Progenic Pharmaceuticals, Inc (New York, New York).

Section 6. Potentially Disruptive Trends 282 Table 6.2. Currently Monitored Trends: 21 Trends

Title Description Threats Opportunities

Allogeneic chimeric Allogeneic (ie, donor-derived) CAR T-cell therapies are cell-based anticancer Might increase the potential for Might reduce costs relative to antigen receptor (CAR) treatments under study as an alternative to existing autologous (ie, patient- adverse events due to the need for autologous CAR T-cell therapies T-cell therapies to derived) CAR T-cell therapies. Although autologous CAR T-cell approaches multiple genetic manipulations Might increase availability and/or treat cancer have been shown to be highly effective in treating certain cancers, they have required to produce allogeneic improve the timeliness of therapy substantial shortcomings in terms of their production. Each autologous CAR product relative to autologous CAR T-cell T-cell therapy must be individually manufactured from the patient’s own Might not be as active or long therapies, potentially improving cells, leading to high costs. Additionally, the manufacturing process lasting as autologous CAR T-cell patient health outcomes introduces a delay between cell collection and reinfusion that is poorly therapies, potentially requiring tolerated in patients with aggressive malignancies. Finally, patients eligible retreatment or additional for autologous CAR T-cell therapies often have undergone multiple treatment treatments for their cancer, which can damage immune cells, rendering them incapable of being used to generate a CAR T-cell therapy product. Therefore, substantial interest exists in generating off-the-shelf CAR T-cell therapies from healthy donors, which could obviate these issues. However, several barriers to use of allogeneic CAR T-cell therapies exist, including the potential for allogeneic cells to generate an immune response against the recipient’s tissues (ie, graft-vs-host disease [GVHD]) and for the recipient’s immune system to substantially reduce the lifespan of allogeneic cells. Multiple companies (eg, Allogene Therapeutics, South San Francisco, California; Cellectis, New York, New York; Celyad, Mont-Saint-Guibert, Belgium, and New York, New York; CRISPR Therapeutics, Cambridge, Massachusetts; Precision Biosciences, Durham, North Carolina) are investigating various gene editing–mediated and transgene-mediated approaches to overcoming these barriers.

Section 6. Potentially Disruptive Trends 283

Title Description Threats Opportunities

Artificial intelligence AI is being harnessed to screen millions of small molecules with diverse Might trigger litigation due to Might decrease the time and costs (AI)–based drug chemical structures and identify compounds that are predicted to selectively convoluted intellectual property required in the early stages of drug discovery bind to the target protein. This would increase efficiency in the drug rights related to AI-based drug development discovery process by generating novel drug candidates, validating and discovery Might help discover novel optimizing drug candidates, and designing preclinical experiments. For Might not predict adverse events treatments that would improve example, Cloud Pharmaceuticals, Inc (Durham, North Carolina), uses patient health outcomes molecular modeling to identify biomarkers, design drug candidates, and produce compounds suitable for preclinical development. Another company in this space, Berkley Lights (Emeryville, California) uses AI to expedite development of cell lines and automate preclinical experiments for cell therapies. A company partnership between Innoplexus (Hoboken, New Jersey) and ChemAxon (Budapest, Hungary) could also provide existing pharmaceutical companies with the ability to detect new chemical compounds by extracting chemical knowledge and structures of existing drugs.

Artificial intelligence AI algorithms that analyze gene expression signatures from available Might cause researchers to Might lead to faster discovery of (AI)–identified drug databases might help scientists predict which combinations of available become too dependent on AI optimized regimens synergies to optimize drugs could better treat various diseases with high unmet needs, including algorithms and abandon other Might improve health outcomes in treatment regimens SARS-CoV-2, the virus that causes COVID-19; cancer; and tuberculosis. These effective methods of rational hard-to-treat conditions AI algorithms might promote and inform studies that accelerate the use of development in the pursuit of cost Might reduce costs of drug existing agents for novel uses or the availability of new agents for patients savings development who need more options. In one AI-based model, investigators found that Might not predict important predicted synergies for treating tuberculosis could be confirmed in vitro 88% adverse events of the time. Researchers purport that AI algorithms based on in vitro studies have successfully identified synergistic regimens confirmed in clinical studies. These findings suggest that AI might save scientists valuable research time in identifying optimized treatment regimens, expediting these options for patients.

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Title Description Threats Opportunities

Artificial intelligence Researchers around the world are pursuing use of AI to develop precision Might raise patient privacy Might improve outcomes for TBI (AI) to identify diagnostics and prognostic modeling to personalize treatment across the concerns and reduce rehabilitative care personalized complete TBI spectrum, from concussion to coma. For example, researchers Might create questions about who burden treatment options for from the Transforming Research and Clinical Knowledge in Traumatic Brain owns the data Might improve quality of life for traumatic brain injury Injury (TRACK-TBI) network are using machine learning (ML) to analyze a Might create controversy about patients with TBI (TBI) complex data set, including imaging, blood tests, and in-person publicly funded TBI research that Might inform, based on TBI assessments. These data, from 3000 patients in the TRACK-TBI study, are essentially subsidizes new research findings, research and being used to identify patterns that eventually can be applied in a clinical proprietary TBI treatments treatment of other neurologic setting to improve TBI outcomes. The researchers have standardized the marketed by private companies disorders way that imaging, clinical data, biomarkers, and treatment outcomes are analyzed across research sites. Researchers in the United Kingdom developed a convolutional neural network that purportedly could automatically detect, quantify, and differentiate different types of brain lesions by analyzing computed tomography brain scans. The algorithm could aid diagnosis of TBI in areas without immediate access to specialized neuroradiologist expertise.

Artificial intelligence Results from the STAR*D trial suggest that fewer than half of patients who Might increase health disparities Might improve patient health (AI) to predict have major depressive disorder (MDD) achieve remission with use of a first- because access to ML algorithms outcomes by finding successful antidepressant line antidepressant medication. This might be because MDD is a biologically and necessary brain imaging treatment sooner and protecting treatment response varied mental health condition that has demonstrated distinct modalities might be prohibitive to against patient discouragement neurophysiological subtypes. Researchers are investigating whether AI could many patients due to large scale of with treatment or treatment be used to predict a patient’s response to an antidepressant medication, depression and socioeconomic discontinuation particularly when applied to electroencephalography (EEG) results. One barriers, and not all psychiatrists Might decrease health care costs study developed an EEG computation model to predict treatment outcomes and health care providers are likely associated with trying several with sertraline, to lay the groundwork for machine learning (ML) to be trained on and using this medications before finding a approaches. The researchers found that participants who were unlikely to technology successful option respond to treatment with sertraline were more likely to respond to Might be cost prohibitive to Might change the current treatment with transcranial magnetic stimulation (TMS). A study undergo such evaluation paradigm of depression treatment investigating the application of ML to EEG to predict treatment response to to be more personalized escitalopram found a prediction accuracy of 79.2% off baseline EEG data. Might improve understanding of depression treatment

Section 6. Potentially Disruptive Trends 285

Title Description Threats Opportunities

Artificial intelligence AI algorithms that analyze cardiovascular imaging scans, electrocardiograms Might create physician resentment Might improve patient outcomes (AI) to predict (ECGs), and other cardiovascular tests have the potential to highlight short- regarding loss of diagnostic by automatically combining cardiovascular events term health risks and improve predictions of patients’ cardiovascular health autonomy multiple data sources into and health outcomes outcomes. Mayo Clinic researchers (Rochester, Minnesota, and Jacksonville, Might prompt medico-legal cardiovascular risk assessment Florida) have applied AI to ECG analysis to estimate physiologic age. The concerns for centers that have not Might leverage existing patient PERFORM machine learning model might predict pulmonary embolism risk. adopted AI risk-assessment tools data to improve cardiovascular risk AI-augmented computed tomography (CT) angiography assessment of Might increase staff workload for assessment without requiring coronary plaques might improve prediction of future cardiac events. An additional patient monitoring and additional testing (in some cases) Artificial Intelligence–Clinical Decision Support System showed comparable follow-up examinations Might improve outcomes by accuracy to heart failure (HF) specialists in reviewing patients presenting Might create risk of cardiovascular allowing primary providers to with dyspnea for possible HF. One developer offers an AI algorithm for a disease overdiagnosis if patient detect subtle arrhythmias and digital stethoscope that allows primary care providers to screen patients for data collected for other indications refer to cardiologists cardiac arrhythmias (eg, atrial fibrillation, murmur). Some researchers have (eg, chest CT scans for lung cancer suggested AI analysis of chest CT for lung cancer screening might detect screening) are overanalyzed undiagnosed heart conditions. Abbott (Abbott Park, Illinois) created an AI algorithm that purportedly provides individualized heart attack detection and confirmation in the emergency department. Cleveland Clinic (Cleveland, Ohio) uses AI-augmented patient monitoring in the hopes of identifying impending cardiac events up to 1 hour in advance, based on clinical data.

