PCORI Health Care Horizon Scanning System Volume 2, Issue 3 Horizon Scanning Status Report September 2020 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 Damian Carlson, MS Christian Cuevas, PhD Andrea Druga, PA-C Marcus Lynch, PhD, MBA Misha Mehta, MS Prital Patel, MPH Brian Wilkinson, MA Donna Beales, MLIS Jennifer De Lurio, MS Eloise DeHaan, BS Eileen Erinoff, MSLIS Cassia Hulshizer, AS Madison Kimball, MS Maria Middleton, MPH Diane Robertson, BA Melinda Rossi, BA Kelley Tipton, MPH Rosemary Walker, MLIS Andrew Furman, MD, MMM, FACEP

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 the potential impact of intervention.

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 St, NW, Suite 900, Washington, DC 20036. ©2020 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org.

Suggested citation: Hulshizer R, Carlson D, Cuevas C, et al. PCORI Health Care Horizon Scanning System: 2020 Horizon Scanning Status Report: Volume 2, Issue 3. Patient-Centered Outcomes Research Institute; September 2020. Prepared by ECRI under Contract No. MSA- HORIZSCAN-ECRI-ENG-2018.7.12.

HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2020 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 third of 4 volumes planned for 2020 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 September 11, 2020. 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].

HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2020 ii

Contents

Preface ...... ii Contents ...... iii Introduction ...... 1 Section 1. Alzheimer’s Disease and Other Dementias: 12 Topics...... 7

Table 1.1. Alzheimer’s Disease and Other Dementias Topics Added Since Last Status Report: 1 Topic ...... 7 Table 1.2. Currently Monitored Alzheimer’s Disease and Other Dementias Topics: 10 Topics ...... 8 Table 1.3. Alzheimer’s Disease and Other Dementias Archived Since Last Status Report: 1 Topic ...... 14 Section 2. Cancer: 102 Topics ...... 15

Table 2.1. Cancer Topics Added Since Last Status Report: 18 Topics ...... 15 Table 2.2. Currently Monitored Cancer Topics: 78 Topics ...... 30 Table 2.3. Cancer Topics Archived Since Last Status Report: 6 Topics ...... 99 Section 3. Cardiovascular Diseases: 23 Topics ...... 104

Table 3.1. Currently Monitored Cardiovascular Diseases Topics: 23 Topics ...... 104 Section 4. Mental and Behavioral Health: 19 Topics ...... 124

Table 4.1. Mental and Behavioral Health Topics Added Since Last Status Report: 3 Topic ...... 124 Table 4.2. Currently Monitored Mental and Behavioral Health Topics: 15 Topics ...... 127 Table 4.3. Mental and Behavioral Health Topics Archived Since Last Status Report: 1 Topics ...... 142 Section 5. Rare Diseases: 128 Topics ...... 143

Table 5.1. Rare Diseases Topics Added Since Last Status Report: 23 Topics ...... 143 Table 5.2. Currently Monitored Rare Diseases Topics: 99 Topics ...... 165 Table 5.3. Rare Diseases Topics Archived Since Last Status Report: 6 Topics ...... 257 Section 6. Potentially Disruptive Trends: 37 Trends ...... 262

Table 6.1. Trends Added Since Last Status Report: 6 Trends ...... 262 Table 6.2. Currently Monitored Trends: 23 Trends ...... 265 Table 6.3. Trends Archived Since Last Status Report: 8 Trends ...... 277 Appendix. Abbreviations and Acronyms ...... 282

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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 an 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 years.

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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 trend 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

HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2020 2

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 if (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 more than 4400 leads has led to the identification of about 560 potential topics across the 5 PCORI priority areas and more than 100 high-level trends occurring in all areas of health care. After subjecting the potential topics to our inclusion criteria and nomination process, 284 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 284 topics and 37 trends are reported in this Status Report.

HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2020 3

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 . The 268 topics included in this report represent 151 diseases/conditions and span the PCORI-defined priority areas as follows (also see Figure 1): • Alzheimer’s disease and other dementias: 12 topics (4%) • Cancer: 102 topics (36%) • Cardiovascular diseases: 23 topics (8%) • Mental and behavioral health: 19 topics (7%) • Rare diseases: 128 topics (45%)

Figure 1. Percentage of Topics by Priority Area

HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2020 4

Across all priority areas, topics in this report represent the following therapeutic classes (also see Figure 2): • Cell therapy: 22 topics (8%) • Device (nonimplantable): 11 topics (4%) • therapy: 17 topics (6%) • Immunotherapy: 3 topics (1%) • Implant: 6 topics (2%) • : 12 topics (4%) • Other biotechnology: 24 topics (8%) • Pharmaceutical: 179 topics (63%) • Procedure (nonsurgical): 1 topic (0.4%) • RNA interference: 3 topics (1%) • Viral vector therapy: 6 topics (2%) Note: Total does not equal 100% because of rounding.

Figure 2. Percentage of Topics by Therapeutic Class

HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2020 5

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: 11 trends (30%) • Health information technology, apps, and smart devices: 7 trends (19%) • Innovative treatment models: 9 trends (24%) • Preventive measures: 2 trends (5%) • Proteomics, genomics, and personalized medicine: 6 trends (16%) • Screening and diagnostics: 2 trends (5%)

Note: Total does not equal 100% because of rounding

Figure 3. Percentage of Trends by Theme

HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2020 6 Section 1. Alzheimer’s Disease and Other Dementias: 12 Topics

Table 1.1. Alzheimer’s Disease and Other Dementias Topics Added Since Last Status Report: 1 Topic

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

Adults aged 50 years or older BAN2401 is a monoclonal antibody specific for amyloid beta Cholinesterase inhibitors AD progression Clinical trial(s): Phase 3 CLARITY who have mild cognitive (Aβ) under study to treat AD. The amyloid hypothesis of AD (eg, donepezil, galantamine, Overall survival primary completion February impairment due to Alzheimer’s suggests that disruptions to the production, accumulation, or rivastigmine) Quality of life 2022; phase 2 primary disease (AD) disposal of Aβ cause AD. In the body, Aβ exists in multiple Supportive care completion January 2022, conformations, including monomers, oligomers, protofibrils phase 2 data reported July (soluble Aβ aggregates), and insoluble fibers. Recent research 2018 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 7 Table 1.2. 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 monoclonal Cholinesterase inhibitors (eg, AD progression PDUFA date: March 7, 2021; who have prodromal to mild antibody against amyloid beta (Aβ) intended as a disease- donepezil, galantamine, Overall survival Alzheimer’s disease (AD) modifying therapy for AD. According to the manufacturer, rivastigmine) Quality of life FDA designation(s): Fast Track aducanumab preferentially binds neurotoxic oligomeric forms Supportive care Clinical trial(s): Phase 3b of Aβ, inhibits new Aβ aggregation, and promotes the 221AD304 primary completion disaggregation of existing Aβ aggregates, including plaques. September 2023; phase 3 In clinical trials, aducanumab was given intravenously at 1 of 2 EMERGE terminated August unspecified doses. 2019, top-line data presented Developer(s): December 2019; phase 3 Biogen (Cambridge, Massachusetts), in collaboration with ENGAGE primary terminated Neurimmune AG (Schlieren-Zurich, Switzerland) and Eisai Co, August 2019, top-line data Ltd (Tokyo, Japan) presented December 2019 Note(s): This topic had been archived in the June 2019 Status Report because aducanumab’s developers had announced discontinuation of their phase 3 clinical trials of the drug, stating that it was unlikely to meet its primary end points. However, in December 2019, Biogen announced that aducanumab had met its primary goal in the subset of patients receiving a high dose of aducanumab and that the company would continue to seek FDA approval for the drug.

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 85 years AGB101 is a proprietary, low-dose, extended-release Supportive care Cognitive performance, Clinical trial(s): Phase 3 who have mild Alzheimer’s formulation of the antiepileptic drug levetiracetam intended to as measured by AD- HOPE4MCI primary completion disease (AD) treat mild cognitive impairment (MCI) due to AD. AGB101 specific clinical ratings September 2022 could be the first disease-modifying treatment that slows the and scales progression and delays the onset of Alzheimer’s dementia, AD progression leading to improved cognitive ability and reduced long-term Quality of life care costs. AGB101 purportedly blocks hippocampal overactivity that is associated with neurodegeneration and memory loss symptoms in patients with MCI due to AD. In clinical trials, AGB101 is given orally at a dosage of 220 mg once daily for 78 weeks. Developer(s): AgeneBio, Inc (Baltimore, Maryland)

Adults aged 55 to 80 years Atuzaginstat (COR388) is a bacterial protease inhibitor that Cholinesterase inhibitors (eg, Cognitive performance, Clinical trial(s): Phase 2/3 GAIN who have mild to moderate targets the infectious pathogen Porphyromonas gingivalis donepezil, galantamine, measured by Alzheimer’s primary completion December Alzheimer’s disease (AD) gingipains, a bacterium purportedly linked to periodontal rivastigmine) Disease Assessment 2021 disease and AD and linked to the production of amyloid beta Memantine (off-label) Scale-Cognitive Subscale (Aβ) in preclinical and clinical models. P gingivalis gingipains is 11 found in the brain tissue and cerebral spinal fluid of people Progression of AD with AD. Atuzaginstat purportedly could be the first disease- Quality of life 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 by mouth 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 55 to 91 years Brexpiprazole (Rexulti) is an atypical antipsychotic Antianxiety drugs Agitation, as measured Clinical trial(s): Phase 3 primary who have Alzheimer’s disease that purportedly reduces agitation in patients with AD by Antidepressants by accepted clinical completion November 2020; (AD)–associated agitation modulating serotonin-dopamine activity in the brain. Although Antipsychotics (eg, ratings and scales phase 3 extension primary antipsychotics are sometimes used off-label to treat this haloperidol) Quality of life completion July 2021; phase 3 condition, they carry an increased risk of death in patients with completed March 2017; phase Atypical antipsychotics (eg, dementia. Brexpiprazole might have a better safety profile 3 completed March 2017, data aripiprazole) than other antipsychotics. According to the manufacturer, published April 2020 Beta-adrenergics brexpiprazole is a partial agonist (ie, activator) of serotonin 1A Note(s): Brexpiprazole is FDA (5-HT1A) and dopamine 2 (D2) receptors and an antagonist of Caregiver intervention and approved to treat serotonin 2A (5-HT2A) receptors. Brexpiprazole might also bind environmental modification schizophrenia and as adjunctive to noradrenaline α1B/2C receptors In clinical trials. Brexpiprazole (eg, removed or alleviated treatment for major depressive is given orally at a dosage of 1 to 3 mg once daily for 10 to 14 stressors) disorder (MDD) weeks. Synthetic Developer(s): tetrahydrocannabinol Otsuka Holdings Co, Ltd (Tokyo, Japan), in collaboration with H Lundbeck A/S (Valby, Denmark)

Adults aged 55 to 79 years Cromolyn and ibuprofen (ALZT-OP1) is a combination therapy Cholinesterase inhibitors (eg, Disease progression Clinical trial(s): Phase 3 who have evidence of early intended to slow or reverse cognitive and functional decline in donepezil, galantamine, Morbidity COGNITE primary completion Alzheimer’s disease (AD) patients with early-stage AD. Cromolyn acts as an amyloid rivastigmine) Survival December 2020, designed beta (Aβ) polymerization inhibitor to purportedly block the under Special Protocol Supportive care Quality of life development and spread of Aβ plaques. The ibuprofen Assessment 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 10

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 (eg, Cognitive performance FDA designation(s): Fast Track who have mild to moderate progesterone receptor member component 1 (PGRMC1) that donepezil, galantamine, Progression of AD Clinical trial(s): Phase 2 primary Alzheimer’s disease (AD) is intended to slow AD’s progression. No disease-modifying rivastigmine) Quality of life completion June 2020; phase treatments for AD are available, and current treatments Memantine (off-label) 1/2 primary completion January address only symptoms. PGRMC1 is a cell-surface 2021 expressed in brain synapses that acts as a receptor for oligomeric amyloid beta (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)

Adults aged up to 90 years Leuco-methylthioninium dihydromethanesulfonate (LMTX) is a Cholinesterase inhibitors (eg, Brain atrophy rate Clinical trial(s): Phase 3 who have early Alzheimer’s tau aggregation inhibitor being developed as a disease- donepezil, galantamine, Cognition and memory, LUCIDITY primary completion disease (AD) modifying treatment for AD. It is intended to reduce levels of rivastigmine) as measured by accepted December 2021 aggregated or misfolded tau in the brain, which are Supportive care clinical ratings and scales believed to contribute to AD pathology. In clinical trials, LMTX Quality of life is given by mouth at a dosage of 8 to 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 11

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

Adults aged 55 years or older Neflamapimod is a small-molecule inhibitor of the intracellular Alternative therapies (eg, Cognitive impairment FDA designation(s): Fast Track who have probable Lewy body p38 alpha mitogen-activated protein (p38 music therapy, pet therapy) Quality of life Clinical trial(s): Phase 2 AscenD- dementia and have received MAPKα) under study to treat Lewy body dementia. Chronically Cholinesterase inhibitors (off- LB primary completion June cholinesterase inhibitor active p38 MAPKα purportedly plays a role in the alpha label) 2020 therapy for longer than 3 synuclein–associated toxicity observed in the brains of patients Parkinson disease months with Lewy body dementia. Neflamapimod purportedly (eg, carbidopa-levodopa) improves 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)

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

Adults aged 50 to 85 years Troriluzole (BHV-4157) is a third-generation, tripeptide- Cholinesterase inhibitors (eg, Symptom severity, as Clinical trial(s): Phase 2/3 T2 who have mild to moderate prodrug conjugate of riluzole being developed as a disease- donepezil, galantamine, measured by accepted Protect AD primary completion Alzheimer’s disease (AD) modifying treatment for AD. In patients with AD, damaged rivastigmine) clinical ratings and scales December 2020 brain cells are susceptible to cellular injury by overactivity of Memantine (off-label) Bioavailability, safety, and the excitatory neurotransmitter glutamate. Riluzole is a sodium dosing channel blocker and glutamate modulator approved by FDA to Disease progression treat amyotrophic lateral sclerosis (ALS). It purportedly reduces Quality of life glutamate-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 orally 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 13 Table 1.3. Alzheimer’s Disease and Other Dementias Archived Since Last Status Report: 1 Topic

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

Adults aged 50 to 90 years Pimavanserin (Nuplazid) is a selective serotonin inverse Supportive care Psychosis symptom severity Stakeholder commenters who have dementia-related agonist that is intended to treat dementia-related psychosis. Frequency of thought that the data from the psychosis FDA has approved no medications for dementia-related hospitalizations late-phase trials showed some psychosis. Pimavanserin is intended to improve patient health Quality of life clinical effect for short-term outcomes and quality of life by reducing hallucinations and health outcomes, but they had delusions, which about 30% of patients with dementia concerns about the risk of experience. Pimavanserin purportedly preferentially inhibits adverse events (eg, confusion the activity of serotonin 2A (5-HT2A) receptor that is associated or hallucinations, weight gain, with dementia-related psychosis. The exact mechanism of prolonged QT interval), which action is unknown. In a clinical trial, pimavanserin was given by they thought would mouth at a dosage of 20 or 34 mg once daily, and patients significantly limit its disruptive were followed for up to 26 weeks or until a relapse of potential. psychosis occurred. Developer(s): Acadia Pharmaceuticals, Inc (San Diego, California)

Section 1. Alzheimer’s Disease and Other Dementias 14 Section 2. Cancer: 102 Topics

Table 2.1. Cancer Topics Added Since Last Status Report: 18 Topics

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

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

Section 2. Cancer 15 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 plus CD20 Progression-free survival FDA designation(s): refractory indolent receptor (CAR) T-cell therapy under study for treating antibody (eg, Overall survival Breakthrough Therapy non-Hodgkin lymphoma (eg, indolent non-Hodgkin lymphoma (eg, follicular lymphoma, , ) Health-related quality of Clinical trial(s): Phase 2 ZUMA- follicular lymphoma, marginal marginal zone lymphoma). Indolent non-Hodgkin CD20 monoclonal life 5 primary completion zone lymphoma) and have lymphomas are incurable B-cell lymphomas that typically antibody February 2022, data presented received at least 2 prior lines respond to initial chemoimmunotherapy. However, for the May 2020 of therapy subset of patients whose disease progresses during Lenalidomide plus CD20 Note(s): FDA previously treatment with multiple agents, limited treatment options are monoclonal antibody approved axicabtagene available and prognosis is poor. To produce axicabtagene ciloleucel to treat adults who ciloleucel, autologous T cells are genetically modified to PI3K inhibitor (eg, , ) have relapsed or refractory express a CAR fusion protein with a CD19-specific antigen large B-cell lymphoma after 2 Tazemetostat recognition domain and a T-cell activation domain. These or more lines of systemic genetically modified cells are expanded in a laboratory therapy, including diffuse before infusion into the patient, where they purportedly large B-cell lymphoma induce a cytotoxic response to CD19-expressing lymphoma (DLBCL) not otherwise cells and normal B cells. In clinical trials, axicabtagene specified, primary mediastinal ciloleucel is given as a single infusion at an unspecified dose. large B-cell lymphoma, high- Developer(s): grade B-cell lymphoma, and Kite Pharma, a Gilead Company (South San Francisco, DLBCL arising from follicular California) lymphoma

Section 2. Cancer 16 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): Fast Track, myelofibrosis or myelofibrosis lysine-specific demethylase 1 (LSD1) under study for treating (eg, , splenomegaly) Orphan Drug arising from polycythemia myelofibrosis, a myeloproliferative neoplasm in which bone ) Progression-free survival Clinical trial(s): Phase 2b trial vera or essential marrow stem cells develop abnormally. Two Janus kinase JAK inhibitors (eg, Overall survival primary completion December thrombocytopenia (JAK) inhibitors (ruxolitinib and fedratinib) have been FDA fedratinib, ruxolitinib) 2020, preliminary data approved for treating myelofibrosis. However, only about presented June 2020 50% of patients respond to these therapies and the therapies have not demonstrated a substantial effect on limiting disease progression. LSD1 plays a role in the regulation of gene expression by altering the histone methylation state. Bomedemstat’s inhibition of LSD1 purportedly increases lysine at amino acid 4 of histone H3 (H3K4) and H3K9 methylation, 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 administered orally once daily at an unspecified dose. Developer(s): Imago Biosciences (South San Francisco, California)

Section 2. Cancer 17

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

Children aged 2 years or older Burosumab-twza (Crysvita) is a fully human, recombinant One or more of the Increase in osteoid surface, Approval date: June 18, 2020 and adults who have monoclonal antibody against FGF23, a hormone that following: thickness, and volume Clinical trial(s): Phase 2 fibroblast growth factor 23 regulates phosphate and vitamin D levels. TIO is a rare Phosphate supplements Quality of life UX023T-CL201 primary (FGF23)–related disease characterized by a reduction of phosphate and (eg, aluminum phosphate, completion July 2017, data hypophosphatemia in tumor- vitamin D levels in the blood, resulting in the weakening and calcium phosphate, presented November 2018 induced osteomalacia (TIO) softening of bones. Tumors that release high levels of FGF23 magnesium phosphate) Note(s): FDA previously associated with phosphaturic are the underlying cause of TIO. Surgical resection of the Vitamin D analogues (eg, approved burosumab-twza to mesenchymal tumors that tumor typically leads to a full recovery in patients with TIO; calcitriol, ergocalciferol, treat X-linked cannot be curatively resected however, patients whose tumor is too small to be localized or paricalcitol) hypophosphatemia or localized is too large or invasive to be surgically removed have no treatment options other than 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 18 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 ornithine decarboxylase following: Progression-free survival Drug, Breakthrough Therapy astrocytoma (AA) after (ODC), an enzyme involved in synthesis of polyamines, which Alkylating agents (eg, Quality of life Clinical trial(s): Phase 3 radiation therapy and are essential for cell proliferation. AA is a rare type of glioma, , temozolomide) STELLAR primary completion adjuvant temozolomide a tumor that occurs in the brain and spinal cord, originating Angiogenesis inhibitors June 2020 treatment from cells called astrocytes that surround and protect (eg, ) neurons. Eflornithine’s inhibition of ODC purportedly causes Vinca alkaloids (eg, a cytostatic effect in rapidly 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)

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

Section 2. Cancer 19 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 Complete response rate FDA designation(s): refractory myelodysplastic mutated form of the enzyme isocitrate dehydrogenase 1 agents (eg, lenalidomide) Overall survival Breakthrough Therapy syndrome (MDS) with a (IDH1) known to occur in about 3% of patients with MDS. Quality of life Clinical trial(s): Phase 1 susceptible IDH1 gene Limited treatment options for MDS exist, and no standard of primary completion December mutation care exists for MDS that is unresponsive to treatment with a 2020; phase 2 primary . The mutant form of IDH1 causes completion January 2022 accumulation of the oncometabolite D-2-hydroxyglutarate Note(s): Ivosidenib is FDA and a decrease in the levels of IDH1’s normal metabolite, α- approved to treat acute ketoglutarate. These shifts purportedly have multiple effects myeloid leukemia (AML) with (eg, histone modification, DNA methylation) that keep cells in a susceptible IDH1 gene a dedifferentiated state characteristic of MDS cells. Inhibiting mutation as detected by an the mutated form of IDH1 with ivosidenib purportedly causes FDA-approved test differentiation of MDS cells, reducing malignancy. Ivosidenib is taken daily as a 500-mg oral tablet. Developer(s): Agios Pharmaceuticals (Cambridge, Massachusetts)

Adults who have ocular /Hepatic Delivery System (HDS) is a catheter-based Cryoablation Overall survival Clinical trial(s): Phase 3 FOCUS metastases in the system used to percutaneously deliver the bifunctional Embolization (ie, Progression-free survival primary completion April liver parenchyma alkylating agent melphalan to the liver while protecting the , Quality of life 2020, designed under Special patient’s system from the toxicity of high-dose immunotherapy, radiation) Protocol Assessment chemotherapy. Blood exiting the liver is filtered outside the Thermal ablation 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 treatment at a dose of 3 mg/kg infusion directly to the liver using the HDS over 30 minutes followed by a 30-minute washout. Treatments are given 6 weeks apart with an acceptable delay for 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 20 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have unresectable is a first-in-class monoclonal antibody specific One or more of the Overall survival FDA designation(s): Orphan locally advanced pancreatic for connective tissue growth factor (CTGF). It is under study following: Progression-free survival Drug, Fast Track cancer (LAPC) to treat unresectable LAPC, which is associated with median Antimetabolites (eg, Quality of life Clinical trial(s): Phase 3 LAPIS survival of 6 to 10 months compared with about 23 months gemcitabine) primary completion for patients with resectable LAPC. CTGF promotes (eg, nab- September 2022; phase 1/2 desmoplasia (the growth of fibrous or connective tissue) ) primary completion December associated with pancreatic tumors, which creates a 2019, data reported June 2018 microenvironment 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)

Adults who have AIDS-related Pomalidomide (Pomalyst) is an FDA-approved, small- One or more of the Overall survival Approval date: May 14, 2020 Kaposi sarcoma that has molecule derivative of thalidomide with immunomodulatory following: Progression-free survival FDA designation(s): Orphan become resistant to activity. Kaposi sarcoma is a rare cancer that usually arises as Anthracyclines (eg, Quality of life Drug, Breakthrough Therapy antiretroviral therapy or who skin lesions but can also develop in lungs, lymph nodes, and ) Clinical trial(s): Phase 1/2 12- have Kaposi sarcoma and test the digestive system. Kaposi herpesvirus infection causes the Antimetabolites (eg, C-0047 primary completion negative for HIV cancer, and immunocompromised individuals, such as those gemcitabine) September 2025, data infected with HIV, are at high risk of the disease. Immunomodulatory published December 2016 Pomalidomide has been designed to modulate immunologic agents (eg, lenalidomide, Note(s): This Accelerated cytokines (eg, tumor necrosis factor-α, -6) and thalidomide) Approval requires the conduct blood vessel–forming factors (ie, vascular epithelial growth of a further clinical trial to factor) and to enhance T-cell stimulation. Pomalidomide is Proteasome inhibitors (eg, verify and describe intended to prevent tumor growth and promote antitumor ) pomalidomide’s clinical immune responses. The recommended dosage in the FDA- Taxanes (eg, nanoparticle benefit. FDA previously approved label is 5 mg taken orally on days 1 to 21 of a 28- albumin-bound paclitaxel) approved pomalidomide to day cycle until disease progression or intolerable toxicity. Vinca alkaloids (eg, treat multiple myeloma. Developer(s): vinorelbine) Celgene Corp (Summit, New Jersey), a subsidiary of Bristol Myers Squibb Co (New York, New York)

Section 2. Cancer 21 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 tyrosine One or more of the Overall survival FDA designation(s): Orphan pancreatic cancer previously derivative under study as a third-line treatment for pancreatic following: Progression-free survival Drug treated with 2 lines of cancer, which has no FDA-approved treatment options. The Antimetabolites (eg, 5- Quality of life Clinical trial(s): Phase 2/3 systemic therapy 5-year overall survival rate for patients with advanced , gemcitabine, Tyme-88-Panc primary pancreatic cancer is less than 3%; median survival is about 3 ) completion December 2020, months. Racemetyrosine purportedly inhibits protein Chemoprotectant (eg, data presented April 2019 synthesis, including the synthesis of the protein MUC1, which leucovorin) leads to increased cellular oxidative stress and exposure to DNA synthesis inhibitor the body’s . In clinical trials, racemetyrosine is (eg, ) given orally at a dosage of 920 mg daily with 3 conditioning agents (MPS: methoxsalen 10 mg, phenytoin 50 mg, sirolimus EGFR inhibitor (eg, 0.5 mg), which are thought to potentiate the effects of erlotinib) racemetyrosine, with sirolimus increasing its uptake or Platinum-based agents methoxsalen and phenytoin increasing levels of reactive (eg, ) species. Developer(s): Tyme Technologies, Inc (New York, New York), in collaboration with Eagle Pharmaceuticals, Inc (Woodcliff Lake, New Jersey)

Section 2. Cancer 22

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

Adults with relapsed or Selinexor (Xpovio) is a first-in-class inhibitor of the nuclear One or more of the Progression-free survival Approval date: June 22, 2020 refractory diffuse large B-cell export protein, XPO1 (also called CRM1). Selinexor is under following: Overall survival FDA designation(s): Fast Track lymphoma (DLBCL), not study for treating DLBCL, an aggressive B-cell non-Hodgkin Alkylating agents (eg, Health-related quality of Clinical trial(s): Phase 2b otherwise specified, including lymphoma. Patients with relapsed or refractory DLBCL bendamustine, life SADAL primary completion DLBCL arising from follicular ineligible for hematopoietic transplantation (HSCT) ) June 2020, data published July lymphoma, after at least 2 or chimeric antigen receptor (CAR) T-cell therapy have Anthracyclines (eg, 2020 lines of systemic therapy limited treatment options and poor prognosis. Selinexor’s doxorubicin) Note(s): FDA previously binding to XPO1 purportedly restores nuclear localization (ie, Antimetabolites (eg, approved selinexor for accumulation in the cell nucleus) of various tumor suppressor , gemcitabine) treating relapsed or refractory proteins, thereby restoring and amplifying their tumor multiple myeloma suppressor function. By restoring tumor suppressor function, Glucocorticoids (eg, selinexor purportedly promotes cancer cell death while dexamethasone, sparing normal cells (ie, selective apoptosis induction). The prednisone) recommended dosage in the FDA-approved label is 60 mg Immunoconjugates (eg, taken by mouth on days 1 and 3 of each week. , Developer(s): ) Karyopharm Therapeutics, Inc (Newton, Massachusetts) Immunomodulatory drugs (eg, lenalidomide) Kinase inhibitors (eg, ibrutinib) Monoclonal antibodies (eg, rituximab) Platinum-based agents (eg, , ) Topoisomerase inhibitors (eg, , ) Vinca alkaloids (eg, vincristine, vinorelbine)

Section 2. Cancer 23 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 Clinical trial(s): Phase 2/3 SEAL older and adults who have selective inhibitor of the nuclear export protein, XPO1 (also following: Progression-free survival primary completion June advanced unresectable called CRM1). Selinexor’s novel mechanism of action is Alkylating agents (eg, Quality of life 2020, top-line data expected dedifferentiated liposarcoma intended to provide an option for patients with previously dacarbazine, in fourth quarter of 2020 (DDLS) and have received at treated DDLS because they have a poor prognosis. temozolomide) Note(s): FDA previously least 2 prior systemic Selinexor’s binding to XPO1 purportedly restores nuclear Antimetabolites (eg, approved selinexor for therapies localization, or the accumulation of tumor suppressor gemcitabine) treating multiple myeloma proteins in the cell nucleus, thereby restoring and amplifying Antitumor antibiotics (eg, and diffuse large B-cell their tumor suppressor function. By restoring tumor anthracyclines, mitomycin- lymphoma suppressor function, selinexor purportedly promotes cancer C) cell death while sparing normal cells (ie, selective apoptosis induction). In clinical trials, selinexor is given orally at a dose Microtubule inhibitors (eg, of 60 mg twice weekly until disease progression or eribulin, vinorelbine) intolerable toxicity. Multikinase inhibitors (eg, Developer(s): pazopanib, regorafenib) Karyopharm Therapeutics, Inc (Newton, Massachusetts) Tropomyosin receptor kinase inhibitor (eg, larotrectinib)

Section 2. Cancer 24 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. RET is a receptor following: Progression-free survival FDA designation(s): RET locally advanced or metastatic tyrosine kinase encoded by the gene that regulates cell Angiogenesis inhibitors Quality of life Breakthrough Therapy non–small cell lung cancer proliferation, migration, and differentiation. About 2% of (eg, bevacizumab, Clinical trial(s): Phase 3 RET (NSCLC) harboring a fusion in NSCLC cases have a gene-fusion event that produces an ) LIBRETTO-431 primary RET a gene called rearranged oncogenically activated form of RET. fusion–positive Anthracyclines (eg, completion December 2023; RET during transfection, NSCLC is an aggressive disease with a poor prognosis and doxorubicin) phase 1/2 LIBRETTO-001 limited treatment options. Selpercatinib has been designed Antimetabolites (eg, primary completion March to inhibit diverse RET fusions and anticipated acquired- , gemcitabine) 2022, data presented May resistance mutations with nanomolar potency. Selpercatinib- 2020 mediated inhibition of RET fusion–positive tumor cells Immune checkpoint Note(s): This Accelerated purportedly prolongs survival of patients with NSCLC and inhibitors (eg, , Approval requires the conduct might improve health outcomes. Patients must undergo ) of a further clinical trial to genetic testing before initiating selpercatinib treatment. The Platinum agents (eg, verify and describe recommended dosage in the FDA-approved label is 160 mg carboplatin, cisplatin) selpercatinib’s clinical benefit. taken by mouth twice daily until disease progression or Taxanes (eg, , FDA has also approved intolerable toxicity. paclitaxel) selpercatinib to treat Developer(s): Vinca alkaloids (eg, medullary thyroid cancer. Loxo Oncology, Inc (Stamford, Connecticut), a subsidiary of , vinorelbine) Eli Lilly and Co, Inc (Indianapolis, Indiana)

Section 2. Cancer 25 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 survival FDA designation(s): refractory follicular lymphoma (CAR) T-cell therapy under study to treat follicular lymphoma, antibody (eg, Overall survival Regenerative Medicine an incurable, indolent B-cell non-Hodgkin lymphoma. obinutuzumab, rituximab) Health-related quality of Advanced Therapy Follicular lymphoma typically responds to initial CD20 monoclonal life Clinical trial(s): Phase 2 ELARA chemoimmunotherapy. However, for the subset of patients antibody primary completion whose disease has progressed on treatment with multiple Ibritumomab tiuxetan November 2020, interim data agents, limited treatment options are available and prognosis Lenalidomide plus CD20 reported August 2020 is poor. To produce tisagenlecleucel, autologous T cells are monoclonal antibody Note(s): FDA previously genetically modified to express a CAR fusion protein with a approved tisagenlecleucel to CD19-specific antigen recognition domain and a T-cell PI3K inhibitor (eg, copanlisib, idelalisib) treat relapsed or refractory activation domain. These genetically modified cells are diffuse large B-cell lymphoma expanded in a laboratory before infusion into the patient, and relapsed or refractory where they purportedly induce a cytotoxic response to CD19- acute lymphoblastic leukemia expressing lymphoma cells and normal B cells. In clinical (ALL) trials, tisagenlecleucel is given as a single infusion at an unspecified dose. Developer(s): 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 have mantle cell (Venclexta) plus ibrutinib (Imbruvica) is a Bendamustine with or Overall survival Clinical trial(s): Phase 3 lymphoma (MCL) and combination therapy approach under study as a treatment without rituximab Progression-free survival SYMPATICO primary received at least one prior for relapsed or refractory MCL. MCL is a rare B-cell non- Bortezomib with or Health-related quality of completion March 2022; treatment regimen that did Hodgkin lymphoma that arises from the mantle zone of the without rituximab life phase 2 trial completed June not achieve a response lymph node. Patients with diagnosed MCL typically respond BTK inhibitors (eg, 2017, data published March to intensive chemotherapy, but MCL invariably relapses, with acalabrutinib, ibrutinib) 2018 increasingly shorter remission periods achieved with with or without rituximab Note(s): FDA previously subsequent lines of therapy. Venetoclax and ibrutinib are 2 Lenalidomide with or approved ibrutinib for treating drugs that have demonstrated clinical activity against various without rituximab MCL (as a monotherapy), B-cell lymphomas, including MCL, through nonoverlapping chronic lymphocytic leukemia R-CHOP (rituximab, mechanisms. Venetoclax inhibits the pro-apoptotic protein (CLL)/small lymphocytic cyclophosphamide, BCL-2, and ibrutinib is an inhibitor of Bruton tyrosine kinase lymphoma (SLL), Waldenstrom doxorubicin, vincristine, (BTK), which plays a key role in the B-cell receptor pathway macroglobulinemia, marginal and prednisone) involved in generating pro-growth signals. Combined use of zone lymphoma, and chronic these drugs could improve on efficacy in treating MCL. In Venetoclax (off-label) graft-versus-host disease clinical trials, ibrutinib is taken by mouth at a dosage of 560 VR-CAP (bortezomib, (GVHD). Venetoclax is FDA mg once daily and venetoclax is also taken by mouth at a rituximab, approved for treating CLL/SLL final dosage of 400 mg once daily. Venetoclax dosing may cyclophosphamide, and . require a ramp-up period, gradually increasing the dose from doxorubicin, and 20 to 400 mg, to avoid the potential of toxicity due to tumor prednisone) lysis syndrome. Developer(s): Pharmacyclics, LLC (Sunnyvale, California), an AbbVie, Inc (North Chicago, Illinois), company

Section 2. Cancer 27 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 HER2- fluoropyrimidine plus Progression-free survival Drug, Fast Track advanced, recurrent or overexpressing GEA. Standard therapy for HER2- cisplatin or oxaliplatin) Quality of life Clinical trial(s): Phase 2 metastatic gastroesophageal overexpressing GEA includes a HER2-targeting monoclonal plus anti-HER2 therapy primary completion February adenocarcinoma (GEA) antibody () used in combination with (eg, trastuzumab) 2022 overexpressing human chemotherapy; however, median overall survival with these epidermal growth factor regimens remains limited to about 14 months. A bispecific receptor 2 (HER2) antibody, zanidatamab is intended to improve 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 28 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have advanced (formerly IMAB362) is a claudin 18.2–specific Two or more of the Overall survival FDA designation(s): Orphan unresectable or metastatic monoclonal antibody intended to treat gastric cancer. following: Progression-free survival Drug gastric adenocarcinomas with Standard therapy for advanced gastric cancer includes Antimetabolites (eg, 5- Quality of life Clinical trial(s): Phase 3 GLOW moderate to strong CLDN18.2 combination chemotherapy with multiple cytotoxic agents; fluorouracil, capecitabine) primary completion October expression and negative HER2 however, median overall survival with these regimens is Platinum-based agents 2021; phase 3 SPOTLIGHT expression about 12 months. Claudin 18.2 is expressed in about 50% to (eg, carboplatin, primary completion February 70% of gastric cancers. In normal epithelial cells, claudin 18.2 oxaliplatin) 2021; phase 2 ILUSTRO is concealed in tight junctions; however, loss of cellular primary completion October polarity during transformation to gastric cancer causes its 2020; phase 2 FAST completed relocation to the cell surface, allowing targeting by January 2019, data published zolbetuximab. Zolbetuximab binding to claudin 18.2 January 2019; phase 2 GM- purportedly triggers antibody-dependent cytotoxicity and IMAB-001-02 completed complement-dependent cytotoxicity, leading to cancer cell August 2015, data published death. In clinical trials, patients receive intravenous September 2019 zolbetuximab every 3 weeks in combination with multiagent systemic chemotherapy. Developer(s): Astellas Pharma, Inc (Tokyo, Japan)

Section 2. Cancer 29 Table 2.2. Currently Monitored Cancer Topics: 78 Topics

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

Adults who have locally (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 inhibitory following: Progression-free Real-Time Oncology Review hepatocellular carcinoma surface molecule expressed by cells to modulate immune Anthracyclines (eg, survival FDA designation(s): Orphan (HCC) and have had no responses. HCC, an aggressive cancer, has limited treatment doxorubicin) Quality of life Drug, Breakthrough Therapy previous systemic therapy options and is a major cause of cancer deaths. A hallmark of Antimetabolites (eg, 5- Clinical trial(s): Phase 3 cancer is its ability to evade an immune response. Several fluorouracil, gemcitabine) IMbrave150 primary types of cancer cells, including HCC, activate an immune Multikinase inhibitors (eg, completion November 2020, checkpoint pathway in T cells by overexpressing PD-L1, which lenvatinib, sorafenib) data published May 2020 binds to the programmed cell death 1 (PD-1) coinhibitory Note(s): FDA has approved receptor and limits the activation of cancer-specific T cells. Platinum agents (eg, atezolizumab to treat many Atezolizumab purportedly prevents the interaction between cisplatin, oxaliplatin) other cancers. See the FDA- PD-1 and PD-L1 to release the brake on the immune approved labeling and checkpoint pathway. Atezolizumab treatment in combination prescribing document for all with bevacizumab is intended to restore anticancer immunity approved indications. 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 30 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have advanced Avapritinib (BLU-285) is purportedly a potent and selective Tyrosine kinase inhibitors Progression-free Submission date: systemic mastocytosis that oral type 1 kinase inhibitor of mutated KIT and (eg, imatinib, midostaurin) survival Supplemental New Drug includes aggressive, indolent, platelet-derived growth factor receptor alpha (PDGFRA). It Overall survival Application planned for fourth or smoldering systemic also binds and inhibits the KIT D816V variant, the primary Quality of life quarter of 2020 mastocytosis driver of disease in up to 95% of patients with systemic FDA designation(s): mastocytosis. No FDA-approved treatments exist for this Breakthrough Therapy patient population. Avapritinib broadly inhibits activating Clinical trial(s): Phase 2 mutations in KIT and PDGFRA, which drive tumor cell division. PATHFINDER primary Avapritinib is designed to act against activation loop completion May 2022; phase 2 mutations in KIT and PDGFRA, which approved multikinase PIONEER primary completion inhibitors do not inhibit. In clinical trials, avapritinib 300 mg is May 2021, data presented given orally once daily until disease progression or June 2020; phase 1 EXPLORER intolerable toxicity. primary completion Developer(s): November 2021, data Blueprint Medicines Corp (Cambridge, Massachusetts) reported June 2019

Adults who are at risk of oral Avasopasem manganese (GC4419) is intended to treat One or more of the Incidence of severe FDA designation(s): mucositis (OM) after patients who are likely to develop OM. No effective following: mucositis Breakthrough Therapy, Fast chemoradiation therapy with treatments are available for OM, a common side effect of Localized therapy (eg, low- Cancer treatment Track cisplatin and intensity- anticancer therapies (eg, chemotherapy, radiation). level laser therapy, oral adherence Clinical trial(s): Phase 3 modulated radiation therapy Avasopasem manganese is a small-molecule superoxide cryotherapy) Quality of life ROMAN primary completion for locally advanced, dismutase mimetic drug intended to detoxify reactive oxygen Supportive care (eg, oral October 2020 nonmetastatic head and neck species (ROS). ROS are overproduced during chemoradiation hygiene protocols) cancer therapy, overwhelming the body’s superoxide dismutase 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 31 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults undergoing Avatrombopag (Doptelet) is an oral thrombopoietin (TPO) Platelet transfusion Proportion of patients FDA designation(s): Orphan chemotherapy who develop receptor agonist (ie, activator) intended to treat severe TPO agonists (eg, who did not require a Drug severe thrombocytopenia, thrombocytopenia that occurs as a side effect of eltrombopag, romiplostim; platelet transfusion or Clinical trial(s): Phase 3 defined as 2 platelet counts chemotherapy. About 10% of patients undergoing off-label) reduction in primary completion August 9 below 50 × 10 /L measured at chemotherapy develop chemotherapy-induced chemotherapy 2020, phase 3 trial top-line least 24 hours apart thrombocytopenia (CIT), and no drugs are approved to treat Proportion of patients data expected fourth quarter it. CIT can complicate surgical procedures and chemotherapy who achieved platelet of 2020 and increases the likelihood of serious bleeding events, which counts of more than Note(s): FDA approved 9 might require hospitalization. Avatrombopag purportedly 50 × 10 /L after avatrombopag in May 2018 stimulates the division and maturation of cells responsible for treatment for treating thrombocytopenia platelet production (ie, megakaryocytes) from Proportion of patients in adults with chronic liver precursor cells. Avatrombopag activates the TPO receptor by without major or disease (CLD) who are binding to a site distinct from the TPO (ie, an nonmajor clinically scheduled to undergo a allosteric site) and, therefore, does not compete with relevant bleeding procedure and in June 2019 naturally occurring TPO. The agent could be used in for treating chronic immune combination with nonallosteric TPO agonists (eg, thrombocytopenia romiplostim). Avatrombopag is taken at an initial dosage of 20 mg (1 tablet) once daily, which is adjusted to maintain a platelet count of 50 × 109/L or greater without exceeding 40 mg daily. Developer(s): Dova Pharmaceuticals, Inc (Durham, North Carolina), a subsidiary of Swedish Orphan Biovitrum AB (Stockholm, Sweden)

Section 2. Cancer 32 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 years or older Azacitidine (CC-486) is a hypomethylating agent under study Hypomethylating agents (eg, Overall survival PDUFA date: September 3, who have acute myeloid as an oral maintenance treatment for AML. Treatments for azacitidine, decitabine) Progression-free 2020; Priority Review leukemia (AML) that is in AML frequently achieve complete remission, which is survival Clinical trial(s): Phase 3 remission after first-line characterized by normalized blood counts and no evidence Quality of life QUAZAR AML-001 primary induction chemotherapy of leukemic blasts in the bone marrow. However, even with completion July 2019, data subsequent therapy after remission, AML frequently recurs. In reported December 2019 particular, older patients ineligible for intensive consolidation therapy (eg, allogeneic transplantation [HSCT]) experience relapse at a rate as high as 70% to 80%. Novel, less-intensive therapies are sought. Azacitidine 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. In clinical trials, oral azacitidine is taken by mouth once daily at 300 mg on days 1 through 14 of a 28-day treatment cycle. Developer(s): Celgene Corp (Summit, New Jersey), a subsidiary of Bristol Myers Squibb Co (New York, New York)

Section 2. Cancer 33 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed or (Blenrep) is an immunoconjugate One or more of the Progression-free Approval date: August 5, 2020 refractory multiple myeloma targeting B-cell maturation antigen (BCMA) under study to following: survival FDA designation(s): Orphan (MM) treat relapsed MM or MM that has not responded to Anti-CD38 monoclonal Overall survival Drug, Breakthrough Therapy treatment. A number of agents have been approved in recent antibodies (eg, Quality of life Clinical trial(s): Phase 2 years to treat MM, but the disease is considered incurable, ) DREAMM-2 primary and most patients develop progressive disease. Approved by Corticosteroids (eg, completion June 2019, data FDA, belantamab mafodotin consists of a humanized, anti- dexamethasone) published February 2020; BCMA monoclonal antibody conjugated to the cytotoxic drug Cytotoxic drugs (eg, phase 3 DREAMM-3 primary monomethyl auristatin F. BCMA has been proposed as a bendamustine, completion December 2021; biomarker for targeting MM because it is highly expressed in cyclophosphamide) phase 3 DREAMM-9 primary malignant plasma cells. Binding of BCMA by belantamab completion June 2025 mafodotin purportedly triggers cell take-up and release of the cytotoxic drug, targeting delivery of the drug to MM cells. inhibitors (eg, ) The recommended dosage in the FDA-approved label is 2.5 Immunomodulatory drugs mg/kg intravenously once every 3 weeks. (eg, lenalidomide, Developer(s): pomalidomide) GlaxoSmithKline (Brentford, United Kingdom) Nuclear export inhibitors (eg, selinexor) Proteasome inhibitors (eg, bortezomib, ) SLAMF7 stimulatory antibodies (eg, )

Section 2. Cancer 34 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 years or Belumosudil (KD025) is an inhibitor of rho-associated coiled- Extracorporeal photopheresis Survival Submission date: New Drug older who have chronic graft- coil kinase 2 (ROCK2) under study for treating chronic GVHD. Hydroxychloroquine Treatment response rate Application planned for fourth versus-host disease (GVHD) A life-threatening immune disorder, GVHD is a frequent Ibrutinib Quality of life quarter of 2020 that has been treated with 2 complication of allogeneic hematopoietic stem cell Imatinib FDA designation(s): Orphan prior systemic GVHD transplantation (HSCT). It arises when donor T cells recognize Drug, Breakthrough Therapy therapies host cells as foreign because of their expression of mTOR inhibitors (eg, sirolimus) Clinical trial(s): Phase 2 alloantigens and mount an immune response against host KD025-208 primary Mycophenolate mofetil tissues, leading to inflammation and fibrosis in multiple body completion October 2020, tissues. The standard treatment for chronic GVHD is data presented February 2020; corticosteroids; however, patients whose disease no longer Rituximab phase 2 KD025-213 primary responds to steroids have poor long-term outcomes, with a completion September 2020, mortality rate of 70% to 80%. ROCK2 has been shown to be interim data presented involved in regulating proinflammatory cytokines, such as February 2020 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 orally at a dosage of 200 mg once or twice daily. Developer(s): Kadmon Holdings, Inc (New York, New York)

Section 2. Cancer 35

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

Adults who have relapsed or Brexucabtagene autoleucel (Tecartus) is a chimeric antigen One or more of the Overall survival Approval date: July 24, 2020 refractory mantle cell receptor (CAR) T-cell therapy consisting of genetically following: Progression-free FDA designation(s): Orphan lymphoma (MCL) modified autologous (ie, self-donated) T cells intended to Cyclophosphamide survival Drug, Breakthrough Therapy generate specific immune responses against the CD19 Cytarabine Quality of life Clinical trial(s): Phase 2 ZUMA- antigen expressed on the surface of B cells. MCL is a rare Dexamethasone 2 primary completion July form of non-Hodgkin lymphoma that arises from cells Doxorubicin 2019, data published April originating in the mantle zone of the lymph node and 2020 typically affects males older than 60 years of age. Brexucabtagene autoleucel uses the same construct as the Platinum agents (eg, existing CAR T-cell therapy axicabtagene ciloleucel (FDA carboplatin, cisplatin) approved for treating large B-cell lymphoma) but Prednisone incorporates the proprietary XLP manufacturing process that Rituximab includes T-cell selection and lymphocyte enrichment. These Vincristine processes are thought to be a necessary step for certain B- cell malignancies with evidence of circulating lymphoblasts to prevent incorporation of malignant cells into the CAR T-cell therapy. The recommended dosage in the FDA-approved label is intravenous infusion at a dose of 2 × 106 CAR-positive viable T cells per kilogram of body weight. Developer(s): Kite Pharma, a Gilead company (South San Francisco, California)

Section 2. Cancer 36 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally (Ilaris) is a human monoclonal antibody that One or more of the Overall survival Clinical trial(s): Phase 3 advanced or metastatic non– binds and neutralizes the immune mediator activity of human following: Progression-free CANOPY-2 primary small cell lung cancer (NSCLC) interleukin-1β (IL-1β), a member of the interleukin-1 (IL-1) ALK inhibitors (eg, alectinib, survival completion February 2021; of squamous or family of cytokines. Canakinumab is intended as an addition crizotinib if ALK Quality of life phase 3 CANOPY-1 primary nonsquamous origin that has to the standard of care and is designed to be a selective rearrangement positive; completion June 2022 not been treated or that has antibody that binds with high affinity to IL-1β but not to any ceritinib, crizotinib if ROS1 Note(s): FDA has approved been previously treated with other member of the IL-1 family or IL-1β from another rearrangement positive) canakinumab to treat many an immune checkpoint species. Canakinumab purportedly elicits an anti- Angiogenesis inhibitors (eg, other diseases. See the FDA- inhibitor in combination with inflammatory response in the tumor microenvironment that bevacizumab, ramucirumab) approved labeling and or after platinum-based blocks tumor proliferation and new blood vessel formation Anthracyclines (eg, prescribing document for all chemotherapy (ie, angiogenesis). Under specific conditions, IL-1β and other doxorubicin) approved indications. inflammatory 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, afatinib, injection at an unspecified dose in combination with erlotinib) if EGFR intravenous docetaxel at a dose of 75 mg/m2 or intravenous rearrangement positive pembrolizumab at a dose of 200 mg plus platinum-based Immune checkpoint chemotherapy every 3 weeks until disease progression or inhibitors (eg, nivolumab, 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 37 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Capmatinib (Tabrecta, INC280) is a potent and selective One or more of the Overall survival Approval date: May 6, 2020 advanced or metastatic non– small-molecule inhibitor of the hepatocyte growth factor following: Progression-free FDA designation(s): Orphan small cell lung cancer (NSCLC) (HGF) receptor. A receptor tyrosine kinase encoded by the Angiogenesis inhibitors (eg, survival Drug, Breakthrough Therapy MET harboring an exon 14– gene, the HGF receptor is typically required for tissue bevacizumab, ramucirumab) Quality of life Clinical trial(s): Phase 3

skipping mutation in the and organ regeneration and damage repair. The incidence of Anthracyclines (eg, CINC280A2301 primary MET MET mesenchymal-epithelial gene alterations in patients with NSCLC, including doxorubicin) completion August 2022; transition gene, MET exon 14–skipping mutation and MET amplification, is about Antimetabolites (eg, phase 2 GEOMETRY mono-1 2% to 4%. MET-driven NSCLC is an aggressive disease with a gemcitabine, pemetrexed) primary completion February poor prognosis and limited treatment options. Approved by Immune checkpoint 2022, data presented May FDA, capmatinib is a novel targeted therapy intended for 2020 patients harboring a MET exon 14–skipping alteration. inhibitors (eg, nivolumab, Note(s): This Accelerated Capmatinib is designed to interact with tyrosine 1230 and a pembrolizumab) Approval requires the conduct hinge motif in the HGF receptor’s kinase domain, which Platinum agents (eg, of a further clinical trial to causes it to adopt a unique autoinhibitory shape that carboplatin, cisplatin) verify and describe prevents access to its ATP binding site. Because capmatinib is Taxanes (eg, docetaxel, capmatinib’s clinical benefit highly specific for the HGF receptor, it purportedly has fewer paclitaxel) off-target effects. In NSCLC cells, capmatinib purportedly Vinca alkaloids (eg, blocks new blood vessel formation (ie, angiogenesis), vinblastine, vinorelbine) proliferation, and 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 of capmatinib taken orally twice daily until disease progression or intolerable toxicity. Developer(s): Novartis AG (Basel, Switzerland), licensed by Incyte Corp (Wilmington, Delaware)