Bacteriophages to Bacteriophages are viruses that infect only bacterial cells and might help Might add significant short-term Might lead to decreased patient treat bacterial treat bacterial infections. They were discovered more than a century ago but costs to infection treatment illness and death infections were not pursued as a treatment in the United States because of safety Might pose a health risk for Might add to the body of scientific concerns and the increased availability of antibiotics. However, with patients because much is still to be knowledge surrounding infection increasing rates of antibiotic resistance and better understanding of learned about bacteriophage and its treatment bacteriophage biology, researchers are now considering using biology Might reduce long-term treatment bacteriophages to treat infections that are multidrug-resistant or Might eventually lead to costs by reducing the time patients characteristically hard to treat with antibiotics. Bacteriophages are in bacteriophage resistance similar to spend in intensive care units (ICUs) numerous clinical trials to treat primary immune deficiency disease, hyper- antibiotic resistance IgM syndrome, urinary tract infections, gastrointestinal tract infections, diabetic foot ulcers, leg ulcers, wound infections, Pseudomonas aeruginosa infections, and Staphylococcus aureus infections. University of California San Diego’s Center for Innovative Phage Applications and Therapeutics (IPATH) treats patients who have life-threatening multidrug-resistant infections with bacteriophages on a case-by-case basis through FDA’s Compassionate Use program. IPATH intends to conduct phase 1/2 trials for chronic infections in cystic fibrosis and infections associated with implantable hardware such as pacemakers and prosthetic joints.

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Bioanalytical services Diagnosis of neurodegenerative disorders such as Alzheimer’s disease can Might increase disparities for some Might be less costly for patients, for neurodegenerative include positron emission tomography (PET) imaging and laboratory tests of who do not have access to these caregivers, and health insurers disorders spinal fluid, which are invasive and expensive. Biomarker analysis using a services than are current brain imaging simple blood test might provide an easier way to assess any neurologic Might lead to overtreatment or scans damage to help inform treatment decisions. C2N Diagnostics (St Louis, inappropriate treatment due to Might be less invasive than spinal Missouri), a diagnostic company, is measuring concentrations of possible false positives in the fluid tests, which require lumbar biomolecules such as neurofilament light protein using sensitive stable analysis punctures isotope labeling to provide novel insights into the normal and abnormal Might reduce burden on the health workings of the brain. Multiple laboratories are developing plasma pTau181 care system due to better hospital tests to measure tau proteins, which are higher in individuals with resource use Alzheimer’s disease than in the general population.

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Title Description Threats Opportunities

Closed-loop glucose Patients with T1DM need to continually monitor and adjust their blood Might pose health risks if Might improve patient quality of monitoring (artificial glucose levels to avoid extreme high or low levels that can cause serious algorithms are imprecise or can be life by allowing more freedom in pancreas) systems for immediate and/or long-term health problems. Glucose monitoring, hacked destructively diet, physical activity, and sleep type 1 diabetes historically a time-consuming, manual task, is moving toward continuous, Might increase health disparities if Might improve patient health mellitus (T1DM) automated systems. FDA approved the first “artificial pancreas” in 2016. The the technology is cost prohibitive outcomes by minimizing periods of closed-loop system consisted of a sensor underneath the skin and an insulin Might decrease patient knowledge harmful low or high blood glucose pump. In automated mode, the system measured blood glucose every 5 and competency of manual blood that contribute to health minutes to automatically administer or withhold insulin according to its glucose monitoring and insulin complications measurements (insulin lowers blood glucose). It had limits, such as not dosing accommodating large meals or exercise, which strongly affect blood glucose levels. One study found that roughly 40% of patients stopped using it in the first 9 months for reasons including difficulty staying in the automated mode, frequent alarms, sensor failure, need for calibration, skin adhesion issues, and sensor-supply problems. Since that time, patients and researchers have worked to improve continuous glucose monitoring systems. At one point, patients began hacking old insulin pumps to sync them with new smartphone apps that had algorithms for controlling blood glucose. Newer closed-loop glucose monitoring systems now integrate with smartphone apps that contain algorithms for more precise blood glucose control and have additional features, including predictive alerts (ie, impending highs or lows 10 to 60 minutes beforehand). Research is demonstrating that closed-loop systems help patients spend more time in target glycemic ranges, thus lowering risk of health complications. One developer, Beta Bionics (Concord, Massachusetts) is working on a bihormonal pancreas system that can administer either insulin or glucagon (raises blood glucose) to control blood glucose better than using insulin only, which would allow patients to eat, work out, and sleep more freely. Because of the bihormonal functionality, its bionic pancreas would be the first true, autonomous, artificial pancreas. It is in phase 3 trials and the developer plans on submitting to FDA for regulatory approval based on data from this trial.

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Title Description Threats Opportunities

Direct-to-consumer Laboratories that offer DTC genetic testing services are considering use of Might pose significant threats to Might provide insight into the best (DTC) genetic testing patient-derived genetic data and volunteered genetic testing questionnaire patient health data privacy targets to pursue for drug partnerships with data as a way to drive drug development and treatment. By partnering with Might lead to a competitive development pharmaceutical pharmaceutical companies, DTC genetic testing companies can provide large disadvantage for drug developers Might enable effective and less- companies to facilitate data sets that might provide insight into new disease targets worth pursuing that choose not to partner with expensive identification of patients drug development and by drug companies. The databases from DTC testing might also make it DTC genetic testing companies and asymptomatic carriers for treatment easier for pharmaceutical companies to identify people who have a disease, clinical trials are asymptomatic, or are carriers for conditions of interest and recruit them Might lead to a more efficient drug for clinical trials in a cost-effective manner. For instance, genetic testing development process for company 23andMe (Sunnyvale, California) has established collaborations personalized medicines with GlaxoSmithKline (Brentford, United Kingdom), and another genetic testing company, Nebula Genomics (San Francisco, California), is collaborating with EMD Serono (Rockland, Massachusetts) to use consumer data to drive the drug development process.

Eye examinations for Several clinical trials are under way using eye examinations as a screening Might increase patient costs over Might provide a convenient, real- screening for tool for neurologic disorders—such as AD—to help identify disorders years the short term to get a type of eye time screening option for patients Alzheimer’s disease before clinical symptoms emerge. Images captured using ophthalmologic examination that insurance might Might reduce overall long-term (AD) and other imaging devices may reveal location of new blood vessels, locate fluid in or not cover cost of care if it aids early neurologic conditions beneath the retina, or show other potential biomarkers of diseases. Eye Might lead to inaccurate diagnoses detection to enable the start of examinations also have the potential to help monitor effects of new that could lead to poor patient treatment treatments intended to halt or reverse disease progression. During the visit, health outcomes health care providers might give dilating eye drops that open the pupil to visualize and image internal parts of the eye. Examples include RetiSpec, using hyperspectral imagery with machine learning (ML) methods, and Eyenuk, using fluorescein angiography with artificial intelligence (AI) technology. Also, several universities are using optical coherence tomography (OCT) examinations. A study conducted by Harvard Medical School suggests that OCT imaging can be used to diagnose individuals with autosomal dominant mutations for AD, years before onset of AD symptoms.

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Title Description Threats Opportunities

Gene editing to treat Clinical trials using gene editing technology are under way. These Might pose significant health risks Might improve quality of life for or prevent disease technologies hold great promise for treating and/or preventing several to patients because much is still patients diseases and conditions. For example, CRISPR (clustered regularly unknown about potential adverse Might reduce overall treatment interspaced short palindromic repeats) is a dynamic, versatile tool that can events related to gene editing costs for patients and the health be programmed to target specific stretches of genetic code and edit DNA at Might pose significant ethical and care system by providing a one- precise locations in the human genome. The technology allows researchers societal threats (eg, unethical time, curative treatment option to permanently modify genes and has the potential to create therapies with alteration of human embryos) Might reduce societal burden and a durable treatment effect. health care costs by preventing and/or eliminating certain genetic disorders

Natural killer (NK) cell– NK cells are part of the innate immune system (first line of defense) that can Might induce weak immune Might lead to improved health based therapies to rapidly seek and destroy infected and transformed cells. NK cells could be responses because of immune outcomes by targeting and clearing treat cancer effective treatments against cancer cells in 2 ways. First, they elicit robust checkpoint proteins expressed on cancer cells cytotoxicity by targeting multiple pathogenic antigens, such as stress cancer cells Might allow the use of donor cells proteins on the cell surface. Second, they induce controlled immune Might trigger dangerous runaway instead of relying only on the responses that reduce risk of cytokine storms or graft-vs-host disease immune responses in the host patient’s cells (GVHD). In addition, these NK cells can be collected from a variety of sources Might be an effective approach to without relying on patient-specific immune cells. Compared with T cells and treat both blood and solid-tumor B cells, NK cells have limited proliferation capability but can undergo robust cancers expansion in a laboratory. With enough cells after expansion, NK cells purportedly promote sustained immune responses to attack and clear cancer cells. Multiple companies (eg, Dragonfly Therapeutics, Waltham, Massachusetts; Nkarta Therapeutics, South San Francisco, California; Takeda Pharmaceutical Co, Tokyo, Japan) are investigating various NK cell–based therapies to treat cancer.

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Title Description Threats Opportunities

N-of-1 trials to N-of-1 trials focus on collecting treatment response data in a single patient Might predispose patients to being Might provide insight into the best research patient- and might represent the optimal form of clinical evaluation for patient- treated unethically by use of precision medicines, centered outcomes centered medicine. Researchers design a mini-investigation for an manufacturers of poorly thereby improving health experimental drug’s safety and efficacy entirely around an individual developed investigational agents outcomes patient’s response, to determine whether a particular treatment works for with small budgets Might make patient-centered that individual. For example, a patient might alternate between drug and Might be viewed as a threat by comparative data more accessible placebo for a couple of weeks at a time, and researchers record the some stakeholders who benefit to patients and physicians outcomes. These trial results can then be used to guide specific treatment from large, population-based, for a patient or be pooled with other n-of-1 trials of the same drug and same randomized controlled trials and experimental design to obtain population-level trends. An advantage of data current data aggregation systems from n-of-1 trials is that they can reveal how responses to treatments might vary among and within patients. N-of-1 trials are best used to evaluate treatments for chronic, slowly progressing conditions or frequently recurring or relapsing diseases. The ideal treatments to test in n-of-1 trials would demonstrate substantial individual differences in treatment effects, uncertainty regarding the best treatment regimen, rapid onset of drug action, or brief and safe washout periods. N-of-1 trial outcomes should be validated, repeatable measures and might include the use of biomarkers.

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Title Description Threats Opportunities

Novel antimicrobial Investigators are developing polymers, alloys, and coating technologies to Might lead to relaxed sanitation Might reduce health care–acquired environmental surface give commonly touched surfaces in health care and public health settings efforts infection rates coatings to prevent inherently sustained antimicrobial properties to limit the spread of Might cause skin irritations or Might improve overall population health care–acquired communicable diseases. Hong Kong researchers developed a Multilevel other adverse events not health when implemented in infections Antimicrobial Polymer (MAP-1) coating that purportedly introduces surface discovered in completed studies public settings moieties that disrupt microbial envelopes and surface molecules, rendering Might increase infrastructure costs Might reduce costs compared with pathogens (viruses, bacteria, and spores) unviable upon contact (up to without substantial impact on other infection-control measures 99.9% of highly infectious viruses and more than 98.7% of drug-resistant infection rates bacteria on hospital privacy curtains in 3 weeks). It can be used on metals, plastics, concrete, wood, glass, textiles, and leathers and without affecting surfaces’ look and feel for up to 90 days. The European Cooperation in Science and Technology (COST; Brussels, Belgium) has also conducted a special collaborative initiative to promote the development, testing, and commercialization of novel antimicrobial surfaces, making it easier for manufacturers and hospitals to implement this public health strategy. More than 60 institutes and companies from 33 European countries contributed to a database of active ingredients for use in antimicrobial coatings, as well as research findings and advice for developers to guide safety and effectiveness during testing. An Australian company, SPEE3D (Melbourne), has developed a way to 3-D print antimicrobial copper onto metal surfaces (eg, door handles, rails, touch plates in hospitals and schools) to improve the speed and cost-effectiveness of implementing antimicrobial surfaces. According to the manufacturer, its modified touch surfaces “contact kill” 96% of SARS-CoV-2, the virus that causes COVID-19, within 2 hours and 99.2% of the virus in 5 hours, compared with no reduction for stainless steel.

Section 6. Potentially Disruptive Trends 292

Title Description Threats Opportunities

Proteomic profiling to Proteomic profiling involves the systematic separation, identification, and Might add to clinician burden by Might improve patient health diagnose cancer and characterization of proteins present in a patient’s tumor or blood sample. In requiring them to learn about outcomes by detecting cancer guide personalized caring for patients suspected of having cancer, clinicians use proteomic protein signatures for different early and matching patients with targeted therapy profiling to identify a cancer-associated protein signature that might confirm cancer types and understand targeted therapies or clinical trials the presence and origin of a specific cancer type. For these patients, which could be drug targets likely to benefit them proteomic profiling helps identify overexpressed proteins that are known to Might increase disparities by being be therapeutic targets, such as those caused by chromosomal available only to patients who are rearrangements. Clinicians then use this information to select a targeted insured or able to pay for therapy, on-label or off-label, that is most likely to benefit a patient with treatment out of pocket cancer or to help enroll patients in clinical trials of investigational therapies. Multiple companies (eg, Biodesix, Boulder, Colorado; BSG, Monmouth Junction, New Jersey; NantOmics, Culver City, California) have developed proteomic assays to analyze specific proteomic biomarkers that might help develop personalized treatment plans for patients who have cancer.