Section 2. Cancer 38 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have Cediranib plus (Lynparza) is a combination drug One or more of the Overall survival Clinical trial(s): Phase 2b platinum-resistant, recurrent regimen under study for treating platinum-resistant, following: Progression-free CONCERTO primary ovarian cancer with no recurrent ovarian cancer. Poly -ribose Angiogenesis inhibitors (eg, survival completion August 2019, data evidence of a deleterious polymerase (PARP) inhibitors (eg, olaparib, ) have bevacizumab) Quality of life published May 2020 germline variant in the breast been approved as monotherapies for recurrent ovarian Anthracyclines (eg, BRCA1 cancer or cancer. However, their use is limited to patients with doxorubicin, pegylated BRCA2 BRCA1 BRCA2 deleterious or variants, which sensitize cancer liposomal doxorubicin) cells to PARP inhibition. Research has demonstrated that Taxanes (eg, docetaxel, cediranib, a small-molecule tyrosine kinase inhibitor with paclitaxel) 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 39

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 GBM, which has very limited Fractionated external beam Overall survival FDA designation(s): Orphan who have glioblastoma treatment options and is associated with poor outcomes. radiation therapy Progression-free Drug multiforme (GBM) that has DCVax-L is an immunotherapy made up of activated One or more of the survival Clinical trial(s): Phase 3 GBM been surgically resected and dendritic cells loaded with tumor antigens derived from the following: Quality of life primary completion treated with adjuvant patient’s own tumor. It is intended to improve outcomes by Alkylating agents (eg, November 2016, interim data radiation therapy and promoting an immune response against residual cyclophosphamide, published May 2018, 3-year chemotherapy glioblastoma cells after surgical resection. DCVax-L is lomustine, ) survival data reported manufactured using monocytes obtained from the patient Angiogenesis inhibitors (eg, November 2018, top-line data through a leukapheresis process. The monocytes are bevacizumab) expected fourth quarter of differentiated into dendritic cells in a laboratory and then 2020 activated and loaded with patient-derived antigens from the mTOR inhibitors (eg, patient’s tumor tissue after surgical resection. The purified everolimus) DCVax-L is then given to elicit adaptive immunity from T cells Platinum agents (eg, and B cells. Treatment begins at least 2 weeks before the first carboplatin, cisplatin) course of DCVax-L is given and involves total or near total Vinca alkaloids (eg, tumor resection followed by conventional external beam vincristine) 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 40

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

Adults aged 50 years or older Devimistat (CPI-613) is intended to provide a new treatment One or more of the Overall survival FDA designation(s): Orphan who have relapsed or option for patients with AML, who have very limited options following: Progression-free Drug refractory acute myeloid and poor outcomes. Devimistat is a small-molecule lipoate Anthracyclines (eg, survival Clinical trial(s): Phase 3 leukemia (AML) analogue drug intended to target the altered energy , ) Quality of life ARMADA 2000 primary metabolism unique to many cancers, including AML. This Antibody-drug conjugate completion October 2022 altered energy metabolism frequently depends on the (eg, gemtuzumab activity of the pyruvate dehydrogenase complex and the α- ozogamicin) ketoglutarate dehydrogenase complex. Devimistat Antimetabolites (eg, purportedly inhibits the catalytic and regulatory functions of , ) these key cancer pathways, leading to tumor cell death. In clinical trials, devimistat is being tested in combination with a Cytokine (eg, granulocyte standard induction regimen of high-dose cytarabine and colony-stimulating factor [G- mitoxantrone. Devimistat 2000 mg/m2 is given intravenously CSF]) on days 1 to 5 of the induction regimen. DNA synthesis inhibitors (eg, Developer(s): etoposide, 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 41 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have pancreatic Devimistat (CPI-613) is intended to treat pancreatic cancer in One or more of the Overall survival FDA designation(s): Orphan adenocarcinoma with distant the first-line setting, because only about 5% of these patients following: Progression-free Drug metastases that have not respond to the standard of care (ie, gemcitabine Antimetabolites (eg, 5- survival Clinical trial(s): Phase 3 been treated chemotherapy). Devimistat is a small-molecule lipoate fluorouracil, gemcitabine) Quality of life AVENGER 500 primary analogue drug intended to target the altered energy Chemoprotectant (eg, completion October 2021 metabolism of many cancers, including pancreatic leucovorin) adenocarcinomas. The altered energy metabolism of cancer DNA synthesis inhibitor (eg, cells frequently depends on the activity of the pyruvate irinotecan) dehydrogenase complex and the α-ketoglutarate dehydrogenase complex. Devimistat purportedly EGFR inhibitor (eg, erlotinib) downregulates metabolic pathways in cancer cells that Platinum-based agents (eg, depend on α-ketoglutarate and acetyl-CoA. In clinical trials, cisplatin, oxaliplatin) devimistat is given by intravenous injection at a dosage of Taxanes (eg, docetaxel, 500 mg/m2 on days 1 and 3 of a 14-day cycle, followed paclitaxel) immediately by intravenous modified 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 that One or more of the Overall survival FDA designation(s): Orphan malignant glioma (eg, causes N7 DNA alkylation. It is intended to treat recurrent following: Progression-free Drug, Fast Track glioblastoma multiforme malignant gliomas, which often become resistant to Alkylating agents (eg, survival Clinical trial(s): Phase 2 DLM- [GBM]) standard-of-care temozolomide therapy because the tumor , Quality of life 16-001 primary completion 6 expresses high levels of an enzyme (O -methylguanine-DNA- cyclophosphamide, September 2020, data methyltransferase [MGMT]) that helps repair DNA. VAL-083’s procarbazine) published December 2019, novel N7 DNA alkylation activity is intended to overcome Angiogenesis inhibitors (eg, data presented June 2020 MGMT-mediated resistance. In clinical trials, VAL-083 is given bevacizumab) as an intravenous infusion at a dosage of 30 mg/m2 on days mTOR inhibitors (eg, 1, 2, and 3 of a 21-day treatment cycle, for up to twelve 21- everolimus) day treatment cycles. Platinum-based drugs (eg, Developer(s): carboplatin, cisplatin) DelMar Pharmaceuticals, Inc (San Diego, California) Vinca alkaloids (eg, vincristine)

Section 2. Cancer 42 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who are at risk of oral Dusquetide (SGX942) is intended to treat OM, which has no One or more of the Duration of severe FDA designation(s): Orphan mucositis (OM) during effective treatments and is a common side effect of following: mucositis Drug, Fast Track chemoradiation therapy with anticancer therapies (eg, chemotherapy, radiation). It affects Analgesics (eg, lidocaine, Incidence of severe Clinical trial(s): Phase 3 DOM- cisplatin and image- about 80% of patients with oropharyngeal cancer. narcotics) mucositis INNATE primary completion modulated radiation therapy Dusquetide is a novel, synthetic, water-soluble, 5-amino-acid Localized therapy (eg, low- Pain June 2020, top-line data for locally advanced, peptide with anti-inflammatory and anti-infective properties. level laser therapy, oral Cancer treatment expected in fourth quarter of nonmetastatic squamous cell It is a member of a drug class called innate defense cryotherapy) adherence 2020 carcinoma of the oral cavity regulators. Dusquetide targets the innate immune system Supportive care (eg, oral Note(s): National Institutes of or oropharynx and binds to an intracellular adaptor protein, sequestosome- Incidence of bacterial hygiene protocols) infection Health selected SGX942 for its 1. Also called p62, this protein has a pivotal function in signal Small Business Innovation Quality of life transduction during activation and control of the innate Research/Small Business immune system. In clinical trials, dusquetide is given as a 4- Technology Transfer minute intravenous infusion at a dosage of 1.5 mg/kg twice Commercialization Accelerator weekly, starting within 3 days after initiating radiation Program in September 2018 therapy and continuing through 2 weeks after completing radiation therapy. Developer(s): Soligenix, Inc (Princeton, New Jersey)

Section 2. Cancer 43 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have metastatic Encorafenib (Braftovi) plus (Erbitux) is a Checkpoint inhibitors (eg, Overall survival Approval date: April 8, 2020 (CRC) that combination therapy for treating metastatic BRAF V600E nivolumab with or without Progression-free Clinical trial(s): Phase 3 has progressed after one or mutation–positive CRC. This type of cancer is associated with , pembrolizumab) survival BEACON CRC completed two previous regimens and poor prognosis, and patients have a median overall survival FOLFIRI (ie, leucovorin Quality of life February 2019, data published has a mutation at V600E in of 4 to 6 months after failure of initial therapy. Unlike [folinic acid], 5-fluorouracil, October 2019 BRAF- the B-Raf proto-oncogene treatments for other mutated cancers (eg, melanoma), and irinotecan) with or Note(s): In June 2018, FDA / kinase gene, BRAF inhibitor monotherapy and BRAF/MEK inhibitor without VEGF inhibitor (eg, approved the combination BRAF BRAF combination therapy have limited activity in V600E bevacizumab, ziv-aflibercept, therapy of encorafenib and BRAF CRC. This is because, in V600E CRC, the mitogen- ramucirumab) binimetinib (Braftovi and activated protein kinase (MAPK) pathway is reactivated FOLFOX (ie, leucovorin Mektovi, respectively) for through epidermal growth factor receptor (EGFR) signaling. [folinic acid], 5-fluorouracil, unresectable or metastatic Combining BRAF/MEK inhibitors with an EGFR inhibitor might and oxaliplatin) with or melanoma with a BRAF V600E improve patients’ overall survival. DNA testing for somatic without bevacizumab or V600K mutation, as BRAF V600E mutation is needed to determine the patient’s Regorafenib detected by an FDA-approved eligibility before starting this combination treatment. The test recommended dosage in the FDA-approved label is 300 mg Trifluridine plus tipiracil of oral encorafenib once daily and standard weekly dosing of cetuximab by infusion. Developer(s): Array BioPharma, Inc (Boulder, Colorado), which was acquired by Pfizer, Inc (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 locally (Padcev) provides an option for patients One or more of the Overall survival Approval date: December 18, advanced or metastatic whose cancer has not responded to standard of care. These following: Progression-free 2019 urothelial cancer (mUC) and patients have limited options and poor outcomes. Alkylating agents (eg, survival FDA designation(s): have previously received a Enfortumab is a monoclonal antibody conjugated to a ) Quality of life Breakthrough Therapy, Priority programmed cell death 1 chemotherapy drug (ie, vedotin) designed to bind the surface Antimetabolites (eg, Review (PD-1) or programmed cell receptor nectin 4. Vedotin is a synthetic auristatin with gemcitabine, pemetrexed) Clinical trial(s): Phase 3 EV-301 death ligand 1 (PD-L1) cytotoxic activity that blocks the formation of . Immune checkpoint primary completion inhibitor and a platinum- The adhesion protein nectin 4 is highly expressed in various inhibitors (eg, atezolizumab, September 2021; phase 2 EV- containing chemotherapy in types of solid tumors, including urothelial cancer. Enfortumab ) 201 primary completion the neoadjuvant/adjuvant, vedotin purportedly triggers internalization of the drug into November 2020, data locally advanced, or the cells. This increases vedotin’s likelihood of targeting and Platinum agents (eg, carboplatin, cisplatin) presented September 2019, metastatic setting killing malignant cells while minimizing cytotoxicity on data published July 2019; Taxanes (eg, docetaxel, normal cells. The recommended dosage in the FDA-approved single-arm clinical trial data paclitaxel) label is 1.25 mg/kg (up to a maximum dose of 125 mg) given presented in FDA-approved as an intravenous infusion over 30 minutes on days 1, 8, and labeling and prescribing 15 of a 28-day cycle until disease progression or document unacceptable toxicity. Note(s): This Accelerated Developer(s): Approval requires the conduct Seattle Genetics, Inc (Bothell, Washington), in collaboration of a further clinical trial to with Astellas Pharma, Inc (Tokyo, Japan) verify and describe Padcev’s clinical benefit

Section 2. Cancer 45 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Eprenetapopt (APR-246) is a small-molecule anticancer drug. Azacitidine Overall survival FDA designation(s): Orphan myelodysplastic syndrome It purportedly restores and reactivates wild-type p53 Decitabine Progression-free Drug, Fast Track, (MDS) with at least one conformation and function in myelodysplastic cells, causing Erythropoiesis-stimulating survival Breakthrough Therapy genetic variant in the tumor initiation of programmed cell death (ie, apoptosis) in cancer agents (eg, darbepoetin alfa, Quality of life Clinical trial(s): Phase 3 TP53 protein p53 gene, cells. Triggering programmed cell death of myelodysplastic epoetin alfa, filgrastim) primary completion cells might restore proper bone marrow function, including Luspatercept-aamt November 2020 blood cell production and function. 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 46 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- encapsulated One or more of the Overall survival Clinical trial(s): Phase 2/3 advanced or metastatic triple- inside donor-derived red blood cells to treat metabolically following: Progression-free TRYbeCA-2 primary negative (TNBC) active tumors. TNBC is a metabolically active cancer Alkylating agents (eg, survival completion December 2020 and have had no previous associated with a poorer prognosis when compared with cyclophosphamide) Quality of life systemic therapy other breast cancer subtypes because of a lack of effective Anthracyclines (eg, treatment options. L-asparaginase is an enzyme that doxorubicin) hydrolyzes the amino acid into aspartic acid and Antimetabolites (eg, ammonia, which inhibits protein synthesis. Eryaspase- capecitabine, gemcitabine) mediated depletion of asparagine purportedly arrests cell proliferation and induces programmed cell death (ie, Immune checkpoint apoptosis). Encapsulating L-asparaginase in donor red blood inhibitors (eg, atezolizumab) cells purportedly prolongs activity and decreases adverse for patients with tumors events. In clinical trials, eryaspase is given as an intravenous expressing programmed cell infusion at a dosage of 100 units/kg on days 1 and 8 of a 3- death ligand-1 (PD-L1) week cycle until disease progression or unacceptable toxicity, Poly adenosine diphosphate- in combination with gemcitabine (1000 mg/m2) plus ribose polymerase (PARP) carboplatin (AUC 2). inhibitors (eg, , Developer(s): olaparib) for patients with BRCA1/2 mutations Erytech Pharma SA (Lyon, France) Taxanes (eg, docetaxel, paclitaxel) Vinca alkaloid (eg, vinorelbine)

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

Section 2. Cancer 48 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 study Hypomethylating agents (eg, Overall survival FDA designation(s): Orphan acute myeloid leukemia (AML) that targets the WT1 antigen to treat AML. Treatments for azacitidine, decitabine) Progression-free Drug, Fast Track in complete remission after AML frequently achieve complete remission, which is survival Clinical trial(s): Phase 3 REGAL second-line induction characterized by normalized blood counts and no evidence Quality of life primary completion December therapy, who are ineligible to of leukemic blasts in the bone marrow. However, even with 2021 receive an allogeneic stem subsequent therapy after remission, AML frequently recurs. In cell transplant, and whose particular, older patients ineligible for intensive consolidation leukemic cells express the therapy (eg, allogeneic hematopoietic stem cell Wilms tumor protein (WT1) transplantation [HSCT]) experience relapse at a rate as high antigen 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, one every 2 weeks; early booster phase of 6 injections, one every 4 weeks; and late booster phase of 6 injections, one every 6 weeks. Each galinpepimut-S administration is preceded by an injection of an immune stimulator (70 ug sargramostim). Developer(s): Sellas Life Sciences Group (New York, New York)

Section 2. Cancer 49 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed and Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor One or more of the Overall survival Submission date: Biologics refractory multiple myeloma (CAR) T-cell therapy that has been engineered to target B-cell following: Progression-free License Application July 2020 (RRMM) that has been treated maturation antigen (BCMA) using autologous T cells isolated Alkylating agents (eg, survival FDA designation(s): Orphan with 3 or more lines of from a patient’s blood sample. Patients whose disease has bendamustine, Quality of life Drug, Breakthrough Therapy chemotherapy that included a progressed after 3 prior treatment lines have a very poor cyclophosphamide) Clinical trial(s): Phase 2 protease inhibitor, an prognosis and no options. The collected T cells are Anthracyclines (eg, KarMMa primary completion immunomodulatory agent, genetically modified with a lentiviral vector (ie, transduction) doxorubicin) November 2024, data and an anti-CD38 antibody encoding CARs with a unique anti-BCMA single-chain Glucocorticoids (eg, reported December 2019; variable fragment (ie, BB2121) fused to the hinge and dexamethasone) phase 3 KarMMa-3 primary transmembrane domains of CD8α, the costimulatory domain completion June 2025 (ie, 4-1BB) of CD137, and the signaling domains of CD3ζ. The Immunomodulatory agents BB2121 CAR-transduced T cells that compose idecabtagene (eg, lenalidomide, vicleucel are proliferated and then reintroduced into the pomalidomide, thalidomide) patient. The treatment purportedly targets malignant BCMA- Monoclonal antibodies (eg, expressing plasma cells in patients with multiple myeloma daratumumab, elotuzumab) cells and promotes robust cellular activity against these cells Proteasome inhibitors (eg, to treat the disease. BCMA has been proposed as a bortezomib, carfilzomib, biomarker for targeting multiple myeloma because it is ) highly expressed in malignant plasma cells. In clinical trials, Topoisomerase inhibitors idecabtagene vicleucel is given as a single intravenous (eg, etoposide) infusion at a dose ranging from 1.5 × 108 to 4.5 × 108 anti- BCMA CAR-T cells. Developer(s): , Inc (Cambridge, Massachusetts), in collaboration with Bristol Myers Squibb Co (New York, New York)

Section 2. Cancer 50 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 55 years or older Iomab-B (apamistamab-I-131) is an antibody-radiation One or more of the Overall survival FDA designation(s): Orphan who have active, relapsed, or conjugate composed of the CD45-specific monoclonal following: Progression-free Drug refractory acute myeloid antibody apamistamab linked to the radioisotope iodine-131. Anthracyclines (eg, survival Clinical trial(s): Phase 3 SIERRA leukemia (AML) with leukemic AML is the most common type of acute leukemia, and daunorubicin, idarubicin) Quality of life primary completion December cells expressing CD45 patients with relapsed or refractory AML have limited Antibody-drug conjugates 2021, data presented February treatment options and poor outcomes. Iomab-B is under (eg, gemtuzumab 2020 study for use as an induction and conditioning agent before ozogamicin) hematopoietic stem cell transplantation (HSCT) or other Antimetabolites (eg, cellular therapies. Apamistamab binding to CD45, a receptor cytarabine, fludarabine) purportedly involved in promoting AML cell proliferation, leads to Iomab-B cell internalization and leukemic cell death B-cell lymphoma-2 (BCL-2) through targeted radiation delivery. In clinical trials, Iomab-B inhibitors (eg, venetoclax) is given as a component of a reduced-intensity conditioning DNA synthesis inhibitors (eg, regimen containing fludarabine and low-dose total body etoposide, mitoxantrone) irradiation before 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 51 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have relapsed and JNJ-4528 is a chimeric antigen receptor (CAR) T-cell therapy One or more of the Overall survival FDA designation(s): Orphan refractory multiple myeloma that has been engineered to target B-cell maturation antigen following: Progression-free Drug, Breakthrough Therapy (MM) that has been treated (BCMA) using T cells isolated from a patient’s own blood Alkylating agents (eg, survival Clinical trial(s): Phase 3 with 2 or more lines of sample. BCMA has been proposed as a potential target for bendamustine, Quality of life CARTITUDE-4 primary therapy including a protease CAR T-cell therapy in MM because BCMA expression is cyclophosphamide) completion April 2026; phase inhibitor, immunomodulatory limited to malignant plasma cells and nonessential normal Anthracyclines (eg, 1/2 CARTITUDE-1 primary agent, or anti-CD38 antibody cells (eg, normal plasma cells, some mature B cells). To doxorubicin) completion September 2021, produce JNJ-4528, autologous (ie, self-donated) T cells are Glucocorticoids (eg, data presented June 2020 transduced with a lentiviral vector encoding CARs with 2 dexamethasone) unique binding domains for BCMA. The BCMA CAR- transduced T cells are expanded in culture and then Immunomodulatory agents reintroduced into the patient. JNJ-4528 is intended to target (eg, lenalidomide, malignant BCMA-expressing plasma cells in patients with pomalidomide) MM and to promote a robust cellular immune response Monoclonal antibodies (eg, against these cells. In clinical trials, JNJ-4528 is given as a daratumumab, elotuzumab) single intravenous infusion containing 7.5 x 105 BCMA CAR-T Proteasome inhibitors (eg, cells/kg. bortezomib, ixazomib) Developer(s): Topoisomerase inhibitors Janssen Pharmaceutical, LLC (Titusville, New Jersey), a (eg, etoposide) subsidiary of Johnson & Johnson, Inc (New Brunswick, New Jersey)

Section 2. Cancer 52 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 self-donated (ie, autologous) T-cell One or more of the Overall survival Submission date: Biologics recurrent, metastatic, or therapy that uses cells isolated from the patient’s cervical following: Disease-free survival License Application planned persistent cervical cancer that cancer. Lifileucel relies on naturally occurring T cells called Alkylating agents (eg, Quality of life for second half of 2020 is unsuitable for surgical tumor-infiltrating lymphocytes (TILs) that can penetrate ifosfamide) FDA designation(s): resection and/or radiation cancerous tumors. TILs isolated from a patient’s tumor are Angiogenesis inhibitors (eg, Breakthrough Therapy, Fast therapy. Patients must have expanded in culture until reaching a count of billions of cells. bevacizumab) Track received at least 1 and no Lifileucel is intended as a tumor-specific therapy that can Antimetabolites (eg, 5- Clinical trial(s): Phase 2 more than 3 prior systemic overcome the tumor’s immune-suppressive environment and fluorouracil, gemcitabine, innovaTIL-04 primary therapy regimens. promote its elimination. In clinical trials, lifileucel is given as pemetrexed) completion December 2021, an intravenous infusion followed by up to 6 doses of data presented May 2019 interleukin-2 (IL-2) to support growth and activation of TILs. DNA synthesis inhibitors (eg, mitomycin-C) Developer(s): Immune checkpoint inhibitor Iovance Biotherapeutics, Inc (San Carlos, California) (eg, pembrolizumab) Taxanes (eg, albumin-bound paclitaxel, docetaxel) Topoisomerase inhibitors (eg, irinotecan)

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

Section 2. Cancer 53 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 VISION progressive prostate-specific therapy made up of a high-affinity targeting ligand specific Progression-free primary completion August membrane antigen (PSMA)– to PSMA that is chemically linked with a radionucleotide survival 2020; phase 2 primary 177 177 positive, metastatic, called lutetium-177 ( Lu). Lu-PSMA-617 is intended to Time to first completion August 2020, data castration-resistant prostate deliver systemic and targeted radiation, causing cell death to symptomatic skeletal presented May 2019, cancer (mCRPC) prostate cancer cells. PSMA protein is highly expressed on event preliminary data published the surface of most prostate cancer cells but absent on most May 2020 Quality of life 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): Endocyte, Inc (West Lafayette, Indiana), a subsidiary of Novartis AG (Basel, Switzerland)

Section 2. Cancer 54 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 no carboplatin, cisplatin) survival Drug platinum-containing regimen longer responds to platinum chemotherapy have limited Topoisomerase inhibitors Quality of life Clinical trial(s): Phase 3 treatment options and a poor prognosis. Lurbinectedin (eg, etoposide, ) ATLANTIS completed February selectively inhibits RNA Pol II activity during the elongation 2020; phase 2 PM1183-B-005- phase of messenger RNA (mRNA) synthesis. Although 14 primary completion lurbinectedin interacts with RNA Pol II, it does not affect the January 2021, data presented activity of RNA Pol I, mitochondrial RNA Pol, or basal June 2019, data published transcription machinery. Lurbinectedin’s binding to RNA Pol II March 2020 and inhibition of mRNA synthesis purportedly induces cancer Note(s): New Drug Application cell death by reducing the expression of cellular factors filed under Accelerated involved in tumor progression. The recommended dosage in Approval regulations the FDA-approved label is intravenous administration over 60 minutes of 3.2 mg/m2 every 21 days; the label also notes 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 55 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have very low– to Luspatercept-aamt (Reblozyl) is a red blood cell (ie, Hypomethylating agents (eg, Red blood cell Approval date: April 3, 2020 intermediate-risk erythrocyte) maturation agent under development to treat azacitidine, decitabine) transfusion dependence Clinical trial(s): Phase 3 myelodysplastic syndrome anemia associated with MDS. Luspatercept-aamt is intended Lenalidomide Overall survival MEDALIST primary completion (MDS) with ring sideroblasts to restore production of normal red blood cells, thus November 2017, data and anemia that has not obviating the need for repeat red blood cell transfusions and published January 2020; phase responded to an the accompanying iron chelation therapy. Luspatercept-aamt 3 COMMANDS primary erythropoiesis-stimulating is a first-in-class biologic that purportedly stimulates completion April 2021; phase agent and requires maturation of erythrocyte precursor cells differently from the 3 extension trial primary transfusion of 2 or more red body’s natural erythropoietin, thereby increasing erythrocyte completion March 2030 blood cell units over 8 weeks production. The drug is a modified activin receptor type IIB Note(s): FDA has also fusion protein that acts as a ligand trap for members of the approved luspatercept-aamt transforming growth factor beta (TGF-beta) superfamily to treat anemia in patients involved in late-stage erythrocyte production. The with β-thalassemia who recommended dosage in the FDA-approved label is 1 mg/kg require regular red blood cell injected under the skin every 3 weeks. transfusions Developer(s): Acceleron Pharma, Inc (Cambridge, Massachusetts), in collaboration with Bristol Myers Squibb Co (New York, New York)

Section 2. Cancer 56 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 stem Alkylating agents (eg, survival Clinical trial(s): Phase 2 multiforme [GBM]) cells, including those in GBM tumors. MDNA55 offers a novel cyclophosphamide, Quality of life MDNA55-05 completed approach for treating IL-4R-expressing tumors because GBM temozolomide) September 2019, data does not respond well to standard therapy. MDNA55 is a Angiogenesis inhibitors (eg, reported May 2020 genetically engineered fusion protein composed of a bevacizumab) circularly permuted interleukin-4 molecule fused to the mTOR inhibitors (eg, catalytic domain of the bacterial Pseudomonas aeruginosa everolimus) exotoxin A (PE) protein. The fusion protein functions as a molecular decoy by binding IL-4R and triggering receptor- Platinum agents (eg, mediated cell take-up (ie, endocytosis) to deliver the carboplatin, cisplatin) cytotoxic PE payload into the cytoplasm. MDNA55 Vinca alkaloids (eg, purportedly has high specificity and affinity for IL-4R- vincristine) 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 57 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 prevents Active surveillance Disease-free survival Clinical trial(s): Phase 3 MA32 without diabetes mellitus who glucose production in the liver) often used to treat type 2 Overall survival primary completion February have localized breast cancer diabetes mellitus (T2DM). Some researchers think the drug Quality of life 2022 that has been treated might benefit patients with breast cancer because surgically followed by retrospective studies of patients with diabetes taking neoadjuvant or adjuvant metformin and window-of-opportunity studies in the chemotherapy 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 58

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

Adults who have low-grade, Mitomycin gel (Jelmyto) is a proprietary form of the small- Endoscopic management Overall survival Approval date: April 15, 2020 noninvasive, upper-tract molecule drug mitomycin-C (MMC) intended to treat low- Surgery (ie, Progression-free FDA designation(s): Orphan urothelial cancer grade upper-tract urothelial cancer. No treatments are nephroureterectomy; might survival Drug, Breakthrough Therapy, approved for this cancer type. Approved by FDA, this require ongoing dialysis or Quality of life Fast Track hydrogel-based form is intended to enable longer exposure organ transplantation) Clinical trial(s): Phase 3 of MMC to urinary tract tissue to enable nonsurgical One or more of the OLYMPUS primary completion treatment of tumors. Mitomycin gel purportedly kills bladder following: April 2019, pivotal data cell tumors by inhibiting DNA synthesis, which is required for Alkylating agents (eg, reported May 2019, final the cells to divide and tumors to grow. The recommended ifosfamide) analysis of primary end point dosage in the FDA-approved label is 4 mg/mL, with a data reported September maximum dose of 15 mL in weekly instillations given a total Antimetabolites (eg, gemcitabine, methotrexate) 2019, data published April of 6 times using a standard urethral catheter or nephrostomy 2020, data presented May Immune checkpoint tube. 2020 Developer(s): inhibitors (eg, atezolizumab, ) UroGene Pharma, Ltd (New York, New York) Platinum agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, paclitaxel)

Section 2. Cancer 59 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, and is chemotherapy with one or survival April 2019, data on first 11 are eligible for autologous associated with disease severity. Motixafortide is intended to more of the following: Quality of life patients reported March 2019 stem cell transplantation mobilize hematopoietic stem cells (HSCs) for autologous (ie, Alkylating agents (eg, Note(s): BioLineRx reported in (ASCT) self-donated) transplantation and delay MM progression bendamustine, August 2020 that it had just after primary high-dose therapy. Motixafortide is a biostable, cyclophosphamide) completed ≈65% enrollment synthetic, cyclic peptide with 14 amino acid residues that Anthracyclines (eg, (n = 177 planned) in the phase + binds CXCR4 with high affinity. Expression of CXCR4 in CD34 doxorubicin) 3 GENESIS trial and planned to HSCs is directly involved in their retention in the bone Glucocorticoids (eg, perform an interim analysis marrow via binding to the CXCL12 chemokine protein. dexamethasone) and report results in early However, in MM, CXCR4 expression is also involved in tumor 2021 progression, angiogenesis, metastasis, and cell survival. As a Immunomodulatory agents CXCR4 antagonist, motixafortide purportedly leads to the (eg, lenalidomide, mobilization of CD34+ HSCs, MM cells, and immune cells into pomalidomide, thalidomide) peripheral blood. Although mobilized CD34+ HSCs can be Proteasome inhibitors (eg, collected through apheresis for autologous transplantation, bortezomib, carfilzomib, mobilized MM cells are no longer protected in the bone ixazomib) marrow and are sensitive to maintenance therapy after Topoisomerase inhibitors transplantation. In clinical trials, motixafortide is given as a (eg, etoposide) 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 60

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

Adults who have bacillus N-803 (formerly ALT-803) is a novel interleukin-15 (IL-15) One or more of the Overall survival FDA designation(s): Fast Track, Calmette-Guérin (BCG)– superagonist complex. NMIBC is unresponsive to standard following: Progression-free Breakthrough Therapy unresponsive, high-grade, BCG treatment in about half of affected patients, whose Anthracyclines (eg, survival Clinical trial(s): Phase 2 QUILT- non–muscle invasive bladder disease then progresses. N-803 is intended to provide an epirubicin, ) Quality of life 3.032 primary completion cancer (NMIBC) option after BCG treatment has failed. N-803 purportedly Antimetabolites (eg, January 2023, preliminary data generates rapid and durable immune responses against gemcitabine) presented May 2019 NMIBC by simultaneously mobilizing both innate and DNA synthesis inhibitors (eg, adaptive immune cells to infiltrate the tumor. While IL-15 and mitomycin-C) IL-15α enhance cytotoxic T-cell proliferation, immunoglobulin G1 Fc domain (IgG1 Fc) activates natural Taxanes (eg, docetaxel) killer (NK) 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 61 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have recurrent Nadofaragene firadenovec (Instiladrin) is a Cystectomy Overall survival Submission date: Biologics non–muscle invasive bladder intended to treat high-grade NMIBC that does not respond Immune checkpoint Progression-free License Application November cancer (NMIBC) and to bacillus Calmette-Guérin (BCG) therapy. About half of inhibitors (eg, survival 25, 2019; Priority Review confirmed carcinoma in situ patients with NMIBC will have recurrent disease after BCG pembrolizumab) Time to cystectomy FDA designation(s): Fast Track, (CIS) only, Ta/T1 high-grade induction therapy, and these patients are more likely to Intravesical chemotherapy (surgery) Breakthrough Therapy disease with concomitant CIS, progress to a more advanced disease stage. Nadofaragene with one or more of the Quality of life Clinical trial(s): Phase 3 or Ta/T1 high-grade disease firadenovec is an adenovirus vector gene therapy containing following: primary completion May 2019, without concomitant CIS the gene interferon alfa-2b. After its administration into the Anthracyclines (eg, data reported December 2019 bladder, it transduces cells in the bladder cell wall, causing epirubicin, valrubicin) them to produce and secrete interferon alfa-2b protein, a naturally occurring protein the body uses to fight cancer. In Antimetabolites (eg, clinical trials, nadofaragene firadenovec is administered gemcitabine) through a catheter into the bladder every 3 months for 12 DNA synthesis inhibitors (eg, months, and patients were followed for 48 months. mitomycin-C) Developer(s): Taxanes (eg, docetaxel) FKD Therapies Oy (Kuopio, Finland), licensed to FerGene, a company of Ferring Pharmaceuticals (Saint-Prex, Switzerland)

Section 2. Cancer 62 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; ABI- One or more of the Overall survival Submission date: New Drug advanced or metastatic 009) is an mTOR inhibitor associated with human albumin following: Progression-free Application planned for fourth perivascular epithelioid cell nanoparticles through noncovalent hydrophobic interactions. Alkylating agents (eg, survival quarter of 2020 tumor (PEComa) Nab-sirolimus has been developed to block the mTOR dacarbazine, temozolomide, Quality of life FDA designation(s): Orphan pathway, which is frequently involved in cell proliferation that ) Drug, Fast Track, is activated in PEComas by genetic mutations in the TSC Anthracyclines (eg, Breakthrough Therapy TSC1 TSC2 complex subunit 1 and/or 2 genes, and/or . doxorubicin, epirubicin, Clinical trial(s): Phase 2 PEComa is a rare type of sarcoma originating from the soft liposomal doxorubicin) AMPECT primary completion tissues lining organs such as the intestines, lungs, and Antimetabolites (eg, September 2020, data stomach. PEComas are malignant in rare cases and have the gemcitabine, ifosfamide) presented May 2020 potential to spread to other body parts. No approved treatments exist for PEComas, and standard sarcoma Microtubule inhibitors (eg, cytotoxic have minimal survival benefit. Nab- eribulin, vinorelbine) sirolimus purportedly enters proliferating tumor cells via mTOR inhibitors (eg, endocytosis and macropinocytosis to have higher everolimus, sirolimus, accumulation and better efficacy than other mTOR inhibitors. temsirolimus) Testing for TSC1/2 mutation status will require use of a Multikinase inhibitors (eg, companion diagnostic test. In clinical trials, nab-sirolimus is imatinib, pazopanib, given by intravenous infusion at a weekly dosage of 100 regorafenib, sorafenib, mg/m2 in a 2-weeks-on, 1-week-off schedule until disease sunitinib) progression or intolerable toxicity. Developer(s): Aadi Bioscience, Inc (Pacific Palisades, California)

Section 2. Cancer 63 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 transcription following: Progression-free CanStem303C primary has been treated with a single 3 (STAT-3) pathway. Napabucasin’s novel mechanism of Angiogenesis inhibitors (eg, survival completion February 2022; systemic chemotherapy action is intended to treat CRC that does not respond to bevacizumab, ramucirumab) Quality of life phase 3 primary completion regimen based on second-line chemotherapy, purportedly by targeting and Antimetabolites (eg, November 2021 fluoropyrimidine and killing cancer stem cells in tumors. Cancer stem cells are capecitabine, 5-fluorouracil) oxaliplatin associated with treatment resistance, metastasis, and poor EGFR antibodies (eg, prognosis. In clinical trials, napabucasin is given by mouth at cetuximab, ) a dosage of 240 mg twice daily in combination with the multiagent cytotoxic FOLFIRI (ie, FOLFIRI leucovorin [folinic acid], 5-fluorouracil, and irinotecan), with FOLFOX (ie, leucovorin or without the addition of bevacizumab, until disease [folinic acid], 5-fluorouracil, progression or intolerable toxicity. and oxaliplatin) Developer(s): Immune checkpoint Boston Biomedical, Inc (Cambridge, Massachusetts), a inhibitors (eg, nivolumab, subsidiary of Sumitomo Dainippon Pharma Co, Ltd (Osaka, pembrolizumab) for patients Japan) with defects in mismatch repair or microsatellite instability Multikinase inhibitors (eg, regorafenib) Platinum agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)

Section 2. Cancer 64 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 22 years or older NovoTTF-100L is a device intended to treat solid tumors by One or more of the Overall survival Clinical trial(s): Phase 3 LUNAR who have metastatic non– exposing them to low-intensity, intermediate-frequency, following: Progression-free primary completion small cell lung cancer (NSCLC) alternating electric fields (ie, tumor-treating fields [TTFs]). Immune checkpoint survival September 2023 that has progressed after TTFs purportedly disrupt cell division through effects on inhibitors (eg, atezolizumab, Quality of life first-line, platinum-based charged macromolecules and organelles within cancer cells, nivolumab) therapy potentially limiting tumor growth. NovoTTF-100L is a battery- Taxanes (eg, docetaxel) 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 by Radiation therapy (eg, Overall survival Clinical trial(s): Phase 3 METIS non–small cell lung cancer exposing them to low-intensity, intermediate-frequency, stereotactic radiosurgery, Progression-free primary completion (NSCLC) and newly diagnosed alternating electric fields (ie, tumor-treating fields [TTFs]). whole-brain radiotherapy) survival September 2022 brain metastases that have TTFs purportedly disrupt cell division through effects on In lieu of upfront radiation Quality of life been treated with stereotactic charged macromolecules and organelles within cancer cells, therapy, systemic therapy radiosurgery potentially limiting tumor growth. The NovoTTF-100M device with one of the following: is a battery-powered field generator coupled to 4 electrically ALK inhibitors (eg, alectinib, insulated electrode arrays attached to the skin of the brigatinib, ceritinib) if ALK patient’s head. In clinical trials, TTF therapy is given in the rearrangement positive home setting 24 hours a day, 7 days a week and is intended EGFR inhibitors (eg, for use in combination with the best supportive treatment osimertinib) if EGFR variant available until disease progression or intolerable toxicity. positive Developer(s): Immune checkpoint Novocure, Ltd (St Helier, Jersey, United Kingdom) inhibitors (eg, nivolumab, pembrolizumab) if programmed cell death ligand 1 (PD-L1) positive

Section 2. Cancer 65 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

Section 2. Cancer 66 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-resistant viral vector therapy intended for recurrent platinum-resistant following: Progression-free Drug ovarian cancer ovarian cancer. Patients with recurrent platinum-resistant Angiogenesis inhibitors (eg, survival Clinical trial(s): Phase 3 OVAL ovarian cancer have a poor prognosis. Ofranergene bevacizumab) Quality of life primary completion December obadenovec is intended to induce programmed cell death in Anthracyclines (eg, 2022, interim data reported endothelial cells that form new blood vessels (ie, doxorubicin, pegylated March 2020, interim data angiogenesis) in the tumor microenvironment as well as liposomal doxorubicin) presented May 2020 induce cellular immune responses against the tumor. Taxanes (eg, docetaxel, Ofranergene obadenovec purportedly targets the angiogenic paclitaxel) 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 67 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 PROpel metastatic, castration- inhibit poly adenosine diphosphate-ribose polymerase Docetaxel survival primary completion April 2021 resistant prostate cancer (PARP), which functions in a DNA repair pathway. Olaparib Enzalutamide Overall survival Note(s): FDA approved (mCRPC) that is being treated might provide a novel and potentially synergistic mechanism Quality of life olaparib to treat ovarian with androgen-deprivation of action when used with abiraterone to treat newly cancer in December 2014, to therapy but has not yet been diagnosed mCRPC. Cancers are often deficient in a DNA treat breast cancer in January treated with chemotherapy or repair pathway, and when PARP is also inhibited the loss of 2 2018, to treat pancreatic a newer hormonal agent (ie, types of DNA repair results in cancer cell death in response cancer in December 2019, and abiraterone or enzalutamide) to DNA damage. Preclinical studies have indicated that cross- to treat previously treated at the mCRPC stage talk might exist between androgen receptor signaling prostate cancer in May 2020 pathways and PARP. In phase 3 clinical trials, olaparib is being studied in combination with the hormone synthesis inhibitor abiraterone. Olaparib is given orally 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 68 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: Initiation of who have a hematologic therapy derived from umbilical cord blood that has been transplantation engraftment rate rolling Biologics License malignancy (ie, acute multiplied in a laboratory using proprietary Pooled unexpanded cord Neutrophil recovery rate Application planned for fourth lymphoblastic leukemia [ALL], (NAM) technology. Omidubicel is intended as a curative blood transplantation Platelet recovery rate quarter of 2020 acute myelogenous leukemia approach for high-risk blood cancers in patients who have no Unexpanded cord blood Overall survival FDA designation(s): Orphan [AML], chronic myelogenous fully matched donor available. The therapy is intended to transplantation Drug, Breakthrough Therapy leukemia [CML], or efficiently and quickly restore blood and immune cells and Clinical trial(s): Phase 3 myelodysplastic syndrome improve resistance to infections and related complications. primary completion December [MDS]) NAM purportedly prevents umbilical cord blood cells from 2019, top-line data differentiating rapidly in culture, resulting in increased stem announced May 2020; phase 3 + – – cells (CD34 CD38 Lin ). NAM works outside the genetic expanded access primary coding region in the DNA (ie, is epigenetic) and purportedly completion December 2022 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 69 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 3 years or older ONC201 is a small-molecule imipridone (a class of anticancer One or more of the Overall survival FDA designation(s): Fast Track, and adults who have a compounds) that acts as an antagonist of the G-protein following: Progression-free Rare Pediatric Disease recurrent high-grade glioma coupled receptor dopamine 2 (D2) receptor. ONC201 has a Alkylating agents (eg, survival Clinical trial(s): Phase 2 that harbors a K27M novel mechanism of action intended to provide an option for carmustine, temozolomide) Quality of life ONC013 primary completion rearrangement in the histone patients who have few effective treatment options and poor Angiogenesis inhibitors (eg, December 2020; phase 2 H3 gene, prognosis after recurrence. ONC201-mediated antagonism of bevacizumab) ONC006 primary completion D2 receptor purportedly inactivates the ras pathway, a driver Vinca alkaloids (eg, December 2020, data of cell growth and proliferation, and activates the integrated vincristine) published October 2019, data stress response, which can activate cell death pathways. published January 2020; Patients with gliomas harboring K27M variants in the H3 unphased Expanded Access gene have a poor prognosis, and preclinical data have Program (EAP) indicated these gliomas might be susceptible to treatment with a D2 antagonist. Eligibility for the therapy will require testing for the H3 K27M variant. In clinical trials, ONC201 is given orally at an unspecified dose and time frame. Developer(s): Oncoceutics, Inc (Philadelphia, Pennsylvania)

Adults who have non–muscle (Vicinium) is an antibody-drug Cystectomy Time to cystectomy Submission date: Rolling invasive bladder cancer conjugate comprising a humanized monoclonal antibody Transurethral resection of Overall survival Biologics License Application (NMIBC) that is refractory to, fragment specific for epithelial cell adhesion molecule bladder tumor (TURBT) Disease-free survival initiated December 2019 Pseudomonas or has relapsed after, at least (EpCAM) linked to a truncated form of Intravesicular chemotherapy FDA designation(s): Fast Track aeruginosa Quality of life 2 intravesicular treatments exotoxin A (PE). PE is a cytotoxic agent that with one or more of the Clinical trial(s): Phase 3 VISTA with bacillus Calmette-Guérin inhibits protein synthesis through inactivation of elongation following: primary completion December (BCG) factor-2. EpCAM is highly expressed by bladder cancer cells. Anthracyclines (eg, 2020, preliminary data Oportuzumab monatox is intended to preferentially deliver valrubicin) reported August 2019 the linked exotoxin to these cells and delay the time to major surgery (ie, cystectomy) and surgery’s associated side effects Antimetabolites (eg, (eg, urinary diversion). In clinical trials, oportuzumab monatox gemcitabine) is given intravesically (ie, into the bladder) at a dose of 30 mg DNA synthesis inhibitors (eg, in an office setting. In a clinical trial, treatment involves a 12- mitomycin-C) week induction phase (12 twice-weekly instillations followed by 6 weekly instillations) and a maintenance phase of instillations once every 2 weeks for up to 2 years. Developer(s): Sesen Bio (Cambridge, Massachusetts)

Section 2. Cancer 70 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 Submission date: New Drug locally advanced or metastatic paclitaxel capsule and an encequidar tablet that is taken following: Progression-free Application planned for third breast cancer for whom orally rather than given intravenously. Paclitaxel is a taxane Anthracyclines (eg, survival quarter of 2020 treatment with intravenous that inhibits cell division, but it is formulated only as an doxorubicin, liposomal Quality of life FDA designation(s): Orphan paclitaxel has been intravenous infusion that contains additives, which increase doxorubicin) Drug recommended the risk of neuropathy and hypersensitivity. These adverse Antimetabolites (eg, Clinical trial(s): Phase 3 KX- reactions often prevent patients from completing the capecitabine, gemcitabine) ORAX-001 primary completion chemotherapy regimen, thereby reducing efficacy and Microtubule inhibitors (eg, July 2019, data presented adversely affecting health outcomes. Paclitaxel has been eribulin, vinorelbine) December 2019 limited to intravenous administration because the drug is a of P-glycoprotein (P-gp), an active transport Poly adenosine diphosphate- protein on the gastrointestinal (GI) tract’s surface that is ribose polymerase (PARP) capable of pumping paclitaxel back into the GI tract. This inhibitors (eg, olaparib, BRCA1/2 limits systemic exposure to paclitaxel taken by mouth. talazoparib) for - Encequidar is a P-gp inhibitor that prevents P-gp-mediated mutated breast cancer efflux of paclitaxel. As an orally administered taxane, oraxol Taxanes (eg, docetaxel, has the potential to decrease the burden of infusion clinic paclitaxel) visits, 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 71 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally OSE2101 (Tedopi) is a therapeutic cancer vaccine designed to One or more of the Overall survival Clinical trial(s): Phase 3 advanced or metastatic non– stimulate T-cell responses against NSCLC. Patients with following: Progression-free ATALANTE 1 primary small cell lung cancer (NSCLC) NSCLC that does not respond to immune checkpoint Angiogenesis inhibitors (eg, survival completion December 2021, that expresses HLA-A2 and inhibitors have limited treatment options and a poor bevacizumab, ramucirumab) Quality of life data reported April 2020 has been previously treated prognosis. OSE2101 is based on a collection of neo-epitopes, Antimetabolites (eg, with an immune checkpoint which are short peptides derived from mutant versions of gemcitabine, pemetrexed) inhibitor and platinum-based proteins expressed by genes mutated in cancer cells, acting Taxanes (eg, docetaxel) chemotherapy as antigens. Because neo-epitopes are 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. OSE2101 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, OSE2101 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 72 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 disease Surgical resection Progression-free Drug, Breakthrough Therapy basal cell carcinoma nevus burden and symptoms in patients with BCCNS. Basal cell Systemic chemotherapy (eg, survival Clinical trial(s): Phase 3 Pelle- syndrome (BCCNS), who have carcinoma is usually treated with surgery, radiation, or vismodegib) Quality of life 926-301 primary completion developed basal cell chemotherapy (topical or systemic), all of which have limited Topical chemotherapy (eg, 5- December 2020 carcinomas efficacy, can be hard to tolerate, and might not prevent new fluorouracil, imiquimod) 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 or experience serious side effects from standard treatment. 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 73 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 the One or more of the Overall survival FDA designation(s): Orphan pleural mesothelioma that enzyme arginine deiminase, which catalyzes the hydrolysis of following: Progression-free Drug has not been treated with arginine, depleting the supply of this essential amino acid Antimetabolites (eg, survival Clinical trial(s): Phase 2/3 systemic therapies and from the bloodstream. Cells of many tumor types cannot pemetrexed) Quality of life ATOMIC primary completion exhibits low expression of the autonomously synthesize arginine and so might be sensitive Platinum agents (eg, October 2020 argininosuccinate synthase 1 to arginine depletion. In particular, tumor cells that express cisplatin) gene, ASS1 low levels of ASS1 (involved in cellular arginine synthesis) might be dependent on exogenous arginine. This is thought to be the case in malignant pleural mesothelioma, 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)

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 is targets the programmed cell death 1 (PD-1) coinhibitory following: Progression-free FDA designation(s): microsatellite instability–high receptor expressed by activated T cells. Pembrolizumab is Angiogenesis inhibitors (eg, survival Breakthrough Therapy (MSI-H) or mismatch repair– intended to provide a targeted option for patients with MSI- bevacizumab) Quality of life Clinical trial(s): Phase 3 deficient (dMMR) and has not H or dMMR colorectal cancers, which make up 15% to 20% Antimetabolites (eg, KEYNOTE-177 primary been previously treated of nonhereditary cases and most hereditary cases. A hallmark capecitabine, 5-fluorouracil) completion December 2021, of cancer is its ability to evade an immune response. Several EGFR antibodies (eg, data presented June 2020 types of cancer cells, including CRC cells, activate an immune cetuximab, panitumumab) Note(s): FDA has approved checkpoint pathway in T cells by overexpressing the pembrolizumab to treat many programmed cell death ligand 1 (PD-L1), which binds to PD-1 FOLFIRI (ie, leucovorin other cancers. See the FDA- and limits the activation of cancer-specific T cells. [folinic acid], 5-fluorouracil, approved labeling and Pembrolizumab purportedly prevents the interaction and irinotecan) prescribing document for all between PD-1 and PD-L1 to overcome CRC’s immune FOLFOX (ie, leucovorin approved indications. tolerance by enhancing cancer-specific T-cell responses. [folinic acid], 5-fluorouracil, Tumors with MSI-H or dMMR are also purportedly more and oxaliplatin) susceptible to pembrolizumab than tumors with low MSI. The Platinum-based agents (eg, recommended dosage in the FDA-approved label is 200 mg oxaliplatin) given as an intravenous infusion once every 3 weeks for up to Topoisomerase inhibitors 24 months. (eg, irinotecan) 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 bacillus Pembrolizumab (Keytruda) is a monoclonal antibody that BCG monotherapy Overall survival Approval date: January 8, 2020 Calmette-Guérin (BCG)– targets the programmed cell death 1 (PD-1) coinhibitory Cystectomy Progression-free Clinical trial(s): Phase 3 unresponsive, high-risk, non– receptor expressed by activated T cells. About half of patients Intravesical chemotherapy survival KEYNOTE-676 primary muscle invasive bladder with NMIBC will have recurrent disease after BCG induction with one or more of the Quality of life completion May 2022; phase 2 cancer (NMIBC) with therapy, and the disease in these patients is more likely to following: KEYNOTE-057 primary carcinoma in situ (CIS) with or advance. Pembrolizumab might provide a treatment option, Anthracyclines (eg, completion June 2022, data without papillary tumors and and it is approved by FDA. A hallmark of cancer is its ability epirubicin, valrubicin) presented February 2019 who are ineligible for or have to evade an immune response. Several types of cancer cells, Note(s): FDA has approved elected not to undergo including NMIBC, activate an immune checkpoint pathway in Antimetabolites (eg, gemcitabine) pembrolizumab to treat many cystectomy T cells by overexpressing the programmed cell death ligand 1 other cancers. See the FDA- DNA synthesis inhibitors (eg, (PD-L1), which binds to PD-1 and limits the activation of approved labeling and mitomycin-C) cancer-specific T cells. Pembrolizumab purportedly prevents prescribing document for all the interaction between PD-1 and PD-L1 to release the brake Taxanes (eg, docetaxel) approved indications. on the immune checkpoint pathway. Pembrolizumab in combination with BCG may overcome 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 75 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 Clinical trial(s): Phase 3 advanced or metastatic targets the programmed cell death 1 (PD-1) coinhibitory following: Progression-free KEYNOTE-590 primary esophageal carcinoma or receptor expressed by activated T cells. Front-line therapy for Anthracyclines (eg, survival completion April 2021 esophagogastric junction esophageal carcinoma relies on platinum-based epirubicin) Quality of life Note(s): FDA has approved (EGJ) carcinoma that is chemotherapy, but response rates are low and no second- Antimetabolites (eg, pembrolizumab to treat many unsuitable for surgery and line therapies exist. Pembrolizumab is intended to provide an capecitabine, 5-fluorouracil) other cancers. See the FDA- has not been previously option for these patients. A hallmark of cancer is its ability to HER2 antibodies (eg, approved labeling and treated evade an immune response. Several types of cancer cells, trastuzumab) prescribing document for all including esophageal and EGJ carcinomas, activate an approved indications. immune checkpoint pathway in T cells by overexpressing the Platinum agents (eg, programmed cell death ligand 1 (PD-L1), which binds to PD-1 carboplatin, cisplatin, and limits the activation of cancer-specific T cells. oxaliplatin) Pembrolizumab purportedly prevents the interaction Taxanes (eg, docetaxel, between PD-1 and PD-L1 to overcome the immune tolerance paclitaxel) 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 76 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, and chemotherapy Progression-free FDA designation(s): Orphan cholangiocarcinoma 3, which play an important role in cell proliferation, survival, Pembrolizumab (for patients survival Drug, Breakthrough Therapy harboring gene mutations, migration, and angiogenesis (ie, formation of new blood with microsatellite Quality of life Clinical trial(s): Phase 3 fusions, or translocations in vessels). The drug is approved by FDA. Cholangiocarcinoma instability–high [MSI-H] or FLIGHT-302 primary the fibroblast growth factor is a rare cancer that forms in bile ducts, which carry fluid mismatch repair–deficient completion October 2023; FGFR2 receptor 2 gene, , between the liver, the gallbladder, and the small intestine. [dMMR] tumors) phase 2 FLIGHT-202 primary whose disease has previously About 20% of cholangiocarcinomas harbor an alteration in completion November 2020, FGFR2 been treated with at least one the gene, which typically involves a gene fusion or data published March 2020 line of systemic therapy translocation that leads to constitutive FGFR2 activity. By Note(s): This Accelerated targeting this aberrant FGFR signaling, pemigatinib Approval requires the conduct purportedly prevents the growth and spread of of a further clinical trial to cholangiocarcinoma tumors, potentially improving outcomes verify and describe of patients who have limited treatment options. Although pemigatinib’s clinical benefit 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 will require use of a genetic test (ie, a companion diagnostic). FDA approved FoundationOneCDx as the registrational companion diagnostic for pemigatinib. The recommended dosage in the FDA-approved label is 13.5 mg given orally in a 2-weeks-on, 1-week-off schedule until disease progression or intolerable toxicity. Developer(s): Incyte Corp (Wilmington, Delaware)