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Psychedelic drugs to Psychedelic drugs (eg, psilocybin; lysergic acid diethylamide [LSD]; N,N- Might result in negative health Might improve health outcomes treat mental and dimethyltryptamine [DMT]; 3,4-methylenedioxymethamphetamine [MDMA]; outcomes for some patients and and quality of life for some behavioral health ketamine) alter one’s state of consciousness, purportedly by altering certain are therefore not recommended patients conditions neurotransmitters in the brain. Their use might provide the user with for every patient Might reduce the prevalence of altered perception, increased introspection, feelings of closeness with Might pose population health and treatment-resistant mental health others, and positive mood states. These experiences are often reported as legal risks related to making conditions and reduce costs deeply profound and life-altering. Although most psychedelics are controlled substances more associated with long-term mental designated as Schedule I drugs in the United States, researchers are accessible health treatment investigating their potential to treat a variety of mental and behavioral Might increase disparities in access Might positively shift the paradigm health disorders that have not responded to conventional treatments. The to care if clinicians hesitate to treat and infrastructure of mental health Multidisciplinary Association for Psychedelic Studies (Santa Cruz, California) patients using controlled care was established in 1986 to research and provide education regarding substances that carry stigma or a Might encourage continued potential therapeutic uses in mental health treatment. In September 2019, significant risk of harm or mental research into additional potential Johns Hopkins Medicine (Baltimore, Maryland) announced the launch of its deterioration therapeutic uses for psychedelic Center for Psychedelic and Consciousness Research to study psychedelic Might be costly in the short term if drugs and might enhance drugs to treat certain mental health conditions. The number of clinical trials significant costs are associated understanding of mental health on the use of psychedelics for mental health conditions is increasing. with building necessary treatment conditions Psilocybin is in clinical trials to investigate treatment for depression, infrastructure anorexia nervosa, obsessive-compulsive disorder, alcohol use disorder, nicotine dependence, cocaine use disorder, and cancer-related anxiety. LSD is being explored to treat anxiety associated with life-threatening illness, other anxiety disorders, and depression. DMT, a drug present in a psychoactive brew called ayahuasca, is being researched to treat depression. MDMA is in phase 3 clinical trials for use during psychotherapy to treat posttraumatic stress disorder (PTSD) and is being investigated as therapy for social anxiety in adults with autism. Most of these psychedelic drugs are not intended for frequent or long-term use, and therapeutic effects have been reported with as few as 2 to 3 treatments (eg, MDMA- assisted psychotherapy for PTSD). Ketamine, while not traditionally considered a psychedelic drug, has some psychedelic properties and is being explored off-label to treat PTSD. A closely related molecule, esketamine (Spravato, Janssen Pharmaceutical, Titusville, New Jersey), has been approved to treat depression.

Section 6. Potentially Disruptive Trends 294

Title Description Threats Opportunities

Smartphone-guided An accurate diagnosis, when made in a timely manner, can provide the best Might pose security risks or expose Might decrease overall costs medical examinations insight into treatment options for patients. A recent telehealth and eHealth patient health data inappropriately related to both patient care and and diagnostics for case study highlighted a patient’s case in which acute appendicitis was Might, because of user or device care delivery by reducing clinician’s use by patients and diagnosed via telehealth, allowing timely surgery to take place. Smartphone errors, lead to misdiagnosis or office visits caregivers apps can deliver examinations and diagnostic services to patients in remote mistreatment Might reduce disparities in terms areas by boosting the use of smartphones as diagnostic devices for multiple of access to care for patients in age groups. These apps are accompanied by handheld examination kits that rural areas allow patients or caregivers to perform guided medical examinations and Might increase patient autonomy share results with their provider for an appropriate diagnosis and treatment and satisfaction by involving options (eg, TytoCare [for ear infection, heart and lung sounds, throat patients and caregivers in the infection diagnosis], MoleScope [for skin screening], RetinaScope [for diagnostic process diabetic eye disease screening]). Might reduce burden on the health system, such as sequelae from overlooked symptoms for which patients did not have time or opportunity to seek in-person evaluation

Smart technology to Researchers are investigating new technologies to improve control of Might increase complication risk if Might improve patient mobility or enhance prosthetic prosthetic legs and restore a more normal gait. Prostheses are being implants are required function control outfitted with sensors, gyroscopes, and accelerometers combined with Might increase disparities based Might enhance quality of life and artificial intelligence (AI) algorithms. The goal is to interpret what the patient on technical complexity or psychological health is trying to do (eg, climb stairs) and move the prosthetic leg in the optimal geographic availability Might increase patient fashion to achieve the desired goal. Other groups are embedding sensors in Might increase treatment costs for productivity, or enable patient prosthetic legs that purportedly transmit real-time sensory feedback to prostheses and continuing device return to work or school wireless electrodes implanted in residual leg nerves to simulate the natural maintenance tactile sensations (eg, weight distribution and movement) of the missing lower limb. Similar research at a much earlier stage is evaluating ways to provide prosthetic hands with sensing technology to simulate touch sensations.

Section 6. Potentially Disruptive Trends 295

Title Description Threats Opportunities

Tumor-specific Surgery can be the only curative option for treating several lethal Might need further research to Might allow a more accurate and conjugated malignancies. Conventional imaging techniques, such as magnetic understand the long-term impacts complete resection of tumor fluorescent imaging resonance imaging (MRI), computed tomography (CT), and ultrasound, and uptake of surgery using tissue, leading to improved patient agents to help provide only limited information to identify small lesions for surgery and tumor-specific fluorescent agents outcomes visualize cancers confirm complete tumor removal after surgery. Near-infrared fluorescent Might increase logistical issues Might reduce costs of lengthy intended for surgical imaging techniques are now widely used during surgeries to address this before surgery postoperative treatments resection issue; however, these techniques are limited because they lack tumor specificity. Fluorescent dyes that are conjugated with tumor-specific antibodies might improve surgical accuracy by allowing real-time visualization of specific cancer cells during surgery. These imaging agents might offer an additional benefit of improving postsurgical assessments. For example, SGM-101, developed by SurgiMab (Montpellier, France), is a tumor- specific antibody conjugated to a dye that selectively targets a marker on the cancer cell surface known as carcinoembryonic antigen (CEA), which is overexpressed in colorectal cancer cells. Another example is cetuximab- IRDye800, a conjugated agent that binds to epidermal growth factor receptor for evaluating pancreatic cancer in patients undergoing surgical resection. Padeliporfin ImPACT (immune photo activated cancer therapy) is another example: an inactivated vascular-targeted drug padeliporfin activates and kills cancer cells locally when the tumor is exposed to low- power laser light. The FDA has granted Fast Track designation for padeliporfin to treat low-grade urothelial cancer to Steba Biotech (Luxembourg City, Luxembourg).

Section 6. Potentially Disruptive Trends 296

Title Description Threats Opportunities

Wearable drug Some drugs used to treat chronic conditions, such as multiple sclerosis, Might have severe health Might improve the injection delivery systems to diabetes mellitus, or rheumatoid arthritis, are injected under the skin. Often, consequences for patients due to experience, which can increase better manage chronic patients choose drug administration via self-injections because it requires device errors patient adherence to treatment conditions less-frequent dosing than does taking oral medications. Wearable drug Might increase costs for patients regimens delivery devices are intended to provide a simple, easy-to-use system to who do not have insurance Might boost patient confidence, improve patients’ adherence to the recommended treatment and improve coverage for these devices driving patients to take greater their health and quality of life. For example, SmartDose (West control of their health Pharmaceutical Services, Exton, Pennsylvania) is a preloaded device that Might increase ability to deliver allows larger volume on-body drug delivery less frequently and continuous high-volume and high-viscosity monitoring that can alert clinicians to make changes in treatment regimens. drug products to improve longer- Omnipod (Insulet, Acton, Massachusetts) is another wearable device that term health outcomes provides up to 72 hours of insulin delivery for patients with diabetes. Might reduce the risk of acquiring an infection in a clinic by changing the care setting to the patient’s home