Section 2. Cancer 77 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have advanced or Plinabulin is a marine fungus–derived microtubule inhibitor Myelosuppressive Neutropenia Submission date: New Drug metastatic cancer (eg, breast intended to prevent chemotherapy-induced neutropenia (ie, chemotherapy with Thrombocytopenia Application planned for fourth cancer, non–small cell lung loss of neutrophils), which occurs in most patients with adjunctive long-lasting G- Infection incidence quarter of 2020 cancer [NSCLC], prostate cancer who are receiving myelosuppressive chemotherapy. CSF (eg, pegfilgrastim) Quality of life Clinical trial(s): Phase 3 cancer) that has progressed Neutropenia renders patients susceptible to complications, Protective-1 primary after at least one previous line including infection, because the cytotoxic regimens they completion October 2020, of treatment receive also deplete blood-forming cells in the bone marrow. data reported November Unlike granulocyte colony-stimulating factor (G-CSF), which 2019, data presented May promotes growth of white blood progenitor cells to restore 2020; phase 3 Protective-2 neutrophils, plinabulin’s novel mechanism of action (ie, primary completion October targets microtubules differently from taxanes and vinca 2020, data presented February alkaloids) purportedly facilitates the release of cytokines that 2020 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)

Male adults who have ProstAtak is a gene-mediated cytotoxic immunotherapy. It Radiation therapy with or Disease-free survival Clinical trial(s): Phase 3 PrTK03 localized prostate cancer that consists of an adenovirus vector containing a herpes simplex without androgen- Overall survival primary completion December is deemed to be intermediate virus thymidine kinase gene (ie, aglatimagene besadenovec) deprivation therapy Quality of life 2022, designed under Special or high risk based on one that is injected into tumors and leads infected cells to express Protocol Assessment; phase 2 factor and has been treated thymidine kinase. After viral injection, a low dose of a ULYSSES primary completion with radiation synthetic guanosine analogue (eg, valacyclovir) activated by September 2020 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 injected into the tumor and coupled with systemic valacyclovir administration in addition to standard radiation therapy with or without androgen-deprivation therapy. Developer(s): Advantagene, Inc (Needham, Massachusetts)

Section 2. Cancer 78

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 donor), Standard HSCT Progression-free FDA designation(s): Orphan hematologic malignancy (ie, off-the-shelf hematopoietic peripheral blood cell transplant survival Drug, Fast Track acute lymphoblastic leukemia (HPBCT). It is developed from donor-sourced, mobilized, Overall survival Clinical trial(s): Phase 1/2 [ALL], acute myeloid leukemia peripheral blood T cells that have been cultured in a Quality of life PROTECT primary completion [AML], chronic myelogenous laboratory in the presence of 2 small-molecule stem cell April 2020, initial data leukemia [CML], or modulators (ie, FT1050 and FT4145) that guide cell reported March 2018, myelodysplastic syndrome differentiation. Many patients with hematologic malignancies expanded enrollment May [MDS]) that will be treated seek curative therapy through hematopoietic stem cell 2019 with allogeneic hematopoietic transplantation (HSCT), but about 50% of patients peripheral blood cell undergoing HSCT die or experience disease recurrence within transplantation the following 2 years. The leading causes of nonrelapse (ie, treatment-related) death are graft-versus-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 79 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 a radiation therapy Progression-free Drug, Breakthrough Therapy glioblastoma multiforme novel oncolytic virus approach intended for patients whose One or more of the survival Clinical trial(s): Phase 2 [GBM], anaplastic cancer has recurred and who have limited options after following: Quality of life Pro00077024 primary astrocytoma [AA]) that has standard therapy. It selectively infects and replicates tumor Alkylating agents (eg, completion August 2023 been treated with surgery, cells that express the poliovirus receptor nectin-like protein 5 carmustine, adjuvant radiation, and (CD155), which is expressed in most types of solid-tumor cyclophosphamide, temozolomide cancers and in other immune cells, including dendritic cells lomustine, procarbazine, and macrophages. In tumor cells, PVSRIPO infection causes temozolomide) neuronal incompetence that results in cytotoxicity and death. Angiogenesis inhibitors (eg, In contrast, PVSRIPO infection of immune cells facilitates bevacizumab) induction of an antitumor immune response that does not kill or limit immune function of dendritic cells and macrophages. mTOR inhibitors (eg, Although immune cells infected by PVSRIPO initiate a type I everolimus) interferon-mediated response, this will not destroy the Platinum agents (eg, oncolytic virus. PVSRIPO purportedly targets and destroys carboplatin, cisplatin) cells in brain tumors and activates tumor-specific immune Vinca alkaloids (eg, responses by stimulating dendritic cell activity and immune vincristine) 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 80 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or (BMS-986016) is a novel human immunoglobulin One or more of the Overall survival Clinical trial(s): Phase 2/3 older and adults who have G4 (IgG4) monoclonal antibody against lymphocyte-activator following: Progression-free primary completion December melanoma that is unsuitable gene-3 (LAG-3), a coinhibitor receptor primarily expressed on Alkylating agents (eg, survival 2020 for surgery or is metastatic exhausted tumor-infiltrating lymphocytes (TILs). Relatlimab is dacarbazine, temozolomide) Quality of life and has not been previously intended to enhance activity of immune checkpoint inhibitors BRAF inhibitors (eg, treated with systemic therapy by stimulating TILs. As an adjunct to a checkpoint inhibitor, dabrafenib, encorafenib, relatlimab might also increase treatment-related costs. vemurafenib) Relatlimab’s binding to LAG-3 prevents inhibitory T-cell Immune checkpoint responses of TILs via interaction with major histocompatibility inhibitors (eg, ipilimumab, complex molecule class II (MHC-II) on dendritic cells and nivolumab, pembrolizumab) melanoma cells. Relatlimab purportedly promotes innate immune responses and FAS-mediated programmed cell MEK inhibitors (eg, death (ie, apoptosis) in melanoma cells expressing high binimetinib, cobimetinib, MHC-II. Relatlimab also synergizes with programmed cell trametinib) death 1 (PD-1) immune checkpoint inhibitors that might Platinum agents (eg, encourage melanoma-specific immune responses. In clinical carboplatin) trials, relatlimab is given intravenously at a dose of 160 mg in Taxane agents (eg, paclitaxel) combination with intravenous nivolumab at a dose of 480 mg, on day 1 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

Infants and children aged up Remestemcel-L (Ryoncil) is an allogeneic mesenchymal Photopheresis alone or Overall survival PDUFA date: September 30, to 17 years who have acute precursor cell therapy that uses donor bone marrow and combined with 8- Progression-free 2020; Priority Review graft-versus-host disease selectively expands mesenchymal stem cells. It is intended for methoxypsoralen survival FDA designation(s): Orphan (GVHD) that has not GVHD that does not respond to steroid treatment. GVHD is a One or more of the following Quality of life Drug, Fast Track responded well to steroids life-threatening immune disorder that is a frequent immunosuppressants: Clinical trial(s): Phase 3 MSB- complication of allogeneic hematopoietic stem cell Alkylating agents (eg, GVHD001 completed January transplantation (HSCT) and affects many organ systems. It cyclophosphamide) 2018, data published May arises when donor T cells recognize host cells as foreign by Antibodies (eg, 2020 virtue of their expression of alloantigens and mount an , antithymocyte immune response. Remestemcel-L purportedly secretes globulin) growth factors and anti-inflammatory cytokines that facilitate tissue repair by downregulating immune and inflammatory Calcineurin inhibitors (eg, responses of immunocompetent T cells contained in the cyclosporine, tacrolimus) graft. In clinical trials, remestemcel-L is given by intravenous Corticosteroids (eg, infusion at a dosage of 2 × 106 cells/kg twice weekly for 4 methotrexate, consecutive weeks. mycophenolate mofetil, Developer(s): prednisone) Mesoblast, Ltd (Melbourne, Australia, and New York, New mTOR inhibitors (eg, York) sirolimus)

Adults aged 18 to 81 years Rigosertib (Estybon) is a small-molecule, multikinase inhibitor Immunomodulatory agents Complete remission rate FDA designation(s): Orphan who have myelodysplastic with activity against both the α and β isoforms of (eg, lenalidomide) Overall survival Drug syndrome that has exhibited phosphoinositide 3 kinase (PI3K) and polo-like kinase 1 Quality of life Clinical trial(s): Phase 3 primary resistance to (). No effective treatment is available for resistant INSPIRE primary completion hypomethylating agents (ie, myelodysplastic syndrome, and patients generally have a December 2020, designed disease progression without poor prognosis when the syndrome has not responded to under Special Protocol attaining a complete or partial treatment with a hypomethylating agent. Inhibiting PI3K is Assessment response or hematologic intended to disrupt that promotes cell growth improvement) and survival. Inhibiting PLK1 might disrupt cell division, leading to cell cycle arrest in cancerous cells. In clinical trials, rigosertib is given intravenously at a dose of 1800 mg daily for 3 days every 2 weeks for 8 cycles, then every 4 weeks until disease progression or intolerable toxicity. Developer(s): Onconova Therapeutics, Inc (Newtown, Pennsylvania)

Section 2. Cancer 82 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have Robotic-assisted nipple-sparing mastectomy using the da Open surgical mastectomy Patient satisfaction Clinical trial(s): Phase 2 MARCI invasive breast cancer or Vinci system has been pioneered by a few European Tissue necrosis (nipple- primary completion ductal carcinoma in situ and investigators as an alternative to open surgery. Compared areola complex) November 2019, data are undergoing total with open surgery, da Vinci robotic-assisted mastectomy Local tumor recurrence published September 2018; mastectomy with immediate purportedly facilitates the performance of technically unphased IEO 562 primary Distant tumor breast reconstruction challenging laparoscopic procedures, enhances cosmesis, completion March 2022 recurrence reduces length of patient stay, and improves patient Note(s): FDA issued a safety Overall survival satisfaction. In clinical trials, surgeons performing the surgery communication on February avoid the nipple-areola tissue by removing the target breast Disease-free survival 28, 2019 cancer tissue through a small incision under the arm (ie, Quality of life axillary access). After the robotically assisted steps, a surgeon manually reconstructs the breast using a conventional breast implant and standard subcutaneous and cutaneous suturing techniques. Developer(s): European Institute of Oncology (Milan, Italy) and Gustave Roussy Cancer Centre (Villejuif, France)

Section 2. Cancer 83 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 innate immune checkpoint inhibitor. SCLC One or more of the Overall survival FDA designation(s): Orphan who have extensive-stage usually responds to first-line platinum doublet chemotherapy following: Progression-free Drug small cell lung cancer (SCLC) but eventually develops resistance. RRx-001 is intended to Alkylating agents (eg, survival Clinical trial(s): Phase 3 that has progressed after 2 or overcome the disease’s resistance to platinum-based cyclophosphamide, Quality of life REPLATINUM primary more lines of systemic chemotherapy and might improve health outcomes of temozolomide) completion November 2020 therapy including prior patients with limited treatment options. SCLC cells activate an Antimetabolites (eg, platinum doublet innate immune checkpoint pathway in macrophages by gemcitabine) chemotherapy overexpressing the protein CD47, which interacts with signal Antitumor antibiotics (eg, regulatory protein-α (SIRPα) to prevent macrophage anthracyclines, mitomycin-C) phagocytosis and render tumor cells less sensitive to innate immune surveillance. Through an unknown mechanism of Microtubule inhibitors (eg, action, RRx-001 decreases the expression of both CD47 on paclitaxel, vinorelbine) tumor 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 84 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have locally -hziy (Trodelvy; IMMU-132) is an One or more of the Overall survival Approval date: April 22, 2020 advanced or metastatic triple- antibody-drug conjugate consisting of a monoclonal following: Progression-free FDA designation(s): Fast Track, negative breast cancer (TNBC) antibody coupled via a cleavable linker to an active Alkylating agents (eg, survival Breakthrough Therapy and have received at least 2 metabolite of the chemotherapy drug irinotecan. It is cyclophosphamide) Quality of life Clinical trial(s): Phase 3 prior systemic therapy approved by FDA. The monoclonal antibody is specific for Anthracyclines (eg, ASCENT primary completion regimens for locally advanced trophoblast cell-surface antigen 2 (Trop-2), and the doxorubicin) June 2020, data reported July or metastatic disease irinotecan metabolite is called SN-38. Trop-2 is a cell-surface Antimetabolites (eg, 2020; phase 1/2 IM-T-IMMU- protein overexpressed by several epithelial cancers, including fluorouracil, gemcitabine) 132-01 primary completion TNBCs. Upon binding to Trop-2, sacituzumab govitecan-hziy Microtubule polymerization June 2020, data published is internalized and the linker is cleaved, releasing the October 2019 chemotherapy drug. By targeting delivery of SN-38 to Trop- inhibitors (eg, eribulin) Note(s): This Accelerated 2-expressing cells, sacituzumab govitecan-hziy purportedly Poly adenosine diphosphate- Approval requires the conduct delivers therapeutic doses of the drug to cancer cells while ribose polymerase (PARP) of a further clinical trial to limiting exposure of noncancer cells. The recommended inhibitors (eg, olaparib) verify and describe dosage in the FDA-approved label is an intravenous infusion Taxanes (eg, docetaxel, sacituzumab govitecan-hziy’s of 10 mg/kg on days 1 and 8 of each 21-day treatment cycle, paclitaxel) clinical benefit until disease progression or intolerable toxicity. Vinca alkaloid (eg, Developer(s): vinorelbine) Immunomedics, Inc (Morris Plains, New Jersey)

Section 2. Cancer 85 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 intended to provide following: Progression-free FDA designation(s): locally advanced or metastatic a targeted treatment option to patients with recurrent Anthracyclines (eg, survival Breakthrough Therapy RET medullary thyroid cancer that medullary thyroid cancer and a gene alteration. The doxorubicin) Quality of life Clinical trial(s): Phase 3 harbors an alteration in a receptor tyrosine kinase RET can be oncogenically activated agents (eg, 5- LIBRETTO-531 primary RET gene called rearranged during by gene fusions or point rearrangements, and activating fluorouracil) completion February 2023; transfection, RET, and has point rearrangements affect about 60% of metastatic Tyrosine kinase inhibitors phase 1/2 LIBRETTO-001 progressed after treatment medullary thyroid cancers. Unlike multikinase inhibitors that (eg, cabozantinib, primary completion March with cabozantinib and/or target specific alterations, selpercatinib has been designed to 2022, data presented RET vandetanib) vandetanib inhibit diverse fusions, activating gene variants, and September 2019 acquired-resistance variants with nanomolar potency. Selpercatinib targets and purportedly inhibits RET-variant tumor cells. Eligibility for the therapy will require testing for a RET gene alteration. The recommended dosage in the FDA- approved label is based on weight: less than 50 kg, 120 mg orally twice daily; 50 kg or greater, 160 mg orally twice daily. The label also says to reduce the dose 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 86 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or older Selumetinib (Koselugo) is a selective small-molecule inhibitor Pain management Progression-free Approval date: April 13, 2020 who have neurofibromatosis of a signaling pathway called ras (rat sarcoma), which is often Radiation therapy survival FDA designation(s): Orphan type 1 (NF1) with overactive in several types of cancers. It is approved by FDA. Systemic chemotherapy (eg, Quality of life Drug, Breakthrough Therapy symptomatic, inoperable About 50% of patients with NF1 develop PNs, benign tumors carboplatin, vincristine) Clinical trial(s): Phase 1/2 plexiform neurofibromas found in peripheral nerve sheaths that can cause substantial Sprint 1 primary completion (PNs) complications, including airway, bladder, and bowel and/or March 2019, data published motor dysfunction, disfigurement, pain, and visual March 2020; phase 1/2 impairment. Patients who have inoperable NF1-related PNs INSPECT primary completion have no approved treatment options. To block the ras August 2020 pathway, selumetinib specifically targets the mitogen- Note(s): This Accelerated activated protein kinase kinases 1 and 2 (MEK1/2) to prevent Approval requires the conduct activation of the downstream extracellular signal-related of a further clinical trial to kinase (ERK), which is associated with cell growth and verify and describe proliferation. Selumetinib purportedly prevents the selumetinib’s clinical benefit 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 87 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Infants and children aged 1 Sodium thiosulfate (Pedmark) is intended to reduce the risk Platinum-based Ototoxicity PDUFA date: August 10, 2020; month to 18 years who have of cisplatin-induced ototoxicity, a common side effect in chemotherapy (eg, cisplatin) Hearing ability Priority Review; localized, nonmetastatic, solid children that can damage hearing and for which no effective alone, without adjuvant Quality of life FDA designation(s): Orphan tumors eligible for cisplatin treatment is available. It is a proprietary formulation that preventive therapy Drug, Fast Track, chemotherapy inactivates the metabolic byproducts of systemic platinum- Breakthrough Therapy based (ie, cisplatin) chemotherapy. Sodium thiosulfate Clinical trial(s): Phase 3 purportedly acts only on cisplatin metabolites in general completed April 2015, data circulation and does not interfere with cisplatin effectiveness published January 2017; phase within targeted tumor cells. In clinical trials, sodium 3 SIOPEL6 completed thiosulfate is given to patients intravenously at a dosage of September 2017, data 2 16 g/m or 533 mg/kg 6 hours after receiving cisplatin-based published June 2018 chemotherapy. Treatment with sodium thiosulfate continues Note(s): On August 11, 2020, until completion of cisplatin treatment. FDA issued a Complete Developer(s): Response Letter indicating Fennec Pharmaceuticals, Inc (Research Triangle Park, North that no further clinical data Carolina) are required, but identified deficiencies with the drug manufacturing facility, which require resolution before approval

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

Section 2. Cancer 88 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults who have Tabelecleucel (Tab-cel) is an off-the-shelf chimeric antigen One or more of the Progression-free Submission date: Biologics received an allogeneic receptor (CAR) T-cell therapy. It is engineered to provide following: survival License Application planned hematopoietic cell transplant specific immune responses against EBV using cytotoxic T Adrenocortical steroid (eg, Overall survival for second half of 2020 or solid organ transplant and lymphocytes (CTLs) from unrelated donors. Tabelecleucel prednisolone) Quality of life FDA designation(s): Orphan developed Epstein-Barr virus– purportedly provides immunity against EBV-associated Alkylating agent (eg, Drug, Breakthrough Therapy associated posttransplant cancers in patients who have received a hematopoietic cell cyclophosphamide, Clinical trial(s): Phase 3 lymphoproliferative disorder transplant or organ transplant. EBV+PTLD can be hard to dacarbazine) MATCH primary completion (EBV+PTLD) that does not treat with standard therapies, and treatment is associated Anthracyclines (eg, November 2020; phase 3 respond to rituximab with many comorbidities. CAR genes are delivered to the doxorubicin) ALLELE primary completion CTLs with an adenovirus vector (AdE1-LMPpoly), which Antitumor antibiotic (eg, November 2020, preliminary targets specific regions of the EBV nuclear antigen 1, latent data reported March 2020 membrane protein 1, and latent membrane protein 2A. AdE1- ) LMPpoly also encodes for a programmed cell death 1 (PD-1)– Vinca alkaloid (eg, dominant negative receptor to shield the CAR CTLs from vinblastine, vincristine) 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 89 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 16 years or Tazemetostat (Tazverik) is a first-in-class, small-molecule One or more of the Overall survival Approval date: January 23, older and adults who have enhancer of zeste homolog 2 (EZH2) inhibitor intended to following: Progression-free 2020 locally advanced or metastatic treat epithelioid sarcoma, a rare and aggressive type of soft Alkylating agents (eg, survival FDA designation(s): Orphan epithelioid sarcoma not tissue sarcoma. Most epithelioid sarcoma cases exhibit dacarbazine, temozolomide, Quality of life Drug eligible for complete increased EZH2 activity that results in many genes being trabectedin) Clinical trial(s): Phase 3 EZH- resection turned off, in particular those involved in differentiation and Anthracyclines (eg, 301 primary completion cell cycle arrest. Approved by FDA, tazemetostat purportedly doxorubicin, epirubicin, September 2020; phase 2 improves health outcomes in patients with limited treatment liposomal doxorubicin) EZH-202 primary completion options by restoring antitumorigenic gene expression that Antimetabolites (eg, May 2023, safety and efficacy prevents epithelioid sarcoma cells from proliferating. The gemcitabine, ifosfamide) data presented June 2019 recommended dosage in the FDA-approved label is 800 mg Note(s): This Accelerated taken orally twice daily, until disease progression or Microtubule inhibitors (eg, Approval requires the conduct intolerable toxicity. eribulin, vinorelbine) of a further clinical trial to Developer(s): mTOR inhibitors (eg, everolimus, sirolimus, verify and describe Epizyme, Inc (Cambridge, Massachusetts) temsirolimus) tazemetostat’s clinical benefit Multikinase inhibitors (eg, imatinib, pazopanib, regorafenib, sorafenib, sunitinib)

Section 2. Cancer 90

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 lymphoma enhancer of zeste homolog 2 (EZH2) inhibitor intended to antibody (eg, obinutuzumab, survival FDA designation(s): Fast Track whose tumors are positive for treat follicular lymphoma, an indolent B-cell non-Hodgkin rituximab) Overall survival Clinical trial(s): Phase 1/2 EZH2 an mutation and who lymphoma. The disease typically responds well to initial CD20 monoclonal antibody Health-related quality of primary completion have received at least 2 prior chemoimmunotherapy, but if disease progresses within 24 Ibritumomab tiuxetan life November 2019, data systemic therapies or have no months of diagnosis and treatment, patients have limited Lenalidomide plus CD20 presented December 2019; satisfactory treatment effective options and poor prognosis. EZH2 is an epigenetic antibody phase 3 primary completion alternatives regulator of gene expression that affects histone methylation. June 2022 Methylation patterns promoted by EZH2 activity promote cell PI3K inhibitor (eg, copanlisib, Note(s): Tazemetostat is also proliferation as well as growth and development of a idelalisib) FDA approved for treating lymphoma (ie, lymphomagenesis). Therefore, tazemetostat metastatic or locally advanced inhibition of EZH2 purportedly has therapeutic potential in epithelioid sarcoma not follicular lymphoma. In particular, about 20% of follicular eligible for complete resection lymphomas harbor gain-of-function variants in the enhancer of the zeste 2 polycomb repressive complex 2 subunit gene, EZH2, 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 91 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 Clinical trial(s): Phase 3 epidermal growth factor taxane drug class (eg, docetaxel, nab-paclitaxel, paclitaxel). following: Progression-free CONTESSA primary receptor 2 (HER2)–negative, Taxanes inhibit mitosis (ie, duplicative cell division) and are Anthracyclines (eg, survival completion September 2020, hormone receptor (HR)– frequently used to treat breast cancer. However, available doxorubicin, liposomal Quality of life top-line data expected in third positive, locally advanced or taxanes are formulated only as intravenous infusions and are doxorubicin) quarter of 2020 metastatic breast cancer frequently associated with hypersensitivity reactions because Antimetabolites (eg, previously treated with a of additives needed as part of the taxane infusion solution. capecitabine, gemcitabine) taxane in the neoadjuvant or These reactions can prevent completion of a taxane regimen, Microtubule inhibitors (eg, adjuvant setting potentially reducing efficacy. Breast cancer also develops eribulin, vinorelbine) resistance over time to these infused taxanes, but oral tesetaxel has demonstrated anticancer activity in tumors that Poly adenosine diphosphate- have previously been exposed to other taxanes and ribose polymerase (PARP) developed resistance. Thus, oral tesetaxel might provide a inhibitors (eg, olaparib, BRCA1/2 more convenient and comfortable administration route that talazoparib) for - improves treatment adherence, as well as a treatment option mutated breast cancer when other taxanes become ineffective. In clinical trials, Taxanes (eg, docetaxel, tesetaxel (27 mg/m2 once every 21 days on day 1 of each paclitaxel) 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 92 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who develop Trilaciclib (G1T28) is a small-molecule inhibitor of cyclin- One or more of the Overall survival Submission date: New Drug myelosuppression during dependent kinases 4 and 6 (CDK4/6) intended to prevent following: Myelosuppression Application June 2020 chemotherapy for extensive- chemotherapy-induced myelosuppression. A common side Blood transfusion Quality of life FDA designation(s): stage small cell lung cancer effect of chemotherapy for many types of cancer is Bone marrow transplantation Breakthrough Therapy (SCLC) suppression of the blood-producing cells in the bone Red blood cell growth Clinical trial(s): Phase 2 G1T28- marrow. Termed myelosuppression, this condition decreases factors (eg, darbepoetin, 05 primary completion July the number of red and white blood cells and in the erythropoietin) 2018, data presented body as chemotherapy continues. Ongoing September 2019 myelosuppression can lead to serious complications. No White blood cell growth preventive options exist—the only options available treat factors (eg, filgrastim, myelosuppression after it has occurred. These approaches lenograstim, pegfilgrastim, include blood transfusions and growth factors intended to sargramostim) restore blood cells. Trilaciclib purportedly makes blood- producing cells less susceptible to the cytotoxic effects of chemotherapy. Trilaciclib purportedly does not negate the antitumor effect of chemotherapy against SCLC tumors, because proliferation of SCLC tumor cells is usually CDK4/6- independent. In clinical trials, trilaciclib is given as an intravenous infusion at a dosage of 240 mg/m2 on days 1, 2, and 3 of each 21-day chemotherapy cycle. Chemotherapy regimens include etoposide plus carboplatin or cisplatin with or without atezolizumab. Developer(s): G1 Therapeutics, Inc (Research Triangle Park, North Carolina)

Section 2. Cancer 93

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

Adults who have locally TT10 is a self-donated (ie, autologous) cell therapy developed One or more of the Overall survival Clinical trial(s): Phase 3 VANCE advanced or metastatic, from EBV-specific T cells (EBVSTs) collected from a patient’s following: Progression-free primary completion February Epstein-Bar virus (EBV)– peripheral blood. It is under study for treating EBV-associated Antimetabolites (eg, survival 2021 associated, recurrent NPC, which has limited treatment options; TT10 T cells could capecitabine, 5-fluorouracil, Quality of life nasopharyngeal carcinoma represent a new option in appropriately selected cases. In gemcitabine, methotrexate) (NPC) that has not been some NPC cases, EBV infection reprograms the EGFR inhibitor (eg, previously treated with nasopharyngeal epithelial cells to drive cellular cetuximab) systemic therapy transformation and proliferation and, therefore, may be Platinum-based drugs (eg, amenable to treatments targeting EBV. To create TT10, carboplatin, cisplatin) autologous EBVSTs are enriched and expanded in the presence of EBV antigen-expressing dendritic cells and Taxanes (eg, docetaxel, cytokines to generate large numbers of T cells that recognize paclitaxel) specific EBV antigens in NPC cells. After being expanded to the required numbers, EBVSTs are frozen until use. TT10 cells purportedly recognize and kill EBV-positive tumor cells and strengthen the patient’s natural T-cell responses against cancer cells expressing EBV antigens. In clinical trials, TT10 cells are given intravenously at an unspecified dose every 2 weeks for 2 cycles after chemotherapy with gemcitabine (1000 mg/m2) plus carboplatin (AUC 2) on days 1, 8, and 15 of a 28-day cycle for 4 cycles. Six weeks after receiving 2 cycles of TT10 cells, patients receive TT10 cells every 8 weeks for 4 cycles. Developer(s): Tessa Therapeutics, Inc (Singapore, Republic of Singapore)

Section 2. Cancer 94

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

Adults aged 18 to 75 years Uproleselan (GMI-1271) inhibits E-selectin, a transmembrane One or more of the Overall survival FDA designation(s): Orphan who have relapsed or glycoprotein that functions as a cell adhesion molecule. following: Progression-free Drug, Breakthrough Therapy, refractory acute myeloid Uproleselan might provide a new treatment option for a Anthracyclines (eg, survival Fast Track leukemia (AML) population of patients with typically poor prognoses and daunorubicin, idarubicin) Quality of life Clinical trial(s): Phase 3 outcomes. E-selectin retains AML cells within the vascular Antibody-drug conjugate primary completion December niches of the bone marrow, where these cells are less (eg, gemtuzumab 2020 susceptible to cytotoxic chemotherapy. Uproleselan ozogamicin) purportedly inhibits E-selectin’s cell adhesion activity, Antimetabolites (eg, mobilizing AML cells out of bone marrow and into the cladribine, , bloodstream and rendering them more sensitive to cytarabine, fludarabine) chemotherapy. In clinical trials, uproleselan is being given in combination with standard induction chemotherapy Cytokine (eg, granulocyte regimens (ie, mitoxantrone, etoposide, and cytarabine [MEC]; colony-stimulating factor [G- or fludarabine, cytarabine, and idarubicin [FAI]). Uproleselan CSF]) is given intravenously at a dose of 10 mg/kg. DNA synthesis inhibitors (eg, Developer(s): etoposide, 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 95 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult females who have stage (ABT-888) is a small-molecule inhibitor of poly For a first-line treatment Overall survival Clinical trial(s): Phase 3 VELIA III or IV, high-grade, epithelial adenosine diphosphate-ribose polymerase (PARP), an setting, combination Progression-free M13-694 primary completion ovarian, fallopian tube, or enzyme involved in DNA repair. Veliparib is the first PARP regimens with the following survival May 2019, data published primary peritoneal carcinoma inhibitor studied in the first-line treatment setting and is agents: Quality of life September 2019, data not previously treated with intended to delay disease progression in the maintenance Angiogenesis inhibitors (eg, reported March 2020 systemic therapy setting. By inhibiting PARP’s DNA repair, veliparib might bevacizumab) potentiate the anticancer activity of cytotoxic chemotherapy Anthracyclines (eg, drugs whose mechanism of action induces DNA damage. doxorubicin, pegylated Additionally, PARP inhibition might exhibit synthetic lethality liposomal doxorubicin) with cells harboring loss-of-function genetic rearrangements Platinum agents (eg, in the breast cancer 1 gene, BRCA1, and/or the breast cancer carboplatin, cisplatin) 2 gene, BRCA2 (an ovarian cancer predisposition gene that is also involved in DNA repair); ovarian cancers frequently Taxanes (eg, docetaxel, harbor such genetic variants. Eligibility for treatment will paclitaxel) require testing for BRCA variant status. In clinical trials, For a maintenance treatment veliparib is given orally at an unspecified dose each day in setting, the recommended combination with carboplatin and paclitaxel for 6 cycles of 21 options include the days. Veliparib maintenance therapy is given for up to 30 following: additional 21-day cycles. Bevacizumab for patients Developer(s): who received bevacizumab AbbVie, Inc (North Chicago, Illinois) as part of primary first-line therapy Observation Olaparib for patients with germline or somatic BRCA1/2 mutations

Section 2. Cancer 96

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 (MM) that has been treated prevents programmed cell death (ie, is antiapoptotic). The Alkylating agents (eg, survival January 2021 with 2 or more therapies that translocation between 11 and 14, abbreviated bendamustine, Quality of life Note(s): FDA approved included a protease inhibitor as t(11;14), is among the most common and routinely tested cyclophosphamide) venetoclax to treat many other and an immunomodulatory genetic abnormalities in patients with MM; about 15% to Anthracyclines (eg, cancers. See the FDA- agent and who harbor a 20% of patients with MM have it. Although this molecular doxorubicin) approved labeling and translocation between subtype is associated with poor prognosis with available Glucocorticoids (eg, prescribing document for all chromosomes 11 and 14 treatments, t(11;14)-positive MM may be particularly dexamethasone) approved indications. sensitive to venetoclax because t(11;14)-positive MM cells purportedly depend on BCL-2 for survival. Therefore, BCL-2 Immunomodulatory agents inhibition by venetoclax purportedly induces programmed (eg, lenalidomide, cell death of t(11;14)-positive MM cells. In clinical trials, pomalidomide) venetoclax is taken by mouth at a dosage of 800 mg once Monoclonal antibodies (eg, daily in combination with dexamethasone taken by mouth at daratumumab, elotuzumab) a dosage of 20 mg once every week of each 28-day cycle Proteasome inhibitors (eg, 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 97 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Females aged 18 years or VGX-3100 is a DNA-based immunotherapy vaccine Colposcopy followed by one Incidence of cervical Clinical trial(s): Phase 3 older who have cervical high- containing plasmids that include expression cassettes for of the following procedures HSIL REVEAL 1 primary completion grade squamous HPV proteins E6 and E7. It is intended to offer a nonsurgical to remove cervical lesions: Incidence of cervical July 2020; phase 3 REVEAL 2 intraepithelial lesion (HSIL) approach to treat certain precancerous cervical lesions that Carbon dioxide laser ablation cancer primary completion April 2021 and confirmed infection with are typically treated surgically. As a noninvasive intervention, Cold knife cone biopsy Incidence of infection human papillomavirus (HPV) VGX-3100’s optimized DNA is delivered into cells, where it is Laser cone biopsy with HPV-16 and/or type 16 and/or 18 translated into the E6 and E7 proteins that act as antigens to HPV-18 induce targeted T-cell and antibody responses. VGX-3100 Loop electrosurgical excision Quality of life purportedly uses this immune system response to clear HPV- 16 and HPV-18 infections and precancerous lesions, enabling patients to 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 98 Table 2.3. Cancer Topics Archived Since Last Status Report: 6 Topics

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

Adults who have advanced (Onzeald) is a novel drug-polymer form of One or more of the Overall survival In early 2020, Nektar breast cancer with stable the topoisomerase I inhibitor irinotecan. The drug-polymer following: Progression-free Therapeutics announced that brain metastases that has form is intended to reduce treatment-related adverse events Alkylating agents (eg, survival it had ceased development for been treated with one or two in patients with breast cancer and brain metastases. cyclophosphamide) Quality of life Onzeald after the drug cytotoxic regimens Etirinotecan pegol links to a macromolecule core. This Anthracyclines (eg, showed no improvement in linkage purportedly renders the drug inert in the doxorubicin) overall survival between bloodstream and allows its slow release as the patient’s body patients receiving Onzeald Antimetabolites (eg, metabolizes the linkages. Slow release extends the time the and patients receiving a fluorouracil, gemcitabine, cancer is exposed to therapeutic levels of the drug and limits treatment of the physician’s pemetrexed) high levels of drug exposure during infusion. Additionally, the choice. large drug-polymer conjugate might preferentially Poly adenosine diphosphate- accumulate in tumor tissues because of the increased ribose polymerase (PARP) permeability of tumor vasculature. In clinical trials, inhibitors (eg, niraparib, etirinotecan pegol is given as an intravenous infusion at a olaparib, rucaparib) dosage of 145 mg/m2 once every 21 days until disease Taxanes (eg, docetaxel, nab- progression or intolerable toxicity. paclitaxel, paclitaxel) Developer(s): Vinca alkaloid (eg, Nektar Therapeutics, Inc (San Francisco, California) vinorelbine)

Section 2. Cancer 99 Potential patient Intervention description Potential comparators Patient-oriented Archive reason population Developer(s)/manufacturer(s) outcome measures

Adults who have locally Infigratinib (BGJ398) is a novel, highly selective, small- One or more of the Overall survival A similar drug (pemigatinib) in advanced or metastatic, molecule inhibitor of 3 members of the fibroblast growth following: Progression-free the same class has been recurrent cholangiocarcinoma factor receptor (FGFR) family (ie, 1, 2, and 3). Antimetabolites (eg, survival approved for this patient that harbors fusions or Cholangiocarcinoma is a rare cancer that forms in bile ducts, gemcitabine) Quality of life population. Therefore, the translocations in the which carry fluid between the liver, the gallbladder, and the Platinum agents (eg, subsequent approval of fibroblast growth factor small intestine. Because about 20% of cholangiocarcinoma cisplatin, oxaliplatin) infigratinib for a similar receptor 2 gene, FGFR2 cases contain FGFR2 genetic alterations, using infigratinib to indication would no longer be target only FGFRs might improve outcomes of patients with considered disruptive. limited treatment options, who usually have poor health outcomes. Infigratinib is designed to specifically target FGFRs (with limited activity against FGFR4) and not bind to similar signaling domains in the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR). Infigratinib purportedly blocks new blood vessel formation (ie, angiogenesis), proliferation, and survival pathways in biliary tract cancer cells by inhibiting constitutive ligand-independent FGFR2 signaling. In some cholangiocarcinoma cases, the presence of activating FGFR alterations, including gene fusions and chromosome translocations, leads to uncontrolled cell proliferation. Eligibility for the therapy requires testing for FGFR2 gene rearrangements. In clinical trials, infigratinib is given daily by mouth at a dose of 125 mg, in a 3-weeks-on, 1-week-off schedule, until disease progression or intolerable toxicity. Developer(s): QED Therapeutics, Inc (San Francisco, California), a subsidiary of BridgeBio Pharma, Inc (Palo Alto, California)

Section 2. Cancer 100 Potential patient Intervention description Potential comparators Patient-oriented Archive reason population Developer(s)/manufacturer(s) outcome measures

Adults who have inoperable, Pamiparib (BGB-290) is a small-molecule inhibitor of 2 One or more of the Overall survival The pivotal phase 3 PARALLEL locally advanced, or enzymes involved in DNA repair, the poly adenosine following: Progression-free 303 trial of pamiparib has metastatic gastric cancer or diphosphate-ribose polymerases I and II (PARP1/2). Anthracyclines (eg, survival been converted to phase gastroesophageal junction Pamiparib’s inhibition of PARP1/2 causes mitotic defects such epirubicin) Quality of life 2, likely moving the cancer that has responded to as centrosome amplification, multipolar spindles, Antimetabolites (eg, 5- intervention out of the time a previous line of platinum- chromosome misalignment, premature loss of cohesion, fluorouracil, capecitabine) scope for the PCORI Health based chemotherapy metaphase arrest, anaphase DNA bridges, lagging Care Horizon Scanning HER2 antibodies (eg, chromosomes, and micronuclei. Patients with advanced System. The time scope is trastuzumab) gastric cancer usually experience recurrence. Maintenance defined as 3 years before an therapy with pamiparib purportedly mediates death of Platinum-based agents (eg, intervention becomes clinically gastric cancer cells that survived platinum-based carboplatin, cisplatin, available outside of the chemotherapy regimens by inhibiting PARP1/2’s DNA repair. oxaliplatin) research setting to 1 year after In clinical trials, pamiparib 60 mg is given orally twice daily Taxanes (eg, docetaxel, an intervention becomes until disease progression or intolerable toxicity. paclitaxel) clinically available. Developer(s): BeiGene, Ltd (Shanghai, China)

Adults who have a Pexidartinib (Turalio) is a small-molecule multikinase inhibitor Imatinib (off-label) Response rate FDA approved pexidartinib to symptomatic tenosynovial approved by FDA. It exhibits activity against several receptor Radiation therapy Patient-reported treat TGCT in August 2019. giant cell tumor (TGCT) that is tyrosine kinases, including colony-stimulating factor 1 physical function (ie, Because it has been clinically associated with severe receptor (CSF1R), FMS-like tyrosine kinase 3, and KIT. TGCTs PROMIS [Patient- available for more than 1 year, morbidity or functional typically overexpress colony-stimulating factor 1 (CSF1), Reported Outcomes it is no longer within the time limitations and is not which is an activating ligand for CSF1R. TGCT-expressed CSF1 Measurement scope for the PCORI Health amenable to improvement leads to recruitment of CSF1R-expressing cells, such as Information System] Care Horizon Scanning with surgery osteoclasts, macrophages, and mast cells, which initiate an physical function scale) System. The time scope is inflammatory reactive process that contributes to TGCT Patient-reported pain defined as 3 years before an pathogenesis. Therefore, inhibiting CSF1R by pexidartinib and stiffness intervention becomes clinically might limit CSF1-/CSF1R-driven attraction via chemotaxis of available outside of the Quality of life inflammatory cells and limit the proinflammatory process research setting to 1 year after underlying TGCT. The recommended dosage in the FDA- an intervention becomes approved label is 200 mg taken twice daily for a total of 400 clinically available. mg until disease progression or intolerable toxicity. The medication is to be taken on an empty stomach, at least 1 hour before or 2 hours after a meal or snack. Developer(s): Daiichi Sankyo, Inc (Tokyo, Japan)

Section 2. Cancer 101 Potential patient Intervention description Potential comparators Patient-oriented Archive reason population Developer(s)/manufacturer(s) outcome measures

Adults who have newly Pracinostat is an oral histone deacetylase (HDAC) inhibitor. Antibody-drug conjugate Complete remission rate In July 2020, Helsinn Group diagnosed acute myeloid HDACs act as epigenetic regulators (ie, functioning (eg, gemtuzumab Overall survival and MEI Pharma announced leukemia (AML), cannot peripherally to the genetic code) that chemically modify the ozogamicin) Quality of life that the phase 3 study of tolerate intensive remission DNA structure or its associated chromosomal proteins (eg, Glasdegib in combination pracinostat in AML had been induction chemotherapy, and histones). Abnormal activity of epigenetic regulators is with low-dose cytarabine discontinued after an interim have Eastern Cooperative thought to contribute to upregulating the accessibility and Low-dose cytarabine futility analysis demonstrated Oncology Group (ECOG) expression of tumor-promoting genes, contributing to the that it was unlikely to meet Low-intensity therapy (eg, performance status of 2 with pathogenesis of AML. The most common type of acute the primary end point. azacitidine and decitabine) significant cardiovascular leukemia, AML has a poor prognosis, and patients who disease or are older than 75 cannot tolerate high doses of chemotherapy need other Venetoclax alone or in years options. Pracinostat might improve patient health outcomes combination with azacitidine in the first-line setting for AML by restoring normal or low-dose cytarabine chromosomal structure and gene expression patterns in AML cells. Pracinostat purportedly inhibits class I, II, and IV HDACs and works synergistically in combination with a hypomethylating agent, such as azacitidine. In a clinical trial, pracinostat was given orally as a 60-mg capsule, once daily 3 times weekly for 3 weeks, followed by 1 week of rest for each 28-day cycle, in combination with azacitidine given as a subcutaneous or intravenous injection at a dose of 75 mg/m2 daily for 7 days of each 28-day cycle. Developer(s): MEI Pharma, Inc (San Diego, California), in collaboration with Helsinn Group (Lugano, Switzerland)

Section 2. Cancer 102 Potential patient Intervention description Potential comparators Patient-oriented Archive reason population Developer(s)/manufacturer(s) outcome measures

Adult females who have Trametinib (Mekinist) is a kinase inhibitor intended to treat One or more of the Overall survival Stakeholder commenters recurrent, low-grade, serous low-grade, serous ovarian or peritoneal cancer, a rare following: Progression-free agreed that trametinib might ovarian or peritoneal cancer subtype of serous cancer characterized by changes in the Anthracyclines (eg, pegylated survival improve patient health that has been treated with mitogen-activated protein kinase (MAPK) signaling pathway. liposomal doxorubicin) Quality of life outcomes (eg, progression- one or more lines of Recurrent, low-grade, serous ovarian or peritoneal cancer Hormone therapies (eg, free survival); however, chemotherapy responds poorly to treatment with cytotoxic chemotherapy. letrozole, tamoxifen) concerns exist about a lack of Trametinib purportedly shrinks tumors by blocking the improvement in patient Taxanes (eg, paclitaxel) activity of the protein MEK, a molecule that functions in the quality of life because of MAPK signaling pathway to regulate cell growth. In a clinical Topoisomerase inhibitors adverse events. Comments trial, trametinib was given as an oral dosage of 2 mg daily (eg, topotecan) suggested that the high costs until disease progression or unacceptable toxicity. of this treatment might Developer(s): increase disparities based on NRG Oncology (Philadelphia, Pennsylvania), in collaboration insurance coverage, and that with the National Institutes of Health’s National Cancer its overall disruption potential Institute (Bethesda, Maryland) is low.

Section 2. Cancer 103 Section 3. Cardiovascular Diseases: 23 Topics

Table 3.1. Currently Monitored Cardiovascular Diseases Topics: 23 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 therapy NYHA HF functional Clinical trial(s): Phase 3 who have New York Heart transplants a patient’s own bone marrow–derived (ie, Barostim neo implant) class CardiAMP primary completion Association (NYHA) functional mononuclear cells into damaged heart muscle. It is intended Cardiac contractility Exercise tolerance December 2021 class II or III heart failure (HF) to improve heart function and exercise capacity through 2 modulation (ie, Optimizer HF-related Note(s): BioCardia announced with chronic ischemic left mechanisms: direct and indirect regeneration. In direct implant) hospitalizations in August 2020 that its phase ventricular dysfunction regeneration, the transplanted cells purportedly travel to Guideline-directed optimal Survival 3 trial, which had been secondary to myocardial injured heart muscle (ie, myocardium) and transform into interrupted by the COVID-19 drug therapy (eg, Quality of life infarction and ventricular new functional heart cells. In indirect regeneration, the angiotensin-converting pandemic, had begun to ejection fraction between transplanted cells purportedly secrete stimulatory cytokines enzyme [ACE] inhibitors, continue enrollment, and 77 20% and 40% that is stable to instruct resident stem cells to regenerate heart tissue. diuretics, hydralazine, of 250 planned subjects had and being treated with Clinicians first collect about 15 cc of bone marrow and send it ivabradine, been enrolled guideline-directed medical to a partner laboratory for proprietary molecular analysis to sacubitril/valsartan) and device therapy 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 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 events CardiAMP CMI primary Cardiovascular Society class III mononuclear cells into damaged heart muscle to improve Guideline-directed drug Exercise tolerance completion December 2022 or IV chronic refractory heart function and exercise capacity. The developer asserts therapy (eg, aspirin, beta- Survival angina from obstructive that improving heart function could also reduce angina blockers, calcium channel Quality of life coronary artery disease that is incidence in patients who are not candidates for conventional blockers, nitrates, ranolazine) unsuitable for conventional revascularization procedures for ischemic coronary artery revascularization disease. CardiAMP therapy purportedly 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 21 to 80 years CLBS14 is an autologous CD34+ cell therapy intended to Enhanced external Angina incidence FDA designation(s): who have Canadian reduce angina by stimulating growth of new counterpulsation Exercise capacity Regenerative Medicine Cardiovascular Society class III microvasculature (ie, angiogenesis) in ischemic myocardial Guideline-directed optimal Major adverse Advanced Therapy or IV chronic refractory tissue. CLBS14 is intended to improve medical therapy for drug therapy (eg, aspirin, cardiovascular events Clinical trial(s): Phase 3 angina and obstructive patients with drug-resistant angina for whom conventional beta-blockers, calcium (MACE) RENEW completed November coronary disease unsuited for revascularization is ineffective or unsuitable. During the channel blockers, nitrates, Survival 2015, pivotal data published conventional revascularization proprietary process, patients receive granulocyte colony- ranolazine) August 2016 Quality of life stimulating factor (G-CSF; 5 mg/kg subcutaneous injection) Note(s): Caladrius reported in + for about 4 days to mobilize their own CD34 cells before an August 2020 quarterly apheresis (ie, plasma exchange) on day 5 to collect cells from report that, after working peripheral blood. Clinicians ship peripheral blood to a closely with FDA, it finalized + processing laboratory to isolate CD34 cells and prepare the design of a confirmatory cell therapy product for transport back to the treating facility. phase 3 trial that will be After about 3 to 4 days, clinicians administer the cell product considered for the registration into ischemic heart muscle via catheter-based of CLBS14. The study design intramyocardial injection. includes a 6-month primary Developer(s): end point, and the Biologics Caladrius Biosciences, Inc (Basking Ridge, New Jersey), which License Application is acquired exclusive worldwide license from Shire plc (Dublin, expected to receive a 6-month Ireland), now part of Takeda Pharmaceutical Co, Ltd (Osaka, review once submitted. The Japan) trial preparatory work is complete; however, the company will not start enrollment until it has sufficient capital dedicated to this program to be able to fund the trial uninterrupted through completion.

Section 3. Cardiovascular Diseases 106 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 45 years or older Dalcetrapib is an inhibitor of cholesteryl ester transfer protein Guideline-directed optimal Major adverse Clinical trial(s): Phase 3 who have a confirmed AA (CETP), a plasma protein responsible for lipid transport. drug therapy (eg, cardiovascular events primary completion January polymorphism at the Dalcetrapib was originally intended to raise high-density angiotensin-converting (MACE), including 2021 rs1967309 location in the lipoprotein levels by modulating CETP activity. It is also enzyme [ACE] inhibitors, cardiovascular death, adenylate cyclase type 9 intended to lower cardiovascular risk by helping lower levels aspirin, beta-blockers, myocardial infarction, gene, ADCY9, and were of harmful low-density lipoproteins. However, although calcium channel blockers, and stroke recently hospitalized for acute dalcetrapib failed to reduce cardiovascular events in large statins) coronary syndrome phase 3 trials, patients treated with dalcetrapib who carried Proprotein convertase the AA polymorphism at the rs1967309 location of the subtilisin kexin type 9 ADCY9 gene showed a 39% drop in cardiovascular adverse (PCSK9) inhibitors 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 test to identify potential candidates for dalcetrapib therapy in a phase 3 trial, which is also testing the drug. Dalcetrapib is given orally 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)

Adults aged 18 years or older Inclisiran is an RNA interference (RNAi) therapeutic designed Bile acid sequestrants Major adverse Submission date: New Drug who have heterozygous to target and reduce the expression of proprotein convertase Ezetimibe cardiovascular events Application December 2019 familial hypercholesterolemia subtilisin kexin type 9 (PCSK9) to treat high cholesterol (ie, Fibrates (MACE) Clinical trial(s): Phase 3 and an elevated low-density hypercholesterolemia). Inhibiting PCSK9 production Niacin Survival ORION-9 primary completion lipoprotein (LDL) cholesterol purportedly increases the number of LDL receptors that are September 2019, data PCSK9-inhibiting monoclonal level despite maximum lipid- recycled and are available on cell surfaces to remove LDL published April 2020 lowering therapies particles from extracellular fluid. Inclisiran is intended to antibodies simplify the dosing regimen as a subcutaneous (ie, under- Statins the-skin) injection every 3 to 6 months rather than an injection of alirocumab or evolocumab every 2 to 4 weeks. In clinical trials, inclisiran is injected under the skin at a dosage of 300 mg on days 1 and 90 and then every 6 months. Developer(s): The Medicines Company (Parsippany, New Jersey), a Novartis company, Novartis AG (Basel, Switzerland), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)

Section 3. Cardiovascular Diseases 107 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Inclisiran is an RNA interference (RNAi) therapeutic designed Bempedoic acid Major adverse Clinical trial(s): Phase 3 atherosclerotic cardiovascular to target and reduce the expression of proprotein convertase Bile acid sequestrants cardiovascular events ORION-10 primary completion disease (coronary, peripheral, subtilisin kexin type 9 (PCSK9) to treat high cholesterol (ie, Ezetimibe (MACE) October 2019, data published or other arteries) and elevated hypercholesterolemia). Inhibiting PCSK9 production April 2020; phase 3 ORION-8 Fibrates Survival low-density lipoprotein (LDL) purportedly increases the number of LDL receptors that are primary completion August cholesterol (ie, greater than recycled and are available on cell surfaces to remove LDL Niacin 2023 70 mg/dL) despite an optimal particles from extracellular fluid. Inclisiran is intended to PCSK9-inhibiting monoclonal dose of statins or other lipid- simplify the dosing regimen as a subcutaneous (ie, under- antibodies lowering therapies if statin- the-skin) injection every 3 to 6 months rather than an Statins intolerant injection of alirocumab or evolocumab every 2 to 4 weeks. In clinical trials, inclisiran is injected under the skin at a dosage of 300 mg on days 1 and 90 and then every 6 months. Developer(s): The Medicines Company (Parsippany, New Jersey), a Norvartis company, Novartis AG (Basel, Switzerland), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)

Section 3. Cardiovascular Diseases 108 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 40 years or older InterAtrial shunt device (IASD) is intended to relieve HF Cardiac contractility NYHA functional class FDA designation(s): who have symptomatic New symptoms by reducing elevated left atrial pressure, a modulation (ie, Optimizer Exercise tolerance Breakthrough Device York Heart Association common feature of HF that causes a backup of blood in the implant) HF-related Clinical trial(s): Unphased (NYHA) class III or ambulatory lungs, leading to pulmonary congestion and breathing Guideline-directed optimal hospitalization pivotal REDUCELAPHF-II class IV heart failure (HF), left difficulty. IASD implantation would disrupt management for drug therapy (eg, Survival primary completion December ventricular ejection fraction patients with HF with preserved left ventricular ejection angiotensin-converting 2020; unphased Quality of life greater than 40%, and fraction (ie, greater than 40%), which relies on drug therapy enzyme [ACE] inhibitors, REDUCELAPHF-I primary elevated left atrial pressure prescribed in an outpatient office setting. IASD implantation diuretics, hydralazine, completion December 2016, despite stable guideline- might also compete with implantation of the recently ivabradine, data published October 2018; directed optimal drug therapy introduced Optimizer electronic implant in a subset of sacubitril/valsartan) REDUCELAPHF-III European patients with left ventricular ejection fraction between 40% postmarket observational and 45%. To implant the IASD, a physician inserts a primary completion July 2021 specialized catheter in the femoral vein at the groin and threads it up into the right atrium to create an opening in the septum, the wall separating the heart’s 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): Corvia Medical, Inc (Tewksbury, Massachusetts)

Section 3. Cardiovascular Diseases 109 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have Canadian Neovasc Reducer is a stent-like implant intended to treat Enhanced external Angina incidence Submission date: Premarket Cardiovascular Society class III chronic angina by improving blood flow to ischemic heart counterpulsation Exercise tolerance Approval Application or IV chronic angina from tissue. This implanted device could provide an option for Guideline-directed medical Device-related adverse December 31, 2019 obstructive coronary artery patients whose angina persists despite optimal medical therapy for ischemic heart events FDA designation(s): disease that is resistant to therapy and who are unable to undergo conventional bypass disease (eg, aspirin, beta- Survival Breakthrough Device optimal medical therapy and surgery. Physicians implant the Neovasc Reducer in the blockers, calcium channel Quality of life Clinical trial(s): Unphased who are unsuitable for coronary sinus, the large vein that drains blood from the blockers, nitrates, ranolazine) REDUCER-1 primary conventional revascularization heart muscle, to create a pressure backflow that purportedly completion December 2022, modulates blood flow through the coronary sinus and interim data reported June redistributes blood to areas of heart muscle with poor 2020; unphased primary circulation. To implant the balloon-expandable, hourglass- completion December 2030 shaped device, a physician inserts the delivery catheter at the Note(s): The FDA Circulatory jugular vein in the neck and advances it into the coronary System Devices Advisory Panel sinus, located on the external heart wall between the left will review the marketing atrium and left ventricle. Implantation purportedly takes application on October 27, about 20 minutes with patients under local anesthesia. 2020, to make a Developer(s): recommendation to FDA Neovasc, Inc (Richmond, British Columbia, Canada)

Section 3. Cardiovascular Diseases 110 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have had an acute Nerinetide (NA-1) is a neuroprotective drug in development Standard-of-care ischemic Stroke-induced Clinical trial(s): Phase 3 ischemic stroke to reduce brain damage caused by ischemic stroke. When a stroke treatment (ie, tissue disability ESCAPE-NA1 completed clot blocks an artery supplying the brain, brain cells can be plasminogen activator Survival November 2019, data damaged by restricted blood flow (ischemia). When blood [alteplase] thrombolysis, Quality of life published February 2020; flow is restored, brain cells can also be harmed by mechanical thrombectomy) phase 3 FRONTIER primary reperfusion injury, which results from an inflammatory without nerinetide completion May 2021 cascade including oxygen-free radicals and proinflammatory neuroprotection cytokines. Reperfusion injury deteriorates the ischemic penumbra, the area of ischemic, but still salvageable, cerebral tissue around the core infarcted (ie, dead) zone. Available treatments are designed to restore blood flow to blocked brain arteries by dissolving blood clots with drugs (thrombolysis) or physically extracting clots (catheter thrombectomy). Nerinetide, if given before other treatments to protect brain cells from ischemic injury and reperfusion injury, could reduce the incidence or severity of stroke- induced disability. Nerinetide could also be given by paramedics in the field before patient transfer to stroke centers. Nerinetide purportedly could also extend the effective treatment window to up to 12 hours. Nerinetide is an inhibitor of the postsynaptic density-95 (PSD-95) protein, which is found in neuronal synapses. The drug purportedly helps protect brain cells by disrupting the pro-death signaling pathways associated with PSD-95. Further, by blocking the enzyme neuronal nitric oxide synthase (nNOS), nerinetide also helps prevent the formation of nitric oxide, a free-radical toxin that combines with superoxides produced by the mitochondria to form a potent neurotoxin. In phase 3 trials, nerinetide is given as a single intravenous infusion at a dosage of 2.6 mg/kg over about 10 minutes. Developer(s): NoNO, Inc (Toronto, Ontario, Canada)

Section 3. Cardiovascular Diseases 111 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 18 to 85 years Omecamtiv mecarbil (AMG 423) is a cardiac myosin activator Guideline-directed optimal NYHA HF functional FDA designation(s): Fast Track who have chronic heart failure intended to increase the duration of cardiac muscle drug therapy (eg, class Clinical trial(s): Phase 3 (HF); New York Heart contractility and improve cardiac muscle performance. The angiotensin-converting Improved exercise GALACTIC-HF primary Association (NYHA) functional mechanism of action purportedly improves cardiac muscle enzyme [ACE] inhibitors, tolerance completion August 2020, class II to IV; left ventricular performance without increasing cellular calcium diuretics, hydralazine, HF-related designed under Special ejection fraction of 35% or concentrations that can occur with other common HF drugs, ivabradine, hospitalization Protocol Assessment; phase 3 less despite maximally thereby avoiding risk of increasing heart rate, blood pressure, sacubitril/valsartan) Survival METEORIC-HF primary tolerated, guideline-directed and arrhythmias. In clinical trials, omecamtiv mecarbil is given completion February 2021 medical therapy; and elevated orally at 25 to 50 mg twice daily. Quality of life levels of B-type natriuretic Developer(s): peptide (BNP) or N-terminal Cytokinetics, Inc (South San Francisco, California), in pro B-type natriuretic peptide collaboration with Amgen, Inc (Thousand Oaks, California) (NTproBNP)

Section 3. Cardiovascular Diseases 112 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: April 14, transplantation organ in a warm, functioning state outside the body for an Overall survival 2014 extended period to optimize donor organ health and allow Quality of life Clinical trial(s): Unphased for continuous clinical evaluation before transplantation. The EXPAND Heart primary OCS Heart is optimized for preserving donor hearts. Many completion December 2019, donor hearts are never transplanted because their condition preliminary data published degrades quickly after harvesting; thus, fewer patients receive April 2019; unphased HEART the heart transplant they need. OCS Heart would represent a EXPAND continued access substantial change to pretransplant procedures for potential protocol primary completion donor organ assessment, procurement, and transport November 2020; unphased compared with static cold storage, which is the current Donors After Circulatory standard. OCS Heart purportedly could increase the volume Death primary completion of heart transplantations, enabling longer-distance transport August 2021; unphased and giving clinicians more clinical data to better assess donor observational clinical use organ suitability. The manufacturer has developed similar cohort primary completion technology to preserve lung and liver grafts. The OCS device December 2021 comprises 2 principal components: a portable battery- Note(s): On March 16, 2020, powered console and an organ-specific perfusion kit that FDA postponed an advisory function together as an integrated system. The system panel meeting to discuss the perfuses donor organs with a proprietary blood-based OCS Heart, originally solution to replenish oxygen and essential nutrients. When scheduled for April 16, 2020, physicians harvest the donor heart, they place it in the until a future undetermined perfusion module and revive it to a beating state. The self- date because of the effects of contained perfusion module maintains the proper the COVID-19 pandemic. FDA temperature and humidity, protects the organ from external approved OCS Lung for contaminants, and allows sterile ultrasound assessment of standard-criteria lung heart function and sterile blood sampling for laboratory preservation in March 2018 analysis. A wireless monitor allows clinicians to assess the and for expanded-criteria lung organ’s status and control system functions. preservation in June 2019. Developer(s): TransMedics, Inc (Andover, Massachusetts)

Section 3. Cardiovascular Diseases 113

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

Adults aged up to 75 years Paradise Renal Denervation System is a catheter-based Guideline-directed optimal Blood pressure Clinical trial(s): RADIANCE- who have essential device intended to ablate the sympathetic nerves that line antihypertensive drug Cardiovascular adverse HTN primary completion June hypertension controlled on the main renal arteries connecting the kidneys to the aorta. therapy with one or more events 2020, interim data published one or two medications or Deactivating the renal sympathetic nerves can purportedly agents (eg, angiotensin- Survival March 2019; RADIANCE-II uncontrolled hypertension on help reduce difficult-to-manage, treatment-resistant high converting enzyme [ACE] pivotal primary completion Quality of life zero to 2 medications blood pressure (ie, hypertension). An interventional inhibitors, angiotensin- December 2020 (average office blood procedure would shift care away from standard office-based receptor blockers [ARBs], pressure between 140/90 and medical management for most patients with uncontrolled calcium channel blockers, 180/110 mm Hg) high blood pressure. A physician inserts the proprietary thiazide diuretics) balloon catheter into the femoral artery in the groin and advances it into the left and right renal arteries, alternately, to deliver 2 to 4 applications of circumferentially delivered ultrasound energy, about 7 seconds each, to each artery. The liquid-cooled balloon purportedly protects the artery walls from thermal damage while the sympathetic nerves are ablated. The physician removes the catheter using standard interventional techniques after treating both renal arteries. Developer(s): ReCor Medical, Inc (Palo Alto, California)

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

Section 3. Cardiovascular Diseases 114

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) system consists of a proprietary catheter, console, coronary intervention (ie, of myocardial infarct (ie, Breakthrough Device elevation myocardial and monitor intended to be used to preserve at-risk heart balloon angioplasty with dead heart muscle) Clinical trial(s): Unphased infarction (STEMI) muscle during an acute heart attack. PiCSO is intended to be stenting) Heart function randomized PiCSO-AMI-I used as an adjunct to the standard percutaneous coronary primary completion intervention for STEMI, balloon angioplasty plus stenting. It September 2020; phase 2 could disrupt current management by adding procedural nonrandomized OxAMI-PICSO steps and capital equipment. During a percutaneous primary completion October coronary intervention procedure, PiCSO therapy is initiated 2020, data published June after blood flow has been restored. Physicians insert the 2018 PiCSO balloon catheter in the femoral vein at the groin and advance it into the coronary sinus vein in the heart using standard catheter-based techniques. Using a proprietary algorithm that continuously monitors coronary sinus pressure changes, a computerized PiCSO console inflates and 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. PiCSO 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 115 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 therapy Guideline-directed optimal NYHA HF functional Clinical trial(s): Phase 3 who have chronic (at least 6- made from human bone marrow–derived, allogeneic (ie, from drug therapy (eg, ACE class DREAM HF-1 primary month duration) ischemic or a donor) adult mesenchymal precursor cells. Standard inhibitors, diuretics, Exercise tolerance completion May 2020 nonischemic New York Heart medical therapy for HF attempts to slow disease progression hydralazine, ivabradine, HF-related Note(s): FDA granted Association (NYHA) functional and relieve symptoms. Rexlemestrocel-L purportedly releases sacubitril/valsartan) hospitalizations rexlemestrocel-L Orphan Drug class II or III heart failure (HF) a range of factors that induce functional recovery within Survival designation in June 2019 for while being treated with damaged heart tissue by activating multiple pathways to preventing mucosal bleeding Quality of life maximally tolerated doses of induce new blood vessel growth, reduce inflammation, after implantation of a left a beta-blocker, an reduce fibrosis and scar tissue formation, and regenerate ventricular assist device angiotensin-converting heart muscle. Rexlemestrocel-L is isolated from bone (LVAD) in adults with end- enzyme (ACE) inhibitor or mononuclear cells with antistromal precursor antigen (STRO)- stage HF angiotensin-receptor blocker 3 antibodies, expanded in a laboratory, and cryopreserved (ARB), and/or an aldosterone until it is given to the patient. The product is intended to be antagonist, plus a diuretic 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 116 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 therapy LVAD implantation alone Mucosal and GI FDA designation(s): Orphan Heart Association (NYHA) made from human bone marrow–derived, allogeneic (ie, from bleeding Drug, Regenerative Medicine functional class IIIB or IV heart a donor) adult mesenchymal stem cells. Patients who have Functional capacity Advanced Therapy failure (HF) that has been end-stage HF and require LVAD implantation face a high risk Treatment-related Clinical trial(s): Phase 2 unresponsive to optimal of serious GI bleeding and repeated hospitalizations. A phase adverse events completed August 2019, data medical management and 2 trial of patients who received an LVAD found that adding Survival published March 2019 who are at risk of rexlemestrocel-L significantly reduced the incidence of major Quality of life Note(s): Future confirmatory gastrointestinal (GI) bleeding GI bleeding by about 76% compared with a control group, phase 3 is planned (no date after implantation of a left although it did not increase the rate of successfully weaning stated) to support a future ventricular assist device patients from LVAD therapy (the trial’s primary outcome). For Biologics License Application (LVAD) patients with end-stage HF requiring an LVAD, for end-stage HF in patients rexlemestrocel-L given immediately after LVAD implantation with an LVAD implant 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, expanded 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 117 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 18 to 80 years RT-100 (Ad5.hAC6) is an adenovirus-based gene therapy Baroreflex activation therapy Exercise tolerance FDA designation(s): Fast Track who have New York Heart product intended to improve heart function in patients with (ie, Barostim neo device) HF-related Clinical trial(s): Phase 3 Association (NYHA) functional chronic HF by increasing expression of the adenylyl cyclase Cardiac contractility hospitalizations FLOURISH withdrawn June class II to IV heart failure (HF) type 6 (AC6) protein. AC6 helps regulate heart function but is modulation (ie, Optimizer NYHA HF functional 2019 to reevaluate product and left ventricular ejection underexpressed in heart muscle cells of patients with HF. RT- device) class development strategy fraction between 10% and 100 is an adenovirus vector (ie, human adenovirus 5 Guideline-directed optimal Survival 35% despite guideline- encoding human AC6 [Ad5.hAC6]) modified to prevent it drug therapy (eg, Quality of life directed optimal medical from replicating. It is designed to enter heart cells to deliver angiotensin-converting therapy the gene encoding for AC6. A physician uses standard cardiac enzyme [ACE] inhibitors, catheterization techniques to administer a single dose of RT- diuretics, hydralazine, 100 into the coronary arteries using an infusion catheter. In a ivabradine, phase 2 trial, patients received 1 of 5 ascending doses from sacubitril/valsartan) 3.2 × 109 to 3.2 × 1012 virus particles. Dose levels in the phase 3 trial have not yet been reported. Developer(s): Renova Therapeutics (San Diego, California)

Section 3. Cardiovascular Diseases 118 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 for prostate, liver, kidney) that is designed to deliver high-dose Quality of life completion July 2018, conventional catheter radiation noninvasively to precise targets in the body while preliminary data published ablation of arrhythmias or avoiding damage to healthy adjacent tissue. Investigators January 2019, additional data additional medical have begun evaluating whether SBRT could offer a presented November 2019; management and noninvasive therapeutic alternative for VT, a potentially fatal phase 1/2 NIRA-VT primary documented, recurrent VT irregular heartbeat, that has not responded to conventional completion December 2019; episodes despite an existing treatments. Although FDA has cleared several radiation unphased RAVENTA primary implantable cardioverter- therapy systems for SBRT for various tumors, SBRT for VT completion June 2021; phase defibrillator (ICD) would be an off-label use. SBRT for refractory VT would 1/2 STRA-MI-VT primary represent a dramatic shift in arrhythmia treatment that would completion September 2022; require substantial collaboration among clinicians in different phase 1/2 SABR for refractory clinical service lines (eg, interventional cardiology, radiation VT primary completion physics) who do not typically collaborate. To receive an SBRT- December 2022; unphased for-VT procedure, patients undergo detailed STAR-VT primary completion electrocardiographic imaging studies that combine cardiac December 2022; unphased electrical mapping with anatomic imaging, which purportedly STAR VTM primary completion allows physicians to pinpoint the VT source and possible December 2023 arrhythmia trajectory. In an early study, physicians delivered a Note(s): As a procedure, rather total dose of 25 Gray in a single fraction (ie, session) without than a drug or medical device, sedation or anesthesia, with an average treatment time of SBRT for VT would not be less than 15 minutes. VT episodes may occur within the first 6 subject to FDA approval or weeks after treatment due to radiation-induced clearance. US investigators inflammation; however, VT episodes are expected to decline typically perform the substantially after radiation-associated inflammation resolves. procedure off-label using Developer(s): radiotherapy systems that Washington University School of Medicine in St Louis (St have FDA clearance to Louis, Missouri) perform SBRT for solid-tumor University of California at Los Angeles (Los Angeles, cancers. California) Varian Medical Systems, Inc (Palo Alto, 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 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 adverse OFF MED pivotal primary ambulatory systolic blood arteries connecting the kidneys to the aorta. Deactivating the therapy with one or more events completion June 2020, data pressure of at least 140 mm renal sympathetic nerves purportedly can help reduce agents (eg, angiotensin- Survival published March 2020; Hg and less than 170 mm Hg difficult-to-manage high blood pressure (ie, hypertension). converting enzyme [ACE] SPYRAL HTN-ON MED Quality of life An interventional procedure would shift care from standard inhibitors, angiotensin- primary completion office-based medical management for most patients with receptor blockers [ARBs], November 2020, preliminary uncontrolled high blood pressure. A physician inserts the calcium channel blockers, data published June 2018, helical ablation catheter into the femoral artery in the groin thiazide diuretics) post hoc data published and advances it into the left and right renal arteries, August 2020; SPYRAL DYSTAL alternately, to deliver radiofrequency energy in a spiral primary completion March pattern, about 1 minute per application, to one or more 2021 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 120 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 nerves resistant PAH) PAH worsening Breakthrough Device in the pulmonary arteries in a process called pulmonary Guideline-directed medical Survival Clinical trial(s): Unphased artery denervation. As an interventional procedure to treat therapy (eg, ambrisentan, Quality of life single-arm TROPHY II primary PAH, TIVUS would disrupt standard PAH treatment, which riociguat, tadalafil, completion July 2020; relies primarily on medical management (ie, drugs). Studies treprostinil) unphased single-arm have suggested that baroreceptors and sympathetic nerve Lung transplantation (for TROPHY1-US primary fibers near the branching (ie, bifurcation) of the main advanced drug-resistant completion April 2019, pulmonary artery might contribute to the elevated blood PAH) preliminary data published pressures seen in PAH. Therefore, ablating the nerves April 2019; unphased single- embedded in the main, left, and right pulmonary arteries arm TROPHY1 primary might reduce high blood pressure in the pulmonary arteries completion October 2018, and lungs in patients with PAH. To perform pulmonary artery preliminary data published denervation, a physician inserts a proprietary catheter into April 2019 the jugular vein in the neck and advances it into the 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 121 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

Adults aged up to 99 years V-Wave interatrial shunt is intended to relieve HF symptoms Baroreflex activation therapy NYHA functional class FDA designation(s): who have New York Heart by reducing elevated left atrial pressure, a common feature of (ie, Barostim neo implant) Exercise tolerance Breakthrough Device Association (NYHA) class III or HF that causes a backup of blood in the lungs, leading to Cardiac contractility HF-related Clinical trial(s): Unphased ambulatory class IV heart pulmonary congestion and breathing difficulty. V-Wave modulation (ie, Optimizer hospitalization randomized RELIEVE-HF failure (HF) despite guideline- device implantation would disrupt patient management for implant) Survival primary completion October directed optimal drug therapy HF, which traditionally relies on office-based drug therapy. V- 2021 Guideline-directed optimal Quality of life and regardless of left Wave implantation might also compete with implantation of drug therapy (eg, ventricular ejection fraction 2 recently introduced electronic devices for HF: the Barostim angiotensin-converting neo and Optimizer implants. To implant the V-Wave shunt, a enzyme [ACE] inhibitors, physician inserts a specialized catheter into the femoral vein diuretics, hydralazine, at the groin and threads it up into the right atrium to create ivabradine, an opening in the septum, the wall separating the left and sacubitril/valsartan) 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 122 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 18 years or older Wireless Stimulation Endocardially for Cardiac Conventional biventricular NYHA HF functional FDA designation(s): who have heart failure (HF) Resynchronization Therapy (WiSE-CRT) is a system that pacing/CRT with epicardial class Breakthrough Device 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 from an Guideline-directed optimal HF-related (SOLVE CRT) primary IIa guideline indication for electrode lead placed within the coronary sinus vein along drug therapy (eg, hospitalizations completion June 2021; CT conventional cardiac the left ventricular wall with endocardial left ventricular angiotensin-converting Survival Guided WiSE-CRT primary resynchronization therapy pacing from a wireless electrode implanted inside the left enzyme [ACE] inhibitors, completion December 2020; Quality of life (CRT) and whose disease has ventricle. A conventional pacemaker implanted under the diuretics, hydralazine, WiCS-LV postmarket registry not responded to CRT or was skin in the chest senses and paces the right ventricle with a ivabradine, primary completion previously untreatable (ie, had conventional right atrial lead and a right ventricular lead. A sacubitril/valsartan) September 2019, data an implanted CRT system wireless electrode (2.7 × 16.3 mm) anchored in the left published March 2020 turned off due to electrode ventricular wall paces the left ventricle. A wireless transmitter lead failure or relative placed 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 123 Section 4. Mental and Behavioral Health: 19 Topics

Table 4.1. Mental and Behavioral Health Topics Added Since Last Status Report: 3 Topic

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 (ie, Atypical antipsychotics Agitation symptoms and Submission date: New Drug who have bipolar I or II under the tongue) film form. It is a selective alpha-2a (eg, severity (eg, excitement, Application planned for first disorder and acute agitation receptor agonist intended to rapidly reduce acute agitation in [intramuscular], off-label hostility, quarter of 2021 patients who have bipolar disorder. Acute agitation haloperidol uncooperativeness) FDA designation(s): Fast Track symptoms in bipolar disorder are usually associated with the [intramuscular]) Rate of infliction of harm (agitation) manic or hypomanic phase and include excessive verbal or (eg, off- to self or others Clinical trial(s): Phase 3 motor activity, irritability, uncooperativeness, and threatening label SERENITY II primary or aggressive behaviors toward oneself or others. Few [intramuscular]) completion April 2020, top- treatment options exist, and BXCL501 might offer a safer Physical restraint line data reported July 2020 alternative compared with intramuscular antipsychotics that can cause movement disorder side effects and off-label use of 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 produces sedative effects by activating alpha-2a receptors in the central nervous system, which might inhibit norepinephrine release and increase inhibitory gamma- aminobutyric acid (GABA) neuron activity. It purportedly produces calming but not sedative effects within 20 minutes and has been shown to produce effects for up to 120 minutes in this patient population. 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 124 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 (ie, Antipsychotics (eg, Agitation symptoms and Submission date: New Drug who have clinically diagnosed under the tongue) film form. It is a selective alpha-2a olanzapine [intramuscular], severity (eg, excitement, Application planned for first schizophrenia, schizoaffective receptor agonist, intended to rapidly reduce acute agitation ziprasidone hostility, quarter of 2021 disorder, or schizophreniform in patients who have schizophrenia. Acute agitation [intramuscular], off-label uncooperativeness) FDA designation(s): Fast Track disorder and who are acutely symptoms in schizophrenia include excessive verbal or motor haloperidol Rate of infliction of harm (agitation) agitated activity, irritability, uncooperativeness, and threatening or [intramuscular]) to self or others Clinical trial(s): Phase 3 aggressive behaviors toward oneself or others. Few treatment Benzodiazepines (eg, off- SERENITY I primary options exist, and BXCL501 might offer a safer alternative label lorazepam completion May 2020, top- than intramuscular antipsychotics that can cause movement [intramuscular]) line data reported July 2020; disorder side effects and off-label use of benzodiazepines Physical restraint phase 1b completed July that can cause respiratory depression. Dexmedetomidine is 2019, data reported July 2019 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 125 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 as Benzodiazepines (eg, Social anxiety symptoms FDA designation(s): Fast Track with social anxiety disorder a rapid-onset treatment for SAD. Unlike current FDA- , ; and severity Clinical trial(s): Phase 3 (SAD) approved therapies for SAD that require daily dosing, PH94B off-label) Quality of life planned; phase 3 completed is intended for as-needed use. SAD, also known as social Beta-blocker (ie, October 2014, data published phobia, is a mental health condition in which social propranolol; off-label) August 2016; phase 2 interactions cause anxiety, fear, self-consciousness, and Selective serotonin completed February 2011, embarrassment. It often leads to avoidance of social reuptake inhibitors (SSRIs; data published June 2014 situations, which can produce feelings of isolation and ie, paroxetine, sertraline) depression and decreases overall quality of life. Given in a Serotonin and nasal spray, PH94B purportedly binds to nasal chemosensory norepinephrine reuptake receptors to activate neural circuits in the brain that suppress inhibitor (SNRI; ie, fear and anxiety. Specifically, it is purported to trigger a venlafaxine) subset of neurons in the main olfactory bulbs that stimulate inhibitory GABAergic neurons in the limbic amygdala to decrease the release of norepinephrine and facilitate fear extinction activity of the limbic-hypothalamic parasympathetic system. In clinical trials, PH94B is administered one time intranasally at a dose of 1.6 µg (two 0.4 µg sprays in each nostril) 15 minutes before lab-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 126 Table 4.2. Currently Monitored Mental and Behavioral Health Topics: 15 Topics

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

Section 4. Mental and Behavioral Health 127 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, applied ADHD symptoms and Approval date: De Novo who have inattentive or improve attention and related cognitive control processes in behavior analysis [ABA], severity clearance June 15, 2020 combined-type attention- children with ADHD. It is a novel intervention that might cognitive behavioral therapy Attentional functioning Clinical trial(s): Unphased deficit/hyperactivity disorder provide a nondrug alternative for treating ADHD. A [CBT]) Executive functioning STARS-ADHD completed (ADHD) behavioral disorder, ADHD is characterized by inattention, External trigeminal nerve Spatial working memory August 2017, data published hyperactivity, and impulsivity that in children can lead to stimulation (eTNS) 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 purportedly guanfacine) STARS-ADHD adjunctive targets and activates the frontoparietal network in the brain, Stimulant medications (eg, completed September 2019, a network thought to play an important role in cognitive dexmethylphenidate, data reported January 2020; function and attention, to improve attention and related lisdexamfetamine, unphased primary completion cognitive control processes in children with ADHD. Users are methylphenidate) January 2020; unphased given tasks such as interference management and sensory CAVES completed May 2015, motor navigation. An embedded algorithm uniquely adapts data published January 2018 to each user’s performance to provide challenging but Note(s): EndeavorRx was tolerable game play. Progress is indicated by earning rewards released for download in April and unlocking new environments. EndeavorRx is an 2020 without 510(k) clearance application that can be downloaded on smart devices and in accordance with FDA used at home. It has been studied alone and in combination guidance on expanding use of with stimulant medication. In clinical trials, EndeavorRx was certain digital health used by the patient at home on a smart tablet for 25 minutes therapeutic devices for (5 sessions of 5 minutes) 5 times a week for 4 weeks. FDA psychiatric disorders for the clearance documentation states, “EndeavorRx should be duration of the public health considered for use as part of a therapeutic program that may emergency related to the include: clinician-directed therapy, medication, and/or COVID-19 pandemic educational programs, which further address symptoms of the disorder.” Developer(s): Akili Interactive Labs, Inc (Boston, Massachusetts)

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 75 years External trigeminal nerve stimulation (eTNS) sends electrical Psychotherapy (eg, cognitive PTSD severity and Clinical trial(s): Phase 1 who have posttraumatic stimulation to the trigeminal nerve through a patch placed behavioral therapy [CBT], eye symptoms completed January 2012, data stress disorder (PTSD) on the patient’s forehead to treat PTSD, which has limited movement desensitization Depression severity and published April 2016; effective treatment options. This small, portable device is and reprocessing [EMDR] symptoms unphased pivotal primary intended to improve symptom severity and quality of life. The therapy, prolonged exposure Functional capacity completion September 2020 eTNS system is a cell phone–sized electrical pulse generator therapy [PET]) Quality of life Note(s): FDA approved eTNS that delivers mild electrical signals via 2 wires connected to a Selective serotonin reuptake in April 2019 for pediatric small single-use electric patch that adheres to the forehead. inhibitors (SSRIs; eg, attention-deficit/hyperactivity The therapy is intended to be used by the patient at home paroxetine, sertraline) disorder (ADHD) nightly for 8 hours while sleeping. The eTNS therapy purportedly changes the neuronal activity in key regions of the brainstem, thalamus, and cortex, increasing activity in underactive regions. It is used in conjunction with pharmacotherapy. Developer(s): Neurosigma (Los Angeles, California), in collaboration with University of California (Los Angeles, California)

Section 4. Mental and Behavioral Health 129 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), previously Dietary modifications and Autism symptoms and FDA designation(s): Fast Track who have autism spectrum called CP-101, is an oral route of stool transplantation. The nutritional counseling severity Clinical trial(s): Phase 2 disorder (ASD) with therapy introduces key strains of purportedly beneficial Fecal microbiota Aberrant behavior SPROUT primary completion gastrointestinal (GI) bacteria to increase microbial biodiversity within the gut transplantation by other Social responsiveness May 2020; phase 2 MTT-ASD symptoms using gut bacteria collected from healthy human donors. means GI symptoms primary completion October About half of individuals with ASD have chronic GI 2020; phase 2 primary symptoms, such as constipation, diarrhea, and abdominal completion June 2021; phase pain. This treatment is intended to improve both GI 1/2 completed April 2016, symptoms and core symptoms in individuals with ASD. data published January 2017, Research has found that individuals with ASD are more likely follow-up data published April to have an abnormal gut microbiome than healthy controls, 2019 which might 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 130 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged up to 65 years Ketamine is an N-methyl-D-aspartate (NMDA) receptor Psychotherapy (eg, cognitive PTSD symptoms and Clinical trial(s): Phase 2/3 who fulfill Diagnostic and antagonist intended to treat PTSD symptoms in adults. behavioral therapy [CBT], eye severity completed January 2020; Statistical Manual of Mental Glutamate, an excitatory neurotransmitter that binds to movement desensitization Depression symptoms phase 2 primary completion Disorders, Fifth Edition (DSM- NMDA receptors, is purported to be highly involved in the and reprocessing [EMDR] and severity December 2020; phase 2 V ) criteria for current civilian stress response and formation of traumatic memories in therapy, prolonged exposure Quality of life completed September 2013, or combat-related PTSD. By decreasing glutamate’s excitatory activity and thus therapy [PET]) data published June 2014 posttraumatic stress disorder reducing stress-related synaptic activity that contributes to Repetitive transcranial (PTSD) PTSD symptoms, ketamine is intended to improve PTSD magnetic stimulation (rTMS; symptoms and patient quality of life. It is intended to have off-label) faster action than currently approved PTSD therapies, Selective serotonin reuptake including psychotherapy and selective serotonin reuptake inhibitors (SSRIs; eg, inhibitors. Ketamine purportedly provides rapid and paroxetine, sertraline) sustained therapeutic effects for patients with PTSD. Its use for this purpose is off-label. In clinical trials, participants are given single 0.2- or 0.5-mg/kg doses of ketamine intravenously for a variable number of infusions (1-8) over 2 to 4 weeks, alone or in combination with focused psychotherapy. After treatment, patients must be monitored for at least 4 hours before discharge. Developer(s): Icahn School of Medicine at Mount Sinai (New York, New York), in collaboration with the Department of Veterans Affairs’ (VA’s) Office of Research and Development (Washington, DC) Yale University (New Haven, Connecticut)

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 aged up to 65 years Ketamine (NRX-100)/cyclurad (NRX-101) is a sequential drug Electroconvulsive therapy Suicidal ideation FDA designation(s): who have severe bipolar plan that includes a single infusion of ketamine (NRX-100) (ECT) Attempted suicide Breakthrough Therapy, Fast depression with acute suicidal followed by an oral, fixed dose of 2 FDA-approved drugs IV ketamine (off-label) Completed suicide Track ideation and behavior (NRX-101). The 2 drugs in NRX-101 are lurasidone, a Lurasidone (monotherapy or Depression symptoms Clinical trial(s): NRX-100/NRX- serotonin 2A (5-HT2A) receptor antagonist, and D-cycloserine in combination with and severity 101: pivotal phase 2 STABIL-B (DCS), an N-methyl-D-aspartate (NMDA) receptor modulator. or ) completed November 2018, This combination therapy purportedly extends ketamine’s Time to relapse Olanzapine/fluoxetine data reported May 2019; NRX- antidepressant and antisuicidal effects and is intended to combination 101: phase 2/3 primary provide both rapid-onset and sustained treatment effects. completion March 2019, Quetiapine The therapy can be given in the outpatient setting after a designed under Special single dose of ketamine in a clinical setting. Lurasidone, alone Supportive care (eg, Protocol Assessment; phase or in combination with lithium or valproate, is an FDA- hospitalization) 2/3 primary completion approved treatment for depressive episodes in bipolar September 2020, designed depression. DCS, an agent used in tuberculosis therapy, acts under Special Protocol as a partial or full agonist of NMDA receptors. Studies of its Assessment; NRX-100: phase 3 use as a cognitive enhancer with other psychosocial primary completion interventions have had mixed results in various psychiatric September 2020 disorders. In trials, one 40-minute intravenous infusion of ketamine (0.5 mg/kg) is given 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 132

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, cognitive PTSD symptoms and FDA designation(s): posttraumatic stress disorder psychotherapy involves treatment with MDMA during an 8- behavioral therapy [CBT], eye severity Breakthrough Therapy (PTSD) hour standardized nondirective psychotherapy session movement desensitization Depression symptoms Clinical trial(s): Phase 3 MAPP1 performed by a therapist team. In the context of therapy, and reprocessing [EMDR] and severity primary completion August MDMA administration is intended to reduce avoidance and therapy, prolonged exposure 2020; phase 3 MAPP2 primary hyperarousal, purportedly leading to a desirable therapy [PET]) completion November 2021; psychological state that enhances the therapeutic process for Selective serotonin reuptake phase 2 completed September patients with severe PTSD, which has limited effective inhibitors (SSRIs; eg, 2010; phase 2 completed treatment options. MDMA, known by the street names paroxetine, sertraline) February 2011; phase 2 Ecstasy and Molly, is a psychedelic compound that is known completed November 2016; to release serotonin, norepinephrine, and dopamine in the phase 2 completed April 2017; brain and to indirectly increase and cortisol levels. phase 2 completed June 2017; MDMA is intended to reduce anxiety and emotional distress phase 2 completed September and increase prosocial behaviors, including communication, 2017, phase 2 pooled data compassion, and introspection. According to the Diagnostic published May 2019, phase 2 and Statistical Manual of Mental Disorders, Fifth Edition (DSM- pooled long-term data V), PTSD’s 4 main symptom categories are arousal and published June 2020; phase 2 reactivity, avoidance of triggers, negative thoughts and open-label completed feelings, and intrusive thoughts and nightmares. In trials, a October 2019, data published flexible dose of MDMA is given orally once a month for 3 February 2020 months, during an 8-hour psychotherapy session. An initial dose (80 to 120 mg) is given, followed by a supplemental half-dose (40 or 60 mg) 1.5 to 2 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 133 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 that is Antidepressants (eg, Social cognition Clinical trial(s): Phase 4 who have schizophrenia known for its association with social bonding and, when selective serotonin reuptake Negative schizophrenia primary completion May 2022; given intranasally, purportedly improves social cognition in inhibitors [SSRIs], serotonin symptoms unphased completed August patients with schizophrenia. Studies have shown that patients and norepinephrine reuptake Quality of life 2012, data published July with schizophrenia have lower oxytocin levels, which has inhibitors [SNRIs]) 2013; phase 2 CIDAR-3 been associated with impaired trust, empathy, and ability to Antipsychotics (oral and completed July 2014; phase 2 interpret mental states. Current antipsychotic drugs have injectable) completed November 2015, been used successfully to treat the positive symptoms of Combination therapy data published April 2016; patients with schizophrenia but have minimal effects on phase 2 completed March Electroconvulsive therapy negative symptoms and cognitive deficits. Increasing 2017 oxytocin levels might reduce negative symptoms and Mood stabilizers normalize social dysfunction associated with schizophrenia. It Psychotherapy (eg, cognitive is being studied as both a standalone and adjunct treatment. behavioral therapy [CBT]) In the most recently completed clinical trial, oxytocin was used in combination 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 134 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 and Clinical trial(s): Phase 2 schizophrenia with agonist and antagonist targeting serotonin 2A (5-HT2A) selective serotonin reuptake symptom severity of ADVANCE (negative predominant negative receptors. It is intended to be used as an adjunct to inhibitors [SSRIs]; off-label) schizophrenia symptoms) completed symptoms antipsychotic medication to treat negative symptoms of Atypical antipsychotics (ie, Quality of life October 2019, top-line data schizophrenia. Pimavanserin might improve patient health cariprazine, risperidone) reported November 2019; outcomes and quality of life, because no FDA-approved Psychosocial interventions phase 3 ENHANCE-I (positive treatments exist specifically for negative symptoms of (eg, arts therapy, cognitive and negative symptoms) schizophrenia. These negative symptoms include loss of behavioral therapy [CBT]) completed June 2019, top-line interest, lack of expression, emotional withdrawal, and data reported July 2019; phase cognitive impairment. Although positive symptoms of 3 extension study (positive schizophrenia (eg, hallucinations, distorted thinking) are and negative symptoms) typically seen as more urgent to treat, negative symptoms primary completion August more commonly impact patients’ ability to live 2020 independently, hold jobs, and maintain relationships. It is Note(s): The developer thought that 5-HT2A receptors play an important role in intended to commence a psychosis, schizophrenia, depression, and other second pivotal trial with the neuropsychiatric disorders. Although the exact mechanism of 34-mg dose in the first half of action is unknown, pimavanserin purportedly exerts its effects 2020. Pimavanserin was FDA by acting on 5-HT2A receptors in the brain. Pimavanserin, FDA approved to treat approved to treat hallucinations and delusions associated hallucinations and delusions with Parkinson disease, carries a warning for cardiac QT associated with Parkinson interval prolongation. In clinical trials, pimavanserin is taken disease psychosis in April by mouth at a dosage of 10, 20, or 34 mg once daily as an 2016. FDA responded to adjunct to the patient’s current antipsychotic medication. safety concerns over the use Developer(s): of pimavanserin in patients Acadia Pharmaceuticals, Inc (San Diego, California) with hallucinations and delusions associated with Parkinson disease in September 2018.

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 21 to 65 years Psilocybin is a psychoactive ingredient found in some Pharmacotherapy (eg, Depression symptoms FDA designation(s): who have moderate to severe mushroom species. Synthetic psilocybin, when used in selective serotonin reuptake and severity Breakthrough Therapy major depressive disorder combination with support from session facilitators, might inhibitors [SSRIs], serotonin Quality of life Clinical trial(s): Phase 2 (MDD) improve patient health outcomes and disrupt the paradigm and norepinephrine reuptake PSIL201 primary completion of depression treatment. Recent research has found a link inhibitors [SNRIs]) February 2021; phase 2 between mental health disorders and hyperconnected, Psychotherapy (eg, cognitive PSIL201-LTFU primary dysfunctional, neural networks in the brain. Psilocybin is behavioral therapy [CBT]) completion October 2022 purported to disrupt dysfunctional networks and help restore healthier connectivity in the 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 136

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

Adults aged up to 54 years Psilocybin is a psychoactive ingredient found in some species Antidepressants (eg, Depression symptoms FDA designation(s): who have treatment-resistant of mushroom. COMP360 is a synthetic form of psilocybin. monoamine oxidase and severity Breakthrough Therapy depression When used in combination with psychological support from inhibitors [MAOIs], selective Quality of life Clinical trial(s): Phase 2 P-TRD trained therapists, it might improve patient health outcomes serotonin reuptake inhibitors primary completion August and disrupt the paradigm of depression treatment. Recent [SSRIs], serotonin and 2020; phase 2 open-label research has found a link between mental health disorders norepinephrine reuptake primary completion January and hyperconnected, dysfunctional, neural networks in the inhibitors [SNRIs], tricyclic 2021 brain. Psilocybin purportedly disrupts those dysfunctional antidepressants [TCAs]) networks and helps restore healthier connectivity in the brain, Brain stimulation (eg, deep thus improving depression symptoms. Psilocybin is thought brain stimulation [DBS], to exert its effects primarily through its metabolite, psilocin, electroconvulsive therapy which demonstrates agonist (ie, activator) or partial agonist [ECT], transcranial magnetic activity at serotonin 2A (5-HT2A) receptors. It produces stimulation [TMS], vagal marked changes in sensory perception, emotion, thought, nerve stimulation [VNS]) and sense of self. In phase 1 clinical trials, patients took Ketamine (off-label) synthetic psilocybin orally at doses of 10 or 25 mg, before Psychotherapy (eg, cognitive receiving one-on-one psychological support from an behavioral therapy [CBT]) assisting therapist throughout a session of unspecified duration. In phase 2 clinical trials, patients take psilocybin orally at unspecified, differing doses (stated as low, medium, and high) before receiving one-on-one psychological support. The number or frequency of treatment sessions a patient might receive is unspecified. Developer(s): Compass Pathways (London, United Kingdom)

Section 4. Mental and Behavioral Health 137

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

Section 4. Mental and Behavioral Health 138

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

Children and adults aged 12 Sodium benzoate (NaBen) is a prescription-strength Antidepressants (eg, Schizophrenia FDA designation(s): Orphan to 55 years who have a formulation of the sodium salt used as a common food selective serotonin reuptake symptoms (positive and Drug, Breakthrough Therapy confirmed diagnosis of preservative. Sodium benzoate is a D-amino acid oxidase inhibitors [SSRIs], serotonin negative) Clinical trial(s): Phase 2b/3 schizophrenia according to (DAAO) inhibitor intended to treat schizophrenia’s positive and norepinephrine reuptake Efficacy of primary completion June criteria of the Diagnostic and and negative symptoms. Existing drugs for treating inhibitors [SNRIs]) antipsychotics 2021; phase 2b/3 primary Statistical Manual of Mental schizophrenia have limited efficacy in reducing both positive Antipsychotics (oral and Quality of life completion June 2021; phase Disorders, Fourth or Fifth and negative symptoms, and many are associated with injectable) 2b/3 primary completion June Edition DSM-IV DSM-V ( or ), serious side effects. A key dysfunction related to Combination therapy 2021 and are clinically stable with schizophrenia is the reduced function of the N-methyl-D- Mood stabilizers residual symptoms; and aspartate (NMDA) receptor in the brain. NaBen addresses this adults aged 18 to 55 years by inhibiting DAAO metabolism to increase DAAO activity, Psychotherapy (eg, cognitive who have treatment- leading to production of more D-serine, which increases behavioral therapy [CBT]) refractory schizophrenia NMDA activity in the hypothalamus. In ongoing phase 2b trials for patients with clinically stable 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, with participants’ current dose of clozapine. 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 139 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 acidergic acamprosate, disulfiram, Alcohol cravings primary completion February disorder (AUD) (GABAergic) and glutamatergic neurotransmission. Approved naltrexone) Alcohol withdrawal 2021; phase 3 completed medications to treat AUD have shown limited effectiveness; Psychotherapy (eg, cognitive symptoms October 2018; pilot unphased only one-third of patients achieve full remission with completed March 2009; pilot behavioral therapy [CBT]) Relapse available therapies. Zonisamide is intended to reduce alcohol phase 4 completed May 2009 consumption in patients with heavy drinking behaviors or Health outcomes AUD; treatment with zonisamide might also ameliorate the associated with symptoms of alcohol withdrawal syndrome. Its exact abstinence mechanism of action is unknown, but zonisamide Quality of life 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 given orally 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 140

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

Section 4. Mental and Behavioral Health 141 Table 4.3. Mental and Behavioral Health Topics Archived Since Last Status Report: 1 Topics

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

Children aged 5 years or older Balovaptan (RG7314) is a small-molecule antagonist of the Atypical antipsychotics Change in adaptive In July 2020, F Hoffman-La and adults who have high- 1a (V1A) receptor intended to improve emotional (eg, aripiprazole, behavior (eg, Roche terminated the phase 3 functioning (IQ ≥ 70) autism processing and reduce social deficits in patients with ASD. risperidone) communication and trial (NCT02901431), stating spectrum disorder (ASD) Impairments of social interaction and communication are Behavioral therapy (eg, socialization) the 24-week analysis core symptoms of ASD that cause multiple challenges and applied behavior analysis Adverse events suggested no clinical or affect quality of life. The neuropeptide vasopressin is an [ABA]) Quality of life statistical benefit for the endocrine hormone that is implicated in the regulation of primary end point and both aggression and affiliation. Blocking vasopressin might terminated the phase 2 trial reduce aggression and anxiety and promote social bonding (NCT03504917), stating a in patients with ASD. In trials, balovaptan is given orally at futility analysis suggested it dosages from 4 to 10 mg once daily. was unlikely the primary end Developer(s): point would be met. F Hoffmann-La Roche (Basel, Switzerland)

Section 4. Mental and Behavioral Health 142 Section 5. Rare Diseases: 128 Topics

Table 5.1. Rare Diseases Topics Added Since Last Status Report: 23 Topics

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

Adults undergoing surgery for ADX-2191 is an intravitreal formulation of 0.8% methotrexate Supportive care Vision loss FDA designation(s): Orphan recurrent retinal detachment that is intended to prevent PVR. PVR is a rare inflammatory Surgery Retinal detachment Drug, Fast Track due to proliferative disorder of the retina that occurs secondary to ocular surgery recurrence rate Clinical trial(s): Phase 3 vitreoretinopathy (PVR) or or trauma and can lead to severe retinal scarring and Quality of life GUARD primary completion retinal detachment caused by blindness. Additionally, PVR is the leading cause of retinal December 2022 open globe injury detachment recurrence after surgical repair of 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)

Section 5. Rare Diseases 143 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 and FDA designation(s): Orphan who have genetically phosphodiesterase type 4D (PDE4D) under study to treat medications (eg, alpha-2 severity Drug confirmed fragile X syndrome patients who have fragile X syndrome, a rare, X agonists, anticonvulsants, Anxiety symptoms and Clinical trial(s): Phase 2 chromosome–linked neurodevelopmental disorder. In antidepressants, beta- severity primary completion July 2020 patients with fragile X syndrome, loss of Fmrp function leads blockers) Hyperactivity symptoms to the development of autism-like symptoms, including and severity anxiety, irritability, aggression, hyperactivity, and restricted Irritability symptoms and and repetitive behaviors. Animal models of fragile X severity syndrome have suggested that one molecular mechanism underlying the syndrome is dysregulation of cyclic adenosine Repetitive behavior monophosphate (cAMP), a signaling molecule that plays a symptoms and severity 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), recently acquired by Shionogi & Co, Ltd (Osaka, Japan)

Section 5. Rare Diseases 144 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 of biochemically or genetically intended to supplement blood and brain copper levels in injections (off-label) Developmental milestones rolling New Drug Application confirmed Menkes disease patients with Menkes disease. Menkes disease is a rare, Supportive care Overall survival planned for fourth quarter of chromosome X–linked pediatric disease caused by mutations 2020 in the 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 symptoms Clinical trial(s): Phase 3 (eg, seizures), and connective tissue problems. No treatments primary completion December are approved for Menkes disease, and many patients die 2021 before 3 years of age. Patient care is generally managed with off-label administration of 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 off-label parenteral copper options. In clinical trials, CUTX-101 is given as a subcutaneous injection at an unspecified dose. Developer(s): Cyprium Therapeutics, Inc (New York, New York), a subsidiary of Fortress Biotech (New York, New York)

Section 5. Rare Diseases 145

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

Adults who have myasthenia Efgartigimod (ARGX-113) is an immunoglobulin G1 Fc Acetylcholinesterase Muscle weakness Submission date: Biologics gravis with generalized domain (IgG1 Fc) antibody fragment under study for treating inhibitor (ie, symptoms and severity License Application planned muscle weakness (ie, gMG. In patients with gMG, a progressive, autoimmune pyridostigmine) Functional activity level for fourth quarter of 2020 generalized myasthenia gravis neuromuscular disorder, the body develops IgG antibodies Corticosteroids (eg, Quality of life FDA designation(s): Orphan [gMG]); meet criteria for against proteins expressed at the neuromuscular junction (eg, prednisolone) Drug Myasthenia Gravis Foundation acetylcholine receptor, muscle-specific kinase). This impairs Intravenous Clinical trial(s): Phase 3 ADAPT of America (MGFA) class II, III, the ability of muscle cells to receive proper signals from immunoglobulin (IVIG) primary completion June IVa, or IVb; and are receiving nerve cells to produce motor movements. No cure is Nonsteroidal 2020, data reported May 2020; standard-of-care treatment available for gMG, and patients often do not respond to immunosuppressant drugs phase 3 ADAPT+ primary for gMG standard-of-care therapies and may experience side effects (eg, azathioprine, completion June 2023 of treatment. Efgartigimod purportedly competes with IgG cyclosporine, for binding to the neonatal Fc receptor (FcRn) to block FcRn- mycophenolate mofetil) mediated rescue of IgG from recycling through lysosomal degradation. Thus, efgartigimod purportedly decreases levels Thymectomy of IgG antibodies (including pathogenic IgG autoantibodies) without impacting levels of IgM antibodies, IgA antibodies, or albumin. In clinical trials, efgartigimod is given intravenously at a dosage of 10 mg/kg once weekly for at least 8 weeks and up to 3 years. Developer(s): argenx BVBA (Zwijnaarde, Belgium)