Section 6. Potentially Disruptive Trends 297

Table 6.3. Trends Archived Since Last Status Report: 3 Trends

Title Description Threats Opportunities Archive reason

Calcitonin gene– CGRP inhibitors have emerged as a novel drug class to Might be difficult for some Might address the unmet The fourth CGRP inhibitor to related peptide prevent chronic and episodic migraine headaches and treat patients to give themselves need of patients with be FDA approved for (CGRP) inhibitors acute migraine headaches. They are monoclonal antibodies under-the-skin injections of migraine headache to migraines, eptinezumab, to prevent and that work by preventing CGRP, a protein found in trigeminal CGRP inhibitors at home, reduce headache frequency was approved in February treat migraine nerve ganglia, from binding to CGRP receptors, either by and there is a risk of and severity, thus improving 2020. As such, this trend headache blocking the receptor or CGRP itself. These actions infection and injection site patient outcomes, overall diffused clinically more than purportedly attenuate trigeminal nerve pain transmission and reactions health, and quality of life 1 year ago, making it no dilation of blood vessels thought to contribute to migraine Might be cost prohibitive to Might cause fewer side longer within the time scope headache. CGRP inhibitors are administered in subcutaneous some patients and effects than do currently for the PCORI Health Care injections at a frequency ranging from monthly to every 3 subsequently increase used preventive Horizon Scanning System. months. FDA-approved CGRP inhibitors to prevent migraine health disparities, medications, including The time scope is defined as headache include erenumab in May 2018, fremanezumab in considering CGRP inhibitors antidepressants, 3 years before an September 2018, galcanezumab in September 2018, and cost about $7000 per year antiepileptics, and intervention becomes eptinezumab in February 2020 . Others are in clinical per patient antihypertensives, which clinically available outside of development. In addition, CGRPs are in clinical development might improve patient the research setting to 1 for the acute treatment of migraine as a nasal spray. As outcomes, overall health, year after an intervention monoclonal antibodies, CGRP inhibitors are highly targeted and quality of life becomes clinically available. against CGRP and have demonstrated a more favorable side Might improve the effect profile compared with traditional migraine medications understanding of migraine including antiepileptics, antidepressants, and pathophysiology and antihypertensives. A 2018 Institute for Clinical and Economic change the standard of care Review (ICER) report looking at clinical trials for prevention of migraine and episodic headaches found that CGRP inhibitors demonstrated greater efficacy than did other preventive medications in reducing the number of headache days per month.

Section 6. Potentially Disruptive Trends 298

Title Description Threats Opportunities Archive reason

Comprehensive CGP involves sequencing a large panel (ie, thousands) of Might lead to overtreatment Might improve health This trend is beginning to genomic profiling cancer-associated genes in DNA and/or RNA isolated from a of some early-stage cancers outcomes for patients who diffuse. Multiple companies (CGP) in patients patient’s tumor tissue or blood sample. CGP is intended to that could resolve on their have limited targeted (eg, Foundation Medicine, who have cancer detect actionable genomic alterations (AGAs) known to be own therapy options Cambridge, Massachusetts; to identify therapeutic targets. Clinicians are using CGP (in both germline Might have limited Might strengthen Guardant Health, Redwood personalized and somatic testing scenarios) to determine the availability of insurance collaborations between City, California; Illumina, San targeted therapy aggressiveness and inheritable factors of cancers upon initial coverage because third- genetic counselors and Diego, California; Life diagnosis (germline testing; ie, in cells without cancer). It is party payers are likely to clinicians, promoting Technologies, Carlsbad, used to select targeted therapies (on-label or off-label) along cover CGP and targeted familiarity with AGAs and California) have developed the patient’s clinical pathway (somatic testing; ie, in cells with therapies for only specific identifying those that might CGP tests, a few of which cancer) to benefit patients with cancers that harbor AGAs. indications and are unlikely be drug targets have been FDA approved (ie, CGP also is being used to help identify patients who are to cover targeted therapies FoundationOne, eligible for clinical trials of investigational therapies for for unapproved indications Guardant360, Oncomine) as cancers with specific AGAs. Might increase disparities by companion diagnostics for being available only to one or more targeted patients who are insured or therapies. Insurance able to pay for treatment companies have also begun out of pocket to offer limited coverage for CGP.

Section 6. Potentially Disruptive Trends 299

Title Description Threats Opportunities Archive reason

Telehealth to treat Telehealth is the use of digital communication modalities to Might pose risks to patient Might improve individual A 150% increase in mental health provide health care services. It can be used to treat a variety confidentiality if and population health telehealth usage was conditions of behavioral health conditions, including anxiety, depression, communications are not outcomes by allowing reported in March 2020 by attention-deficit/hyperactivity disorder, and substance use secure patients quicker, more the CDC. Because it has disorders. While initially positioned as a tool that might help Might pose risks to patient convenient, and wider been widely diffused provide psychiatric assessments and treatment to patients to safety if health care access to mental health care clinically for more than 1 help address growing access-to-care issues and psychiatrist providers are not as readily and by allowing patients to year, it is no longer within shortages nationwide, the COVID-19 pandemic accelerated its able as during face-to-face pick providers who are best the time scope for the clinical diffusion and uptake. The Centers for Disease Control visits to collect crucial suited for them PCORI Health Care Horizon and Prevention (CDC) noted a 150% increase in telehealth information such as vital Might reduce health care Scanning System. usage in March 2020. This rise in usage persisted over the signs for medical decision costs by reducing the following months and provided proof of concept for clinicians, making amount of time patients are legislators, and payers. Telehealth will likely remain integrated Might be difficult to treat away from work, reducing into the health care system after the pandemic. patients with serious health money spent traveling to issues, like active suicidal appointments, and reducing ideation or alcohol overall treatment time withdrawal, from a distance, especially if providers are unfamiliar with local inpatient facilities and mental health resources Might impede a health care provider from establishing patient rapport as readily (compared with in-person visits), and providers might not understand a patient’s geographical and/or psychosocial context as well (compared with in-person visits)

Section 6. Potentially Disruptive Trends 300

Appendix. Abbreviations and Acronyms

A2E N-retinylidene-N-retinylethanolamine ADAMTS13 von Willebrand factor–cleaving protease AA anaplastic astrocytoma ADA-SCID adenosine deaminase–severe combined AADC aromatic l-amino acid decarboxylase immunodeficiency AADCD aromatic l-amino acid decarboxylase deficiency ADCY9 adenylate cyclase type 9 AAT alpha-1 antitrypsin ADHD attention-deficit/hyperactivity disorder AAV ANCA-associated vasculitis adRP autosomal-dominant retinitis pigmentosa AAV2 adeno-associated virus serotype 2 ADT androgen deprivation therapy AAV5 adeno-associated virus serotype 5 ADL activities of daily living AAV5-hFIXco-Padu codon-optimized human factor IX Padua gene AGA actionable genomic alteration AAV6 adeno-associated virus serotype 6 AHP acute hepatic porphyria AAV9 adeno-associated virus serotype 9 aHUS atypical hemolytic uremic syndrome Aβ amyloid beta AI artificial intelligence ABA applied behavior analysis ALAS1 aminolevulinic acid synthase 1 ABCA4 ATP binding cassette subfamily A member 4 ALD adrenoleukodystrophy ABCD1 ATP binding cassette subfamily D member 1 ALDP adrenoleukodystrophy protein AC6 adenylyl cyclase type 6 ALK ALK receptor tyrosine kinase ACC American College of Cardiology ALK2 activin receptor-like kinase-2; ACVR1 ACE angiotensin-converting enzyme ALL acute lymphoblastic leukemia AchR acetylcholine receptor ALS amyotrophic lateral sclerosis ACTH adrenocorticotropic hormone AMBAR Alzheimer Management by Albumin Replacement ACVR1 activin A receptor type 1 AML acute myeloid leukemia AD Alzheimer’s disease AMN adrenomyeloneuropathy Ad5.hAC6 adenovirus 5 encoding human AC6 AMP adenosine monophosphate ADA adenosine deaminase α-MSH alpha-melanocyte stimulating hormone ADAMTS13 ADAM metallopeptidase with thrombospondin ANCA antineutrophil cytoplasmic antibody type 1 motif, 13 Apo E apolipoprotein E