Section 5. Rare Diseases 146 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 is treatments are available acuity (BCVA) Drug macular atrophy secondary to intended to inhibit the accumulation of a toxic retinal Disease progression Clinical trial(s): Phase 3 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 that completed December 2017, causes gradual deterioration of photoreceptors within the data published June 2020 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 of 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 147

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 of Antiepileptic drug Behavioral disturbance FDA designation(s): Orphan who have CDKL5 deficiency gamma-aminobutyric acid receptor A (GABAA). It is intended combinations (eg, symptoms and severity Drug, Rare Pediatric Disease disorder (CDD) with a to treat seizures associated with CDD by restoring electrical benzodiazepines, Seizure duration Clinical trial(s): Phase 3 genetically confirmed balance to the seizing brain. CDD is a rare, chromosome X– glutamate blockers, Seizure frequency MARIGOLD primary mutation in the cyclin- linked, genetic disorder characterized by early onset seizures sodium channel blockers) Sleep quality completion July 2020; phase 2 dependent kinase-like 5 gene, and severe neurodevelopmental impairment. CDD-related Vagal nerve stimulation primary completion January Quality of life CDKL5, with at least 16 seizures are difficult to control and often do not respond to (VNS) 2018, data reported December primary-type seizures current antiepileptic medications. Children with CDD often 2018, data presented occurring within 28 days that cannot walk, talk, or feed themselves and often use December 2018 are refractory to 2 or more wheelchairs and depend heavily on caretakers for activities of antiseizure medications daily living. Ganaxolone purportedly reduces seizures and anxiety in patients with CDD through positive allosteric modulation at synaptic and extrasynaptic GABAA receptors. Through this mechanism, it is purported to block seizure propagation and elevate 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 148 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 function Drug confirmed Friedreich ataxia intended to treat FRDA by restoring mitochondrial function Survival Clinical trial(s): Phase 2 (FRDA) and energy production to improve motor function. It might Quality of life FRAMES primary completion improve patient health outcomes and quality of life for a March 2020 disorder that has no cure or 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, causing 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 cardiomyopathy. 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 149 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males aged up to 65 Leriglitazone, also known as MIN-102, is a selective Hematopoietic stem cell Ambulatory and motor FDA designation(s): Orphan years who have genetically peroxisome proliferator-activated receptor gamma (PPARγ) transplantation (HSCT) function Drug, Fast Track confirmed chromosome X– agonist intended to treat X-ALD by promoting mitochondrial Supportive care Cognitive function Clinical trial(s): Phase 2/3 linked adrenoleukodystrophy homeostasis and reducing inflammation and Survival ADVANCE primary completion (X-ALD) neurodegeneration. It might improve patient health Quality of life October 2020 outcomes and quality of life for a disorder that has no cure or approved treatments. X-ALD is a rare, inherited, neurodegenerative disorder characterized by 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 administered 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 150 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or (AK002) is a humanized monoclonal antibody Dietary modification Dysphagia symptoms FDA designation(s): Orphan older and adults who have specific for Siglec-8 under study to treat eosinophilic Protein pump inhibitors Quality of life Drug active, biopsy-confirmed esophagitis. A rare disease of the digestive system, Systemic corticosteroids Clinical trial(s): Phase 2/3 eosinophilic esophagitis that eosinophilic esophagitis is caused by accumulation of large Topical corticosteroids primary completion December is inadequately controlled by numbers of eosinophils in the esophagus and characterized 2021 standard-of-care treatment by vomiting, pain in the stomach or chest, difficulty (eg, proton pump inhibitors, swallowing, and failure to thrive. Mast cells and eosinophils corticosteroids, dietary are thought to act as drivers of eosinophilic esophagitis modification) 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 leads to the inhibition of 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 151

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

Adults with biopsy-confirmed Lirentelimab (AK002) is a humanized monoclonal antibody Azathioprine Abdominal symptoms (eg, FDA designation(s): Orphan eosinophilic gastritis or specific for Siglec-8 under study to treat eosinophilic gastritis Corticosteroids pain, cramping, loss of Drug eosinophilic duodenitis whose and eosinophilic duodenitis (formerly known as eosinophilic Dietary modification appetite, bloating) Clinical trial(s): Phase 3 disease is inadequately gastroenteritis). Eosinophilic gastritis and eosinophilic Proton pump inhibitors Quality of life primary completion December controlled by standard-of- duodenitis are rare diseases of the digestive system caused 2021 care therapies (eg, proton by accumulation of large numbers of eosinophils in the lining pump inhibitors, 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 leads to the inhibition of 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 152

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 p38α/β mitogen- Supportive care (eg, Ambulatory function FDA designation(s): Orphan who have genetically activated protein kinase (p38 MAPKα/β) that is intended to assistive devices, pain Muscle strength Drug DUX4 confirmed treat FSHD1 by reducing overactive gene expression in control, physical therapy) Survival Clinical trial(s): Phase 2 facioscapulohumeral muscular muscle cells and reducing inflammation. It might improve Quality of life primary completion dystrophy (FSHD) type 1 patient health outcomes by slowing disease progression and November 2020; phase 2 (FSHD1) with 1 to 9 repeats in improving quality of life. FSHD is a form of muscular open-label extension primary the D4Z4 region of dystrophy characterized by muscle weakness and atrophy completion February 2024; chromosome 4 that arises most often in the face, shoulder blades, and upper phase 2 primary completion arms but can also affect other body parts. Symptoms typically December 2020 emerge in adolescence. About 95% of cases are categorized as FSHD1. FSHD1 is associated with a shortened D4Z4 macrosatellite repeat on chromosome 4, which leads to overexpression of the DUX4 gene that is thought to contribute to muscle cell damage. Losmapimod inhibition 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 orally at a dosage of 15 mg twice daily for 48 to 52 weeks. Developer(s): Fulcrum Therapeutics, Inc (Cambridge, Massachusetts)

Children aged 12 years or Mavorixafor is an allosteric CXC chemokine receptor 4 Granulocyte colony- Infection rate FDA designation(s): Orphan older and adults who have a (CXCR4) inhibitor, which purportedly prevents most stimulating factor (G-CSF; Severity of infections Drug, Breakthrough Therapy clinical diagnosis of WHIM leukocytes from homing to and localizing in the bone infection prevention) Wart control (warts, marrow. Retention of leukocytes in the bone marrow is a Imiquimod (warts) Hematologic and Clinical trial(s): Phase 3 hypogammaglobulinemia, characteristic of WHIM syndrome, a rare primary Intravenous immunologic parameters primary completion infections, and myelokathexis) immunodeficiency typically caused by gain-of-function immunoglobulin (IVIG; Quality of life September 2021 syndrome mutations in the C-X-C motif chemokine receptor 4 gene, infection prevention) CXCR4. The mutations associated with the syndrome cause immune dysfunction, which increases infection risk and other complications, including wart 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 153 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 years or older Nedosiran (DCR-PHXC) is an RNA interference (RNAi) therapy Diet management and Change in urinary oxalate FDA designation(s): Orphan and adults who have primary targeting lactate dehydrogenase under study for treating PH. fluid intake excretion from baseline Drug, Rare Pediatric Disease hyperoxaluria (PH) type 1, 2, An ultra-rare, life-threatening disorder, PH is caused by Organ transplantation (ie, Hospitalizations Clinical trial(s): Phase 3 DCR- or 3 genetic mutations in the glyoxylate metabolism pathway that isolated or combined liver Quality of life for patients PHXC-301 primary completion lead to overproduction of oxalate. This causes kidney and kidney) and caregivers December 2023, interim data damage. Nedosiran is intended to inhibit expression of Renal dialysis reported August 2020; phase lactate dehydrogenase (LDH), a key enzyme in the production Shockwave lithotripsy 2 DCR-PHXC-201 primary of oxalate. The liver is responsible for most oxalate completion June 2020 overproduction, and the nedosiran siRNA is 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 at unspecified monthly doses subcutaneously. Developer(s): Dicerna Pharmaceuticals, Inc (Lexington, Massachusetts)

Section 5. Rare Diseases 154 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 of One or more of the Progression-free survival FDA designation(s): Orphan tumors that cannot be γ-secretase under study for treating desmoid tumors. These following: Quality of life Drug, Fast Track managed by surgery or are rare, benign, soft tissue tumors that can invade Anti-inflammatory agents Clinical trial(s): Phase 3 DeFi radiation therapy surrounding healthy tissue in joints, organs, and muscles. No (eg, , sulindac) primary completion March therapies are approved for treating desmoid tumors, and Hormone therapy (eg, 2021 patients have only palliative options to manage desmoid fulvestrant, tamoxifen) tumor–associated morbidities, which include disfigurement, Tyrosine kinase inhibitors internal bleeding, range-of-motion loss, severe pain, (eg, imatinib, sorafenib) weakness, and even death. Desmoid tumors frequently exhibit aberrant signaling by the transmembrane receptor Notch, which is involved in the tumors’ proliferation, survival, migration, angiogenesis, 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 155 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have new onset or Nomacopan (rVA576) is a small protein inhibitor of Antimicrobial anti- Blister and hive severity FDA designation(s): Orphan relapsing mild to moderate complement component 5 (C5) and lipid mediator inflammatories (eg, Itch severity Drug bullous pemphigoid (BP) leukotriene B4 (LTB4) under study to treat BP by blocking dapsone, doxycycline) Quality of life Clinical trial(s): Phase 2 their role in driving inflammation in the disorder. Nomacopan Corticosteroids (eg, primary completion March might improve patient health outcomes, compared with systemic prednisolone, 2020, top-line data reported current therapies, by targeting specific pathways with fewer topical clobetasol) May 2020 side effects, and it might reduce health care costs of Immunosuppressants (eg, hospitalizations for BP exacerbations. BP is a rare, azathioprine, autoimmune, skin disorder in which the immune system methotrexate) 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 (London, United Kingdom)

Section 5. Rare Diseases 156

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

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

Developer(s): Akari Therapeutics plc (New York, New York; London, United Kingdom)

Section 5. Rare Diseases 157

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

Adults who have a confirmed Pegcetacoplan (APL-2) is an immune complement system Allogeneic hematopoietic Hemoglobin levels FDA designation(s): Fast Track diagnosis of paroxysmal inhibitor in development to treat PNH. Pegcetacoplan could stem cell transplantation Red blood cell transfusion Clinical trial(s): Phase 3 nocturnal hemoglobinuria disrupt patient management by replacing intravenous (ASCT) need PEGASUS primary completion (PNH) infusions (every 2 weeks to 2 months) of complement Anticomplement therapy, November 2019, data component 5 (C5) inhibitors with twice-weekly self- intravenous (eg, presented June 2020; phase 3 administered subcutaneous injections. Pegcetacoplan is a eculizumab, ravulizumab- PRINCE primary completion synthetic cyclic peptide that targets the complement cwvz) January 2021 component 3 (C3) pathway, which operates earlier in the Oral anticoagulation (to complement cascade than C5. The C3 protein helps regulate prevent recurrent blood opsonization (ie, tagging cell surfaces for immune system clots; eg, warfarin, targeting), inflammation, and formation of the membrane rivaroxaban) attack complex on cell surfaces, which pierces cell membranes, causing cells to lyse (ie, rupture) and die. By targeting C3, pegcetacoplan purportedly offers broader inhibition of the complement cascade than that of 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 158

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

Adults who have genetically PTX-022 is an anhydrous gel containing the mTOR inhibitor Botulin toxin (off-label) Palmoplantar keratoderma FDA designation(s): Fast Track, confirmed pachyonychia rapamycin under study as a topical treatment for patients Fluorouracil (off-label) symptoms Orphan Drug congenita (PC) with PC. An autosomal-dominant inherited keratinizing Oral (off-label) Quality of life Clinical trial(s): Phase 2/3 disorder, PC is caused by genetic variants in keratins Phenytoin (off-label) VALO primary completion upregulated after tissue stress (ie, inducible keratins). The April 2020, data expected disorder primarily affects the skin and nails, and patients with fourth quarter of 2020 PC develop blisters and calluses on the 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 pathogenesis 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 159 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults aged up Recombinant ADAMTS13 (BAX930) is a genetically Plasma infusions Acute TTP episodes FDA designation(s): Fast Track to 70 years who have a engineered version of the ADAMTS13 enzyme under Anemia Clinical trial(s): Phase 3 confirmed diagnosis of development to treat hereditary TTP. In hereditary TTP, Quality of life primary completion February hereditary thrombotic genetic variants of the ADAMTS13 gene cause insufficient 2023 thrombocytopenic purpura levels and activity of the ADAMTS13 protein (ie, von (TTP) Willebrand factor–cleaving protease), an enzyme involved in regulating blood clotting. ADAMTS13 deficiency results in dysregulated clotting in the small blood vessels, 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, BAX930 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 160 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 (deuterated Supportive care Ambulatory and motor FDA designation(s): Orphan 10 years who have infantile linoleic acid) intended to treat INAD by stabilizing function Drug neuroaxonal dystrophy mitochondrial and cell membranes. It might improve health Cognitive function Clinical trial(s): Pivotal phase (INAD), are homozygous for outcomes and quality of life for patients with a disease that Developmental delay or 2/3 primary completion June PLA2G6 gene deficiency, and has no cure or approved treatments. INAD, a subtype of regression 2020 have impairment in at least 2 PLA2G6-associated neurodegeneration, or Seitelberger Seizure frequency assessed categories at disease, is an ultra-rare, inherited, neurodegenerative disease baseline that affects the central nervous system, autonomic nervous Survival system, and peripheral nerves. Symptoms of developmental Quality of life 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 cellular health. In clinical trials, RT001 is taken by mouth as 4 capsules daily (each capsule is 960 mg) for a total daily dose of 3.84 g. Developer(s): Retrotope, Inc (Los Altos, California)

Section 5. Rare Diseases 161 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 (deuterated Supportive care Ambulatory and motor FDA designation(s): Orphan who have Friedreich ataxia linoleic acid) intended to treat FRDA by stabilizing function Drug (FRDA); biallelic pathogenic mitochondrial and cellular membranes. It might improve Survival Clinical trial(s): Phase 3 variants in the frataxin gene, patient health outcomes and quality of life for a disorder that Quality of life primary completion February FXN; and are ambulatory has no cure or approved treatments. FRDA is a rare, inherited, 2021 (with or without assistive neurodegenerative disorder best characterized by loss of devices) coordination and muscle strength and heart disease. It is caused by a variant in the FXN gene that results in 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 patients’ late 30s, usually related to cardiomyopathy. 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 3 times daily for a total daily dose of 8.64 g or as 3 capsules twice daily for a total daily dose of 5.76 g. Developer(s): Retrotope, Inc (Los Altos, California)

Section 5. Rare Diseases 162 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 in development to Supportive care to Chronic wound severity FDA designation(s): Orphan renal disease (ESRD) receiving treat CUA, also called calciphylaxis. A rare disease, CUA is manage pain, treat Pain Drug maintenance hemodialysis in characterized by calcium buildup and scarring of small blood ulcerated wounds, and Quality of life Clinical trial(s): Phase 3 a health care facility for at vessels in skin and fat tissue that can cause blood clots and adjust medications to CALCIPHYX primary least 2 weeks and with a painful skin ulcers, which can develop potentially fatal reduce calcium completion March 2022; clinical diagnosis of calcific infections. CUA occurs primarily, but not exclusively, in concentration or phase 2 CaLIPSO completed uremic arteriolopathy (CUA) patients with advanced kidney disease. A disease-modifying accumulation September 2019, data and at least one ulcerated treatment that could slow or halt the abnormal calcium published November 2019, CUA skin lesion accumulation in blood vessels causing CUA could disrupt data presented June 2020 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 163 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 diagnosed inhibitor of the enzyme myeloperoxidase (MPO) intended to assistive devices, function Drug, Fast Track or suspected multiple system treat MSA by reducing microglial activation and symptomatic treatment Independence Clinical trial(s): Phase 3 M- atrophy (MSA) who can neuroinflammation. It might improve patient health with dopamine agonists Survival STAR primary completion ambulate at least 10 steps outcomes and quality of life by slowing disease progression. [eg, amantadine, Quality of life October 2021; phase 2 (patient may have assistance MSA is a rare, neurodegenerative disorder characterized by levodopa; off-label], completed September 2016 from devices but not other progressive damage to neurons in the brain and scarring that physical therapy) persons) and have a life contributes to impairments in motor movement and expectancy of at least 3 years coordination and autonomic 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 164 Table 5.2. Currently Monitored Rare Diseases Topics: 99 Topics

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, progressive, ratings and scales Clinical trial(s): Phase 1/2 mucopolysaccharidosis type inherited metabolic disorder caused by a mutation in NAGLU. NAGLU enzyme activity Transpher B primary III B [MPSIIIB]) Sanfilippo syndrome type B (about 30% of all Sanfilippo Heparan sulfate levels completion October 2022, syndrome cases) has no cure, and patients typically do not interim data presented survive beyond their 20s. Treatment consists of supportive February 2020, preliminary care. Patients with the disorder cannot break down the data reported April 2020 polysaccharide heparan 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 165 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 transplantation Age-related FDA designation(s): Orphan older and adults who have carrying a wild-type copy of the N-sulfoglucosamine Supportive care developmental scores Drug, Fast Track, Rare Sanfilippo syndrome type A sulfohydrolase gene, SGSH. It is intended to treat Sanfilippo Behavior, as measured Pediatric Disease, (also called syndrome type A, a childhood-onset, progressive, inherited by accepted clinical Regenerative Medicine mucopolysaccharidosis type metabolic disorder caused by a mutation in SGSH. Patients ratings and scales Advanced Therapy III A [MPSIIIA]) and a with the disorder cannot break down the polysaccharide Brain, liver, and spleen Clinical trial(s): Phase 1/2 SGSH minimum cognitive heparan sulfate, a process normally mediated by the - volume Transpher A primary developmental quotient (DQ) encoded enzyme heparan-N-sulfamidase. Buildup of heparan Cognitive and motor completion December 2022, of 60 or above, or children or sulfate in cells of the central nervous system causes function, as measured preliminary data presented adults (age unspecified) who degeneration that manifests as behavioral problems, by accepted clinical April 2020; phase 1/2 primary have middle- or advanced- sleeplessness, loss of speech and cognitive skills, mental ratings and scales completion December 2022 phase MPSIIIA and a DQ retardation, heart problems, seizures, and loss of mobility. No below 60 cure exists for Sanfilippo syndrome type A (about 60% of all Heparan sulfate levels Sanfilippo syndrome cases), and patients typically do not Sleep quality and survive past their 20s. Treatment consists of supportive care. duration In these patients, ABO-102 purportedly restores sulfamidase Sulfamidase enzyme enzyme function, blocks central nervous system activity degeneration, and reduces disease-related symptoms. In Quality of life 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 166 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults aged up Adrabetadex (VTS-270, cyclodextrin, 2-hydroxypropyl-β- Glucosylceramide synthase Disability Clinical trial(s): Pivotal phase to 21 years who have cyclodextrin) is intended to treat neurologic manifestations of inhibitor (ie, miglustat; off- Disease progression 2/3 primary completion genetically confirmed Niemann-Pick disease type C (NPC) by regulating intracellular label) Disease symptoms and September 2021; phase 2/3 Niemann-Pick disease type C1 cholesterol in NPC-1-deficient cells. NPC is a rare, Supportive treatment (eg, severity open-label extension primary (NPC-1) or type C2 (NPC-2) neurodegenerative, lysosomal storage disorder caused by completion December 2021; bowel regimen, Survival with neurologic mutations in the NPC intracellular cholesterol transporter 1 or bronchoalveolar lavage, phase 2 primary completion Quality of life manifestations 2 genes, NPC1 or NPC2. Lack of the encoded NPC1 or NPC2 bronchodilation therapy, October 2022 protein disrupts intracellular cholesterol and other lipid gastrostomy tube, physical Note(s): In July 2020, trafficking, leading to excessive lipid accumulation in tissues therapy) Mallinckrodt announced including the 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 a dystonia); and cognitive deterioration. About one-third of 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 promotes insufficient to demonstrate cholesterol transport, restores normal cholesterol metabolism efficacy 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 to 21 years, 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 Sucampo Pharmaceuticals (Rockville, Maryland), which, in turn, acquired original developer Vtesse, Inc (Gaithersburg, Maryland)

Section 5. Rare Diseases 167 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have a history of Afamelanotide (Scenesse) is a melanocortin 1 receptor (MC1- Beta-carotene Duration of sunlight Approval date: October 8, phototoxic reactions from R) agonist indicated to increase pain-free light exposure in supplementation tolerated without pain 2019 erythropoietic protoporphyria adults who have EPP. A rare genetic metabolic disorder, EPP Lifestyle modification (ie, Number and severity of FDA designation(s): Orphan (EPP) causes phototoxicity and anaphylactoid reactions when the sunlight avoidance) phototoxic reactions Drug, Priority Review patient’s skin is exposed to light. The drug is a chemical Quality of life Clinical trial(s): Phase 3 analogue of alpha-melanocyte stimulating hormone (α- completed July 2013, data MSH), a naturally occurring peptide hormone released by published July 2015; phase 3 skin cells in response to ultraviolet radiation (UVR). α-MSH completed May 2011 stimulates melanocytes to express melanin. Approved by FDA, afamelanotide is a linear, 13-amino-acid peptide with 2 modified amino acids intended to increase the peptide’s half- life. The peptide analogue purportedly increases the melanin content of skin without requiring exposure to damaging UVR. Melanin absorbs, scatters, and quenches ultraviolet light, and so increased skin melanin levels are purportedly photoprotective. The peptide is administered as a controlled- release subcutaneous implant (16 mg) that is about the size of a grain of rice. The FDA-approved label states it “should be administered by a healthcare professional who is proficient in the subcutaneous implantation procedure and has completed training prior to administration” and uses “implantation devices that have been determined by the manufacturer to be suitable for implantation.” The implant is given every 2 months. Developer(s): Clinuvel, Ltd (Melbourne, Australia)

Section 5. Rare Diseases 168 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have amyotrophic Arimoclomol (BRX-345) is a small-molecule amine intended Edaravone Disability FDA designation(s): Orphan lateral sclerosis (ALS) to treat ALS by helping regulate proteins involved with the Riluzole Disease progression Drug, Fast Track disease. ALS is a rare and fatal neurodegenerative disease in Supportive care Functional capacity Clinical trial(s): Phase 3 which the death of nerve cells (ie, neurons) in the brain and Survival ORARIALS-01 primary spinal cord leads to a loss of voluntary muscle function, completion December 2020; wasting of muscle mass, and eventual death. Although the phase 3 ORARIALS-2 open- exact cause of the disease is unknown, the cause is thought label extension primary to be accumulations of abnormal proteins in neural cells. completion August 2022; FDA-approved drugs to treat the disease (eg, edaravone, phase 2/3 (patients with SOD1 riluzole) can decrease symptom severity, but do not prevent mutation) completed disease progression. Arimoclomol is intended to reduce November 2016, data abnormal protein accumulation and help deconstruct published February 2018 abnormal proteins, slowing disease progression and Note(s): Headline results are improving patient quality of life by prolonging motor expected in the first half of function. Arimoclomol purportedly increases the activity of 2021 heat shock factor 1, a transcription factor that promotes expression of heat shock proteins. 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 169 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 to 18 years Arimoclomol (BRX-345) is a small-molecule drug intended to Glucosylceramide synthase Disability Submission date: Rolling New who have Niemann-Pick treat NPC by amplifying production of reparative heat shock inhibitor (ie, miglustat; off- Disease progression Drug Application completed disease type C (NPC) proteins (HSPs) to slow disease progression. NPC is a rare, label) Disease symptoms and July 20, 2020 neurodegenerative, lysosomal storage disorder caused by Supportive treatment (eg, severity FDA designation(s): Orphan mutations in the NPC intracellular cholesterol transporter 1 or bowel regimen, Survival Drug, Fast Track, 2 genes, NPC1 or NPC2. Lack of the encoded NPC1 or NPC2 bronchoalveolar lavage, Breakthrough Therapy, Rare Quality of life protein disrupts intracellular cholesterol and other lipid bronchodilation therapy, Pediatric Disease trafficking, leading to excessive lipid accumulation in tissues, gastrostomy tube, physical Clinical trial(s): Phase 2/3 including the brain, liver, and spleen. This results in therapy) primary completion June symptoms and complications, including enlarged liver and 2018, data reported January spleen; eye, liver, and lung disease; feeding difficulties; 2019, interim open-label hearing loss; motor impairment (including cataplexy and extension data reported dystonia); and cognitive deterioration. About one-third of January 2020 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 170 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 45 years or older Arimoclomol (BRX-345) is a small-molecule drug intended to Immunosuppressants (eg, Disease progression Submission date: New Drug who have sporadic inclusion treat sIBM by increasing the production of reparative heat azathioprine, methotrexate, Functional capacity Application planned for body myositis (sIBM) shock proteins (HSPs) in damaged muscle cells. A prednisone) Survival second half of 2021 degenerative muscle disease of unknown cause, sIBM Supportive care Quality of life FDA designation(s): Orphan develops most often after 50 years of age and causes Drug, Fast Track progressive loss of muscle strength and volume over 10 to 15 Clinical trial(s): Pivotal phase years. No cure or treatment is available. Patients progress to 2/3 primary completion severe disability, requiring the use of a wheelchair and help February 2021; phase 2/3 with daily activities. Complications, including aspiration completed September 2012, pneumonia, increase the risk of death. Investigators suspect data published March 2016; that sIBM-induced muscle degeneration might be caused by phase 3 open-label extension the accumulation of abnormal and misfolded proteins in primary completion May 2022 muscle cells. Arimoclomol purportedly increases the activity Note(s): Pivotal trial final of heat shock factor 1, a transcription factor that promotes results are expected in the first HSP expression in cells experiencing stress or toxicity. HSPs half of 2021 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 171 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 intended Liver transplantation Rate of liver fibrosis FDA designation(s): Orphan who have alpha-1 antitrypsin for liver disease associated with AAT deficiency, a rare (reserved for end-stage liver Liver function Drug, Fast Track (AAT) deficiency and biopsy- inherited disease affecting mostly the lungs and liver. AAT disease) Quality of life Clinical trial(s): Phase 2/3 confirmed liver fibrosis deficiency is caused by genetic variants in the serpin family A Supportive care to prevent or SEQUOIA primary completion member 1 gene, SERPINA1, which codes for AAT protein reduce the complications of May 2023 production. In AAT deficiency caused by certain genetic chronic liver disease (CLD; variants, misfolded copies of the AAT protein cannot be eg, ascites, portal vein secreted normally into the blood, so they build up in and hypertension, injure the liver. No approved disease-modifying therapies are gastrointestinal hemorrhage) available for AAT deficiency–related liver damage; treatment consists mainly of 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 and maximum of 9 doses. Developer(s): Arrowhead Pharmaceuticals, Inc (Pasadena, California)

Section 5. Rare Diseases 172 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 25 to 65 years ASO-HTT (RG6042; formerly tominersen) is an antisense Symptomatic care (eg, Disease progression FDA designation(s): Orphan who have genetically oligonucleotide intended to treat HD by preventing the antipsychotics for chorea or Motor and ambulatory Drug confirmed, symptomatic production of toxic, mutant, huntingtin (HTT) protein that agitation [off-label], physical function Clinical trial(s): Phase 3 Huntington disease (HD) leads to neurodegeneration and disease progression. HD is therapy, speech therapy, Cognitive function GENERATION HD1 primary an inherited (autosomal dominant), progressive, tetrabenazine to treat Survival completion March 2022; neurodegenerative disease caused by mutations in the chorea) phase 3 open-label extension Quality of life huntingtin gene, HTT. Mutant, elongated HTT proteins are primary completion June cleaved into smaller, neurotoxic fragments that accumulate in 2024; phase 1/2 completed neurons, causing neurodegeneration that manifests as November 2017, data uncontrolled movements (ie, chorea), cognitive decline, and published June 2019; phase 2 mood changes. Symptoms typically begin in the fourth or open-label extension fifth decade of life, and typical life expectancy after symptom completed October 2019 onset is about 20 years. There is no cure or disease- modifying treatment for HD. ASO-HTT 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, ASO-HTT 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 173

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, Galactitol concentration Submission date: New Drug who have classic galactosemia reductase. Galactosemia is a rare genetic disease that affects avoidance of dairy products in plasma from baseline Application planned for confirmed by evidence of patients’ ability to metabolize galactose, a simple sugar and other sources of Cognitive decline from second half of 2020 absent or significantly found in foods and produced during normal metabolism. galactose) baseline FDA designation(s): Orphan decreased galactose-1 Elevated circulating galactose is converted by aldose Cataract formation from Drug phosphate uridyl reductase into galactitol, a toxic metabolite that causes long- baseline Clinical trial(s): Phase 2 (GALT) activity term complications including central nervous system damage Sepsis incidence from ACTION-Galactosemia pivotal (eg, convulsions, irritability, lethargy, developmental delays) baseline primary completion December and cataracts. Galactosemia has no cure or approved 2019, data presented July treatments. AT-007 purportedly penetrates tissues, including 2020 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 174

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

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

Section 5. Rare Diseases 175

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

Adults aged up to 75 years Autologous mesenchymal stem cells secreting neurotrophic Edaravone Disease progression FDA designation(s): Orphan who have rapidly progressing factors (MSC-NTF; NurOwn) is a bone marrow–derived Riluzole Disability Drug, Fast Track amyotrophic lateral sclerosis therapy intended to treat ALS. A rare and fatal Supportive care Quality of life Clinical trial(s): Phase 3 BCT- (ALS) neurodegenerative disease, ALS is characterized by the death 002 primary completion of nerve cells (ie, neurons) in the brain and spinal cord that October 2020, data presented leads to a loss of voluntary muscle function, wasting of April 2020, top-line data muscle mass, and eventual death. In patients with ALS, the expected fourth quarter of presence of abnormal proteins in the brain and spinal cord 2020; phase 2 completed causes neuronal death and contributes to disease September 2015, data progression. The exact cause of these aggregates is published March 2016, data unknown. FDA-approved drugs to treat the disease (eg, published November 2017; riluzole, edaravone) decrease symptom severity in some phase 2 completed July 2016, patients but do not prevent neuronal injury and ALS data published November progression. MSC-NTF grows the patient’s bone marrow cells 2019 in a proprietary culture media to differentiate mesenchymal Note(s): BrainStorm Cell stromal cells into astrocyte-like cells. The cultured cells Therapeutics met with FDA in purportedly secrete neurotrophic and growth factors, February 2020 to discuss a including glial-derived neurotrophic factor, brain-derived regulatory pathway and neurotrophic factor, vascular endothelial growth factor possible expedited pathway (VEGF), and hepatocyte growth factor (HGF), which 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 176 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 Submission date: New Drug diagnosed or relapsed drug that purportedly binds and inhibits the complement cyclophosphamide followed Response time Application July 9, 2020 antineutrophil cytoplasmic anaphylatoxin C5a from triggering inflammatory reactions by azathioprine Estimated glomerular FDA designation(s): Orphan antibody (ANCA)–associated through C5 receptors, which are associated with AAV Prednisone with rituximab filtration rate (eGFR) Drug vasculitis (AAV) requiring pathogenesis. Patients with AAV have limited treatment followed by azathioprine Vasculitis Damage Index Clinical trial(s): Phase 3 treatment with options and increased risk of death from inflammatory Quality of life ADVOCATE completed cyclophosphamide or vascular complications arising in various organs (often the November 2019, top-line data rituximab kidneys). Avacopan is intended to reduce inflammation, reported November 2019 vascular tissue damage, and subsequent organ failure 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 177 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

Section 5. Rare Diseases 178 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 1 Supportive care to minimize Wound healing FDA designation(s): Orphan older and adults who have (HSV-1) vector–based gene therapy intended for chronic or and manage skin wounds Quality of life Drug, Fast Track, Rare dystrophic epidermolysis recurring wounds in patients with DEB. This rare, debilitating Pediatric Disease, bullosa (DEB) and have at connective tissue disorder has no approved treatments. Regenerative Medicine least one wound between 10 Patients with DEB carry a genetic variant in a gene called Advanced Therapy 2 and 20 cm in size collagen type VII alpha 1 chain, COL7A1. This variant prevents Clinical trial(s): Phase 3 GEM-3 cells from producing type VII collagen, causing severe, primary completion August painful, and/or itchy epidermal wounds that can affect a 2021; phase 2 GEM-1 primary patient’s longevity and quality of life. Beremagene completion February 2020, geperpavec is a recombinant, replication-incompetent, HSV-1 data presented May 2020 vector that contains a full-length copy 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 179

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

Children aged 12 years or Berotralstat (BCX7353) is a plasma kallikrein inhibitor C1 esterase inhibitors (eg, Number of angioedema PDUFA date: December 3, older and adults who have intended to treat type I or II HAE. A rare inherited genetic Cinryze, Haegarda) attacks 2020 type I or type II hereditary disorder, HAE is caused by a mutation in the gene encoding Plasma kallikrein inhibitors Quality of life, as FDA designation(s): Orphan angioedema (HAE) the C1 esterase inhibitor protein (C1-INH). Berotralstat is (eg, ianadelumab-flyo) measured by accepted Drug, Fast Track intended to prevent the onset of HAE attacks by providing an clinical ratings and Clinical trial(s): Phase 3 APeX-2 oral alternative to injectable HAE treatments, which might scales primary completion April improve treatment adherence. C1-INH normally regulates 2019, data reported production and activity of the plasma serine protease November 2019, data kallikrein, which in turn regulates production and activity of reported March 2020, data the inflammatory mediator bradykinin. Unregulated kallikrein presented June 2020 and bradykinin activity due to the absence of C1-INH causes fluid leakage from blood vessels and swelling of surrounding tissues. Patients with type I or II HAE, also known as C1 inhibitor deficiency, typically experience severe swelling (ie, edema) of the hands, abdomen and gastrointestinal (GI) tract, upper and lower extremities, and throat. Stress, injury, illness, or hormone fluctuations trigger symptoms. Swelling of the abdomen and intestines causes severe abdominal pain and GI upset, and swelling of the throat can lead to asphyxiation. In clinical trials, patients receive berotralstat by mouth at a dosage of 110 or 150 mg once daily for up to 48 weeks. Developer(s): BioCryst Pharmaceuticals, Inc (Durham, North Carolina)

Section 5. Rare Diseases 180 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

Male children aged 10 years BIIB112 (NSR-RPGR) is a recombinant adeno-associated viral Supportive care Best corrected visual Clinical trial(s): Phase 2/3 or older and adults who have vector that delivers a codon-optimized form of the retinitis Vitamin and nutritional acuity (BCVA) XIRIUS primary completion retina specialist–confirmed pigmentosa GTPase regulator-open reading frame 15 gene, supplementation Retinal sensitivity March 2021, preliminary safety RPGR-ORF 15. chromosome X–linked This gene encodes a full-length functional Peripheral vision and efficacy data reported retinitis pigmentosa (XLRP) protein intended to treat XLRP. No effective treatments are September 2018, preliminary Recovery time and RPGR-ORF 15 gene approved for this rare condition, and BIIB112 could become data presented May 2019, variants the first retinal gene therapy to delay XLRP or reverse vision Quality of life data published February 2020 loss. XLRP is the most common form of RP caused by variants in the eye-specific form of the RPGR 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 181

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

Adult females aged up to 45 Blarcamesine (ANAVEX2-73) is a small-molecule sigma-1 Supportive care (eg, Behavioral symptom FDA designation(s): Orphan years who have genetically receptor activator intended to treat Rett syndrome, a rare, anticonvulsants, assistive severity, as measured by Drug, Fast Track, Rare confirmed Rett syndrome postnatal, progressive neurologic disorder. Rett syndrome is devices, noninvasive accepted clinical ratings Pediatric Disease caused by a mutation in the methyl CpG binding protein 2 ventilation, nutritional and scales Clinical trial(s): Phase 2/3 gene, MECP2. Located on the , MECP2 support, oxygen treatment, Seizure frequency primary completion June encodes the MeCP2 protein that normally mediates gene physical and occupational Sleep quality and 2021; phase 2 primary expression in neuronal and glial cells. Loss of MeCP2 function therapy, speech/language duration completion October 2020, results in nerve cell dysfunction, which is thought to be therapy) preliminary (Part A) data reversible. Patients with Rett syndrome develop normally presented September 2019; until 6 to 18 months of age and subsequently experience phase 2 AVATAR primary developmental delays and regression of previously learned completion November 2020 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 182 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults aged 18 years or older Budesonide (Nefecon) is a synthetic corticosteroid intended Corticosteroids Proteinuria change from FDA designation(s): Orphan who have biopsy-proven to treat IgA nephropathy. A kidney disease, IgA nephropathy Immunosuppressants (eg, baseline Drug immunoglobulin A (IgA) occurs when an antibody subtype called IgA accumulates in azathioprine, Occurrence of end- Clinical trial(s): Phase 3 nephropathy (Berger disease) the kidneys and causes local inflammation that can gradually cyclophosphamide, stage renal disease Nefigard primary completion and an estimated glomerular affect kidney function. The disease can cause end-stage renal mycophenolate) Change in eGFR from October 2020 filtration rate (eGFR) between disease (ESRD) within 10 to 20 years in up to 40% of affected baseline 45 and 90 mL/min/1.73 m2 patients. No treatments are approved for IgA nephropathy. Change in quality of life (stage 2 to 3A chronic kidney The standard of care (ie, high-dose systemic corticosteroids) from baseline disease) and medically is controversial because of the increased risks of adverse controlled blood pressure events and 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 orally at a dosage of 16 mg once daily for 9 months. Developer(s): Calliditas Therapeutics AB (Stockholm, Sweden)

Section 5. Rare Diseases 183 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 10 years or older CAP-1002 is a cell-based therapy intended for DMD, an Corticosteroids (eg, Ambulatory function, as FDA designation(s): Orphan who have genetically inherited, X chromosome–linked genetic disorder caused by deflazacort, prednisone) measured by accepted Drug, Rare Pediatric Disease, confirmed Duchenne rearrangements or deletions in the dystrophin gene, DMD. clinical ratings and Regenerative Medicine muscular dystrophy (DMD), DMD encodes the dystrophin protein, which helps promote scales (eg, time to stand, Advanced Therapy are either ambulatory or muscle function. The absence of wild-type dystrophin protein time to run/walk/climb; Clinical trial(s): Phase 2 HOPE- nonambulatory, and are causes progressive muscle fiber death and eventual 6-minute walk test, 2 completed March 2020, top- receiving stable doses of widespread muscle weakness. No cure for DMD exists, and North Star Ambulatory line data reported May 2020 systemic glucocorticoids first-line corticosteroid treatment addresses symptoms but Assessment) does not prevent disease progression and has significant side Muscle strength and effects. FDA approved 2 gene therapies for patients who have function (eg, a specific mutation in DMD (ie, in exon 51 or exon 53); Performance of Upper however, patients who have other DMD mutations are Limb [PUL] clinical scale) ineligible for these therapies. CAP-1002 contains Cardiac function cardiosphere-derived cells (CDCs) from donor heart tissue. The CDCs in CAP-1002 purportedly secrete growth 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)

Section 5. Rare Diseases 184 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 7 to 18 years (LV-101) is an analogue of the hormone oxytocin Cognitive behavioral therapy Hyperphagia symptoms FDA designation(s): Fast Track who have Prader-Willi intended to treat nutritional phase 3 hyperphagia in children (CBT) and severity Clinical trial(s): Phase 3 CARE- syndrome (PWS) with with PWS. Hyperphagia is abnormally increased appetite Diazoxide (off-label) Rate of comorbidities PWS primary completion May nutritional phase 3 without feelings of satiety (ie, fullness after eating). PWS is a Diet and food intake control (eg, cardiovascular 2020, data reported August hyperphagia genetic condition with a loss of function in genes on Exercise disease, diabetes 2020 chromosome 15 that results in slowed development, mellitus, obesity) Note(s): Phase 3 enrollment intellectual disability, behavioral problems, and various Glucagon-like peptide 1 (GLP-1) receptor agonist (eg, Quality of life paused in April 2020 because physical manifestations. A hallmark symptom is hyperphagia, of issues related to the which begins in childhood and often results in morbid exenatide, liraglutide; off- label) COVID-19 pandemic, not a obesity if food intake is not restricted. The exact cause of the suspension of institutional increased appetite in this population is unknown but might review board (IRB) approval be linked to 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 –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 185 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 7 to 23 years who Casimersen (SRP-4045) is a phosphorodiamidate morpholino Corticosteroids (eg, Ambulatory function, as PDUFA date: February 25, have Duchenne muscular oligomer (PMO; DNA analogue) intended to treat DMD, an deflazacort, prednisone) measured by accepted 2021 dystrophy (DMD) with a inherited, X chromosome–linked genetic disorder caused by clinical ratings and FDA designation(s): Orphan rearrangement in the rearrangements or deletions in the DMD gene. DMD encodes scales Drug DMD dystrophin gene, , that the dystrophin protein, which is involved in muscle function, Quality of life Clinical trial(s): Phase 3 involves exon 45 and who are and the absence of wild-type dystrophin protein causes ESSENCE primary completion on a stable dose of progressive muscle fiber necrosis and eventual widespread May 2022, top-line data corticosteroids muscle weakness. Casimersen purportedly binds exon 45 of reported March 2019; phase 3 dystrophin pre-messenger RNA (mRNA; ie, precursor RNA open-label extension primary composed of introns and exons) and promotes skipping of completion August 2026 exon 45 during mRNA processing. This allows for synthesis of an internally truncated, but functional, dystrophin protein. Casimersen treatment is intended to promote skeletal muscle function and prevent or delay disease progression in patients with DMD who have DMD exon 45 variants. In clinical trials, casimersen is given intravenously at a dosage of 30 mg/kg once weekly for up to 144 weeks. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 186 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 Clinical trial(s): Phase 3 PRIMIS who have large duct primary receptor (FXR) agonist (ie, activator) being developed to treat cholangioscopy) with or progression primary completion August sclerosing cholangitis (PSC) PSC. In PSC, the bile ducts narrow severely for reasons not without stents to widen Need for liver 2023; phase 2 completed May and stage F0 to F3 liver clearly understood, preventing bile acid from leaving the liver narrowed bile ducts transplantation 2020, data published January fibrosis and causing progressive inflammation and scarring (ie, Liver transplantation Quality of life 2019 fibrosis) of liver tissue. Most care is supportive and targets (reserved for advanced liver symptom relief. Liver transplantation is potentially curative disease) but generally reserved for patients with end-stage liver Long-term antibiotics (to disease. Additionally, PSC reportedly recurs often after liver treat and prevent frequent transplantation (in up to 45% of patients in some reports). infections caused by blocked Cilofexor purportedly works by multiple mechanisms to bile ducts) regulate bile acid synthesis and excretion. FXR Supportive care to reduce downregulation by cilofexor in the intestine purportedly itching (eg, bile acid leads to release of a hormone that downregulates the rate- sequestrants, antihistamines, 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 administered as an oral tablet of 100 mg taken 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 187 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or -tmca (Adakveo) is a humanized Blood transfusions Amount and length of Approval date: November 15, older and adults who have immunoglobulin G2 (IgG2) antibody against P-selectin, which Hematopoietic stem cell intravenous opioid use 2019 (SCD) promotes the inflammation and adhesion involved in vaso- transplantation (HSCT) Frequency of VOCs FDA designation(s): Orphan occlusive crises (VOCs). It is approved by FDA. Crizanlizumab- Hydroxyurea Hospital length of stay Drug, Breakthrough Therapy, tmca is intended to improve treatment efficacy by blocking Priority Review Pharmaceutical-grade L- Rehospitalizations P-selectin to prevent abnormal red blood cell clumping in glutamine (ie, Endari) within 3 days of Clinical trial(s): Phase 3 STAND small blood vessels and maintain blood flow. In SCD, sickled discharge primary completion May 2022; red blood cells are more susceptible to oxidative damage, Voxelotor (ie, Oxbryta) Quality of life phase 2 SUSTAIN data inappropriate clumping (ie, adhesion), and vessel blockage, published February 2017, post leading to VOCs that cause severe pain, requiring hoc data presented November hospitalization. VOC complications can include circulating 2019 blood clots, stroke, organ failure, or early death, and available Note(s): FDA approval is based treatments are often ineffective. Hydroxyurea, which has on phase 2 SUSTAIN data been a mainstay of treatment for VOC, can reduce its incidence but is ineffective in only about one-third of adult patients. Crizanlizumab-tmca is indicated to reduce the frequency of VOCs in patients with SCD. The recommended dosage in the FDA-approved label is 5 mg/kg given intravenously over 30 minutes on week 0, week 2, and every 4 weeks after that. Developer(s): Novartis AG (Basel, Switzerland)

Section 5. Rare Diseases 188 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 4 years or older Diazoxide choline controlled release (DCCR) is an Cognitive behavioral therapy Hyperphagia symptoms FDA designation(s): Orphan and adults who have Prader- investigational, proprietary crystalline salt formulation of (CBT) and severity Drug, Fast Track Willi syndrome (PWS) with diazoxide, a potassium channel activator that inhibits insulin Diet and food intake control Rate of comorbidities Clinical trial(s): Phase 3 hyperphagia secretion. It is intended to treat hyperphagia (ie, abnormally Exercise (eg, cardiovascular DESTINY C601 completed May increased appetite) in patients with PWS. PWS is a rare Glucagon-like peptide 1 disease, diabetes 2020, data reported June genetic disease (about 8000-11 000 US patients) caused by (GLP-1) receptor agonist (eg, mellitus, obesity) 2020; phase 3 C602 open- lack of expression of several genes on chromosome 15. It is exenatide, liraglutide; off- Survival label extension primary often managed with off-label diazoxide (Proglycem), which is label) Quality of life completion April 2021; phase approved to treat low blood glucose. However, patients with 3 C603 open-label primary PWS require a lower dose of diazoxide than the current completion March 2023 formulation, which often causes high blood glucose as a side effect. DCCR purportedly blocks the production and release of 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 189 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 monoclonal Acetylcholinesterase Disease severity FDA designation(s): Orphan who have refractory antibody intended to treat gMG in children by blocking inhibitors (eg, Functional activity level Drug generalized myasthenia gravis complement system activation that contributes to pyridostigmine) Quality of life Clinical trial(s): Phase 3 (gMG) and test positive for inflammation and destruction of the muscle membrane at the Corticosteroids (eg, primary completion June 2021 anti-acetylcholine receptor neuromuscular junction. Eculizumab is FDA approved for use prednisone) Note(s): In October 2017, FDA (anti-AchR) antibodies in adults and was the first complement inhibitor approved for Nonsteroidal approved eculizumab (Soliris) gMG. In gMG, a progressive, autoimmune neuromuscular immunosuppressive agents for treating adults with gMG disorder, the body develops at the neuromuscular junction (eg, cyclosporine, who test positive for anti- antibodies against AchRs, which are necessary to turn nerve methotrexate, AchR antibodies. Eculizumab signals into muscle movements. The disorder manifests as mycophenolate mofetil, is also FDA approved (and muscle weakness that often begins in the eyes and eyelids tacrolimus) available only under a Risk and generalizes to more areas of the body, including the Thymus gland removal Evaluation and Mitigation head, neck, trunk, limbs, and chest. No cure is available for Strategy) to treat paroxysmal gMG, and some patients do not respond to standard nocturnal hemoglobinuria to immunosuppressive therapies. Eculizumab purportedly binds reduce hemolysis, atypical with high affinity to the complement protein C5 (a soluble hemolytic uremic syndrome to component of the innate immune system) to reduce inhibit complement-mediated activation of the complement pathway that causes thrombotic microangiopathy, inflammation and muscle membrane destruction at the and relapsing neuromyelitis neuromuscular junction that contributes to gMG pathology optica. and symptoms. 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 190 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 4 to 12 years who Edasalonexent (CAT-1004) is a small-molecule inhibitor of Corticosteroids (eg, Ambulatory function Submission date: New Drug have Duchenne muscular nuclear factor kappa-light-chain-enhancer of activated B cells deflazacort, prednisone) (eg, North Star Application anticipated in dystrophy (DMD) (NF-kB). It is intended to treat DMD, an inherited X Supportive care Ambulatory Assessment, early 2021 chromosome–linked genetic disorder caused by 4-stair climb velocity, FDA designation(s): Orphan rearrangements or deletions in the dystrophin gene, DMD. stand from supine Drug, Fast Track, Rare DMD encodes the dystrophin protein that helps keep muscle velocity, 10-meter Pediatric Disease cells intact. The absence of wild-type dystrophin protein walk/run velocity) Clinical trial(s): Pivotal phase 3 causes progressive muscle fiber death and eventual Muscle strength PolarisDMD primary widespread muscle weakness and purportedly leads to the completion September 2020, persistent activation of NF-kB, which contributes to disease top-line data expected in progression. DMD has no cure, and first-line corticosteroid fourth quarter of 2020; phase treatment (eg, deflazacort) manages symptoms but does not 3 GalaxyDMD open-label prevent disease progression and has significant side effects. extension primary completion FDA approved 2 gene therapies for patients who have a September 2022; phase 2 DMD specific mutation in (ie, in exon 51 or exon 53), but MoveDMD completed August DMD patients who have other variants are ineligible for these 2019, data presented April therapies. Edasalonexent therapy is intended for all patients 2018, data presented March with DMD regardless of genetic variant status. By blocking 2020 NF-kB activity, edasalonexent purportedly improves skeletal muscle function, preserves cardiac function, and reduces the risk of bone fracture in patients with DMD. In clinical trials, patients receive edasalonexent orally at a dosage of 100 mg/kg daily (divided into 3 equal doses) for up to 104 weeks. Developer(s): Catabasis Pharmaceuticals, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 191 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, data to ursodeoxycholic acid causing bile to accumulate in the liver and leading to diarrhea due to fat reported April 2019 (UDCA) treatment irreversible liver scarring and, potentially, liver failure. malabsorption, fatigue, Elafibranor is intended to provide a safer alternative to itching) 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 192

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

Males aged 12 years or older Elamipretide is a peptide compound designed to treat Supportive care directed at Exercise tolerance FDA designation(s): Orphan 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 of linked mitochondrial disorder characterized by degeneration infection, heart failure) Clinical trial(s): Phase 2/3 more than 30 kg with of heart muscle (ie, dilated cardiomyopathy) and skeletal TAZPOWER primary estimated glomerular muscle (ie, myopathy), recurrent infections due to completion April 2021, filtration rate (eGFR) greater neutropenia (ie, low white cells), and short stature. Barth preliminary data reported 2 than 90 mL/min/1.73 m or syndrome is managed primarily with supportive care because April 2019, additional data body weight of more than 40 no pharmacologic therapies have yet demonstrated clinical presented November 2019 kg and eGFR greater than 60 benefits. In Barth syndrome, mutations in the tafazzin gene, but less than 90 mL/min/1.73 TAZ, result in production of dysfunctional tafazzin protein. m2 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 193

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

Children aged 12 years or Elexacaftor/tezacaftor/ivacaftor (Trikafta) and ivacaftor is a CFTR modulator dual therapy Respiratory function Approval date: October 21, older and adults who have regimen of triple combination therapy intended to treat CF in (ie, lumacaftor/ivacaftor, Survival 2019 CFTR cystic fibrosis (CF) with a patients who have a F508del variant in the gene. tezacaftor/ivacaftor) Quality of life FDA designation(s): Orphan F508del variant in at least one Approved by FDA, the therapy purportedly makes proteins CFTR modulator Drug, Fast Track, copy of the cystic fibrosis produced by the mutant CFTR gene more effective. This drug monotherapy (ie, ivacaftor) Breakthrough Therapy transmembrane conductance targets a much larger population of patients with CF (ie, 90%, Clinical trial(s): Phase 3 CFTR regulator gene, an estimated 27 000 patients in the United States) than other completed December 2018, CF gene therapies already on the market. This therapy can be data published November used in patients who have CF with at least one F508del 2019; phase 3 completed April CFTR variation in the gene. Elexacaftor/tezacaftor/ivacaftor 2019, data published and ivacaftor purportedly work with a combined effect to November 2019; phase 3 CFTR increase the quantity and function of F508del- at the primary completion CFTR cell surface. This results in increased activity, as September 2020; phase 3 - measured by CFTR mediated chloride transport. Elexacaftor primary completion June

and tezacaftor bind to different sites on the CFTR protein and 2020; phase 3 primary have an additive effect in facilitating the cellular processing completion January 2023; CFTR and trafficking of F508del- to increase the amount of phase 3 open-label primary