APPENDIX. ABBREVIATIONS AND ACRONYMS 301

AQP4 aquaporin-4 BOS bronchiolitis obliterans syndrome AQP4-IgG aquaporin-4-immunoglobulin G BP bullous pemphigoid ARB angiotensin-receptor blocker BRAF B-Raf proto-oncogene serine/threonine kinase ARG1 arginase 1 BRCA breast cancer ARSA arylsulfatase A BRCA1 breast cancer 1 ASBT apical sodium-dependent bile acid transporter BRCA2 breast cancer 2 ASD autism spectrum disorder BTK Bruton tyrosine kinase ASMD acid sphingomyelinase deficiency C1 complement component 1 ASS1 argininosuccinate synthase 1 C1-INH C1 esterase inhibitor ATP adenosine triphosphate C1q complement component 1q ATP7A P-type adenosine triphosphatase alpha C3 complement component 3 AUC area under the curve C3a completment component 3a anaphylatoxin AUD alcohol use disorder fragment B7-H3 human B7 family, homolog 3 C5 complement component 5 BCCNS basal cell carcinoma nevus syndrome C5a complement 5a anaphylatoxin fragment B cell bursa of Fabricius–maturing cell; B lymphocyte C5b-9 complement 5b complex 9 BCG bacillus Calmette-Guérin CAD cold agglutinin disease BCL-2 B-cell lympohma-2 CAH congenital adrenal hyperplasia BCMA B-cell maturation antigen CALD cerebral adrenoleukodystrophy BCVA best corrected visual acuity cAMP cyclic adenosine monophosphate BMI body mass index CAR chimeric antigen receptor BMP bone morphogenetic protein CAR-T chimeric antigen receptor T cells BMP2 bone morphogenetic protein 2 CB2 cannabinoid receptor 2 β-MSH beta-melanocyte stimulating hormone CBD cannabidiol BNP B-type natriuretic peptide CBT cognitive behavioral therapy cc cubic centimeters

APPENDIX. ABBREVIATIONS AND ACRONYMS 302

ccRCC clear cell renal cell carcinoma CEA carcinoembryonic antigen CD3 cluster of differentiation 3 CED convection-enhanced delivery CD3ζ cluster of differentiation 3ζ cells/kg cells of biologic agent per kilogram of body CD4+ cluster of differentiation 4–positive weight CD8+ cluster of differentiation 8–positive CEP290 centrosome protein 290 CD8α cluster of differentiation 8α CETP cholesteryl ester transfer protein CD19 cluster of differentiation 19 CF cystic fibrosis CD20 cluster of differentiation 20 CFTR cystic fibrosis transmembrane conductance regulator CD28 cluster of differentiation 28 CGG cytosine, guanine, guanine CD33 cluster of differentiation 33 cGMP cyclic guanosine monophosphate CD34+ cluster of differentiation 34–positive CGP comprehensive genomic profiling CD38 cluster of differentiation 38 CGRP calcitonin gene–related peptide CD38– cluster of differentiation 38–negative CH24H cholesterol 24-hydroxylase CD45 cluster of differentiation 45 CHARGE coloboma, heart defects, atresia choanae, CD47 cluster of differentiation 47 retarded growth and development, genital CD80 cluster of differentiation 80 hypoplasia, and ear abnormalities and deafness CD86 cluster of differentiation 86 CHM choroideremia CD123 cluster of differentiatino 123 CIS carcinoma in situ CD137 cluster of differentiation 137 CIT chemotherapy-induced thrombocytopenia CD155 poliovirus receptor nectin-like protein 5 CLD chronic liver disease CDC cardiosphere-derived cell CLL chronic lymphocytic leukemia CDD CDKL5 deficiency disorder cm2 square centimeters CDK4/6 cyclin-dependent kinases 4 and 6 CML chronic myelogenous leukemia CDKL5 cyclin-dependent kinase-like 5 CNTF ciliary neurotrophic factor CE Conformité Européene (European conformity) COL7A1 collagen

APPENDIX. ABBREVIATIONS AND ACRONYMS 303

COL7A1 collagen type VII alpha 1 chain D2 dopamine 2

COST Cooperation in Science and Technology DAAO D-amino acid oxidase COVID-19 coronavirus disease of 2019 DBS deep brain stimulation C-PLGD congenital plasminogen deficiency DBT dialectical behavior therapy cPMP cyclic pyranopterin monophosphate DCS D-cycloserine CPP cell-penetrating peptide DDC dopa decarboxylase CRC colorectal cancer DDLS dedifferentiated liposarcoma

CRF1 corticotropin-releasing factor type 1 DEA US Drug Enforcement Administration CRISPR clustered regularly interspaced short palindromic DEB dystrophic epidermolysis bullosa repeats DLBCL diffuse large B-cell lymphoma CRL Complete Response Letter DMD Duchenne muscular dystrophy CRM1 chromosome region maintenance 1; XPO1 DMD dystrophin CRT cardiac resynchronization therapy dMMR mismatch repair–deficient CSF-1R colony-stimulating factor-1 receptor DMT N,N-dimethyltryptamine CT computed tomography DQ developmental quotient CTCL cutaneous T-cell lymphoma DSM-IV Diagnostic and Statistical Manual of Mental CTGF connective tissue growth factor Disorders, Fourth Edition CTL cytotoxic T lymphocyte DSM-5 Diagnostic and Statistical Manual of Mental CTLA cytotoxic T lymphocyte-associated protein Disorders, Fifth Edition CTLA-4 cytotoxic T lymphocyte-associated protein 4 DTC direct-to-consumer CUA calcific uremic arteriolopathy DUX4 double homeobox 4 CXCL12 CXC chemokine ligand 12 E6 early expression 6 CXCR4 CXC chemokine receptor 4 E7 early expression 7 CXCR4 C-X-C motif chemokine receptor 4 EAP Expanded Access Program CYP21A2 cytochrome P450 family 21 subfamily EBV Epstein-Barr virus A member 2

APPENDIX. ABBREVIATIONS AND ACRONYMS 304

EBV+PTLD Epstein-Barr virus–associated posttransplant FcRn neonatal Fc receptor lymphoproliferative disorder FDA US Food and Drug Administration EBVST Epstein-Barr virus–specific T cell FGF23 fibroblast growth factor 23 ECG electrocardiogram FGFR fibroblast growth factor receptor ECT electroconvulsive therapy FGFR2 fibroblast growth factor receptor 2 EDS excessive daytime sleepiness FGFR3 fibroblast growth factor receptor 3 EEG electroencephalography FIX alias for coagulation factor IX gene, F9 EGFR epidermal growth factor receptor FLT3 fms-like tyrosine kinase 3 eGFR estimated glomerular filtration rate FMR1 fragile X mental retardation 1 EGJ esophagogastric junction Fmrp Fmr1 protein EMDR eye movement desensitization and reprocessing FOLFIRI leucovorin (folinic acid), 5-fluorouracil, and EpCAM epithelial cell adhesion molecule irinotecan EPP erythropoietic protoporphyria FOLFIRINOX leucovorin (folinic acid), 5-fluorouracil, irinotecan, ERK extracellular signal-related kinase and oxaliplatin ESA erythropoiesis-stimulating agent FOLFOX leucovorin (folinic acid), 5-fluorouracil, and oxaliplatin ESRD end-stage renal disease FOP fibrodysplasia ossificans progressiva eTNS external trigeminal nerve stimulation FOXN1 Forkhead Box N1 EZH2 enhancer of zeste homolog 2 FRDA Friedreich ataxia EZH2 enhancer of the zeste 2 polycomb repressive complex 2 subunit FSHD facioscapulohumeral muscular dystrophy F9 factor IX FSHD1 facioscapulohumeral muscular dystrophy type 1 FACIT Functional Assessment of Chronic Illness Therapy FT1050 small-molecule stem cell modulator (made by Fate Therapeutics) FAI fludarabine, cytarabine, and idarubicin FT4145 small-molecule stem cell modulator (made by FAS FS-7-associated surface antigen Fate Therapeutics) Fc crystallizable fragment FXN frataxin Fcγ crystallizable fragment-gamma

APPENDIX. ABBREVIATIONS AND ACRONYMS 305

FXR fornesoid X receptor 5-HT2A 5-hydroxytryptamine 2A; serotonin 2A FXS fragile X syndrome 24HC 24S-hydroxycholesterol GABA gamma-aminobutyric acid H3 histone

GABAA gamma-aminobutyric acid receptor A H3K4 lysine at amino acid 4 of histone H3 GABAergic gamma-aminobutyric acidergic H3K9 lysine at amino acid 9 of histone H3 GALT galactose-1 phosphate uridyl transferase hAAT human α1-antitrypsin GBM glioblastoma multiforme HAE hereditary angioedema GBq gigabecquerel HAP hydroxyapatite

GBS Guillain-Barré syndrome HbA1c glycated hemoglobin gc/g genome copies per gram of target tissue HBB hemoglobin subunit beta gc/kg genome copies per kilogram of body weight HCC hepatocellular carcinoma G-CSF granulocyte colony-stimulating factor HCHSS PCORI Health Care Horizon Scanning System GEA gastroesophageal adenocarcinoma HD Huntington disease GI gastrointestinal HDAC histone deacetylase GLP-1 glucagon-like peptide 1 HER2 human epidermal growth factor receptor 2 g/m2 grams per square meter of body surface area HES hypereosinophilic syndrome gMG generalized myasthenia gravis HF heart failure GnRH gonadotropin-releasing hormone HGF hepatocyte growth factor GO glycolate oxidase HIF hypoxia-inducible factor GPR40 G-protein coupled receptor 40 HIF-2α hypoxia-inducible factor-2 alpha GPR84 G-protein coupled receptor 84 HIPAA Health Insurance Portability and Accountability GTPase (guanosine triphosphate) superfamily of enzymes Act GVHD graft-vs-host disease HLA-A2 human leukocyte antigen serotype A2 gy gray (absorbed dose) HO heterotopic ossification HPBCT hematopoietic peripheral blood cell transplant 5-HT1A 5-hydroxytryptamine 1A; serotonin 1A HPV human papillomavirus

APPENDIX. ABBREVIATIONS AND ACRONYMS 306

HPV-16 human papillomavirus type 16 IL-2 interleukin-2 HPV-18 human papillomavirus type 18 IL-4R interleukin-4 receptor HR hormone receptor IL-4R interleukin-4 receptor HSC hematopoietic stem cell IL-5 interleukin-5 HSCT hematopoietic stem cell transplantation IL-5α interleukin-5 α chain HSCT-TMA hematopoietic stem cell transplantation– IL-15 interleukin-15 associated thrombotic microangiopathy IL-15α interleukin-15α HSIL high-grade squamous intraepithelial lesion IL-17 interleukin-17 HSP heat shock protein IL-21 interleukin-21 HSV-1 herpes simplex virus 1 IL-31 interleukin-31 HTT huntingtin IL-31α interleukin-31 α ICD implantable cardioverter-defibrillator INAD infantile neuroaxonal dystrophy ICU intensive care unit iPATH the Center for Innovative Phage Applications and IDH icocitrate dehydrogenase Therapeutics IDH1 icocitrate dehydrogenase 1 IPF idiopathic pulmonary fibrosis IDS iduronate-2-sulfatase IRB institutional review board IgA immunoglobulin A ITP immune thrombocytopenia IGF-1 insulinlike growth factor 1 IU international unit IGF-1R insulinlike growth factor 1 receptor IU/dL international unit per deciliter IgG immunoglobulin G IVIG intravenous immunoglobulin IgG1 Fc immunoglobulin G1 Fc domain JAK Janus kinase IgG2 immunoglobulin G2 JSCDH Journal of Sickle Cell Disease and IgG4 immunoglobulin G4 Hemoglobinopathies IgM immunoglobulin M Keap1/Nrf2 Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1/nuclear factor IL-1 interleukin-1 erythroid 2-related factor 2 IL-1β interleukin-1β

APPENDIX. ABBREVIATIONS AND ACRONYMS 307

KIT KIT proto-oncogene receptor tyrosine kinase MC4 melanocortin-4 177Lu lutetium-177 mCi millicurie LAG-3 lymphocyte-activator gene-3 MCI mild cognitive impairment LAPC locally advanced pancreatic cancer MCL mantle cell lymphoma LCA10 Leber congenital amaurosis 10 mCRPC metastatic, castration-resistant prostate cancer LDH lactate dehydrogenase MCSF monthly convulsive seizure frequency LDL low-density lipoprotein MDD major depressive disorder LGMD2D limb-girdle muscular dystrophy type 2D; α- MDM2 mouse double minute 2 homologue sarcoglycanopathy MDMA 3,4-methylenedioxymethamphetamine LGMD2E limb-girdle muscular dystrophy type 2E MDS myelodysplastic syndrome LHON Leber hereditary optic neuropathy MEC mitoxantrone, etoposide, and cytarabine

Lin– lineage cells–negative MeCP2 methyl CpG binding protein 2 LMNA lamin A/C MECP2 methyl CpG binding protein 2 LSD lysergic acid diethylamide MEK MAPK kinase kinase LSD1 lysine-specific demethylase 1 MEK1 MAPK kinase 1 LTB4 leukotriene B4 MEK2 MAPK kinase 2 LVAD left ventricular assist device MET mesenchymal-epithelial transition 6MWT 6-minute walk test g/dL milligram per deciliter MAC membrane attack complex MGFA Myasthenia Gravis Foundation of America MACE major adverse cardiovascular events g/kg microgram per kilogram of body weight MacTel macular telangiectasia mg/m2 milligram per square meter of body surface area MAOI monoamine oxidase inhibitor mg/mL milligram per milliliter of solution MAPK mitogen-activated protein kinase MGMT O6-methylguanine-DNA-methyltransferase MASP-2 mannan-binding lectin-associated serine MHC-II major histocompatibility complex molecule protease-2 class II MC1-R melanocortin-1 receptor ML machine learning

APPENDIX. ABBREVIATIONS AND ACRONYMS 308

μL microliter MUC1 mucin-1 mL/min/1.73 m2 milliliter per minute per 1.73 square meters of NADH nicotinamide adenine dinucleotide

body surface area NAGLU N-acetyl-alpha-D-glucosaminidase MLD metachromatic leukodystrophy NAM nicotinamide MM multiple myeloma ND4 NADH dehydrogenase 4 MMC mitomycin-C NDA New Drug Application mm Hg millimeters of mercury NET neuroendocrine tumor MoCD molybdenum cofactor deficiency NF1 neurofibromatosis type 1 MoCo molybdenum cofactor NF-kB nuclear factor kappa-light-chain-enhancer of MOCS1 molybdenum cofactor synthesis 1 activated B cells MPM malignant pleural mesothelioma NK natural killer MPO myeloperoxidase NK neurotrophic keratitis

MPS methoxsalen, phenytoin, and sirolimus NMDA N-methyl-D-aspartate MPS mucopolysaccharidosis NMIBC non–muscle invasive bladder cancer MPSII mucopolysaccharidosis type II; Hunter syndrome NMOSD neuromyelitis optica spectrum disorder MPSIIIA mucopolysaccharidosis type III A; Sanfilippo nNOS neuronal nitric oxide synthase syndrome type A NPC nasopharyngeal carcinoma MPSIIIB mucopolysaccharidosis type III B; Sanfilippo NPC Niemann-Pick disease type C syndrome type B NPC1 NPC intracellular cholesterol transporter 1 MRI magnetic resonance imaging NPC-1 Niemann-Pick disease type C1 mRNA messenger RNA NPC2 NPC intracellular cholesterol transporter 2 MSA multiple system atrophy NPC-2 Niemann-Pick disease type C2 MSI microsatellite instability NPD-A/B Niemann-Pick disease type A/B MSI-H microsatellite instability–high NPD-B Niemann-Pick disease type B mTOR mammalian target of rapamycin NSAA North Star Ambulatory Assessment mUC metastatic urothelial cancer NSAID nonsteroidal anti-inflammatory drug