CFTR protein delivered to the cell surface compared with completion May 2022; phase 3 either molecule alone. Ivacaftor potentiates the channel open primary completion August

probability (or gating) of the CFTR protein at the cell surface. 2022, data reported July 2020 The recommended dosage in the FDA-approved label is 2 Note(s): Vertex tablets containing elexacaftor 100 mg, tezacaftor 50 mg, and Pharmaceuticals will receive a ivacaftor 75 mg taken by mouth in the morning and one Rare Pediatric Disease Priority ivacaftor 150-mg tablet taken in the evening; the morning Review voucher for and evening doses are to be taken about 12 hours apart and developing this therapy with fat-containing food. Developer(s): Vertex Pharmaceuticals, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 194

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) gene therapy consists Factor IX replacement Bleeding episodes FDA designation(s): Orphan moderate to severe of adeno-associated viral vector serotype 5 (AAV5) therapy (human plasma– Treatment-related Drug, Breakthrough Therapy congenital (ie, inherited) containing a codon-optimized human factor IX Padua gene derived or recombinant) complications Clinical trial(s): Phase 3 HOPE- AAV5-hFIXco-Padua hemophilia B and are ( ). The adeno-associated viral vector Survival B primary completion receiving factor IX prophylaxis delivers a copy of the Padua variant of the factor IX gene, F9 Quality of life September 2020; single-arm with more than 150 days’ or FIX. It purportedly has an 8-fold increase in activity phase 2 primary completion exposure to factor IX protein compared with wild-type (ie, not caused by any known October 2018, data published treatment genetic variant) factor IX to provide sustained coagulation. As October 2019, further data a single-treatment gene therapy, AMT-061 could eliminate presented December 2019 the need for repeated coagulation-factor replacement. The manufacturer asserts that nearly all patients screened in clinical trials, potentially even patients with some preexisting antibodies to the AAV5 viral vector, are eligible for therapy. In clinical trials, AMT-061 is given as a single intravenous infusion at a dose of 2 × 1013 gc/kg. Developer(s): uniQure NV (Amsterdam, the Netherlands)

Children aged 2 years or older FCX-007 is a cell-based gene therapy consisting of patient- Supportive care for pain and Change in wound size FDA designation(s): Orphan and adults who have recessive derived dermal fibroblasts (ie, skin cells) treated to produce a infection risk from baseline Drug, Fast Track, Rare dystrophic epidermolysis functional copy of the collagen type VII alpha 1 chain gene, Time to wound closure Pediatric Disease, bullosa (RDEB) COL7A1. The cell therapy is delivered by injection into the from baseline Regenerative Medicine patient’s skin lesions to promote wound healing. RDEB is a Advanced Therapy rare genetic disease caused by mutations in the collagen Clinical trial(s): Phase 3 FCX- COL7A1 protein, which is needed for maintaining proper skin 007 primary completion April integrity. Loss of COL7A1 expression in RDEB leads to 2022; phase 1/2 FI-FCX-007 widespread blistering, resulting in severe scarring, vision loss, primary completion May 2020, disfigurement, and other serious medical problems. FCX-007 interim data reported May is intended to prevent blistering and promote wound healing 2018 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, FCX-007 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 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, , Monthly convulsive Approval date: June 25, 2020 who have Dravet syndrome amphetamine derivative intended as an adjunctive therapy stiripentol, topiramate, seizure frequency FDA designation(s): Orphan and are taking one or more for Dravet syndrome. A rare, severe, infantile-onset form of valproate) (MCSF) Drug, Fast Track antiepileptic drugs epilepsy, Dravet syndrome is usually caused by a variant in Ketogenic diet Convulsive seizure Clinical trial(s): Phase 3 the sodium voltage-gated channel alpha subunit 1 gene, Plant-derived CBD duration completed January 2019, data SCN1A . Approved by FDA, Fintepla is intended as an option Seizure-free interval published December 2019; for patients who have prolonged seizures that are difficult to Functional capacity phase 3 primary completion control with available antiepileptic drugs. In addition, patients Quality of life July 2020; phase 3 primary typically experience cognitive impairment, behavioral completion July 2020, pooled problems, muscle weakness, and sleep disorders. FDA has data published December approved cannabidiol (CBD) to treat the disease, but it can 2019; phase 3 open-label cause hepatic impairment, especially when used in extension primary completion conjunction with certain antiepileptics; the drug also can December 2020, data cause sleepiness, sedation, and suicidal behavior. In patients presented December 2018, with Dravet syndrome, fenfluramine hydrochloride low-dose data presented October 2019; purportedly promotes serotonin release and stabilizes nerve phase 3 long-term follow-up activity in the brain, which might decrease seizure frequency primary completion April 2023 and duration. The recommended dosage in the FDA- Note(s): Approval required approved label is 0.1 mg/kg twice daily administered as an both a Risk Evaluation and oral solution and may be increased to a maximum of 26 mg Mitigation Strategy and total daily in patients not taking adjunctive stiripentol or a classification as a Schedule IV maximum of 17 mg total daily in patients taking adjunctive controlled substance until the stiripentol and clobazam. US Drug Enforcement Agency Developer(s): (DEA) has made a final Zogenix, Inc (Emeryville, California) scheduling decision

Section 5. Rare Diseases 196 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, clobazam, Frequency of seizures FDA designation(s): Orphan who have Lennox-Gastaut amphetamine derivative intended as an adjunctive therapy stiripentol, topiramate, that result in drops (ie, Drug syndrome that is being for Lennox-Gastaut syndrome. The syndrome is a rare, severe, valproate) falls) Clinical trial(s): Pivotal phase 3 treated with 1 to 4 infantile- or childhood-onset form of epilepsy. Fintepla might Ketogenic diet Duration of seizures that primary completion December antiepileptic drugs improve health outcomes in patients with Lennox-Gastaut Plant-derived CBD result in drops (ie, falls) 2020, top-line data reported syndrome, who often experience multiple types of seizures Seizure-free interval February 2020; phase 2 (eg, atonic, tonic, atypical absence, drop attacks) difficult to Functional capacity primary completion control with FDA-approved antiepileptic drugs. In addition, September 2018, data Quality of life patients typically experience cognitive impairment, published August 2018; phase intellectual disability, behavioral problems, delayed 3 long-term follow-up primary development, and muscle weakness. FDA has approved completion April 2023 cannabidiol (CBD) to treat the disease, but it might cause Note(s): Zogenix planned to hepatic impairment, especially when used in conjunction with meet with FDA in September certain antiepileptics; the drug can also cause sleepiness, 2020 to discuss plans for sedation, and suicidal behavior. In patients with Lennox- supplemental New Drug Gastaut syndrome, fenfluramine hydrochloride low-dose Application 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 197 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 16 years or Fezagepras (PBI-4050; 3-pentylbenzeneacetic acid sodium Organ transplantation Change from baseline in FDA designation(s): Orphan older who have Alström salt) is a novel, synthetic, medium-chain fatty acid derivative, Supportive care skin pathology Drug, Rare Pediatric Disease syndrome oral antifibrotic (ie, reduces scar tissue formation). It is Change from baseline in Clinical trial(s): Phase 2/3 intended to treat Alström syndrome, a rare genetic fasting plasma glucose primary completion July 2020, syndrome. Alström syndrome is characterized by obesity in Change from baseline in preliminary data presented childhood or adolescence and type 2 diabetes mellitus plasma insulin April 2018; pivotal phase 3 (T2DM), often with severe insulin resistance, dyslipidemia, Change from baseline in planned high blood pressure, and severe life-threatening multiorgan glycated hemoglobin fibrosis involving the bladder, kidney, liver, and heart. (HbA1c) Progressive loss of vision and hearing, dilated cardiomyopathy, and short stature might also occur. Change from baseline in Fezagepras is intended to alleviate development of insulin blood glucose, as resistance, dyslipidemia, and hypertension and severe measured by weekly 4- multiorgan fibrosis. The drug purportedly has stimulating point profile activity toward the G-protein coupled receptor 40 (GPR40) Change from baseline in and inhibiting activity toward a related receptor, GPR84. This liver stiffness activity reduces fibrotic activity in macrophages, fibroblasts and 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 to therapy (human plasma– Treatment-related Drug, Breakthrough Therapy severe hemophilia B (factor IX treat hemophilia B. As a single-treatment gene therapy, derived or recombinant) complications Clinical trial(s): Phase 3 single- activity of 2% or less) and fidanacogene elaparvovec could eliminate the need for Survival arm BENEGENE-2 primary have received routine factor repeated injections of coagulation-factor replacement. The Quality of life completion April 2022 IX replacement therapy for at therapy uses an adeno-associated viral vector to deliver a least 6 months high-activity factor IX gene whose expression is driven by a liver-specific apolipoprotein E (Apo E) enhancer/human α1- antitrypsin (hAAT ) promoter. In clinical trials, fidanacogene elaparvovec is given as a single intravenous infusion (dose not stated). Developer(s): Pfizer, Inc (New York, New York)

Section 5. Rare Diseases 198 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

Infants and children aged up Fosdenopterin (BBP-870, ORGN001) is a synthetic version of Anticonvulsants Ability to sit upright Submission date: Rolling New to 5 years who have cyclic pyranopterin monophosphate (cPMP). It is intended to Breathing (ie, ventilator) independently for at Drug Application initiated molybdenum restore molybdenum cofactor (MoCo) levels and sulfite support least 30 seconds at 12 December 3, 2019, with deficiency (MoCD) type A oxidase activity to enable clearance of sulfite from patients Supportive care months completion expected in 2020 with MoCD type A. An ultra-rare genetic metabolic disorder, Bayley Scales of Infant FDA designation(s): Orphan MoCD type A causes catastrophic and irreversible neurologic Development at 12 Drug, Breakthrough Therapy, damage within the first weeks of life. MoCD type A has no months Rare Pediatric Disease effective treatments. It is caused by a mutation in the Pediatric Evaluation of Clinical trial(s): Phase 2 MOCS1, molybdenum cofactor synthesis 1 gene, which turns Disability Inventory primary completion December guanosine triphosphate to cPMP, an intermediate in the (PEDI) at 12 months 2020; phase 2/3 primary body’s production of MoCo. MoCo is a key component of the Survival at 12 months completion December 2021 sulfite oxidase enzyme, which clears the neurotoxic metabolic byproduct sulfite from the body. In a clinical trial, fosdenopterin is given intravenously, at a dosage of 80 to 320 μg/kg daily. Developer(s): Origin Biosciences (Palo Alto, California), a subsidiary of BridgeBio Pharma (Palo Alto, California)

Section 5. Rare Diseases 199 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 syndrome muscimol, a compound found in the mushroom Amanita anticonvulsants for seizures incidence and severity, Drug, Fast Track (FXS) muscaria. It is intended to treat FXS, a rare, noninherited, X and/or behavior stabilization, as measured by Clinical trial(s): Phase 2 chromosome–linked neurodevelopmental disorder caused by behavior-stabilizing accepted clinical ratings ROCKET completed February mutations in the fragile X mental retardation 1 gene, FMR1, medications [eg, alpha2 and scales 2020, data reported May 2020 responsible for encoding Fmr1 protein (Fmrp). Fmrp, which is agonists, antidepressants, expressed in neurons and glial cells, is thought to promote beta-blockers], educational synapse formation and adaptation (ie, synaptic plasticity) in interventions, sensory the brain and is thought to be important for learning, integration techniques) memory, and 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 200 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 2 to 49 years Gaboxadol (OV101) is a small-molecule derivative of Supportive care (eg, Motor function, as FDA designation(s): Orphan who have genetically muscimol, a compound found in the mushroom Amanita anticonvulsants for seizures, measured by accepted Drug, Fast Track, Rare confirmed Angelman muscaria. It is intended to treat Angelman syndrome, a rare, assistive devices, clinical ratings and Pediatric Disease syndrome noninherited, X chromosome–linked neurodevelopmental benzodiazepines for sleep scales Clinical trial(s): Pivotal phase 3 disorder caused by a mutation in the ubiquitin protein disturbances, occupational Time to sleep onset NEPTUNE primary completion UBE3A UBE3A E3a gene, . encodes the UBE3A protein, which therapy, physical therapy, Total sleep time November 2020; phase 2 mediates cellular protein degradation and is expressed in speech/language therapy) Behavioral disturbances, completed June 2018, data both excitatory and inhibitory neurons in the brain. A loss of as measured by presented October 2018, data UBE3A protein is thought to lead to disruption of normal accepted clinical ratings presented May 2019; phase 2 inhibitory brain cell function, resulting in motor dysfunction. and scales ELARA open-label extension Patients with Angelman syndrome experience severe primary completion July 2020 developmental delays, intellectual disability, impaired speech and motor function, behavioral and sleep disturbances, and seizures. No cure exists, and treatment consists of supportive care. If effective, gaboxadol could decrease symptom severity in patients with the disease. 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 Angelman syndrome. In clinical trials, patients receive gaboxadol 10 to 25 mg once or twice daily for up to 52 weeks. Developer(s): Ovid Therapeutics, Inc (New York, New York)

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 is a small-molecule histone deacetylase (HDAC) Corticosteroids (eg, Ambulatory function FDA designation(s): Orphan who have Duchenne muscular inhibitor intended to treat DMD, an inherited X deflazacort, prednisone) (eg, 6-minute walk test Drug, Fast Track dystrophy (DMD), are chromosome–linked genetic disorder caused by mutations or distance, time to rise Clinical trial(s): Phase 3 ambulatory, and are receiving deletions in the dystrophin gene, DMD. DMD encodes the from floor, North Star primary completion March a stable dose of dystrophin protein, which helps keep muscle cells intact. The Ambulatory 2022; phase 2/3 long-term corticosteroids absence of wild-type dystrophin protein causes progressive Assessment) follow-up primary completion muscle fiber necrosis and eventual widespread muscle Muscle strength December 2023 weakness. Patients with DMD also have increased HDAC levels that might be caused by dystrophin loss. HDAC overactivity prevents gene expression, including that of genes responsible for muscle cell regeneration and normal function, and it might trigger inflammation. No cure exists for DMD, and first-line corticosteroid treatment (eg, deflazacort) manages symptoms but does not prevent disease progression and 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 acute Givosiran (Givlaari) is an RNA interference (RNAi) therapeutic Carbohydrate perfusion Rate of attacks Approval date: November 20, hepatic porphyria (AHP) that reduces the expression of synthase 1 (acute) Rate of 2019 (ALAS1) to treat AHP. A group of rare metabolic disorders, Hemin injection (acute) administration FDA designation(s): Orphan AHPs are caused by genetic mutations (usually autosomal Supportive therapy (acute) Pain score change from Drug, Breakthrough Therapy dominant) in enzymes that are involved in heme production Trigger avoidance (acute) baseline Clinical trial(s): Phase 3 in the liver and converge in their respective metabolic Nausea score change ENVISION primary completion pathways on the ALAS1 enzyme. This convergence is thought from baseline January 2019, data published to increase the production of heme intermediates in the liver June 2020 that are toxic to nerves and contribute to developing AHP. Fatigue score change The manifestations include intermittent porphyria, from baseline aminolevulinic acid dehydratase-deficiency porphyria, hereditary coproporphyria, and variegate porphyria. Common symptoms from these manifestations can include confusion; fatigue; nausea; weakness; blisters on sun-exposed skin; and severe, diffuse abdominal pain. The disorders are chronic and are associated with serious illness. Acute flares can be life threatening. Givosiran is designed to reduce the expression of ALAS1 enzyme in the liver, reduce buildup of neurotoxic heme intermediates, and prevent or reduce recurrent AHP attacks. It is the first treatment to obtain FDA approval to prevent attacks or treat chronic manifestations of these disorders. The recommended dosage in the FDA-approved label is 2.5 mg/kg once monthly by injection under the skin. Developer(s): Alnylam Pharmaceuticals, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 203 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults with Golodirsen (Vyondys 53) is a phosphorodiamidate Corticosteroids (eg, Ambulatory capacity, as Approval date: December 12, Duchenne muscular morpholino oligomer (PMO; DNA analogue) intended to deflazacort, prednisone) measured by accepted 2019 dystrophy (DMD) who have a treat DMD, an inherited, X chromosome–linked genetic clinical ratings and FDA designation(s): Orphan confirmed mutation in the disorder caused by rearrangements or deletions in the scales Drug DMD DMD DMD gene that is amenable dystrophin gene, . encodes the dystrophin protein, 6-minute walk test Clinical trial(s): Phase 2 to exon 53 skipping which helps keep muscle cells intact. The absence of wild- distance completed March 2019, data type dystrophin protein causes progressive muscle fiber Quality of life published March 2020; phase necrosis and eventual widespread muscle weakness. No cure 3 ESSENCE primary exists for DMD, and first-line corticosteroid treatment completion May 2022; phase 3 manages symptoms but does not prevent disease open-label extension primary progression and has significant side effects. FDA approved completion August 2026 this and one other gene therapy for patients with a specific Note(s): FDA approved this mutation in DMD (ie, in exon 51), but patients who have indication under Accelerated other DMD variants are ineligible for these therapies. Approval “based on an Golodirsen purportedly binds exon 53 of dystrophin pre- increase in dystrophin mRNA (ie, precursor RNA composed of introns and exons) production in skeletal muscle and promotes skipping of exon 53 during mRNA processing. observed in patients treated This allows for synthesis of an internally truncated but with VYONDYS 53. Continued functional dystrophin protein. Therefore, golodirsen approval for this indication treatment might promote skeletal muscle function and may be contingent upon prevent or delay disease progression in patients who have verification of a clinical benefit mutations in DMD exon 53. The recommended dosage in the in confirmatory trials.” The trial FDA-approved label is 30 mg/kg once weekly as an that served as the basis for the intravenous infusion given over 35 to 60 minutes. approval was a 2-part study Developer(s): on a total of 25 patients. Sarepta Therapeutics, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 204 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 10 years or older Idebenone (Puldysa) is a small-molecule benzoquinone drug Corticosteroids (eg, Forced vital capacity Submission date: New Drug who have Duchenne muscular intended to treat DMD, an inherited, X chromosome–linked deflazacort, prednisone) (total, percentage Application planned for dystrophy (DMD) genetic disorder caused by mutations or deletions in the predicted) second half of 2021 dystrophin gene, DMD. DMD encodes the dystrophin protein, Percentage predicted FDA designation(s): Orphan which helps keep muscle cells intact. The absence of wild- peak expiratory flow Drug, Fast Track, Rare type dystrophin protein causes progressive muscle fiber Percentage predicted Pediatric Disease necrosis and eventual widespread muscle weakness. No cure forced expiratory Clinical trial(s): Phase 3 exists for DMD, and first-line corticosteroid treatment volume in 1 second SIDEROS primary completion manages symptoms but does not prevent disease Muscle strength August 2021; phase 3 progression and has significant side effects. FDA approved 2 Quality of life SIDEROS-E open-label gene therapies for patients who have a specific mutation in extension primary completion DMD (ie, in exon 51 or exon 53), but patients who have other December 2023; phase 3 DMD variants are ineligible for these therapies. Idebenone is DELOS completed April 2014, similar to coenzyme Q10 and purportedly facilitates electron data published April 2015, transport within mitochondria. According to the additional data presented manufacturer, maintaining correct electron balance is December 2017, additional essential for normal energy metabolism, particularly in nerve long-term follow-up data and muscle cells, which demand more energy, making them presented March 2020 more prone to rapid cell damage or death from Note(s): The developer stated mitochondrial dysfunction. In patients with DMD, preserving in May 2020 that US mitochondrial function and protecting cells from oxidative regulatory filing might be stress through idebenone treatment might prevent cell earlier than expected damage and increase energy production within impaired respiratory nerve and muscle tissue, potentially improving symptoms. In clinical trials, patients take idebenone by mouth or caregivers give it at a dosage of 900 mg daily divided into 3 equal doses of two 150-mg tablets each, taken with meals. Developer(s): Santhera Pharmaceuticals (Pratteln, Switzerland)

Section 5. Rare Diseases 205

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) in development to treat Crizanlizumab-tmca occlusive crises (VOCs) Drug, Fast Track, Rare SCD. Donor stem cell transplantation is the only potentially Hematopoietic stem cell and hospitalization Pediatric Disease curative treatment for SCD but is not widely available transplantation (HSCT) Number of blood Clinical trial(s): Phase 2 because of the difficulty of finding a closely matched donor Hydroxyurea transfusions required randomized primary to increase the chance of success. IMR-687 could represent a Quality of life completion September 2020, Pharmaceutical-grade L- disease-modifying treatment that is more widely available. interim data presented June glutamine The oral drug purportedly prevents destruction of and 2020; phase 2 extension increases levels of cyclic guanosine monophosphate (cGMP). Voxelotor primary completion June Higher cGMP levels in turn increase production of fetal 2024; phase 2 primary hemoglobin while reducing the sickling of red blood cells completion December 2021 and the stickiness of white 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 dosage of either 50 or 100 mg once daily for up to 24 weeks. Developer(s): Imara, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 206 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have (Uplinza) is a humanized monoclonal antibody Azathioprine Attack rate Approval date: June 11, 2020 neuromyelitis optica or intended to bind to CD19, which is expressed on a broad Eculizumab plus Functional impairments FDA designation(s): Orphan neuromyelitis optica spectrum range of B cells. Inebilizumab is intended to bind to and immunosuppressants (eg, vision, mobility, Drug, Breakthrough Therapy disorder (NMOSD), regardless deplete autoreactive B cells involved in the Intravenous corticosteroids bowel or bladder Clinical trial(s): Phase 2/3 N- of aquaporin-4- neurodegenerative disease course of NMOSD, for which no Mycophenolate mofetil incontinence) change MOmentum primary immunoglobulin G (AQP4- cure exists. NMOSD is a rare autoimmune disease that affects from baseline Plasmapheresis completion October 2018, IgG) antibody presence, and myelin in the eyes, spinal cord, and other parts of the body. Hospitalizations pivotal study data published who have had one relapse Patients with NMOSD can have pain, paralysis, vision loss, Rituximab Quality of life change October 2019 requiring rescue therapy in and bladder and bowel problems. Inebilizumab is approved from baseline the previous year by FDA; other approved treatments are immunosuppressants and/or add-on 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; the lable says 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 207 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have diffuse Lenabasum (JBT-101) is a novel synthetic anti-inflammatory Combined autologous Disease progression Submission date: New Drug cutaneous systemic sclerosis and antiscarring (ie, antifibrotic) medication under hematopoietic stem cell Skin fibrosis and Application planned for 2021 investigation to treat systemic sclerosis, a rare, incurable, transplantation (HSCT) and inflammation FDA designation(s): Orphan autoimmune, connective tissue disease. Conventional high-dose Survival Drug, Fast Track immunosuppressive therapy has limited efficacy in immunosuppressive therapy Quality of life Clinical trial(s): Phase 3 preventing disease progression or reducing mortality rates. Low-dose (RESOLVE-1) primary The disease is marked by vasculopathy, skin thickening due immunosuppressive therapy completion March 2020 to collagen accumulation, autoantibody formation, and Symptom-based palliative inflammation, which leads to fibrosis in skin and internal pharmacotherapy (eg, organs. Patients with limited cutaneous systemic sclerosis angiotensin-converting have fairly high survival rates but are at increased risk of enzyme [ACE] inhibitors, pulmonary arterial hypertension. Patients with diffuse nonsteroidal anti- cutaneous systemic sclerosis have worse survival rates. inflammatory drugs Preclinical studies suggest that lenabasum preferentially [NSAIDs]) activates specific immune cell cannabinoid receptors (ie, CB2). Lenabasum purportedly binds CB2 receptors and triggers inflammation resolution, 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 208 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 15 years or Lenadogene nolparvovec (LUMEVOQ) is a gene therapy Supportive care Visual acuity Submission date: New Drug older and adults who have intended for LHON, a rare maternally inherited genetic Quality of life Application planned for Leber hereditary optic disease of mitochondrial DNA that leads to irreversible vision second half of 2021 neuropathy (LHON) caused by loss. Lenadogene nolparvovec is intended to restore vision FDA designation(s): Orphan a mutation in the NADH loss and quality of life in patients with LHON caused by a Drug ND4 ND4 dehydrogenase 4 gene, mutation in the gene. Lenadogene nolparvovec is an Clinical trial(s): Phase 3 adeno-associated virus serotype 2 (AAV2) vector that delivers REFLECT primary completion ND4 a functional copy of the gene into cells. The therapy June 2024, developed under uses a mitochondrial targeting sequence that carries Special Protocol Assessment; therapeutic messenger RNA (mRNA) transcribed from this phase 3 RESCUE completed transgene from the nucleus of treated cells directly to the July 2019, data reported mitochondria, where functional ND4 proteins are produced September 2019; phase 3 and incorporated, treating the deficiency. In clinical trials, REVERSE completed lenadogene nolparvovec is given as a single intravitreal (ie, December 2018, data reported 10 into the eye) injection at a dose of 9 × 10 vg in 90 μL of May 2019; phase 3 GS-LHON- balanced salt solution plus 0.001% Pluronic F68. CLIN-06 primary completion Developer(s): July 2022, data reported July Gensight Biologics, Inc (New York, New York) 2020

Section 5. Rare Diseases 209 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged up to 17 years Lenti-D is a bone marrow–derived gene therapy product Hematopoietic stem cell CALD progression Submission date: Biologics who have active cerebral intended for adrenoleukodystrophy (ALD). A rare, X transplantation (HSCT) Functional disability License Application planned adrenoleukodystrophy chromosome–linked, inherited metabolic disorder, ALD is Lorenzo’s oil (4 parts glyceryl Quality of life for third quarter of 2021 caused by mutations in the ATP binding cassette subfamily D trioleate to 1 part glyceryl FDA designation(s): Orphan member 1 gene, ABCD1. The disorder leads to accumulation trierucate) Drug, Breakthrough Therapy of abnormally high levels of unbranched, saturated, very- Clinical trial(s): Phase 2/3 long-chain fatty acids in patients’ brains and adrenal Starbeam primary completion cortexes. Cerebral ALD (CALD) is the most severe form and April 2021, data reported involves neurodegeneration, including the breakdown of the September 2019; phase 3 protective myelin sheath of nerve cells in the brain. primary completion February Symptoms occur in early childhood and progress rapidly, 2024 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. Lenti-D 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. Lenti-D 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, Lenti-D 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 210 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 2 to 50 years LentiGlobin (BB305) consists of patient-derived Blood transfusions Frequency of VOCs and FDA designation(s): Orphan who have severe sickle cell hematopoietic stem cells transduced with a functional copy Crizanlizumab-tmca hospitalizations Drug, Regenerative Medicine HBB, disease (SCD) of the human hemoglobin subunit beta gene, which are Hematopoietic stem cell Number of blood Advanced Therapy then reintroduced to the patient. In SCD, sickled red blood transplantation (HSCT) transfusions required Clinical trial(s): Phase 3 single- cells are more susceptible to oxidative damage, inappropriate Hydroxyurea Quality of life arm primary completion adhesion, and vascular obstruction, leading to vaso-occlusive November 2023; phase 1/2 Pharmaceutical-grade L- crises (VOCs) that cause severe pain, requiring primary completion February glutamine hospitalization. VOC complications can include circulating 2022, interim data presented blood clots, stroke, organ failure, or early death. LentiGlobin Voxelotor June 2020 has a unique amino acid substitution in the HBB gene that promotes antisickling of red blood cells. By replacing dysfunctional human HBB genes, LentiGlobin might address SCD’s underlying cause rather than just reduce symptoms. LentiGlobin is given by intravenous infusion as a single dose after myeloablative conditioning with busulfan. Developer(s): bluebird bio, 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

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 no corticosteroids, oxygen) completion September 2021; standardized treatment protocols are available. Cyclosporine phase 3 BOSTON-1 primary A is a potent immunosuppressive drug for preventing completion December 2021; transplant rejection, but systemic administration has phase 3 BOSTON-3 open- insufficient penetration into the lungs to treat BOS and label extension primary carries a risk of nephrotoxicity. L-CsA-i uses a proprietary completion March 2023 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 (Menlo Park, California)

Section 5. Rare Diseases 212 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients of any age who have Lumasiran (ALN-GO1) is an RNA interference (RNAi) Diet management and fluid Change in urinary PDUFA date: December 3, primary hyperoxaluria type 1 therapeutic intended to reduce glycolate oxidase (GO) intake oxalate excretion from 2020; Priority Review (PH1) expression in PH1. A rare inherited disorder, PH1 is Organ transplantation (ie, baseline FDA designation(s): Orphan characterized by development of kidney and bladder stones isolated or combined liver Hospitalizations Drug, Breakthrough Therapy from the buildup of excessive oxalate. Lumasiran is intended and kidney) Quality of life for Clinical trial(s): Phase 3 to improve health outcomes in patients with PH1 by reducing Renal dialysis patients and caregivers ILLUMINATE-A primary illness from oxalate crystals accumulating in the kidneys and Shockwave lithotripsy completion November 2019, urinary tract. No pharmacologic treatments are available for data reported December 2019, PH1. Lumasiran purportedly lowers liver levels of GO, which data presented June 2020; produces the substrate necessary for the subsequent phase 3 ILLUMINATE-B production of oxalate. Limiting the substrate necessary for primary completion June oxalate production is intended to limit its buildup. In clinical 2020; phase 3 ILLUMINATE-C trials, lumasiran is given subcutaneously by injection at a primary completion May 2021; dosage of 3 mg/kg/month. phase 1/2 completed January Developer(s): 2019, data reported February Alnylam Pharmaceuticals (Cambridge, Massachusetts) 2019 Note(s): Top-line data expected for ILLUMINATE-B in mid-2020.

Section 5. Rare Diseases 213 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have β- Luspatercept-aamt (Reblozyl) is a red blood cell (ie, Allogeneic stem cell Blood transfusion Approval date: November 8, thalassemia that requires erythrocyte) maturation agent under development to treat β- transplantation (ASCT) dependence 2019 regular red blood cell thalassemia. Luspatercept-aamt is intended to restore Repeated blood transfusions Incidence of iron FDA designation(s): Orphan transfusions production of normal red blood cells, thus obviating the overload Drug, Fast Track need for repeat transfusions and the accompanying iron Organ function Clinical trial(s): Phase 3 chelation therapy. β-thalassemia is caused by a BELIEVE primary completion HBB. Quality of life rearrangement in the hemoglobin subunit beta gene, November 2017, data This prevents normal erythrocyte maturation, resulting in published March 2020; phase severe anemia requiring chronic blood transfusions for 2 single-arm completed survival plus nightly iron chelation to prevent iron overload. November 2015, data Approved by FDA, luspatercept-aamt is a first-in-class published March 2019 biologic that purportedly stimulates maturation of erythrocyte precursor cells differently from the body’s natural erythropoietin, thereby correcting the maturation defect and restoring normal erythrocyte production. Luspatercept-aamt is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the transforming growth factor beta (TGF-beta) superfamily involved in late-stage erythrocyte production. The recommended dosage in the FDA-approved label is 1 mg/kg every 3 weeks injected under the skin to treat β-thalassemia-associated anemia in patients who require regular red blood cell transfusions. Developer(s): Acceleron Pharma, Inc (Cambridge, Massachusetts), in collaboration with Bristol Myers Squibb Co (New York, New York)

Section 5. Rare Diseases 214 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 for Supportive care Developmental and FDA designation(s): Orphan older and adults who have Sanfilippo syndrome type A, a childhood-onset, progressive, cognitive delays, as Drug, Fast Track, Rare genotypically confirmed inherited metabolic disorder caused by a variant in the N- measured by MPS Pediatric Disease Sanfilippo syndrome type A sulfoglucosamine sulfohydrolase gene, SGSH. Patients with clinical ratings and Clinical trial(s): Phase 2/3 (also called the disorder cannot break down the polysaccharide heparan scales AAVance primary completion mucopolysaccharidosis type sulfate, a process normally mediated by the SGSH-encoded Independence, as March 2022 III A [MPSIIIA]) enzyme heparan-N-sulfamidase. Buildup of heparan sulfate measured by MPS Note(s): A clinical hold has in central nervous system cells causes degeneration that clinical ratings and been placed on the phase 2/3 manifests as behavioral problems, sleeplessness, loss of scales AAVance trial after discussions speech and cognitive skills, mental retardation, heart Sleep duration with FDA and while recent problems, seizures, and loss of mobility. No cure exists for Quality of life magnetic resonance imaging Sanfilippo syndrome type A (about 60% of all Sanfilippo (MRI) findings in patients are syndrome cases), and patients typically do not survive past investigated. their 20s. Treatment consists of supportive care. LYS-SAF302 is a 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 215 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 (UDCA) Liver function FDA designation(s): Orphan who have progressive familial dependent bile acid transporter (ASBT). It purportedly Need for surgical Drug, Breakthrough Therapy intrahepatic cholestasis (PFIC) prevents bile acids from accumulating in the liver of patients intervention Clinical trial(s): Phase 2 with PFIC subtypes 1, 2, 3, and 4. A progressive disease, PFIC Quality of life INDIGO completed May 2020, can require surgical intervention or liver transplantation and data reported June 2020; has minimally effective therapy. PFIC is characterized by phase 3 MARCH-PFIC primary variants in key genes leading to decreased bile acid flow completion December 2020; through the liver. Accumulation of bile acid in the liver can phase 3 extension primary lead to jaundice, intense itching, gallstones, abdominal pain, completion November 2022 nausea, vomiting, and liver damage, as well as a higher risk of hepatocellular carcinoma. Maralixibat binds to ASBTs and prevents bile acid accumulation in the liver by blocking bile acid transport from the intestine to 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 216 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 12 years or (Nucala) is a monoclonal antibody specific for Corticosteroids Annualized rate of HES Submission date: New Drug older and adults who have interleukin-5 (IL-5), a cytokine responsible for promoting Cytotoxic drugs (eg, flares from baseline Application submitted May hypereosinophilic syndrome eosinophil activation and inflammatory responses. HES is a cyclophosphamide, Fatigue score from 2020; Priority Review (HES) group of rare inflammatory disorders characterized by the hydroxyurea, vincristine) baseline FDA designation(s): Orphan chronic overproduction of eosinophils. These eosinophils Imatinib Overall survival Drug, Fast Track infiltrate tissues and might damage organs such as the heart Quality of life Clinical trial(s): Phase 3 and lungs, which can negatively impact quality of life and completed December 2019; increase risk of death. Treatment options are limited. phase 3 completed August Mepolizumab purportedly binds to IL-5 and prevents it from 2019, data reported binding to the IL-5 receptor on the surface of eosinophils, November 2019, data which inhibits inflammatory signaling and reduces eosinophil presented May 2020; phase 3 levels in circulation without completely depleting them from completed September 2010 the body. In clinical trials, mepolizumab was given as an Note(s): FDA approved injection under the skin of 300 mg every 4 weeks. mepolizumab to treat severe Developer(s): asthma in November 2015, to GlaxoSmithKline plc (Brentford, United Kingdom) treat eosinophilic 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 217 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

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

Section 5. Rare Diseases 218 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 Renal function from FDA designation(s): Orphan immunoglobulin A (IgA) antibody that binds an enzyme called mannan-binding lectin- Immunosuppressants (eg, baseline Drug, Breakthrough Therapy nephropathy associated serine protease-2 (MASP-2). Narsoplimab is azathioprine, Urine protein excretion Clinical trial(s): Phase 3 intended to reduce excessive complement-mediated cyclophosphamide, from baseline primary completion August inflammation and endothelial damage characteristic of IgA mycophenolate) 2020 nephropathy while leaving other immune system functions Supportive care 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 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 219 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 specific for mannan-binding lectin-associated serine Plasma therapy (ie, plasma from baseline Drug, Fast Track primary atypical hemolytic protease-2 (MASP-2), the effector enzyme of the lectin infusion or plasmapheresis) Glomerular filtration Clinical trial(s): Phase 3 uremic syndrome (aHUS) pathway in the complement system. An ultra-rare genetic rate from baseline primary completion February disease, aHUS results in chronic uncontrolled complement TMA events from 2020 activation, leading to complement-mediated thrombotic baseline microangiopathy (TMA). TMA is characterized by the Disease remission rate 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 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 Eculizumab (off-label) Inflammation Submission date: Rolling hematopoietic stem cell antibody specific for an enzyme called mannan-binding Rituximab with biomarkers from Biologics License Application transplantation (HSCT)– lectin-associated serine protease-2 (MASP-2). Narsoplimab is plasmapheresis baseline initiated October 2019; 3 of 4 associated thrombotic being investigated to treat HSCT-TMA. About 10% to 25% of Supportive care (eg, Red blood cell parts had been submitted as microangiopathy (TMA) HSCTs lead to TMA and, in high-risk patients (eg, patients antibiotics, antihypertensives, transfusion of August 2020 with comorbid graft-versus-host disease [GVHD] whose TMA erythropoietin, requirements from FDA designation(s): Orphan has not responded to modified immunosuppressive therapy), thrombopoietin) baseline Drug, Breakthrough Therapy the death rate is more than 90%. No treatments are FDA Platelet requirements Clinical trial(s): Phase 2 approved for HSCT-TMA. TMA is characterized by formation from baseline primary completion October of blood clots in small blood vessels throughout the body Survival 2019, data presented June that can progressively damage organs, including the kidneys, 2020 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 221

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

Adults with severe itching (ie, Nemolizumab (CD14152) is a novel monoclonal antibody that Antihistamines (eg, Anxiety and depression FDA designation(s): prurigo) associated with blocks signaling of interleukin-31 (IL-31) to treat itching (ie, diphenhydramine, symptoms and severity Breakthrough Therapy moderate to severe prurigo pruritus) associated with prurigo nodularis. A chronic skin hydroxyzine; off-label) Itch frequency and Clinical trial(s): Phase 3 nodularis with at least 20 disease, prurigo nodularis is characterized by hard lumps (ie, Immunosuppressants (eg, severity primary completion October nodules on the body nodules) that form on the skin, causing intense itching, which cyclosporine, methotrexate; Sleep quality 2021; phase 3 primary often leads to patients scratching the areas until they bleed. off-label) Quality of life completion December 2021; Current therapies often do not provide adequate Over-the-counter lotions (eg, phase 3 primary completion symptomatic relief. Scratching can cause more nodules to containing calamine, August 2022; phase 2 appear. The disease cause is unknown, although some camphor, menthol, completed September 2018, patients have underlying skin conditions or allergies that are pramoxine hydrochloride) data published February 2020 thought to contribute. Prurigo nodularis can be highly Phototherapy (ie, narrow disruptive to patients’ daily lives because it can negatively band ultraviolet B, psoralen affect sleep quality, mental health, concentration, and body plus ultraviolet A; off-label) image and confidence. Nemolizumab purportedly reduces itching by blocking the binding of the inflammatory cytokine Topical (off-label) IL-31 to IL-31 alpha receptors that are thought to play a key Topical corticosteroids (eg, role in itch signaling to the brain in prurigo nodularis. In betamethasone, clobetasol; phase 2 clinical trials, nemolizumab was injected under the off-label) skin (ie, subcutaneously) at a dosage of 0.5 mg/kg once every 4 weeks for a total of 3 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 aged 21 to 80 years NT-501 (Renexus) is an eye implant containing genetically Vascular endothelial growth Neurodegeneration, as FDA designation(s): Orphan who have macular modified human cells that secrete neuropeptide ciliary factor (VEGF) inhibitors measured by changes in Drug, Fast Track telangiectasia (MacTel) type 2 neurotrophic factor (CNTF). No implants are approved to macular ellipsoid zone Clinical trial(s): Phase 3 NTMT- carry biologics for MacTel type 2, a neurodegenerative Macular thickness 03-B primary completion disorder that causes gradual central vision loss over a period Visual acuity March 2022; phase 3 NTMT- of 10 to 20 years. Therefore, NT-501 might represent a novel Retinal sensitivity 03-A primary completion treatment option for these patients. NT-501 allows controlled March 2022; phase 2 NTMT- Reading speed release of biologic drugs and is intended to slow retinal 02 completed April 2017, data degeneration. CNTF purportedly diffuses into the retina from published April 2019 the cells contained within the Renexus device to stimulate retinal cell growth and protect the cells from damage. In clinical trials, Renexus is surgically implanted into the vitreous humor and contains an unspecified dose of CNTF. The implant purportedly secretes CNTF for up to 2 years after placement. Developer(s): Neurotech Pharmaceuticals (Cumberland, Rhode Island), in collaboration with Lowy Medical Research Institute (La Jolla, California)

Section 5. Rare Diseases 223 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 months to 18 Odevixibat (A4250) inhibits the apical sodium-dependent bile Cholestyramine Liver function FDA designation(s): Orphan years who have genetically acid transporter (ASBT), also known as the ileal bile acid Phenobarbital Need for surgical Drug, Rare Pediatric Disease, confirmed progressive familial transporter. It is in development to treat PFIC, including PFIC Rifampicin intervention Fast Track intrahepatic cholestasis type 1 subtypes 1, 2, 3, and 4 (preliminary focus on subtypes 1 and Sodium 4-phenylbutyrate Quality of life Clinical trial(s): Phase 3 (PFIC1) or type 2 (PFIC2) 2). In PFIC, inherited alterations in genes that regulate bile randomized PEDFIC1 primary UDCA acid flow cause a buildup of bile acid in the liver, eventually completion July 2020; phase 3 leading to poor growth and progressive liver disease. No single-arm extension PEDFIC2 drugs are FDA approved for treating patients with PFIC, and primary completion December off-label treatments (eg, cholestyramine, rifampicin, 2021 ursodeoxycholic acid [UDCA]) are ineffective in some patients. Nonresponders may require surgical management (eg, biliary diversion, liver transplantation) to address symptoms of bile acid accumulation and progressive liver damage. Odevixibat purportedly binds to ASBT to prevent bile acid buildup in the liver by blocking bile acid transport from the intestine to 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 224 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults who have Olipudase alfa (GZ402665) is an enzyme replacement therapy Blood transfusions Fatigue Submission date: Biologics chronic visceral acid consisting of recombinant human acid sphingomyelinase Hyperlipidemia drugs Lung function License Application planned sphingomyelinase deficiency intended to treat ASMD. ASMD is a rare, genetic lysosomal Supplemental oxygen Pain for second half of 2021 (ASMD; also known as storage disease in which the enzyme acid sphingomyelinase, Supportive care (eg, Survival FDA designation(s): Orphan Niemann-Pick disease type B normally found in lysosomes and responsible for nutritional counseling, Drug, Breakthrough Therapy [NPD-B]) or chronic metabolizing the lipid sphingomyelin, is deficient or absent. Quality of life occupational therapy, Clinical trial(s): Phase 2/3 neurovisceral ASMD (also This leads to an accumulation of excess sphingomyelin in physical therapy) ASCEND primary completion known as Niemann-Pick cells, which leads to cell death, organ enlargement, and October 2019, data reported disease type A/B [NPD-A/B]) malfunction of major organ systems. Olipudase alfa is January 2020; phase 2 intended to replace the deficient acid sphingomyelinase ASCEND-peds completed enzyme and purportedly breaks down sphingomyelin in December 2019, data reported lysosomes to prevent excess accumulation of sphingomyelin. January 2020; phase 2 primary Initial studies of olipudase alfa indicated that it did not affect completion December 2023, ASMD’s neurologic symptoms; therefore, studies of olipudase interim data published alfa are currently limited to treating less-severe forms of the January 2018, interim data disease (ie, chronic visceral ASMD [NPD-B], chronic published June 2020 neurovisceral ASMD [NPD-A/B]) characterized by reduced or absent neurologic involvement. In clinical trials, olipudase alfa is given intravenously at a dose 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 225 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 30 days to 17 OTL-101 is a bone marrow–derived gene therapy product Bone marrow transplantation Event-free survival FDA designation(s): Orphan years who have adenosine intended for ADA-SCID, a rare and life-threatening inherited Enzyme replacement Overall survival Drug, Breakthrough Therapy, deaminase–severe combined disease of the immune system due to a faulty adenosine Quality of life Rare Pediatric Disease immunodeficiency (ADA- deaminase gene, ADA. This gene is essential for T-cell and B- Clinical trial(s): Phase 2/3 SCID) and are ineligible for cell (ie, lymphocyte) production. Patients with ADA-SCID primary completion August allogeneic bone marrow produce no functional lymphocytes, leading to susceptibility 2020; phase 1/2 completed transplantation from a to serious and life-threatening infections. Without enzyme October 2018, initial data matched family donor replacement therapy, patient life expectancy is short. OTL- reported February 2019; full 101 was designed to restore lymphocyte development and integrated analysis of the immunity in patients with ADA-SCID (also known as bubble registrational data set with + boy disease). OTL-101 consists of patient-derived CD34 2-year follow-up reported stem cells that are harvested from the patient and treated April 2020 (abstract 1300) at with a lentivirus vector that stably inserts a functional copy of American Society of Gene & the ADA gene into the cells. The cells are then multiplied in Cell Therapy meeting; phase culture to facilitate uptake. In clinical trials, OTL-101 is given 1/2 primary completion July as a single intravenous infusion of an unspecified dose. 2021 Developer(s): Orchard Therapeutics, Ltd (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 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 in Immunoglobulin infusion platelet infusions for fourth quarter of 2021 WAS (WAS) the WASP actin nucleation promoting factor gene, . The Platelet infusion Rate of hospitalizations FDA designation(s): Orphan WAS gene is a cytoskeleton regulator expressed only in for infection or bleeding Drug, Regenerative Medicine blood-forming (ie, hematopoietic) cells. WAS deficiency leads episodes Advanced Therapy to eczema, petechiae, thrombocytopenia, reduced blood Clinical trial(s): Phase 1/2 clotting, and susceptibility to infections. A bone marrow TIGET-WAS primary transplant from an allogeneic (ie, unmatched) donor can completion October 2018, potentially cure WAS. OTL-103 is intended to relieve WAS data published May 2019; WAS symptoms by repopulating the bone marrow with - phase 2 primary completion expressing hematopoietic stem cells to restore growth, February 2022 replication, 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 227 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children and adults who have OTL-200 (Libmeldy in the European Union) is a gene therapy Supportive care (eg, Gross motor function, as Submission date: Biologics genetically confirmed consisting of autologous CD34+ hematopoietic stem cells nutritional therapy; measured by accepted License Application planned metachromatic transduced in the laboratory with a lentiviral vector occupational, physical, and MLD clinical ratings and for first half of 2021 leukodystrophy (MLD) containing the arylsulfatase A gene, ARSA. It is intended to speech therapy) scales FDA designation(s): Orphan treat patients who have MLD, a progressive inherited Neurocognitive Drug, Rare Pediatric Disease lysosomal storage disorder caused by variants in both alleles function, as measured Clinical trial(s): Phase 1/2 ARSA. of The gene normally encodes the enzyme by accepted MLD primary completion April arylsulfatase A, which breaks down sphingolipids. Lack of clinical ratings and 2018, data presented March arylsulfatase A activity leads to sphingolipid accumulation in scales 2019, data presented the brain, gall bladder, kidneys, liver, and spleen, which in Quality of life September 2019; phase 2 turn causes myelin loss on nerve fibers of the central nervous primary completion August system. Affected patients experience convulsions, motor 2022, data presented October disturbances, paralysis, personality changes, progressive 2019; phase 3 open-label dementia, seizures, spasticity, and visual impairment. No cure extension primary completion exists for MLD, and the disease is fatal; treatment consists of January 2032 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 228 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, assistive New HO formation FDA designation(s): Orphan older and adults who have (RARγ) agonist (ie, potentiator) being developed to treat FOP. devices, corticosteroids, Number of body Drug, Breakthrough Therapy, fibrodysplasia ossificans A rare connective tissue disorder, FOP leads to the abnormal nonsteroidal anti- regions with HO Fast Track, Rare Pediatric progressiva (FOP) growth of bone in muscles, tendons, and ligaments, known as inflammatory drugs Flare rate Disease heterotopic ossification (HO). Palovarotene treatment is [NSAIDs], occupational Range of motion, as Clinical trial(s): Phase 3 MOVE intended to prevent HO in patients with FOP. HO flares can therapy) measured by accepted primary completion occur spontaneously or after physical trauma (eg, injury, clinical ratings and September 2022; phase 2 infection). Once formed, the heterotopic bone cannot be scales completed May 2016; phase 2 removed because tissue disruption causes additional HO long-term extension primary Physical function, as episodes. HO progressively interferes with normal body completion May 2021 functions, including walking, bending, breathing, chewing, measured by accepted clinical ratings and Note(s): Palovarotene is under and swallowing. FOP is caused by a mutation in the activin A partial clinical hold in patients ACVR1 scales receptor type 1 gene, , which encodes for the younger than 14 years of age ACVR1/ALK2 receptor. ALK2 normally regulates the bone morphogenetic protein (BMP) pathway, which is 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): Clementia, an Ipsen Company (Montreal, Québec, Canada)

Section 5. Rare Diseases 229 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 2 years or older Pegzilarginase (AEB1102) is a modified version of the human Low-arginine diet Mobility (eg, 2-minute FDA designation(s): Orphan and adults who have arginase arginase 1 enzyme. It is intended to treat arginase 1 Nitrogen-scavenging drugs walk test, Functional Drug, Breakthrough Therapy, 1 deficiency deficiency, a rare, inherited metabolic disorder caused by (eg, sodium phenylacetate, Mobility Assessment) Rare Pediatric Disease mutations in the arginase 1 gene, ARG1. Lack of the ARG1- sodium benzoate) Adaptive behavior (eg, Clinical trial(s): Phase 3 PEACE encoded arginase enzyme, which is part of the cellular urea Seizure medications (eg, Vineland Adaptive primary completion March cycle, leads to excessive nitrogen accumulation in the blood carbamazepine, Behavior Scale II) 2021, top-line data expected and cerebrospinal fluid. Affected patients typically experience phenobarbital) in first quarter of 2021; phase seizures, growth impairment, and intellectual disability. 2 primary completion June According to the manufacturer, pegzilarginase is modified to 2021, data presented May increase enzyme activity and stability compared with native 2020 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 230 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 (CXCR4) Granulocyte colony- Infection rate FDA designation(s): Orphan older and adults aged up to inhibitor. It purportedly prevents most leukocyte subsets stimulating factor (G-CSF; for Severity of infections Drug 75 years who have a clinical from homing in and localizing in the bone marrow, a infection prevention) Wart control Clinical trial(s): Phase 2/3 diagnosis of WHIM (warts, characteristic of WHIM syndrome. A rare primary Imiquimod (to treat warts) Hematologic and primary completion October hypogammaglobulinemia, immunodeficiency, WHIM syndrome is caused by several Intravenous immunoglobulin immunologic 2020 infections, and myelokathexis) different mutations in the C-X-C motif chemokine receptor 4 (IVIG; for infection parameters Note(s): In December 2008, syndrome with a gene, CXCR4. The mutations associated with the syndrome prevention) Quality of life FDA approved plerixafor for heterozygous mutation in the cause dysfunction of the immune system, which increases use in combination with G- CXCR4 C-tail of the gene, infection risk and other complications resulting in many types CSF to mobilize hematopoietic documented neutropenia, of bacterial infection that can be mild to severe with serious stem cells (HSCs) to the and history of severe or sequelae. No cure exists. Standard treatment involves peripheral blood for collection recurrent infections antibiotic prophylaxis, immune stimulation, and treatment of and subsequent autologous infections and their consequences. Plerixafor is intended to transplantation in patients reduce infection risk. In a clinical trial, it is given by an with non-Hodgkin lymphoma injection of 0.02 to 0.04 mg/kg daily for 6 months. and multiple myeloma (MM) Developer(s): National Institutes of Health's National Institute of Allergy and Infectious Diseases (Bethesda, Maryland)