APPENDIX. ABBREVIATIONS AND ACRONYMS 309

NSCLC non–small cell lung cancer PDUFA Prescription Drug User Fee Act NTproBNP N-terminal pro B-type natriuretic peptide PE Pseudomonas aeruginosa exotoxin A NTRK neurotrophic tyrosine receptor kinase PEComa perivascular epithelioid cell tumor NY-ESO-1 New York esophageal squamous cell carcinoma-1 PEDI Pediatric Evaluation of Disability Inventory NYHA New York Heart Association PET positron emission tomography OCT optical coherence tomography PET prolonged exposure therapy ODC ornithine decarboxylase PF pemphigus foliaceus OM oral mucositis PFIC progressive familial intrahepatic cholestasis p38 MAPKα p38 alpha mitogen-activated protein kinase PFIC1 progressive familial intrahepatic cholestasis p38 MAPKα/β p38 alpha/beta mitogen-activated protein kinase type 1 p53 tumor suppressor protein 53 PFIC2 progressive familial intrahepatic cholestasis type 2 p62 tumor suppressor protein 62; sequestosome-1 P-gp P-glycoprotein PAH pulmonary arterial hypertension PGRMC1 progesterone receptor member component 1 PARP poly adenosine diphosphate-ribose polymerase pH potential of hydrogen PBC primary biliary cholangitis PH primary hyperoxaluria PB-TURSO sodium phenylbutyrate and taurursodiol PH1 primary hyperoxaluria type 1 PC pachyonychia congenita PI3K phosphoinositide 3 kinase PCORI Patient-Centered Outcomes Research Institute PICO patient population, intervention, comparators, PCSK9 proprotein convertase subtilisin kexin type 9 outcomes PD-1 programmed cell death 1 PKD pyruvate kinase deficiency PDE4D phosphodiesterase type 4D PKLR pyruvate kinase L/R PDE9 phosphodiesterase type 9 PLA2G6 phospholipase A2, group VI PDGFR platelet-derived growth factor receptor PLG plasminogen PDGFRA platelet-derived growth factor receptor alpha PLK1 polo-like kinase 1 PD-L1 programmed cell death ligand 1 PMO phosphorodiamidate morpholino oligomer

APPENDIX. ABBREVIATIONS AND ACRONYMS 310

PN plexiform neurofibroma rC7 recombinant collagen type VII PNH paroxysmal nocturnal hemoglobinuria R-CHOP rituximab, cyclophosphamide, doxorubicin, Pol polymerase vincristine, and prednisone Pol I polymerase I RDEB recessive dystrophic epidermolysis bullosa Pol II polymerase II REP1 Rab escort protein 1 POMC proopiomelanocortin RET rearranged during transfection PPAR peroxisome proliferator-activated receptor RHO rhodopsin PPARα peroxisome proliferator-activated receptor alpha RNAi RNA interference PPARδ peroxisome proliferator-activated receptor delta ROCK2 rho-associated coiled-coil kinase 2 PPARγ peroxisome proliferator-activated receptor ROS reactive oxygen species gamma ROS1 ROS proto-oncogene 1 receptor tyrosine kinase PSC primary sclerosing cholangitis RP retinitis pigmentosa PSD-95 postsynaptic density-95 RPE-65 retinal pigment epithelium protein-65 PSMA prostate-specific membrane antigen RPGR retinitis pigmentosa GTPase regulator PST problem solving therapy RPGR-ORF 15 retinitis pigmentosa GTPase regulator-open PTC1 phosphatase type 2 C reading frame 15 PTCH1 patched 1 RRMM relapsed and refractory multiple myeloma PTSD posttraumatic stress disorder RTK receptor tyrosine kinase PV pemphigus vulgaris rTMS repetitive transcranial magnetic stimulation PVR proliferative vitreoretinopathy SAD social anxiety disorder PWS Prader-Willi syndrome SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 QT ventricular depolarization interval from the start SBRT stereotactic body radiotherapy of the Q wave to the end of the T wave SCA spinocerebellar ataxia Rab ras genes from rat brains SCD sickle cell disease RARγ retinoic acid receptor gamma SCLC small cell lung cancer ras rat sarcoma SCN1A sodium voltage-gated channel alpha subunit 1

APPENDIX. ABBREVIATIONS AND ACRONYMS 311

SCT stem cell transplantation STEAP1 six-transmembrane epithelial antigen of the SERPINA1 serpin family A member 1 prostate 1 SGCA sarcoglycan alpha STEMI ST-segment elevation myocardial infarction SGCB sarcoglycan beta STRO antistromal precursor antigen SGSH N-sulfoglucosamine sulfohydrolase T1DM type 1 diabetes mellitus sIBM sporadic inclusion body myositis T2DM type 2 diabetes mellitus Siglec-8 sialic-acid-binding immunoglobulin-like lectin 8 t(11;14) translocation between chromosomes 11 and 14 siRNA short interfering RNA TAA tumor-associated antigen SIRPα signal regulatory protein-α TAAR1 trace amine-associated receptor 1 SLAMF7 signaling lymphocytic activation molecule family TAZ tafazzin member 7 Tβ4 thymosin beta 4 SLL small lymphocytic lymphoma TBI traumatic brain injury SMA spinal muscular atrophy TCA tricyclic antidepressant Smad Sma/mothers against decapentaplegic homolog T cell thymus-originating cell; T lymphocyte Smad1 Sma/mothers against decapentaplegic homolog 1 TED thyroid eye disease Smad5 Sma/mothers against decapentaplegic homolog 5 TFPI tissue factor pathway inhibitor Smad8 Sma/mothers against decapentaplegic homolog 8 TGF-beta transforming growth factor beta SMN survival of motor neuron Th17 T helper 17 SMN1 survival of motor neuron 1, telomeric TIL tumor-infiltrating lymphocyte Smo Smoothened TIO tumor-induced osteomalacia SN-38 7-ethyl-10-hydroxycamptothecin TK2 thymidine kinase 2 SNRI serotonin and norepinephrine reuptake inhibitor TK2d thymidine kinase 2 deficiency SOD1 superoxide dismutase 1 TMA thrombotic microangiopathy SSRI selective serotonin reuptake inhibitor TMS transcranial magnetic stimulation STAT-3 signal transducer and activator of transcription 3 TNBC triple-negative breast cancer TP53 tumor protein p53

APPENDIX. ABBREVIATIONS AND ACRONYMS 312

TPO thrombopoietin VR-CAP bortezomib (Velcade), rituximab, TRACK-TBI Transforming Research and Clinical Knowledge in cyclophosphamide, doxorubicin (Adriamycin), and Traumatic Brain Injury prednisone TRBA T-cell redirecting bispecific antibody VT ventricular tachycardia Trop-2 trophoblast cell-surface antigen 2 wAIHA warm autoimmune hemolytic anemia TSC tuberous sclerosis complex WAS WASP actin nucleation promoting factor TSC1 TSC complex subunit 1 WAS Wiskott-Aldrich syndrome TSC2 TSC complex subunit 2 WASP Wiskott-Aldrich syndrome protein TTF tumor-treating field WHIM warts, hypogammaglobulinemia, infections, and myelokathexis TTP thrombotic thrombocytopenic purpura WT1 Wilms tumor protein TURBT transurethral resection of bladder tumor X-ALD chromosome X–linked adrenoleukodystrophy UBE3A ubiquitin protein ligase E3a XLRP X-linked retinitis pigmentosa UDCA ursodeoxycholic acid XPO1 exportin 1; chromosomal region maintenance 1 units/kg units of agent per kilogram of body weight (CRM1) US United States Z-AAT Z-alpha1 antitrypsin UVR ultraviolet radiation

VA US Department of Veterans Affairs VEGF vascular endothelial growth factor VEGFR vascular endothelial growth factor receptor vg viral genomes vg/kg viral genomes per kilogram of body weight VHL von Hippel Lindau VLCFA very-long-chain fatty acid VNS vagal nerve stimulation VOC vaso-occlusive crisis

APPENDIX. ABBREVIATIONS AND ACRONYMS 313