Section 5. Rare Diseases 231

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 viral vector containing bromocriptine, pramipexole, measured by accepted License Application planned genetically confirmed, a functional copy of the human dopa decarboxylase gene, ropinirole, rotigotine) clinical ratings and for second half of 2020 symptomatic aromatic L- DDC. It is intended to treat patients who have AADCD, a Monoamine oxidase scales FDA designation(s): Orphan amino acid decarboxylase childhood-onset, progressive, inherited neurometabolic inhibitors (eg, selegiline, Developmental delays Drug, Rare Pediatric Disease DDC deficiency (AADCD) disorder. AADCD is caused by a rearrangement in that tranylcypromine) Dyskinesia Clinical trial(s): Phase 1/2 results in the loss of the gene’s encoded enzyme, aromatic L- Vitamin B6 Quality of life primary completion December amino acid decarboxylase (AADC). This enzyme is critical for 2020, data published converting neurotransmitter precursors into dopamine, December 2017; phase 2 epinephrine, norepinephrine, or serotonin. Patients with MIND primary completion AADCD experience symptoms including severe December 2020; pooled data developmental delays, weak muscle tone, involuntary presented May 2018, pooled movements of the arms and legs, and seizures. Existing data presented October 2019 treatments only manage symptoms and do not prevent (abstracts 207, 231) disease 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 232 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have recessive PTR-01 is a form of recombinant collagen type VII (rC7) Supportive care for pain and Change in wound size FDA designation(s): Orphan dystrophic epidermolysis intended to improve RDEB lesions and other symptoms and infection risk from baseline Drug, Fast Track bullosa (RDEB) complications. It purportedly replaces defective collagen type Time to wound closure Clinical trial(s): Phase 1/2 VII with functional recombinant collagen at skin lesion sites from baseline primary completion to promote healing. No cure exists for RDEB, and treatment Evidence of collagen 7 November 2020, interim data relies on preventing blister formation and managing anchoring in tissue presented July 2020 symptoms. RDEB is a rare genetic disease caused by mutations in the collagen type VII alpha 1 chain gene, COL7A1, and is characterized by widespread blistering that leads to severe scarring. The scars can lead to vision loss, disfigurement, and other serious medical problems, such as poor nutrition and slow 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. 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 233 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 supplementation Best corrected visual FDA designation(s): Orphan dominant retinitis pigmentosa treating adRP caused by a variant (P23H) in the RHO gene. A Supportive care acuity (BCVA) Drug, Fast Track (adRP) caused by the P23H rare genetic disease, adRP causes progressive vision loss, Retinal sensitivity Clinical trial(s): Phase 1/2 variant in the rhodopsin gene, typically leading to blindness by mid-adulthood. In adRP Peripheral vision AURORA primary completion RHO caused by the RHO P23H variant, the mutated rhodopsin Quality of life October 2021 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 234 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 1 month or Ravulizumab-cwvz (Ultomiris) is a humanized, long-acting, Eculizumab Platelet count change Approval date: October 18, older and adults who have monoclonal antibody that purportedly provides immediate Plasma therapy (ie, plasma from baseline 2019 atypical hemolytic uremic and complete inhibition of the C5 complement protein in the infusion or plasmapheresis) Glomerular filtration Clinical trial(s): Phase 3 trial syndrome (aHUS) and terminal complement cascade. An ultra-rare genetic disease, rate from baseline primary completion evidence of complement- aHUS results in chronic uncontrolled complement activation, TMA events from November 2018, data mediated thrombotic leading to complement-mediated TMA. TMA is characterized baseline reported January 2019; phase microangiopathy (TMA) by the formation of blood clots in small blood vessels Disease remission rate 3 primary completion July throughout the body that can progressively damage organs, 2020 including the kidneys, and carries a high risk of serious illness Note(s): Ravulizumab-cwvz and death. Approved by FDA, ravulizumab-cwvz is intended was approved to treat adults to inhibit C5 activation leading to excessive complement- with paroxysmal nocturnal mediated inflammation and endothelial damage hemoglobinuria (PNH) in characteristic of aHUS while leaving other aspects of the December 2018. immune system intact. Ravulizumab-cwvz is given as an intravenous infusion in pediatric patients 1 month of age or older and adults. The FDA-approved label provides a dosing table that starts with a loading dose based on weight (600 mg for 5 kg body weight and a sliding scale up to 3000 mg for 100 kg body weight). After the loading dose, for patients weighing 5 to 20 kg, the drug is given at a maintenance dosage of 300 or 600 mg every 4 weeks. For patients weighing 20 to 100 kg, the maintenance dosage is 2100 to 3600 mg every 8 weeks. Developer(s): Alexion Pharmaceuticals (Boston, Massachusetts)

Section 5. Rare Diseases 235 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 reuptake Amphetamines Cataplexy attack FDA designation(s): Orphan who have narcolepsy with inhibitor intended to treat patients who have EDS and Antidepressants (eg, frequency Drug, Breakthrough Therapy excessive daytime sleepiness cataplexy from narcolepsy, a chronic neurologic sleep selective serotonin reuptake EDS symptoms and Clinical trial(s): Phase 3 (EDS) and cataplexy disorder. Narcolepsy treatments typically address either EDS inhibitors [SSRIs], tricyclic severity planned; phase 2 CONCERT or cataplexy, whereas reboxetine purportedly addresses both. antidepressants [TCAs]) Wakefulness completed November 2019, Narcolepsy is caused by impaired production of hypocretin, Nonamphetamine stimulants Quality of life top-line data reported an excitatory neuropeptide that regulates the sleep-wake (eg, armodafinil, modafinil) December 2019 cycle. About 60% to 70% of patients with narcolepsy also Note(s): More than 40 experience cataplexy, a disorder characterized by sudden, Solriamfetol countries outside of the uncontrollable muscle weakness or paralysis that occurs United States have approved during the daytime and is often triggered by a strong reboxetine to treat major emotion, such as crying, excitement, or laughter. Reboxetine depressive disorder (MDD) purportedly promotes wakefulness and increases the activity of the excitatory neurotransmitter norepinephrine. In clinical trials, patients receive an unspecified dose of reboxetine orally 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)

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, which is active at sites Pirfenidone Exercise capacity Drug, Breakthrough Therapy pulmonary fibrosis (IPF) of tissue damage and has demonstrated broad antifibrotic Survival Clinical trial(s): Phase 2 activity in preclinical models. Unlike available therapies for Quality of life primary completion May 2018, IPF that slow only the rate of disease progression, RG6354 is data published June 2018, an agonist (ie, activator) that purportedly reverses IPF data published May 2019 pathology. RG6354 purportedly turns off the proliferation pathway mediated by proinflammatory and profibrotic macrophages that leads to 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): Promedior, Inc (Lexington, Massachusetts), part of F Hoffman-La Roche AG (Basel, Switzerland)

Section 5. Rare Diseases 236 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adults who have stage 2 or 3 RGN-259 is a sterile and preservative-free eye drop form of Antibiotic eye drops Visual acuity FDA designation(s): Orphan neurotrophic keratopathy in thymosin beta 4 (Tβ4), a naturally occurring regenerative Bandage contact lenses Corneal sensitivity Drug at least one eye peptide. RGN-259 is intended to treat neurotrophic keratitis Cenegermin eye drops Quality of life Clinical trial(s): Phase 3 SEER-1 (NK), a rare degenerative disease of the corneal epithelium Surgery completed March 2020, data that has no effective treatments. NK is characterized by reported May 2020 decreased corneal sensitivity and poor corneal wound healing, which makes the cornea sensitive to injury and decreases reflex tear production. RGN-259 purportedly promotes cell migration and laminin-5 production, reducing both cell death and inflammation in 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)

Section 5. Rare Diseases 237

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

Males aged 4 months to 5 RGX-121 is a recombinant, adeno-associated viral vector (ie, Supportive care Cognitive, behavioral, FDA designation(s): Orphan years who have Hunter AAV9) carrying the human iduronate-2-sulfatase gene, IDS. It and adaptive function, Drug, Fast Track, Rare syndrome (also called is intended to treat Hunter syndrome. This childhood-onset, as measured by Pediatric Disease mucopolysaccharidosis type II progressive, inherited metabolic disorder is caused by a accepted MPSII-specific Clinical trial(s): Phase 1/2 RGX- [MPSII]) mutation in IDS. Patients with the disorder cannot break clinical ratings and 121-101 primary completion down the polysaccharides dermatan sulfate and heparan scales December 2020, interim data sulfate, which is normally mediated by the IDS-encoded Quality of life reported December 2019 enzyme iduronate-2-sulfatase. Buildup of dermatan sulfate and 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. 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 238

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 (BTK) prednisone) Morbidity Drug chronic, or relapsing that is intended as an ongoing therapy to reduce the number Immunosuppressants (eg, Death Clinical trial(s): Pivotal phase 3 moderate to severe of skin lesions in moderate to severe PV and PF. azathioprine, Pain PEGASUS primary completion pemphigus vulgaris (PV) or Complications with current treatments can be life cyclophosphamide, December 2021; phase 2 Quality of life pemphigus foliaceus (PF) threatening, and rilzabrutinib might induce complete disease mycophenolate) completed December 2019, remission and reduce steroid and immunosuppressant use. Monoclonal antibody (ie, part A data reported October Pemphigus is an autoimmune blistering skin disorder that rituximab) 2019, part B data reported most often occurs in middle-aged adults. PV and PF are the 2 June 2020 most common types. PV 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 (South San Francisco, California)

Section 5. Rare Diseases 239 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

Section 5. Rare Diseases 240

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

Infants and children who have RVT-802 is an allogeneic (ie, unmatched) donor thymus– Hematopoietic stem cell T-cell proliferation Submission date: FDA primary immune deficiency derived, cell-based therapy intended to restore immune transplantation (HSCT) Survival accepted Rolling Biologics from congenital athymia (ie, function in patients with primary immune deficiencies from Supportive care License Application June 2019; lack of a thymus), which congenital athymia, which includes complete DiGeorge Priority Review includes complete DiGeorge genetic anomaly, CHARGE syndrome, and FOXN1 deficiency. FDA designation(s): Orphan genetic anomaly; coloboma, Patients with congenital athymia have a high risk of death Drug, Rare Pediatric Disease, heart defects, atresia choanae, (often by 24 months of age) due to chromosomal mutations Breakthrough Therapy, retarded growth and that disrupt T-cell production. The absence of functional Regenerative Medicine development, genital mature T cells or B cells severely compromises immunity. Advanced Therapy hypoplasia, and ear RVT-802 is intended to restore the patient’s ability to Clinical trial(s): Phase 2 abnormalities and deafness produce naïve T cells with a broad T-cell receptor repertoire, completed April 2009; phase 2 (CHARGE) syndrome; and conferring effective immune responses. Isolated thymocytes completed November 2010 Forkhead Box N1 (FOXN1) are cultured in a manufacturing facility for 14 to 21 days. In Note(s): FDA declined to deficiency clinical trials, RVT-802 is given by placing a cultured thymus approve RVT-802 because of slice into a small hole in the quadriceps muscle, which is then manufacturing concerns on pulled over the slice using an insoluble stitch. The dose is 4 December 5, 2019, but on to 18 g/m2 of thymus tissue per patient body weight in December 27, 2019, the kilograms. original developer completed Developer(s): a strategic alliance with Sumitovant Biopharma, Ltd (London, United Kingdom), a Sumitomo Dainippon that subsidiary of Sumitomo Dainippon Pharma Co (Osaka, Japan) might help address the manufacturing concerns

Section 5. Rare Diseases 241 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 peroxisome Obeticholic acid Overall survival FDA designation(s): Orphan who have primary biliary proliferator-activated receptor delta (PPARδ) agonist (ie, Rate of progression to Drug, Breakthrough Therapy cholangitis (PBC) that activator) in development for treating PBC. An autoimmune liver failure Clinical trial(s): Phase 3 responded inadequately to disease, PBC damages the liver’s bile ducts, causing bile to Symptom relief (eg, ENHANCE primary completion ursodeoxycholic acid (UDCA) accumulate in the liver and leading to irreversible liver diarrhea due to fat December 2020, data reported treatment or who could not scarring and potential liver failure. Seladelpar is intended to malabsorption, fatigue, August 2020; phase 2/3 tolerate it provide a safer alternative to obeticholic acid (Ocaliva) for itching) primary completion December treating PBC in patients for whom initial therapy with UDCA Quality of life 2020 is inadequate or who cannot tolerate it. Seladelpar Note(s): On November 25, purportedly has anticholestatic and anti-inflammatory effects 2019, CymaBay Therapeutics that might reduce itching (ie, pruritus), inflammation, and suspended clinical trials for all destruction of the intrahepatic bile ducts. In a phase 3 clinical indications and halted trial, seladelpar is taken as a 5- or 10-mg tablet once daily for seladelpar development after 52 weeks. identifying abnormal liver Developer(s): findings in some trials. CymaBay Therapeutics (Newark, California) However, the company 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 242 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 8 years or older Sepofarsen (QR-110) is a first-in-class investigational RNA- Supportive care Visual acuity FDA designation(s): Orphan and adults who have Leber based oligonucleotide that targets homozygous or Mobility course Drug, Fast Track, Rare congenital amaurosis 10 compound heterozygous mutations due to aberrant splicing Full-field light sensitivity Pediatric Disease (LCA10) of centrosome protein 290 (CEP290) messenger RNA Quality of life Clinical trial(s): Phase 2/3 (mRNA). This aberration causes LCA10, the leading genetic ILLUMINATE primary cause of childhood blindness. Sepofarsen is intended to completion December 2020 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 243 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 6 years or older Setmelanotide (RM-493) is a selective melanocortin-4 (MC4) Lifestyle modifications (eg, Hunger symptoms and PDUFA date: November 27, and adults who have receptor agonist (ie, activator) peptide intended to treat diet, exercise) severity 2020; Priority Review proopiomelanocortin (POMC) patients with POMC deficiency obesity. This is a rare, Psychotherapy (eg, cognitive Rate of comorbidities FDA designation(s): Orphan deficiency genetic obesity recessive, genetic disorder in which patients are often behavioral therapy [CBT]) (eg, cardiovascular Drug, Breakthrough Therapy, severely obese by 1 year of age, remain obese for life, and disease, diabetes Rare Pediatric Disease experience a variety of obesity-related complications. mellitus, obesity) Clinical trial(s): Phase 2/3 Setmelanotide might improve patient quality of life and Weight primary completion July 2020, health outcomes by reducing insatiable hunger, obesity, and Quality of life top-line data reported August obesity-related complications. POMC deficiency obesity is 2019, additional data (body POMC, caused by variants in the proopiomelanocortin gene, mass index [BMI] and that result in insufficient production of adrenocorticotropic cardiovascular) reported hormone (ACTH), alpha-melanocyte stimulating hormone (α- November 2019; phase 2/3 MSH), and beta-melanocyte stimulating hormone (β-MSH). primary completion May 2021; Normally, α-MSH and β-MSH bind to MC4 receptors in the phase 2/3 long-term brain and help suppress appetite. A lack of α-MSH and β- extension trial primary MSH in patients with POMC deficiency is thought to lead to completion March 2023 excessive 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. In clinical trials, setmelanotide is given as an injection underneath the skin at an unspecified dose, once daily. Developer(s): Rhythm Pharmaceuticals, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 244 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Males aged 4 to 17 years who SGT-001 is an adeno-associated viral vector (ie, AAV9) Corticosteroids (eg, Microdystrophin protein FDA designation(s): Orphan have genetically confirmed containing a synthetic version of the dystrophin gene, DMD. deflazacort, prednisone) production Drug, Fast Track, Rare Duchenne muscular It is intended to treat DMD, an inherited, X chromosome– Pediatric Disease dystrophy (DMD), are on a linked genetic disorder caused by rearrangements or Clinical trial(s): Phase 1/2 stable dose of corticosteroids, deletions in the DMD gene. DMD encodes the dystrophin IGNITE DMD primary and have levels of anti-AAV9 protein, which helps keep muscle cells intact. The absence of completion March 2023 (see antibodies below a specified wild-type dystrophin protein causes progressive muscle fiber note), interim data presented threshold death and eventual widespread muscle weakness. No cure May 2020 exists for DMD. First-line corticosteroid treatment manages Note(s): FDA placed a clinical symptoms but does not prevent disease progression and has hold on the IGNITE DMD trial significant side effects. FDA approved 2 gene therapies for in November 2019. The DMD patients who have a specific mutation in (ie, in exon 51 developer announced in July DMD or exon 53), but patients who have other mutations are 2020 after several DMD ineligible for these therapies. The synthetic gene in communications with FDA SGT-001 encodes for microdystrophin, a truncated but that the trial is still on hold. 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 245 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 recombinant, Exercise 100-meter timed walk FDA designation(s): Orphan who have genetically adeno-associated viral vector carrying the human Physical therapy test Drug, Rare Pediatric Disease SGCB confirmed, early symptomatic sarcoglycan beta gene, . It is intended to treat LGMD2E Supportive care Mobility Clinical trial(s): Phase 1/2 limb-girdle muscular (also called β-sarcoglycanopathy), a progressive, inherited Muscle strength IRB17-00253 primary dystrophy type 2E (LGMD2E) neuromuscular disorder caused by a mutation in SGCB. The Quality of life completion December 2020, gene normally encodes the protein β-sarcoglycan, which is data reported June 2020 part of a complex involved in muscle function, regulation, and repair. Without β-sarcoglycan function, these patients develop weakness and atrophy of muscles connected to the limb girdles (ie, bony structures in the shoulder and pelvis). Early symptoms include difficulty running, jumping, and climbing stairs, but as the disease progresses, patients typically depend on wheelchairs and develop more severe symptoms, such as scoliosis, joint contractures, 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 246 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

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

Adults who have moderate to -trbw (Tepezza) is a fully human monoclonal Corticosteroids Vision Approval date: January 21, severe active thyroid eye antibody specific for insulinlike growth factor 1 receptor (IGF- Orbital decompression Light sensitivity 2020 disease (TED) 1R) intended to treat TED. It is approved by FDA. TED is a rare surgery Quality of life FDA designation(s): Orphan autoimmune condition in which inflammation and increased Drug, Breakthrough Therapy, volume of muscles and fatty tissues behind the eye cause the Fast Track eyes to be pushed forward and bulge outward. IGF-1R plays Clinical trial(s): Phase 3 OPTIC a central role in TED pathogenesis, promoting the structural completed February 2019, changes driving the disease. Teprotumumab-trbw inhibition data published January 2020; of IGF-1R-mediated signaling might provide a noninvasive phase 3 OPTIC-X extension alternative to surgical treatment for patients with TED. The primary completion recommended dosage in the FDA-approved label is 10 September 2020, top-line data mg/kg for the first dose and 20 mg/kg thereafter given reported July 2020; phase 2 intravenously over 60 to 90 minutes, every 3 weeks over 21 RV001 primary completion weeks for a total of 8 infusions. March 2016, data published Developer(s): May 2017 Horizon Therapeutics plc (Dublin, Ireland)

Section 5. Rare Diseases 247 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 the Glucocorticoids (eg, Disease progression FDA designation(s): Orphan adrenal hyperplasia (CAH) corticotropin-releasing factor type 1 (CRF1) receptor. It might dexamethasone, Measures of disease Drug due to 21-hydroxylase help improve health outcomes in patients who have CAH by hydrocortisone, prednisone) severity (eg, serum Clinical trial(s): Phase 2 deficiency reducing symptoms associated with adrenal enlargement and levels of 17- primary completion December excessive androgen production and reducing chronic hydroxyprogesterone, 2021; phase 2 completed May treatment with high-dose steroids. CAH is a group of genetic androstenedione, and 2019, data reported March disorders characterized by abnormal hormone production in ACTH) 2019; phase 2 completed the adrenal gland. Accounting for approximately 95% of Symptom severity September 2019, data cases, CAH due to 21-hydroxylase deficiency occurs when Quality of life reported September 2019 variations in the CYP21A2 gene cause a deficiency of 21- hydroxylase, an enzyme necessary for the 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 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 patients with CAH. 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 248 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Adult males who have Timrepigene emparvovec (BIIB111/AAV2-REP1) is an adeno- Low-vision aids (eg, Best corrected visual FDA designation(s): Orphan genetically confirmed associated virus serotype 2 (AAV2) vector that delivers a telescopic and magnifying acuity (BCVA) Drug, Regenerative Medicine (CHM) recombinant human CHM-associated gene. The gene lenses) Color vision Advanced Therapy encodes 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–linked Retinal sensitivity primary completion genetic retinal disorder primarily affecting males, for which November 2020 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 249 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 intended Edaravone Disability Clinical trial(s): Phase 3 VALOR amyotrophic lateral sclerosis to treat a variation in the SOD1 gene (in SOD1-ALS disease). Riluzole Disease progression primary completion July 2021; (ALS) and a confirmed It does this by lowering the level of abnormal SOD1 protein Supportive care Functional capacity phase 3 extension study variation of the superoxide that is thought to cause motor neuron death and contribute primary completion June 2023 Survival dismutase 1 gene, SOD1 to ALS pathology. 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. While 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 250 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 the Supportive care (eg, Symptom frequency and FDA designation(s): Orphan who have genetically amino‐terminal tripeptide of insulinlike growth factor 1 (IGF- anticonvulsants; assistive severity Drug, Fast Track, Rare confirmed Rett syndrome 1) intended to treat Rett syndrome. A rare, postnatal, devices; noninvasive Motor function Pediatric Disease progressive neurologic disorder, Rett syndrome is caused by ventilation; nutritional Quality of life Clinical trial(s): Phase 3 a mutation in the methyl CpG binding protein 2 gene, support; oxygen treatment; LAVENDER primary MECP2. Located on the X chromosome, MECP2 encodes the physical, occupational, and completion September 2021; MeCP2 protein that normally mediates gene expression in speech/language therapy) phase 3 LILAC open-label neuronal and glial cells. Loss of MeCP2 function results in extension primary completion nerve cell dysfunction, which is thought to be reversible. October 2022; phase 2 Rett- Patients with Rett syndrome develop normally until 6 to 18 001 completed September months of age and subsequently experience developmental 2014, data published delays and regression of previously learned motor and verbal November 2017; phase 2 Rett- skills. The disease eventually causes additional symptoms, 002 completed January 2017, such as repeated hand movements, impaired gait, slowed data published April 2019 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 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 251 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 severity Clinical trial(s): Phase 3 who have genetically prodrug conjugate of riluzole being developed to treat therapy Activities of daily living primary completion October confirmed spinocerebellar certain autosomal-dominant (ie, inherited) types of SCA. A Supportive care Daily functioning 2020; phase 2/3 primary ataxia (SCA) type 1, 2, 3, 6, 7, progressive neurodegenerative disease, SCA is generally Use of assistive devices capacity completion August 2017, 8, or 10 characterized by loss of balance and motor coordination, preliminary post hoc data Quality of life abnormal speech, vision problems, and cognitive impairment. released March 2019 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 252 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Male adults who have Valoctocogene roxaparvovec (BMN 270), also known as Emicizumab-kxwh Bleeding episodes PDUFA date: August 21, 2020; hemophilia A and residual valrox, is an adeno-associated virus vector gene therapy Factor VIII replacement Treatment-related Priority Review factor VIII levels of 1 IU/dL or intended to cure hemophilia A. It is intended to eliminate or (human plasma–derived or adverse events FDA designation(s): Orphan lower despite stable factor VIII reduce the need for repeated treatments with factor VIII recombinant, porcine Survival Drug, Breakthrough Therapy replacement therapy replacement or emicizumab-kxwh. Valoctocogene recombinant) Quality of life Clinical trial(s): Phase 3 roxaparvovec purportedly delivers a functional copy of the primary completion December gene encoding for coagulation factor VIII to correct deficient 2022; phase 3 GENEr8-1 factor VIII levels inherent in hemophilia A. In clinical trials, the primary completion December 13 agent is given as an intravenous infusion at a dose of 1 × 4 2022; phase 3 GENEr8-3 13 to 1 × 6 vg/kg, once. primary completion December Developer(s): 2021; phase 1/2 primary BioMarin Pharmaceutical, Inc (San Rafael, California) completion March 2024, preliminary data published December 2017, long-term data published January 2020; phase 1/2 in patients with AAV5 antibodies primary completion June 2025 Note(s): On August 18, 2020, FDA issued a Complete Response Letter making a new recommendation for 2-year data from the ongoing 270- 301 phase 3 trial to provide more evidence on annualized bleeding rate as the primary end point

Section 5. Rare Diseases 253 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Children aged 5 years or older Vosoritide (BMN 111) is a recombinant C-type natriuretic Human growth hormone Health complications Submission date: New Drug and adults who have peptide analogue intended to treat achondroplasia by Limb-lengthening surgery Quality of life Application planned for third achondroplasia promoting long-bone growth. Achondroplasia, the most quarter of 2020 common form of human dwarfism, is a genetic disorder that FDA designation(s): Orphan results in irregular bone growth, short stature, and serious Drug health complications, including extra fluid in the brain and Clinical trial(s): Phase 2 compression of the spinal cord. Less severe complications, completed October 2017; but nonetheless limiting, include bowed legs, recurrent ear phase 2 primary completion infections, and sleep apnea. Vosoritide might lessen October 2022, height data achondroplasia’s health impacts by allowing normal reported November 2019; conversion of cartilage into bone at growth plates as a child unphased primary completion ages. Achondroplasia results from a defect in the fibroblast October 2024; pooled phase 2 FGFR3 . growth factor receptor 3 gene, The defect promotes and unphased data published overactivity of negative regulators of bone growth. Vosoritide July 2019; phase 3 completed purportedly interrupts intracellular pathways that contribute October 2019, data reported to the overactivity. In clinical trials, vosoritide is given as a December 2019; phase 3 daily injection under the skin at a dose of 15 mg/kg. primary completion October Developer(s): 2024 BioMarin Pharmaceutical, Inc (Novato, California)

Section 5. Rare Diseases 254 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 12 years or Voxelotor (Oxbryta, GBT440) is intended as a disease- Blood transfusions Opioid use for pain Approval date: November 25, older who have sickle cell modifying agent to treat SCD. Some other recently Crizanlizumab-tmca management 2019 disease (SCD) developed drugs may target SCD’s root cause , but they do Hematopoietic stem cell Frequency of VOCs FDA designation(s): Orphan not work in all patients and have side effects that many transplantation (HSCT) Number of blood Drug, Rare Pediatric Disease, patients cannot tolerate. In SCD, sickled red blood cells are Hydroxyurea transfusions required Breakthrough Therapy, Fast more susceptible to oxidative damage, inappropriate Hospitalized days Track clumping, and vessel blockage, leading to vaso-occlusive Pharmaceutical-grade L- glutamine Quality of life Clinical trial(s): Phase 3 GBT crises (VOCs) that cause severe pain, requiring HOPE completed October hospitalization. Approved by FDA, voxelotor purportedly 2019, pivotal data published binds mutated hemoglobin and prevents it from sickling and August 2019, post hoc data aggregating, increasing native hemoglobin’s affinity for reported November 2019; oxygen. Because oxygenated sickled hemoglobin does not phase 3 extension primary polymerize, voxelotor purportedly reduces polymerization completion October 2024 and the resultant sickling and destruction of red blood cells. With the potential to improve hemolytic anemia and oxygen delivery, voxelotor might modify the underlying SCD disease process rather than merely decrease symptoms. The recommended dosage in the FDA-approved label is 1500 mg (three 500-mg tablets) taken once daily. Developer(s): Global Blood Therapeutics, Inc (South San Francisco, California)

Section 5. Rare Diseases 255 Potential patient Intervention description Potential comparators Patient-oriented Regulatory information population Developer(s)/manufacturer(s) outcome measures

Patients aged 3 to 18 years Zygel (ZYN002) is a laboratory-manufactured, transdermal Behavior-stabilizing Aggression symptoms FDA designation(s): Orphan who have genetically gel formulation of cannabidiol (CBD) intended to treat medications (eg, alpha-2 and severity Drug, Fast Track confirmed fragile X syndrome behavioral symptoms of FXS, a rare, noninherited, X agonists, anticonvulsants, Anxiety symptoms and Clinical trial(s): Phase 2/3 (FXS) and moderate to severe chromosome–linked neurodevelopmental disorder. In antidepressants, beta- severity CONNECT-FX completed June behavioral symptoms patients with FXS, loss of the protein Fmrp function blockers) Hyperactivity symptoms 2020, data reported June purportedly disrupts protein translation, synaptic plasticity, Plant-derived oral CBD and severity 2020; phase 2/3 open-label and intracellular signaling, leading to development of autism- Irritability symptoms extension primary completion like symptoms, including anxiety, irritability, aggression, and severity February 2022 hyperactivity, and restricted and repetitive behaviors. Some Note(s): Plans for marketing patients also experience seizures. The endocannabinoid Repetitive behavior symptoms and severity submission are on hold until system, which regulates cellular homeostasis, is also the company meets with FDA disrupted in patients with FXS. These patients often take to establish a regulatory path behavior-stabilizing medications, which cause significant side forward in light of trial results effects. Patients may also take oral, plant-derived CBD, but that did not meet end points, oral bioavailability of the drug is low (about 6%), and oral but a preplanned ad hoc CBD administration is associated with liver impairment, analysis of the most severely nausea, diarrhea, and changes in appetite. Transdermal affected patients showed delivery of Zygel purportedly allows CBD delivery to the improvement bloodstream, which increases bioavailability and decreases side effects associated with taking oral CBD. In clinical trials, patients or caregivers apply Zygel to the skin of the upper arms or shoulders, at a weight-based dose of 250 mg (one 125-mg sachet applied every 12 hours) or 500 mg (two 125- mg sachets applied every 12 hours) for up to 52 weeks. Developer(s): Zynerba Pharmaceuticals, Inc (Devon, Pennsylvania)

Section 5. Rare Diseases 256 Table 5.3. Rare Diseases Topics Archived Since Last Status Report: 6 Topics

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

Adults who have oral ulcers Apremilast (Otezla) is a small-molecule, anti-inflammatory Corticosteroids Pain, frequency, or FDA approved apremilast July associated with Behçet oral drug that inhibits phosphodiesterase type 4 (PDE4 ). Immunosuppressants (eg, duration of oral ulcers 19, 2019, to treat Behçet disease Behçet disease is a rare disease caused by blood vessel azathioprine, cyclosporine) from baseline disease. Because it has been inflammation that can cause skin symptoms, including oral Nonsteroidal anti- Disease progression clinically available for more ulcers, for which few effective treatment options (ie, inflammatory drugs Quality of life than 1 year, it is no longer immunosuppressant therapy) exist. Investigators have linked (NSAIDs) within the time scope for the Behçet disease to overactive T helper 17 (Th17) cells and PCORI Health Care Horizon increased interleukin-17 (IL-17) production. Approved by Scanning System. The time FDA, apremilast’s PDE4 inhibitory activity purportedly scope is defined as 3 years increases cyclic adenosine monophosphate in immune cells. before an intervention This decreases production of proinflammatory mediators, becomes clinically available such as tumor necrosis factor-α, IL-17, and IL-23, which outside of the research setting purportedly alleviates blood vessel inflammation and to 1 year after an intervention symptoms. The FDA-approved label recommends a 5-day becomes clinically available. titration period of an initial oral dose of 10 mg on day 1, gradually increased by day 5 to 20 mg in the morning and 30 mg in the evening. Thereafter, the maintenance dosage is 60 mg daily (30 mg in morning and 30 mg in evening). This titration is intended to reduce the gastrointestinal (GI) symptoms associated with initial therapy. Developer(s): Celgene Corp (Summit, New Jersey), a subsidiary of Bristol Myers Squibb Co (New York, New York)

Section 5. Rare Diseases 257 Potential patient Intervention description Potential comparators Patient-oriented Archive reason population Developer(s)/manufacturer(s) outcome measures

Adults who have Eculizumab (Soliris) is an FDA-approved recombinant Azathioprine Functional impairments FDA approved eculizumab to neuromyelitis optica spectrum humanized monoclonal antibody that binds with high affinity Hematopoietic stem cell (eg, vision, mobility, and treat NMOSD in June 2019. disorder (NMOSD) and who to the complement protein C5 (ie, a soluble component of transplantation (HSCT) bowel or bladder Because it has been clinically test positive for anti- the innate immune system). Eculizumab is intended to relieve Intravenous incontinence) change from available for more than 1 year, aquaporin-4 (AQP4) the autoimmune and neurodegenerative symptoms and corticosteroids baseline it is no longer within the time antibodies pathology of neuromyelitis optica by binding C5 and scope for the PCORI Health Mycophenolate mofetil Incidence of relapse from inhibiting its cleavage to C5a and C5b. This action prevents baseline Care Horizon Scanning Plasmapheresis the downstream formation and activation of the cell-lysing Quality of life change from System. The time scope is Rituximab terminal complement complex C5b-9, which damages cell baseline defined as 3 years before an membranes targeted with the complexes. C5b-9 complex Thymus transplantation intervention becomes clinically production is thought to directly drive the uncontrolled (donor matched) available outside of the complement activation that promotes some autoimmune research setting to 1 year after reactions. The FDA-approved label recommends 900 mg an intervention becomes weekly for the first 4 weeks, followed by 1200 mg for the fifth clinically available. dose 1 week later, and 1200 mg every 2 weeks thereafter. Developer(s): Alexion Pharmaceuticals, Inc (Boston, Massachusetts)

Adults who have episodic Galcanezumab-gnlm (Emgality) is a humanized monoclonal Corticosteroids Weekly cluster headache FDA approved galcanezumab cluster headache antibody against calcitonin gene–related peptide (CGRP) Topiramate (off-label) frequency (Emgality) to treat episodic intended to treat episodic cluster headache. Galcanezumab- Verapamil (off-label) Cluster headache severity, cluster headache in June 2019. gnlm is the first biologic approved by FDA to treat these as measured by accepted Because it has been clinically headaches. CGRP is a neuropeptide thought to contribute to clinical ratings and scales available for more than 1 year, pain signaling of the trigeminal sensory nerve, leading to it is no longer within the time headache development. Galcanezumab purportedly prevents scope for the PCORI Health CGRP from binding to its receptor, which might reduce Care Horizon Scanning cluster headache frequency. The FDA-approved label states System. The time scope is the recommended dosage is 300 mg (3 consecutive under- defined as 3 years before an the-skin injections of 100 mg each that patients take intervention becomes clinically themselves) at the onset of the cluster period, and then available outside of the monthly until the end of the cluster period. A missed dose research setting to 1 year after during a cluster period is recommended to be taken as soon an intervention becomes as possible. clinically available. Developer(s): Eli Lilly and Co (Indianapolis, Indiana)

Section 5. Rare Diseases 258

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

Adults who have genetically jCell is an allogeneic (ie, unrelated donor) stem cell therapy Supportive care Best corrected visual The company plans to initiate confirmed retinitis that uses human retinal progenitor cells that have been Vitamin and nutritional acuity (BCVA) a pivotal study in 2021, pigmentosa (RP) cultured and expanded. No effective treatments are available supplementation Retinal sensitivity suggesting the clinical for RP, so jCell could be the first nonsurgical therapy for the Peripheral vision availability will be out of the disease. It is intended to delay RP progression or reverse time scope for the PCORI Recovery time vision loss through the release of neurotrophic factors that Health Care Horizon Scanning might rescue diseased retinal cells and possibly differentiate Quality of life System. The time scope is into new rod cells in the retina. In clinical trials, jCell has been defined as 3 years before an given as 3 × 106 or 6 × 106 human retinal progenitor cells intervention becomes clinically suspended in medium. It is injected intravitreally under local available outside of the anesthesia into the eye with the poorest visual acuity or, if research setting to 1 year after vision is comparable in both eyes, the nondominant eye. an intervention becomes Developer(s): clinically available. jCyte, Inc (Newport Beach, California), in collaboration with California Institute of Regenerative Medicine (Oakland, California)

Section 5. Rare Diseases 259

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

Adults who have systemic Nintedanib (Ofev) is an oral kinase inhibitor and antifibrotic Azathioprine Breathing function FDA approved nintedanib to sclerosis–associated drug approved by FDA to treat SSc-ILD. Patients with Cyclophosphamide Disease progression treat SSc-ILD in September interstitial lung disease (SSc- systemic sclerosis, also known as scleroderma, have Mycophenolate mofetil Survival 2019. Because it has been ILD) thickening and scarring of connective tissue in multiple clinically available for more Rituximab Quality of life organs. Most develop interstitial lung disease (ILD), which is than 1 year, it is no longer the leading cause of death in these patients. No cure exists Supportive care within the time scope for the for SSc-ILD, and before Ofev’s approval, available treatments PCORI Health Care Horizon only managed symptoms and did not prevent disease Scanning System. The time progression. Nintedanib purportedly binds to and blocks scope is defined as 3 years intracellular signaling of the following receptor tyrosine before an intervention kinases (RTKs): platelet-derived growth factor receptor alpha becomes clinically available and beta (PDGFRA and PDGFRB); fibroblast growth factor outside of the research setting receptor 1, 2, and 3 (FGFR1, FGFR2, FGFR3 ); and vascular to 1 year after an intervention endothelial growth factor receptor 1, 2, and 3 (VEGFR1, becomes clinically available. VEGFR2, VEGFR3). These RTKs are thought to contribute to lung tissue fibrosis in both ILD and a related condition, idiopathic pulmonary fibrosis. The FDA-approved label states the drug is indicated to slow “the rate of decline in pulmonary function in patients with SSc-ILD.” The recommended dosage is 150-mg capsules taken twice daily with food, about 12 hours apart. Developer(s): Boehringer Ingelheim Pharmaceuticals, Inc (Ridgefield, Connecticut)

Section 5. Rare Diseases 260

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

Adults who have ocular graft- OCU300 is a proprietary nanoemulsion of brimonidine Dry eye treatment for Bulbar redness In June 2020, Ocugen versus-host disease (oGVHD) tartrate eye drop solution intended to treat oGVHD. No FDA- symptom management Dry eye symptoms announced its decision to stop approved treatments exist for oGVHD, and patients are (off-label) Ocular discomfort the OCU300 phase 3 trial sometimes given off-label dry eye treatment to manage (NCT03591874) because of Light sensitivity symptoms. A debilitating immune disorder, oGVHD is a poor results in the interim frequent complication of allogeneic bone marrow transplants Quality of life sample size analysis. and affects the ocular surface and tear-producing glands. OCU300 purportedly has an anti-inflammatory effect on the eye surface and mediates vasoconstriction, resulting in relief from dry eyes, eye pain, severe light sensitivity, and other clinical presentations of oGVHD. The nanoemulsion formulation of OCU300 purportedly prolongs retention of the agent on the eye surface. In clinical trials, OCU300 is given by eye drop at a dosage of 0.18% twice daily for 12 weeks. Developer(s): Ocugen, Inc (Malvern, Pennsylvania)

Section 5. Rare Diseases 261 ` Section 6. Potentially Disruptive Trends: 37 Trends

Table 6.1. Trends Added Since Last Status Report: 6 Trends

Title Description Threats Opportunities

Artificial intelligence AI is being harnessed to screen millions of small molecules with diverse chemical Might trigger litigation due to Might decrease the time and costs (AI)–based drug structures and identify compounds that are predicted to selectively bind to the convoluted intellectual property required in the early stages of drug discovery target protein. This would increase efficiency in the drug discovery process by rights related to AI-based drug development generating novel drug candidates, validating and optimizing drug candidates, discovery Might help discover novel and designing preclinical experiments. For example, Cloud Pharmaceuticals, Inc Might not predict adverse events treatments that would improve (Durham, North Carolina), uses molecular modeling to identify biomarkers, patient health outcomes 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) Results from the STAR*D trial suggest that fewer than half of patients who have Might increase health disparities Might improve patient health to predict major depressive disorder (MDD) achieve remission with use of a first-line because access to ML algorithms outcomes by finding successful antidepressant antidepressant medication. This might be because MDD is a biologically varied and necessary brain imaging treatment sooner and protecting treatment response mental health condition that has demonstrated distinct neurophysiological modalities might be prohibitive to against patient discouragement with subtypes. Researchers are investigating whether AI could be used to predict a many patients due to large scale of treatment or treatment patient’s response to an antidepressant medication, particularly when applied to depression and socioeconomic discontinuation electroencephalography (EEG) results. One study developed an EEG computation barriers, and not all psychiatrists and Might decrease health care costs model to predict treatment outcomes with sertraline, to lay the groundwork for health care providers are likely to be associated with trying several machine learning (ML) approaches. The researchers found that participants who trained on and using this technology medications before finding a were unlikely to respond to treatment with sertraline were more likely to Might be cost prohibitive to undergo successful option respond to treatment with transcranial magnetic stimulation (TMS). A study such evaluation Might change the current paradigm investigating the application of ML to EEG to predict treatment response to of depression treatment to be more escitalopram found a prediction accuracy of 79.2% off baseline EEG data. personalized Might improve understanding of depression treatment

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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 treat rapidly seek and destroy infected and transformed cells. NK cells could be responses because of immune outcomes by targeting and clearing 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 proteins on cancer cells Might allow the use of donor cells the cell surface. Second, they induce controlled immune responses that reduce Might trigger dangerous runaway instead of relying only on the risk of cytokine storms or graft-versus-host disease (GVHD). In addition, these immune responses in the host patient’s cells NK cells can be collected from a variety of sources without relying on patient- Might be an effective approach to specific immune cells. Compared with T cells and B cells, NK cells have limited treat both blood and solid-tumor proliferation capability but can undergo robust expansion in a laboratory. With a cancers sufficient number of cells after expansion, NK cells purportedly promote sustained immune responses to attack and clear cancer cells. Multiple companies (eg, Asclepius Technology, Dragonfly Therapeutics, Ivy Life Sciences, Nkarta Therapeutics, Takeda Pharmaceutical Company, in collaboration with MD Anderson Cancer Center) are investigating NK cell-based therapies to treat cancer.

T-cell redirecting Bispecific antibodies are antibody-based biologic drugs with binding domains Might increase cost of treating Might improve patient health bispecific antibodies for specific for 2 distinct epitopes. One type of bispecific antibody being studied for various cancers, potentially outcomes by providing a novel treating cancer treating cancer is T-cell redirecting bispecific antibodies (TRBAs), which exacerbating existing disparities mechanism of action for treating incorporate a binding domain for a T cell–specific antigen (eg, CD3, CD28) and a based on socioeconomic status cancers tumor-associated antigen (TAA). By bringing T cells and tumor cells into close Might carry the potential for severe Might provide an off-the-shelf proximity, TRBAs purportedly lead to T-cell activation and proliferation and immune-related adverse events alternative for T-cell recruitment to tumor cell death. The first TRBA approved in the United States was the tumor cells, rather than approaches CD3/CD19 bispecific (Blincyto, Amgen, Thousand Oaks, like chimeric antigen receptor (CAR) California), which was approved in 2014 for treating relapsed or refractory B-cell T-cell therapy precursor acute lymphoblastic leukemia (ALL). Since that time, a large number of clinical trials have been initiated on more than 50 additional TRBAs. Most investigational TRBAs are being studied for treating hematologic malignancies, including acute myeloid leukemia (AML), by targeting CD33 or CD123, multiple myeloma by targeting B-cell maturation antigen, and non-Hodgkin lymphoma by targeting CD20. TRBAs are also being studied as treatments for solid tumors such as breast cancer by targeting HER2 and prostate cancer by targeting PSMA or STEAP1.

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Telemedicine stations Improving patient safety and health equity have been key aims for the US health Might increase privacy and security Might allow clinicians to accurately for remote disease care system. HIPAA-compliant telemedicine stations could address these by concerns for users diagnose various conditions diagnosis, treatment, allowing real-time consultations with a clinician and dispensing prescribed Might increase drug safety concerns remotely and monitoring medications to patients. For example, OnMed (Clearwater, Florida) stations not due to malfunctioning of the Might increase access to health only offer high-definition video and audio capabilities but also are equipped automated dispensing system services for patients in rural areas with medical devices patients can use to take their own vital signs and receive Might alleviate the burden on health common medications dispensed through a secure automated vault. These systems and provide continuity of stations have privacy glass and high-output ultraviolet surfaces and air care for those suffering from chronic sanitization, which purportedly eliminate pathogens after every patient visit. conditions Another telemedicine company, H4D (Paris, France), is using its Consult Station, Might reduce medication errors by a class II medical device cleared by FDA and also CE marked in the European efficient automated dispensing and Union, for detecting various diseases, including COVID-19. tracking

Tumor-specific Surgery can be the only curative option for treating several lethal malignancies. Might need further research to Might allow a more accurate and conjugated fluorescent Conventional imaging techniques, such as magnetic resonance imaging (MRI), understand the long-term impacts complete resection of tumor tissue, imaging agents to help computed tomography (CT), and ultrasound, provide only limited information to and uptake of surgery using tumor- leading to improved patient visualize cancers identify small lesions for surgery and confirm complete tumor removal after specific fluorescent agents outcomes intended for surgical surgery. Near-infrared fluorescent imaging techniques are now widely used Might increase logistical issues Might reduce costs of lengthy resection during surgeries to address this issue; however, these techniques are limited before surgery postoperative treatments 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.

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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 treat derived) CAR T-cell therapies. Although autologous CAR T-cell approaches have multiple genetic manipulations Might increase availability and/or cancer 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 T- product relative to autologous CAR T-cell cell therapy must be individually manufactured from the patient’s own cells, Might not be as active or long- therapies, potentially improving leading to high costs. Additionally, the manufacturing process introduces a delay lasting as autologous CAR T-cell patient health outcomes between cell collection and reinfusion that is poorly tolerated in patients with therapies, potentially requiring aggressive malignancies. Finally, patients eligible for autologous CAR T-cell retreatment or additional treatment therapies often have undergone multiple 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-versus-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.

Artificial intelligence (AI) Several researchers and companies have each developed AI software algorithms Might be limited to larger imaging Might improve patient health for image triage to to screen imaging scans in high volumes in hospital emergency departments or centers with more resources because outcomes if most-acute cases prioritize emergency other urgent care settings. The intent is to identify the most serious cases that of the cost and complexity of receive appropriate care sooner cases might not be apparent with traditionally recognized parameters or markers and screening systems Might improve workflow to prioritize to mark them for priority review by a radiologist. The AI algorithm pushes these Might be difficult to operationalize higher-urgency cases when cases to the front of the work queue based on identified markers learned by or maintain because many software radiologist availability is limited reviewing a multitude of images. Over time, some algorithms purportedly systems need to work together Might add a layer of protection become more accurate at screening as they review more images. Some products Might pose litigation risk for against potential litigation for missed have already received FDA 510(k) clearance for specific indications using providers who are unable to events or cases in imaging conventional x-rays, computed tomography (CT), and ultrasound, including implement these systems identification of probable fractures in the cervical spine, intracranial hemorrhage, Might be viewed by some abdominal aortic tears, and brain aneurysms. radiologists as a threat to their autonomy as clinicians

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

Artificial intelligence (AI) Cardiac ultrasound (ie, echocardiography) is widely used to diagnose heart Might increase health information Might improve outcomes by making operator guidance for conditions. However, the diagnostic quality of echocardiograms is highly technology costs and complexity diagnostic-quality echocardiograms cardiac ultrasound dependent on the operator’s ultrasound skills. New AI algorithms have been Might elevate data security risks available to more patients in lower- scans developed that purportedly allow less-experienced operators to perform through increased automation resource areas diagnostic-quality echocardiograms through real-time feedback that simulates Might increase the workload of Might allow earlier detection of heart guidance from an experienced sonographer in positioning the probe and cardiologists and demand for follow- conditions that could be effectively capturing images. The first AI-assisted echocardiography operator guidance up testing if high volumes of managed system, Caption Guidance (Caption Health, Brisbane, California), received FDA De patients are referred from primary

Novo marketing authorization on February 7, 2020. care practices

Artificial intelligence (AI) Researchers around the world are pursuing use of AI to develop precision Might raise patient privacy concerns Might improve outcomes for TBI and to identify personalized diagnostics and prognostic modeling to personalize treatment across the Might create questions about who reduce rehabilitative care burden treatment options for complete TBI spectrum, from concussion to coma. For example, researchers from owns the data Might improve quality of life for traumatic brain injury the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Might create controversy about patients with TBI (TBI) (TRACK-TBI) network are using machine learning (ML) to analyze a complex data publicly funded TBI research that Might inform research and set, including imaging, blood tests, and in-person assessments. These data, from essentially subsidizes new treatment of other neurologic 3000 patients in the TRACK-TBI study, are being used to identify patterns that proprietary TBI treatments disorders, based on TBI research eventually can be applied in a clinical setting to improve TBI outcomes. The marketed by private companies findings researchers have standardized the way that imaging, clinical data, biomarkers, and treatment outcomes are analyzed across research sites. The network will help lead clinical trials of TBI treatments in development by matching candidates to investigational interventions.

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Artificial intelligence (AI) AI algorithms that analyze cardiovascular imaging scans, electrocardiograms Might create physician resentment Might improve patient outcomes by to predict (ECGs), and other cardiovascular tests have the potential to highlight short-term regarding loss of diagnostic automatically combining multiple cardiovascular events health risks and improve predictions of patients’ cardiovascular health outcomes. autonomy data sources into cardiovascular risk and health outcomes Mayo Clinic researchers have applied AI to ECG analysis to estimate physiologic Might prompt medico-legal assessment age. The PERFORM machine learning model might predict pulmonary embolism concerns for centers that have not Might leverage existing patient data risk. AI-augmented computed tomography (CT) angiography assessment of adopted AI risk-assessment tools to improve cardiovascular risk coronary plaques might improve prediction of future cardiac events. An Artificial Might increase staff workload for assessment without requiring Intelligence–Clinical Decision Support System showed comparable accuracy to additional patient monitoring and additional testing (in some cases) heart failure (HF) specialists in reviewing patients presenting with dyspnea for follow-up examinations Might improve outcomes by possible HF. One developer offers an AI algorithm for a digital stethoscope that Might create risk of cardiovascular allowing primary providers to detect allows primary care providers to screen patients for cardiac arrhythmias (atrial disease overdiagnosis if patient data subtle arrhythmias and refer to fibrillation, murmur). Some researchers have suggested AI analysis of chest CT collected for other indications (eg, cardiologists for lung cancer screening might detect undiagnosed heart conditions. Abbott chest CT scans for lung cancer (Abbott Park, Illinois) has an AI algorithm that purportedly provides screening) are overanalyzed 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 treat Bacteriophages are viruses that infect only bacterial cells and might help treat Might add significant short-term Might lead to decreased patient bacterial infections bacterial infections. They were discovered more than a century ago but were not costs to infection treatment illness and death pursued as a treatment in the United States because of safety concerns and the Might pose a health risk for patients Might add to the body of scientific increased availability of antibiotics. However, with increasing rates of antibiotic because much is still to be learned knowledge surrounding infection resistance and better understanding of bacteriophage biology, researchers are about bacteriophage biology and its treatment now considering using bacteriophages to treat infections that are multidrug- Might eventually lead to Might reduce long-term treatment resistant or characteristically hard to treat with antibiotics. Bacteriophages are in bacteriophage resistance similar to costs by reducing the time patients clinical trials to treat primary immune deficiency disease, hyper-IgM syndrome, antibiotic resistance spend in intensive care units (ICUs) urinary tract infections, gastrointestinal tract infections, diabetic foot ulcers, leg ulcers, wound infections, Pseudomonas aeruginosa infections, and Staphylococcus aureus infections. The Center for Innovative Phage Applications and Therapeutics (IPATH; La Jolla, California) 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 The typical screening for evaluating central nervous system disorders uses Might increase disparities for some Might be less costly for patients, for neurodegenerative positron emission tomography (PET) imaging and laboratory tests of spinal fluid, who do not have access to these caregivers, and health insurers than disorders which is invasive and expensive. Biomarker analysis using a simple blood test services current brain imaging scans might provide an easier way to assess any neurologic damage to help inform Might lead to overtreatment or Might be less invasive than spinal treatment decisions. C2N Diagnostics (St Louis, Missouri), a diagnostic company, inappropriate treatment due to fluid tests, which require lumbar is measuring concentrations of biomolecules such as neurofilament light protein possible false positives in the punctures using sensitive stable isotope labeling to provide novel insights into the normal analysis Might reduce burden on the health and abnormal workings of the brain. Multiple labs are developing plasma care system due to better hospital pTau181 tests to measure tau proteins, which are higher in individuals with resource use Alzheimer’s disease than in the general population.

Calcitonin gene–related CGRP inhibitors have emerged as a novel drug class to prevent chronic and Might be difficult for some patients Might address the unmet need of peptide (CGRP) episodic migraine headaches and treat acute migraine headaches. They are to give themselves under-the-skin patients with migraine headache to inhibitors to prevent monoclonal antibodies that work by preventing CGRP, a protein found in injections of CGRP inhibitors at reduce headache frequency and and treat migraine trigeminal nerve ganglia, from binding to CGRP receptors, either by blocking the home, and there is a risk of infection severity, thus improving patient headache receptor or CGRP itself. These actions purportedly block trigeminal nerve pain and injection site reactions outcomes, overall health, and quality transmission and dilation of blood vessels thought to contribute to migraine Might be cost prohibitive to some of life headache. CGRP inhibitors are administered in subcutaneous injections at a patients and subsequently increase Might cause fewer side effects than frequency ranging from monthly to every 3 months. FDA-approved CGRP health disparities, considering CGRP currently used preventive inhibitors to prevent migraine headache include erenumab (approved May inhibitors cost about $7000 per year medications, including 2018), fremanezumab (approved September 2018), galcanezumab (approved antidepressants, antiepileptics, and September 2018), and eptinezumab (approved February 2020). Others are in antihypertensives, which might clinical development. In addition, CGRPs are in clinical development as a nasal improve patient outcomes, overall spray for the acute treatment of migraine. As monoclonal antibodies, CGRP health, and quality of life inhibitors are highly targeted against CGRP and have demonstrated a more Might improve the understanding of favorable side effect profile than traditional migraine medications, including migraine pathophysiology and antiepileptics, antidepressants, and antihypertensives. A 2018 Institute for change the standard of care Clinical and Economic Review report looking at a total of 19 trials of drugs to prevent migraine and episodic headaches found that CGRP inhibitors demonstrated greater efficacy than other preventive medications in reducing the number of headache days per month.

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Closed-loop glucose Patients with T1DM need to continually monitor and adjust their blood glucose Might pose health risks if algorithms Might improve patient quality of life monitoring (artificial levels to avoid extreme high or low levels that can cause serious immediate are not precise or can be hacked by allowing more freedom in diet, pancreas) systems for and/or long-term health problems. Glucose monitoring, historically a time- destructively physical activity, and sleep type 1 diabetes mellitus consuming, manual task, is moving toward continuous, automated systems. FDA Might increase health disparities if Might improve patient health (T1DM) approved the first “artificial pancreas” in 2016. The closed-loop system consisted the technology is cost prohibitive outcomes by minimizing periods of of a sensor underneath the skin and an insulin pump. In automated mode, the Might decrease patient knowledge harmful low or high blood glucose system measured blood glucose every 5 minutes to automatically administer or and competency of manual blood that contribute to health withhold insulin according to its measurements (insulin lowers blood glucose). glucose monitoring and insulin complications Among its limits, it did not accommodate large meals or exercise, which strongly dosing affect blood glucose levels. One study found that roughly 40% of patients stopped using the system in the first few months for reasons including difficulty keeping it in the automated mode, frequent alarms, sensor failure, need for calibration, skin adhesion issues, and sensor supply problems. 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 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.

Comprehensive CGP involves sequencing a large panel (ie, thousands) of cancer-associated Might lead to overtreatment of some Might improve health outcomes for genomic profiling (CGP) genes in DNA and/or RNA isolated from a patient’s tumor tissue or blood early-stage cancers that could patients who have limited targeted in patients who have sample. CGP is intended to detect actionable genomic alterations (AGAs) known resolve on their own therapy options cancer to identify to be therapeutic targets. Clinicians are using CGP (in both germline and somatic Might have limited availability of Might strengthen collaborations personalized targeted testing scenarios) to determine the aggressiveness and inheritable factors of insurance coverage because third- between genetic counselors and therapy cancers upon initial diagnosis (germline testing; ie, in cells without cancer). It is party payers are likely to cover CGP clinicians, promoting familiarity with used to select targeted therapies (on- or off-label) along the patient’s clinical and targeted therapies for only AGAs and identifying those that pathway (somatic testing; ie, in cells with cancer) to benefit patients with cancers specific indications and are unlikely might be drug targets that harbor AGAs. CGP also is being used to help identify patients who are to cover targeted therapies for eligible for clinical trials of investigational therapies for cancers with specific unapproved indications AGAs. Might increase disparities by being available only to patients who are insured or able to pay for treatment out of pocket

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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 data patient health data privacy targets to pursue for drug partnerships with 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 by that choose not to partner with DTC expensive identification of patients drug development and drug companies. The databases from DTC testing might also make it easier for genetic testing companies and asymptomatic carriers for clinical treatment pharmaceutical companies to identify people who have a disease, are trials asymptomatic, or are carriers for conditions of interest and recruit them for Might lead to a more efficient drug clinical trials in a cost-effective manner. For instance, genetic testing company development process for 23andMe (Sunnyvale, California) has established collaborations with personalized medicines 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 tool Might increase patient costs over the Might provide a convenient, real- screening for for neurologic disorders—such as AD—to help identify disorders years before short term to get a type of eye time screening option for patients Alzheimer’s disease clinical symptoms emerge. Images captured using ophthalmologic imaging examination that insurance might Might reduce overall long-term cost (AD) and other devices may reveal location of new blood vessels, locate fluid in or beneath the not cover of care if it aids early detection to neurologic conditions retina, or show other potential biomarkers of diseases. Eye examinations also Might lead to inaccurate diagnoses enable the start of treatment have the potential to help monitor effects of new treatments intended to halt or that could lead to poor patient reverse disease progression. During the visit, health care providers might give health outcomes 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.

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

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Integrated electronic Several products are available to collect physiologic data from cardiovascular Might generate further data security Might improve outcomes if clinicians health solutions to patients through wearables or smartphones and transfer the data to databases risks, as well as questions about who and patients can interact in a timely improve cardiovascular that clinicians can access. Most products are limited in scope (eg, blood pressure owns or controls the data and where manner and adjust care as needed care or electrocardiogram alone). Product availability and consumer marketing has to store it Might increase technical efficiencies largely outpaced clinical research on the true clinical use of these technologies in Might increase clinical staff’s compared with multiple separate cardiovascular care. Limited early data have suggested some integrated digital workload significantly if the systems that track blood pressure, health interventions introduced during hospitalizations from heart attacks might additional patient data monitoring heart rate, weight, and related health reduce 30-day readmissions and related health care costs compared with requirements are substantial statistics historical controls. The American College of Cardiology (ACC) has issued a set of Might create system compatibility principles intended to guide appropriate integration of eHealth or mobile health problems, potentially limiting technologies into cardiovascular care. ACC calls for more research of digital usefulness for effective patient health applied to cardiovascular care to ensure patient safety, care quality, and monitoring, depending on the positive health outcomes. ACC advises that these technologies should improve technology and standards involved the patient experience, care quality, patient safety, and outcomes without Might raise quality control concerns hampering clinical workflow. regarding device maintenance and data integrity Might raise concerns about who will pay for the technology upfront and for its continued maintenance and quality control Might increase disparities if the technology’s cost or complexity filters out poorer, older, or less technically minded patients

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N-of-1 trials to research N-of-1 trials focus on collecting treatment response data in a single patient and Might predispose patients to being Might provide insight into the best patient-centered might represent the optimal form of clinical evaluation for patient-centered treated unethically by manufacturers use of precision medicines, thereby outcomes medicine. Researchers design a mini-investigation for an experimental drug’s of poorly developed investigational improving health outcomes safety and efficacy entirely around an individual patient’s response, to determine agents with small budgets Might make patient-centered whether a particular treatment works for that individual. For example, a patient Might be viewed as a threat by some comparative data more accessible to might alternate between drug and placebo for a couple of weeks at a time, and stakeholders who benefit from large, patients and physicians researchers record the outcomes. These trial results can then be used to guide population-based, randomized specific treatment for a patient or be pooled with other n-of-1 trials of the same controlled trials and current data drug and same experimental design to obtain population-level trends. An aggregation systems advantage of data 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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Novel antimicrobial Investigators are developing polymers, alloys, and coating technologies to give Might lead to relaxed sanitation Might reduce health care–acquired environmental surface commonly touched surfaces in health care and public health settings inherently efforts infection rates coatings to prevent sustained antimicrobial properties to limit the spread of communicable diseases. Might cause skin irritations or other Might improve overall population health care–acquired Hong Kong researchers developed a Multilevel Antimicrobial Polymer (MAP-1) adverse events not discovered in health when implemented in public infections coating that purportedly introduces surface moieties that disrupt microbial completed studies settings envelopes and surface molecules, rendering pathogens (viruses, bacteria, and Might increase infrastructure costs Might reduce costs compared with spores) unviable upon contact (up to 99.9% of highly infectious viruses and more without substantial impact on other infection control measures than 98.7% of drug-resistant bacteria on hospital privacy curtains in 3 weeks). It infection rates 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, schools) to improve the speed and cost- effectiveness of implementing antimicrobial surfaces. According to the manufacturer, its modified touch surfaces “contact kill” 96% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 2 hours and 99.2% of the virus in 5 hours, compared with no reduction for stainless steel.

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 early guide personalized caring for patients suspected of having cancer, clinicians use proteomic profiling protein signatures for different and matching patients with targeted targeted therapy to identify a cancer-associated protein signature that might confirm the cancer types and understand which therapies or clinical trials likely to presence and origin of a specific cancer type. For these patients, proteomic could be drug targets benefit them profiling helps identify overexpressed proteins that are known to be therapeutic Might increase disparities by being targets, such as those caused by chromosomal rearrangements. Clinicians then available only to patients who are use this information to select a targeted therapy, on- or off-label, that is most insured or able to pay for treatment likely to benefit a patient with cancer or to help enroll patients in clinical trials of out of pocket investigational therapies.

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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 and treat mental and dimethyltryptamine [DMT]; 3,4-methylenedioxymethamphetamine [MDMA]; outcomes for some patients and are quality of life for some patients behavioral health ketamine) alter one’s state of consciousness, purportedly by altering certain therefore not recommended for Might reduce the prevalence of conditions neurotransmitters in the brain. Their use might provide the user with altered every patient treatment-resistant mental health perception, increased introspection, feelings of closeness with others, and Might pose population health and conditions and reduce costs positive mood states. These experiences are often reported as deeply profound legal risks related to making associated with long-term mental and life-altering. Although most psychedelics are designated as Schedule I drugs controlled substances more health treatment in the United States, researchers are investigating their potential to treat a accessible Might positively shift the paradigm variety of mental and behavioral health disorders that have not responded to Might increase disparities in access and infrastructure of mental health conventional treatments. The Multidisciplinary Association for Psychedelic to care if clinicians are hesitant to care Studies (Santa Cruz, California) was established in 1986 to research and provide treat patients using controlled Might encourage continued research education regarding potential therapeutic uses in mental health treatment. In substances that carry stigma or a into additional potential therapeutic September 2019, Johns Hopkins Medicine (Baltimore, Maryland) announced the significant risk of harm or mental uses for psychedelic drugs and launch of its Center for Psychedelic and Consciousness Research to study deterioration might enhance understanding of psychedelic drugs to treat certain mental health conditions. The number of Might be costly in the short term if mental health conditions clinical trials on the use of psychedelics for mental health conditions is significant costs are associated with increasing. Psilocybin is in clinical trials to investigate treatment for depression, building necessary treatment anorexia nervosa, obsessive-compulsive disorder, alcohol use disorder, nicotine infrastructure 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 274 `

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 related medical examinations insight into treatment options for patients. A recent telehealth and eHealth case patient health data inappropriately to both patient care and care and diagnostics for use study highlighted a patient’s case in which acute appendicitis was diagnosed via Might, because of user or device delivery by reducing clinician’s office by patients and telehealth, allowing timely surgery to take place. Smartphone apps can deliver errors, lead to misdiagnosis or visits caregivers examinations and diagnostic services to patients in remote areas by boosting the mistreatment Might reduce disparities in terms of use of smartphones as diagnostic devices for multiple age groups. These apps access to care for patients in rural are accompanied by handheld examination kits that allow patients or caregivers areas to perform guided medical examinations and share results with their provider for Might increase patient autonomy an appropriate diagnosis and treatment options (eg, TytoCare [for ear infection, and satisfaction by involving patients heart and lung sounds, throat infection diagnosis], MoleScope [for skin and caregivers in the diagnostic screening], RetinaScope [for diabetic eye disease screening]). process 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 prosthetic Might increase complication risk if Might improve patient mobility or enhance prosthetic legs and restore a more normal gait. Prostheses are being outfitted with sensors, implants are required function control gyroscopes, and accelerometers combined with artificial intelligence (AI) Might increase disparities based on Might enhance quality of life and algorithms. The goal is to interpret what the patient is trying to do (eg, climb technical complexity or geographic psychological health stairs) and move the prosthetic leg in the optimal fashion to achieve the desired availability Might increase patient productivity, goal. Other groups are embedding sensors in prosthetic legs that purportedly Might increase treatment costs for or enable patient return to work or transmit real-time sensory feedback to wireless electrodes implanted in residual prostheses and continuing device school leg nerves to simulate the natural tactile sensations (eg, weight distribution and maintenance 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 275 `

Title Description Threats Opportunities

Telehealth to treat Telehealth, the use of digital communication modalities to provide health care, is Might pose risks to patient Might improve individual and mental health being increasingly harnessed to provide psychiatric assessments and treatment confidentiality if communications are population health outcomes by conditions to patients to help address access-to-care issues. A 2017 report found that 77% not secure allowing patients quicker, more of US counties reported a severe shortage of psychiatrists. Recent estimates of Might pose risks to patient safety if convenient, and wider access to health care provider-to-patient ratios reveal an increasing scarcity of mental health care providers aren’t as mental health care and by allowing health resources, especially in rural areas. Telehealth aims to help narrow the gap readily able as during face-to-face patients to pick providers who are by improving patient access to providers and helping patients receive mental visits to collect crucial information best suited for them health care faster and more conveniently, because communication takes place such as vital signs for medical Might reduce health care costs by online. Telehealth psychiatry is increasingly being used to treat behavioral health decision making reducing the amount of time conditions including anxiety, depression, attention-deficit/hyperactivity disorder, Might be difficult to treat patients patients are away from work, and substance use disorders. with serious health issues like active reducing money spent traveling to suicidal ideation or alcohol appointments, and reducing overall withdrawal from a distance, treatment time 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)

Wearable drug delivery Some drugs used to treat chronic conditions, such as multiple sclerosis, diabetes Might have severe health Might improve the injection systems to better mellitus, or rheumatoid arthritis, are injected under the skin. Often, patients consequences for patients due to experience, which can increase manage chronic choose drug administration via self-injections because it requires less-frequent device errors patient adherence to treatment conditions dosing than taking oral medications. Wearable drug delivery devices are Might increase costs for patients regimens intended to provide a simple, easy-to-use system to improve patients’ who do not have insurance coverage Might boost patient confidence, adherence to the recommended treatment and improve their health and quality for these devices driving patients to take greater of life. For example, SmartDose (West Pharmaceutical Services, Exton, control of their health Pennsylvania) is a preloaded device that allows larger volume on-body drug Might enable increased delivery of delivery less frequently and continuous monitoring that can alert clinicians to high-volume and high-viscosity drug make changes in treatment regimens. Omnipod (Insulet, Acton, Massachusetts) products to improve longer-term is another wearable device that provides up to 72 hours of insulin delivery for health outcomes 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 276 ` Table 6.3. Trends Archiveda Since Last Status Report: 8 Trends

Title Description Threats Opportunities

Artificial intelligence In this application of AI, a software program analyzes magnetic resonance Might lead, due to algorithmic Might help detect cancer at earlier (AI) analysis of imaging imaging (MRI), computed tomography (CT), or ultrasound scans from patients detection errors, to false-negative or stages, thereby enabling earlier scans to screen for suspected of having cancer and generates a probability-of-malignancy score. A false-positive reports that could have treatment and potentially improving cancer or confirm a standard risk score that could be used, for example, is the Breast Imaging health and/or legal implications patient health outcomes cancer diagnosis Reporting and Data System (BI-RADS). The machine learning AI software (eg, Might lead to overdiagnosis (ie, a Might reduce human error rates in convolutional neural networks) is used with conventional picture archiving and true-positive diagnosis with little or cancer detection and diagnosis communications systems to learn the features of malignancy and point out no health consequences that could problematic areas in images. This AI software is intended to improve lead to unnecessary treatment or radiologists’ ability to detect abnormal lumps and nodules and to help undue negative psychological impact determine whether they are dangerous. It does this by scanning all dimension on the patient) slices at once, homing in on regions of interest, and providing a cancer risk Might be viewed by some score. radiologists as a threat to their autonomy as clinicians

Artificial intelligence AI is being harnessed to analyze what users choose to share on social media Might pose an ethical concern Might decrease health disparities if (AI) to predict mental platforms to predict the presence of mental health conditions and symptoms in because this can be seen as a threat more people are screened for mental health status through those users. A 2018 study demonstrated that a machine learning (ML) algorithm to social media users’ privacy health conditions and prompted to social media primed with markers could use content shared on Facebook to predict a future Might breach patient confidentiality receive care sooner or at all occurrence of depression in users’ medical records. Facebook uses ML as a if data collected constitute protected Might improve patient health suicide prevention tool, identifying posts with language expressing suicidal health information (PHI) and are not outcomes, overall health, and quality thoughts to intervene with resources. ML has also successfully identified markers handled in a HIPAA-compliant of life if patients receive mental of depression on Instagram using statistical features computationally extracted manner health care sooner or at all from photos (eg, color analysis, metadata components, and algorithmic face Might result in data collected being detection). The resulting models exceeded unassisted diagnostic success rates by compromised (eg, hacking) and used general practitioners. The use of AI in this context might provide an opportunity inappropriately for earlier detection of and intervention in mental health disorders. Might undermine research efforts or harm patients psychologically if errors in prediction occur

a Deemed by ECRI internal stakeholders to be unlikely to cause significant disruption to health care in the United States within the next 3 years.

Section 6. Potentially Disruptive Trends 277 `

Title Description Threats Opportunities

Human microbiome An increasing body of research has proposed using human microbiome analysis Might cause overdiagnosis of certain Might facilitate new understanding analysis and as a way to predict disease and death risk. Artificial intelligence (AI) and machine conditions of certain diseases or conditions manipulation to prevent learning (ML) techniques will become increasingly important tools for harnessing Might cause anxiety in some Might allow earlier intervention or or manage disease that information and translating it into clinically meaningful new approaches to patients, depending on predictions preventive measures before serious manage various diseases or prevent their development. Two recent analyses disease occurs suggest that (1) the genetic signature of a person’s gut microbes was 20% more predictive of a person’s health than the person’s own genes, and that (2) individuals with an abundance of Enterobacteriaceae bacteria (including Escherichia coli and Salmonella) are 15% more likely to die in the next 15 years. Based on findings and predictions, some preventive measures might be possible to modify risks and slow or prevent disease development. Interventions include use of prebiotic and probiotic supplements to prevent neonatal sepsis and adjustment of antibiotic regimens to reduce the growth of potential pathogenic microbes in the gut. Researchers at Georgia Tech are studying how to alter and personalize antibiotic therapy in patients with cystic fibrosis (CF) to prevent destruction of beneficial bacteria that normally provide some protection against pathogenic bacteria in the lungs by keeping their numbers in check. Other research attempts to improve outcomes in inflammatory bowel disease by altering the gut microbiome to modulate the immune system’s response.

Pet therapy using Pet therapy using robotic pets might provide supportive care to patients with Might increase disparities by limiting Might provide a nondrug treatment robotic pets for patients agitation and depression due to Alzheimer’s disease or dementia. Pet therapy availability to those who can afford option for some patients who have Alzheimer’s using robotic pets might reduce caregiver burden by providing a nondrug to pay for these robots Might reduce caregiver burden and disease or dementia therapy option to promote sensory processing and control negative behavioral long-term costs of care symptoms. For example, PARO is a pet robot intended for use by patients with dementia. The robot is designed to recognize and respond to tactile sensors, light, audio, temperature, and posture. PARO is powered by artificial intelligence (AI) and learns a patient’s behavior and preferences. It is intended to improve mood and other behavioral and psychological symptoms of dementia.

Section 6. Potentially Disruptive Trends 278 `

Title Description Threats Opportunities

Pharmacogenomic Clinical guidelines recommend standard drug regimens for patients with Might increase disparities if genomic Might improve patient outcomes by testing to personalize cardiovascular disease, based on well-defined clinical trial populations. However, testing is unavailable to all improved drug selection cardiovascular medical many patients in general clinical practice have complex coexisting conditions appropriate patients Might lower costs by reducing therapy and are excluded from trials. They may respond differently to guideline-directed Might increase inappropriate overuse of more-expensive or riskier medical therapy. FDA has noted available data indicate a potential demand for cardiovascular genetic drugs pharmacogenetic association between genetic mutations and several testing without patient and/or Might improve patient adherence to cardiovascular drugs that might affect drug safety or response. Drugs include provider education therapy if more-effective drugs are CYP2D6 carvedilol, metoprolol, nebivolol, and propranolol ( gene); simvastatin selected sooner and rosuvastatin (SLCO1B1); and hydralazine and procainamide (nonspecific variants). Some drugs in development, including apabetalone and dalcetrapib, might be targeted toward patients who have cardiovascular disease and certain genetic variations. Past research has addressed genetic profiles affecting patients’ responses to warfarin (VKORC1) and clopidogrel (CYP2C19). Continuing research from groups like the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Implementing Genomics in Practice (IGNITE) consortium is likely to expand the genomics-related recommendations for cardiovascular medication prescribing.

Screening programs for Men have no established breast cancer screening procedures because the Might have limited coverage Might improve health outcomes by men at high risk of disease is rare in this group. Most cases of breast cancer in men are diagnosed because third-party payers are detecting early-stage breast cancer breast cancer only when the disease is symptomatic. Men with breast cancer caused by unlikely to cover male breast cancer Might reduce costs associated with inherited gene mutations usually have poor prognosis compared with outcomes screening unless it is proved to be late-stage cancer treatment by in similar patients with cancer caused by acquired gene mutations. Men with a cost effective enabling earlier curative intervention family history of breast cancer might harbor inherited gene mutations that Might increase disparities by being increase their risk of developing the disease. For these men, screening programs available only to patients who are that include clinical examination, family history, genetic testing, and insured or able to pay for screening mammography purportedly detect occult early-stage breast cancer and guide out of pocket patient management to improve health outcomes. Might lead to overtreatment of some early-stage cancers that never develop into life-threatening disease

Section 6. Potentially Disruptive Trends 279 `

Title Description Threats Opportunities

Stem cell therapy to At least 3 biotechnology companies (Athersys, Inc, Cleveland, Ohio; ReNeuron Might increase disparities due to Might reduce stroke-induced reduce stroke-induced Group plc, Pencoed, United Kingdom; Stemedica Cell Technologies, Inc, San potential high cost and limited disability and improve quality of life disability Diego, California) are pursuing development of allogeneic (ie, donor) stem cell availability Might lower the need for long-term products intended to reduce chronic disability that develops after stroke caused Might increase short-term treatment rehabilitation therapy and nursing by a blood clot (ie, ischemic stroke). Phase 2 and phase 3 trials are under way. costs, especially if demand or care Independent investigators at several international sites are also investigating awareness is high Might reduce long-term treatment autologous (ie, a patient’s own) or allogeneic stem cells derived from various costs despite higher short-term tissue types (eg, adipose [fat] or nerve cells) to treat or reduce existing stroke- therapy costs induced disability. Treatment approaches and timelines for administration are not yet standardized. Most stem cell products are administered intravenously, although at least one (ReNeuron) is injected into stroke-damaged brain tissue in a neurosurgical procedure. Cells are delivered from several days up to 5 years after ischemic stroke. Not all purported mechanisms of action are fully clarified. Developers purport that their respective products might reduce or reverse stroke-induced disability through one or more mechanisms, including reducing inflammation by suppressing an overactive immune system, providing neuroprotection of at-risk brain cells, and promoting new blood vessel growth (ie, angiogenesis) and tissue repair by stimulating the release of certain proteins and growth factors. Suggestions that transplanted nerve stem cells might migrate and replace damaged nerve cells at the injury site to restore lost brain function have not yet been definitively shown in early clinical trials.

Section 6. Potentially Disruptive Trends 280 `

Title Description Threats Opportunities

Tissue of origin– Oncology drugs have traditionally been approved by FDA for cancers arising Might increase costs by requiring Might provide a pathway to FDA agnostic, molecularly from specific tissues or organs (eg, breast, prostate, lung, blood). With the more widespread testing of tumors approval in instances of indications targeted oncology increasing recognition that some genetic changes drive the development of using whole genome sequencing or that might not be suited for drugs cancers arising across different organs or tissues, investigators began defining very large gene panels upon initial traditional clinical trial designs patient populations in terms of their molecular subtype. These observations were diagnosis of a patient to identify all Might create new collaboration made in so-called basket trials or umbrella trials—the same clinical trial enrolled potential therapeutic targets opportunities for laboratories and patients with cancers originating in different tissues or organs and researchers Might involve a substantial learning companies that offer whole genome observed a signal of efficacy for a molecular target of a drug across those curve for providers and exome sequencing cancers. This led to expansion of cohorts or creation of tissue of origin–specific Might lead to poor outcomes in trials with the intent that the manufacturer seek FDA drug approval for that certain patients with a molecular tissue of origin (eg, ALK inhibitors for non–small cell lung cancer [NSCLC], BRAF driver and tissue-of-origin inhibitors for melanoma or Erdheim Chester disease). However, FDA has recently combination for which the targeted approved 3 drugs for use in molecularly defined patient populations. Examples therapy is ineffective include pembrolizumab (Keytruda), which received approval to treat unresectable or metastatic, microsatellite instability–high (MSI-H), or mismatch repair–deficient (dMMR) solid tumors in adult and pediatric patients. Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) were approved to treat solid tumors that have a neurotrophic tyrosine receptor kinase gene fusion without a known acquired-resistance mutation. This change in approach raises issues regarding clinical trial conduct to provide the supporting evidence for regulatory submissions. It also raises potential issues with the varied responses to molecularly targeted therapies across different cancer types, particularly for rare cancers or cancers in which a molecular target rarely occurs.

Section 6. Potentially Disruptive Trends 281 ` Appendix. Abbreviations and Acronyms

A2E 2 mol vitamin A aldehyde and 1 mol ethanolamine AA anaplastic astrocytoma AADC aromatic L-amino acid decarboxylase AADCD aromatic L-amino acid decarboxylase deficiency AAT alpha-1 antitrypsin AAV ANCA-associated vasculitis AAV2 adeno-associated virus serotype 2 AAV5 adeno-associated virus serotype 5 AAV5-hFIXco-Padu codon-optimized human factor IX Padua gene AAV9 adeno-associated virus serotype 9 Aβ amyloid beta ABA applied behavior analysis ABCA4 ATP binding cassette subfamily A member 4 ABCD1 ATP binding cassette subfamily D member 1 AC6 adenylyl cyclase type 6 ACC American College of Cardiology ACE angiotensin-converting enzyme AchR acetylcholine receptor ACTH adrenocorticotropic hormone ACVR1 activin A receptor type 1 AD Alzheimer’s disease Ad5.hAC6 adenovirus 5 encoding human AC6 ADA ADAMTS13 ADAM metallopeptidase with thrombospondin type 1 motif, 13 ADAMTS13 von Willebrand factor–cleaving protease ADA-SCID adenosine deaminase/severe combined immunodeficiency

APPENDIX. ABBREVIATIONS AND ACRONYMS 282 ` ADCY9 adenylate cyclase type 9 ADHD attention-deficit/hyperactivity disorder adRP autosomal-dominant retinitis pigmentosa AGA actionable genomic alteration AHP acute hepatic porphyria aHUS atypical hemolytic uremic syndrome AI artificial intelligence ALAS1 aminolevulinic acid synthase 1 ALD adrenoleukodystrophy ALDP adrenoleukodystrophy protein ALK ALK receptor tyrosine kinase ALK2 activin receptor-like kinase-2; ACVR1 ALL acute lymphoblastic leukemia ALS amyotrophic lateral sclerosis AMBAR Alzheimer management by albumin replacement AML acute myeloid leukemia AMN adrenomyeloneuropathy α-MSH alpha-melanocyte stimulating hormone AMP adenosine monophosphate ANCA antineutrophil cytoplasmic antibody Apo E apolipoprotein E AQP4 aquaporin-4 AQP4-IgG aquaporin-4-immunoglobulin G ARB angiotensin-receptor blocker ARG1 arginase 1 ARSA arylsulfatase A ASBT apical sodium-dependent bile acid transporter

APPENDIX. ABBREVIATIONS AND ACRONYMS 283 ` ASCT allogeneic stem cell transplantation ASCT autologous stem cell transplantation ASD autism spectrum disorder ASMD acid sphingomyelinase deficiency ASS1 argininosuccinate synthase 1 ATP ATP7A P-type adenosine triphosphatase alpha AUC area under the curve AUD alcohol use disorder BCCNS basal cell carcinoma nevus syndrome B cell bursa of Fabricius–maturing cell; B lymphocyte BCG bacillus Calmette-Guérin BCL-2 B-cell lymphoma-2 BCMA B-cell maturation antigen BCVA best corrected visual acuity BI-RADS Breast Imaging Reporting and Data System BMI body mass index BMP bone morphogenetic protein BMP2 bone morphogenetic protein 2 β-MSH beta-melanocyte stimulating hormone BNP B-type natriuretic peptide BOS bronchiolitis obliterans syndrome BP bullous pemphigoid BRAF B-Raf proto-oncogene serine/threonine kinase BRCA breast cancer BRCA1 breast cancer 1 BRCA2 breast cancer 2

APPENDIX. ABBREVIATIONS AND ACRONYMS 284 ` BTK Bruton tyrosine kinase C1 complement component 1 C1-INH C1 esterase inhibitor C3 complement component 3 C5 complement component 5 C5a complement 5a anaphylatoxin fragment C5b complement 5b anaphylatoxin fragment C5b-9 complement 5b complex 9 CAD cold agglutinin disease CAH congenital adrenal hyperplasia CALD cerebral adrenoleukodystrophy cAMP cyclic adenosine monophosphate CAR chimeric antigen receptor CAR-T chimeric antigen receptor T cells

CB2 cannabinoid receptor 2 CBD cannabidiol CBT cognitive behavioral therapy cc cubic centimeters CD3 cluster of differentiation 3 CD3ζ cluster of differentiation 3ζ CD8+ cluster of differentiation 8 positive CD8α cluster of differentiation 8α CD19 cluster of differentiation 19 CD20 cluster of differentiation 20 CD28 cluster of differentiation 28 CD33 cluster of differentiation 33 CD34+ cluster of differentiation 34 positive

APPENDIX. ABBREVIATIONS AND ACRONYMS 285 ` CD38 cluster of differentiation 38 CD38– cluster of differentiation 38 negative CD45 cluster of differentiation 45 CD47 cluster of differentiation 47 CD123 cluster of differentiation 123 CD137 cluster of differentiation 137 CD155 poliovirus receptor nectin-like protein 5 CDC cardiosphere-derived cell CDK4/6 cyclin-dependent kinases 4 and 6 CDKL5 cyclin-dependent kinase-like 5 CEA carcinoembryonic antigen CED convection-enhanced delivery cells/kg cells of biologic agent per kilogram of body weight CEP290 centrosome protein 290 CETP cholesteryl ester transfer protein CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator CGG cytosine, guanine, guanine cGMP cyclic guanosine monophosphate CGP comprehensive genomic profiling CGRP calcitonin gene–related peptide CHARGE coloboma, heart defects, atresia choanae, retarded growth and development, genital hypoplasia, and ear abnormalities and deafness CHM choroideremia CIS carcinoma in situ CIT chemotherapy-induced thrombocytopenia CLD chronic liver disease CLL chronic lymphocytic leukemia

APPENDIX. ABBREVIATIONS AND ACRONYMS 286 ` cm2 square centimeters CML chronic myelogenous leukemia CNTF ciliary neurotrophic factor COL7A1 collagen COL7A1 collagen type VII alpha 1 chain COST Cooperation in Science and Technology COVID-19 coronavirus disease of 2019 CPIC Clinical Pharmacogenetics Implementation Consortium cPMP cyclic pyranopterin monophosphate CRC colorectal cancer

CRF1 corticotropin-releasing factor type 1 CRISPR clustered regularly interspaced short palindromic repeats CRL Complete Response Letter CRM1 chromosomal maintenance 1 CRT cardiac resynchronization therapy CSF1 colony-stimulating factor 1 CSF1R colony-stimulating factor 1 receptor CT computed tomography CTCL cutaneous T-cell lymphoma CTGF connective tissue growth factor CTL cytotoxic T lymphocyte CUA calcific uremic arteriolopathy CXCL12 CXC chemokine ligand 12 CXCR4 CXC chemokine receptor 4 CXCR4 C-X-C motif chemokine receptor 4 CYP2C19 cytochrome P450 family 2 subfamily C member 19 CYP2D6 cytochrome P450 family 2 subfamily D member 6

APPENDIX. ABBREVIATIONS AND ACRONYMS 287 ` CYP21A2 cytochrome P450 family 21 subfamily A member 2 3-D three-dimensional

D2 dopamine 2 DAAO D-amino acid oxidase DBS deep brain stimulation DCS D-cycloserine DDC dopa decarboxylase DDLS dedifferentiated liposarcoma DEA US Drug Enforcement Agency DEB dystrophic epidermolysis bullosa DFMO α-difluoromethylornithine DLBCL diffuse large B-cell lymphoma DMD Duchenne muscular dystrophy DMD dystrophin dMMR mismatch repair–deficient DMT N,N-dimethyltryptamine DQ developmental quotient DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition DSM-V Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DTC direct-to-consumer DUX4 double homeobox 4 E6 early expression 6 E7 early expression 7 EAP Expanded Access Program EBV Epstein-Barr virus EBV+PTLD Epstein-Barr virus–associated posttransplant lymphoproliferative disorder EBVSTs Epstein-Barr virus–specific T cells

APPENDIX. ABBREVIATIONS AND ACRONYMS 288 ` ECG electrocardiogram ECOG Eastern Cooperative Oncology Group ECT electroconvulsive therapy EDS excessive daytime sleepiness EEG electroencephalography EGFR epidermal growth factor receptor eGFR estimated glomerular filtration rate EGJ esophagogastric junction EMDR eye movement desensitization and reprocessing EpCAM epithelial cell adhesion molecule EPP erythropoietic protoporphyria ERK extracellular signal-related kinase ESA erythropoiesis-stimulating agent ESRD end-stage renal disease EZH2 enhancer of zeste homolog 2 EZH2 enhancer of the zeste 2 polycomb repressive complex 2 subunit F9 factor IX FACIT Functional Assessment of Chronic Illness Therapy FAI fludarabine, cytarabine, and idarubicin FAS FS-7-associated surface antigen Fc crystallizable fragment FcRn neonatal Fc receptor FDA US Food and Drug Administration FGF23 fibroblast growth factor 23 FGFR fibroblast growth factor receptor FGFR1 fibroblast growth factor receptor 1 FGFR2 fibroblast growth factor receptor 2

APPENDIX. ABBREVIATIONS AND ACRONYMS 289 ` FGFR3 fibroblast growth factor receptor 3 FGFR4 fibroblast growth factor receptor 4 FIX alias for coagulation factor IX gene, F9 FLT3 fms-like tyrosine kinase 3 FMR1 fragile X mental retardation 1 Fmrp Fmr1 protein FOLFIRI leucovorin (folinic acid), 5-fluorouracil, and irinotecan FOLFIRINOX leucovorin (folinic acid), 5-fluorouracil, irinotecan, and oxaliplatin FOLFOX leucovorin (folinic acid), 5-fluorouracil, and oxaliplatin FOP fibrodysplasia ossificans progressiva FOXN1 Forkhead Box N1 FRDA Friedreich ataxia FSHD facioscapulohumeral muscular dystrophy FSHD1 facioscapulohumeral muscular dystrophy type 1 FT1050 small-molecule stem cell modulator (made by Fate Therapeutics) FT4145 small-molecule stem cell modulator (made by Fate Therapeutics) FXN frataxin FXR farnesoid X receptor FXS fragile X syndrome GABA gamma-aminobutyric acid

GABAA gamma-aminobutyric acid receptor A GABAergic gamma-aminobutyric acidergic GALT galactose-1 phosphate uridyl transferase GBM glioblastoma multiforme GBq gigabecquerel gc/g genome copies per gram of target tissue gc/kg genome copies per kilogram of body weight

APPENDIX. ABBREVIATIONS AND ACRONYMS 290 ` G-CSF granulocyte colony-stimulating factor GEA gastroesophageal adenocarcinoma GI gastrointestinal GLP-1 glucagon-like peptide 1 g/m2 grams per square meter of body surface area gMG generalized myasthenia gravis GO glycolate oxidase GPR40 G-protein coupled receptor 40 GPR84 G-protein coupled receptor 84 GTPase (guanosine triphosphate) superfamily of enzymes GVHD graft-versus-host disease H3 histone H3K4 lysine at amino acid 4 of histone H3 H3K9 lysine at amino acid 9 of histone H3 hAAT human α1-antitrypsin HAE hereditary angioedema HAP hydroxyapatite

HbA1c glycated hemoglobin HBB hemoglobin subunit beta HCC hepatocellular carcinoma HCHSS PCORI Health Care Horizon Scanning System HD Huntington disease HDAC histone deacetylase HER2 human epidermal growth factor receptor 2 HES hypereosinophilic syndrome HF heart failure HGF hepatocyte growth factor

APPENDIX. ABBREVIATIONS AND ACRONYMS 291 ` HIPAA Health Insurance Portability and Accountability Act HLA-A2 human leukocyte antigen serotype A2 HO heterotopic ossification HPBCT hematopoietic peripheral blood cell transplant HPV human papillomavirus HPV-16 human papillomavirus type 16 HPV-18 human papillomavirus type 18 HR hormone receptor HSC hematopoietic stem cell HSCT hematopoietic stem cell transplantation HSCT-TMA hematopoietic stem cell transplantation–associated thrombotic microangiopathy HSIL high-grade squamous intraepithelial lesion HSP heat shock protein HSV-1 herpes simplex virus 1 5-HT1A 5-hydroxytryptamine 1A; serotonin 1A 5-HT2A 5-hydroxytryptamine 2A; serotonin 2A HTT huntingtin ICD implantable cardioverter-defibrillator ICU intensive care unit IDE Investigational Device Exemption IDH isocitrate dehydrogenase IDH1 isocitrate dehydrogenase 1 IDS iduronate-2-sulfatase IgA immunoglobulin A IGF-1 insulinlike growth factor 1 IGF-1R insulinlike growth factor 1 receptor IgG immunoglobulin G

APPENDIX. ABBREVIATIONS AND ACRONYMS 292 ` IgG1 Fc immunoglobulin G1 Fc domain IgG2 immunoglobulin G2 IgG4 immunoglobulin G4 IgM immunoglobulin M IGNITE Implementing Genomics in Practice IL-1 interleukin-1 IL-1β interleukin-1β IL-2 interleukin-2 IL-4R interleukin-4 receptor IL-5 interleukin-5 IL-5α interleukin-5 α chain IL-15 interleukin-15 IL-15α interleukin-15α IL-17 interleukin-17 IL-21 interleukin-21 IL-23 interleukin-23 IL-31 interleukin-31 ILD interstitial lung disease INAD infantile neuroaxonal dystrophy IPATH Center for Innovative Phage Applications and Therapeutics IPF idiopathic pulmonary fibrosis IQ intelligence quotient IRB institutional review board IU international unit IU/dL international unit per deciliter IV intravenous IVIG intravenous immunoglobulin

APPENDIX. ABBREVIATIONS AND ACRONYMS 293 ` JAK Janus kinase JSCDH Journal of Sickle Cell Disease and Hemoglobinopathies KIT KIT proto-oncogene receptor tyrosine kinase LAG-3 lymphocyte-activator gene-3 LAPC locally advanced pancreatic cancer LCA10 Leber congenital amaurosis 10 LDH lactate dehydrogenase LDL low-density lipoprotein LGMD2E limb-girdle muscular dystrophy type 2E LHON Leber hereditary optic neuropathy LSD lysergic acid diethylamide LSD1 lysine-specific demethylase 1 LTB4 leukotriene B4 177Lu lutetium-177 LVAD left ventricular assist device MAC membrane attack complex MACE major adverse cardiovascular events MacTel macular telangiectasia MAOI monoamine oxidase inhibitor MAPK mitogen-activated protein kinase MASP-2 mannan-binding lectin-associated serine protease-2 MC1-R melanocortin 1 receptor MC4 melanocortin-4 MCI mild cognitive impairment MCL mantle cell lymphoma mCRPC metastatic, castration-resistant prostate cancer MCSF monthly convulsive seizure frequency

APPENDIX. ABBREVIATIONS AND ACRONYMS 294 ` MDD major depressive disorder MDMA 3,4-methylenedioxymethamphetamine MDS myelodysplastic syndrome MEC mitoxantrone, etoposide, and cytarabine MeCP2 methyl CpG binding protein 2 MECP2 methyl CpG binding protein 2 MEK MAPK kinase kinase MEK1/2 MAPK kinases 1 and 2 MET mesenchymal-epithelial transition MGFA Myasthenia Gravis Foundation of America mg/m2 milligram per square meter of body surface area mg/mL milligram per milliliters of solution MGMT O6-methylguanine-DNA-methyltransferase MHC-II major histocompatibility complex molecule class II μg/kg microgram per kilogram of body weight μL microliter ML machine learning MLD metachromatic leukodystrophy MM multiple myeloma MMC mitomycin-C mm Hg millimeters of mercury MoCD molybdenum cofactor deficiency MoCo molybdenum cofactor MOCS1 molybdenum cofactor synthesis 1 MPO myeloperoxidase MPS methoxsalen, phenytoin, and sirolimus MPS mucopolysaccharidosis

APPENDIX. ABBREVIATIONS AND ACRONYMS 295 ` MPSII mucopolysaccharidosis type II; Hunter syndrome MPSIIIA mucopolysaccharidosis type III A; Sanfilippo syndrome type A MPSIIIB mucopolysaccharidosis type III B; Sanfilippo syndrome type B MRI magnetic resonance imaging mRNA messenger RNA MSA multiple system atrophy MSI microsatellite instability MSI-H microsatellite instability–high mTOR mammalian target of rapamycin mUC metastatic urothelial cancer MUC1 Mucin 1 NADH nicotinamide adenine dinucleotide NAGLU N-acetyl-alpha-D-glucosaminidase NAM nicotinamide ND4 NADH dehydrogenase 4 NDA New Drug Application NF1 neurofibromatosis type 1 NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells NK natural killer NK neurotrophic keratitis NMDA N-methyl-D-aspartate NMIBC non–muscle invasive bladder cancer NMOSD neuromyelitis optica spectrum disorder nNOS neuronal nitric oxide synthase NPC nasopharyngeal carcinoma NPC Niemann-Pick disease type C NPC1 NPC intracellular cholesterol transporter 1

APPENDIX. ABBREVIATIONS AND ACRONYMS 296 ` NPC-1 Niemann-Pick disease type C1 NPC2 NPC intracellular cholesterol transporter NPC-2 Niemann-Pick disease type C2 NPD-A/B Niemann-Pick disease type A/B; chronic neurovisceral ASMD NPD-B Niemann-Pick disease type B NSAID nonsteroidal anti-inflammatory drug NSCLC non–small cell lung cancer NTproBNP N-terminal pro B-type natriuretic peptide NTRK neurotrophic tyrosine receptor kinase NY-ESO-1 New York esophageal squamous cell carcinoma-1 NYHA New York Heart Association OCT optical coherence tomography ODC ornithine decarboxylase oGVHD ocular graft-versus-host disease OM oral mucositis p38 MAPKα alpha isoform of p38 mitogen-activated protein kinase p38 MAPKα/β alpha and beta isoforms of p38 mitogen-activated protein kinase p53 tumor protein 53 p62 tumor protein 62; sequestosome-1 PAH pulmonary arterial hypertension PARP poly adenosine diphosphate-ribose polymerase PARP1/2 poly adenosine diphosphate-ribose polymerases I and II PBC primary biliary cholangitis PCORI Patient-Centered Outcomes Research Institute PCSK9 proprotein convertase subtilisin kexin type 9 PD-1 programmed cell death 1 PDE4 phosphodiesterase type 4

APPENDIX. ABBREVIATIONS AND ACRONYMS 297 ` PDE4D phosphodiesterase type 4D PDE9 phosphodiesterase type 9 PDGFR platelet-derived growth factor receptor PDGFRA platelet-derived growth factor receptor alpha PDGFRB platelet-derived growth factor receptor beta PD-L1 programmed cell death ligand 1 PDUFA User Fee Act PE Pseudomonas aeruginosa exotoxin A PEComa perivascular epithelioid cell tumor PEDI Pediatric Evaluation of Disability Inventory PET positron emission tomography PET prolonged exposure therapy PF pemphigus foliaceus PFIC progressive familial intrahepatic cholestasis PFIC1 progressive familial intrahepatic cholestasis type 1 PFIC2 progressive familial intrahepatic cholestasis type 2 P-gp P-glycoprotein PGRMC1 progesterone receptor member component 1 pH potential of hydrogen PH primary hyperoxaluria PH1 primary hyperoxaluria type 1 PHI protected health information PI3K phosphoinositide 3 kinase PICO patient population, intervention, comparators, outcomes PKD pyruvate kinase deficiency PKLR pyruvate kinase L/R PLA2G6 phospholipase A2, group VI

APPENDIX. ABBREVIATIONS AND ACRONYMS 298 ` PLK1 polo-like kinase 1 PMO phosphorodiamidate morpholino oligomer PN plexiform neurofibroma PNH paroxysmal nocturnal hemoglobinuria Pol polymerase Pol I polymerase I Pol II polymerase II POMC proopiomelanocortin PPAR peroxisome proliferator-activated receptor PPARα peroxisome proliferator-activated receptor alpha PPARδ peroxisome proliferator-activated receptor delta PPARγ peroxisome proliferator-activated receptor gamma PROMIS Patient-Reported Outcomes Measurement Information System PSC primary sclerosing cholangitis PSD-95 postsynaptic density-95 PSMA prostate-specific membrane antigen PTC1 phosphatase type 2 C PTCH1 patched 1 PTSD posttraumatic stress disorder PUL Performance of Upper Limb PV pemphigus vulgaris PVR proliferative vitreoretinopathy PWS Prader-Willi syndrome QT ventricular depolarization interval from the start of the Q wave to the end of the T wave Rab ras genes from rat brains RARγ retinoic acid receptor gamma ras rat sarcoma

APPENDIX. ABBREVIATIONS AND ACRONYMS 299 ` rC7 recombinant collagen type VII R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone RDEB recessive dystrophic epidermolysis bullosa REP1 RET rearranged during transfection RHO rhodopsin RNAi RNA interference ROCK2 rho-associated coiled-coil kinase 2 ROS reactive oxygen species ROS1 ROS proto-oncogene 1 receptor tyrosine kinase RP retinitis pigmentosa RPGR retinitis pigmentosa GTPase regulator RPGR-ORF 15 retinitis pigmentosa GTPase regulator-open reading frame 15 RRMM relapsed and refractory multiple myeloma RTK receptor tyrosine kinase rTMS repetitive transcranial magnetic stimulation SAD social anxiety disorder SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 SBRT stereotactic body radiotherapy SCA SCD sickle cell disease SCLC small cell lung cancer SCN1A sodium voltage-gated channel alpha subunit 1 SEC US Securities and Exchange Commission SERPINA1 serpin family A member 1 SGCB sarcoglycan beta SGSH N-sulfoglucosamine sulfohydrolase

APPENDIX. ABBREVIATIONS AND ACRONYMS 300 ` sIBM sporadic inclusion body myositis Siglec-8 sialic acid-binding Ig-like lectin 8 siRNA short interfering RNA SIRPα signal regulatory protein-α SLAMF7 signaling lymphocytic activation molecule family member 7 SLCO1B1 solute carrier organic anion transporter family member 1B1 SLL small lymphocytic lymphoma Smad Sma/mothers against decapentaplegic homolog Smad 1 Sma/mothers against decapentaplegic homolog 1 Smad 5 Sma/mothers against decapentaplegic homolog 5 Smad 8 Sma/mothers against decapentaplegic homolog 8 Smo Smoothened SN-38 7-ethyl-10-hydroxycamptothecin SNRI serotonin and norepinephrine reuptake inhibitor SOD1 superoxide dismutase 1 SSc-ILD systemic sclerosis–associated interstitial lung disease SSRI selective serotonin reuptake inhibitor STAT-3 signal transducer and activator of transcription 3 STEAP1 six-transmembrane epithelial antigen of the prostate 1 STEMI ST-segment elevation myocardial infarction STRO antistromal precursor antigen T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus t(11;14) translocation between chromosomes 11 and 14 TAA tumor-associated antigen TAAR1 trace amine-associated receptor 1 TAZ tafazzin

APPENDIX. ABBREVIATIONS AND ACRONYMS 301 ` Tβ4 thymosin beta 4 TBI traumatic brain injury TCA tricyclic antidepressant T cell thymus-originating cell; T lymphocyte TED thyroid eye disease TGCT tenosynovial giant cell tumor TGF-beta transforming growth factor beta Th17 T helper 17 TIL tumor-infiltrating lymphocyte TIO tumor-induced osteomalacia TK2 thymidine kinase 2 TK2d thymidine kinase 2 deficiency TMA thrombotic microangiopathy TMS transcranial magnetic stimulation TNBC triple-negative breast cancer TP53 tumor protein p53 TPO thrombopoietin TRACK-TBI Transforming Research and Clinical Knowledge in Traumatic Brain Injury TRBA T-cell redirecting bispecific antibodies Trop-2 trophoblast cell-surface antigen 2 TSC tuberous sclerosis complex TSC1 TSC complex subunit 1 TSC2 TSC complex subunit 2 TTF tumor-treating field TTP thrombotic thrombocytopenia purpura TURBT transurethral resection of bladder tumor UBE3A ubiquitin protein ligase E3a

APPENDIX. ABBREVIATIONS AND ACRONYMS 302 ` UDCA ursodeoxycholic acid UVR ultraviolet radiation V1A vasopressin 1a VA US Department of Veterans Affairs VEGF vascular endothelial growth factor VEGFR vascular endothelial growth factor receptor VEGFR1 vascular endothelial growth factor receptor 1 VEGFR2 vascular endothelial growth factor receptor 2 VEGFR3 vascular endothelial growth factor receptor 3 vg viral genomes vg/kg viral genomes per kilogram of body weight VKORC1 vitamin K epoxide reductase complex subunit 1 VLCFA very long-chain fatty acids VNS vagal nerve stimulation VOC vaso-occlusive crisis VR-CAP bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone VT ventricular tachycardia WAS WASP actin nucleation promoting factor WAS Wiskott-Aldrich syndrome WASP Wiskott-Aldrich syndrome protein WHIM warts, hypogammaglobulinemia, infections, and myelokathexis WT1 Wilms tumor protein X-ALD chromosome X–linked adrenoleukodystrophy XLRP X-linked retinitis pigmentosa XPO1 nuclear export protein

APPENDIX. ABBREVIATIONS AND ACRONYMS 303