PCORI Health Care Horizon Scanning System Volume 2 Issue 2 Horizon Scanning Status Report June 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 Misha Mehta, MS Brian Wilkinson, MA Donna Beales, MLIS Jennifer De Lurio, MS Eloise DeHaan, BS Eileen Erinoff, MSLIS Madison Kimball, MS Maria Middleton, MPH Diane Robertson, BA Kelley Tipton, MPH Rosemary Walker, MLIS Karen Schoelles, MD, SM

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 Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI.

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

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

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

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

All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of PCORI or its Board of Governors. This publication was developed through a contract to support PCORI’s work. Questions or comments may be sent to PCORI at [email protected] or by mail to 1828 L Street, NW, Suite 900, Washington, DC 20036. ©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 2. Patient-Centered Outcomes Research Institute; June 2020. Prepared by ECRI Institute under Contract No. MSA- HORIZSCAN-ECRI-ENG-2018.7.12.

HORIZON SCANNING STATUS REPORT ● JUNE 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 second 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 June 13, 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 ● JUNE 2020 ii Contents

Preface ...... ii Contents ...... iii Introduction ...... 1 Section 1. Alzheimer’s Disease and Other Dementias: 11 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 Section 2. Cancer: 92 Topics ...... 13

Table 2.1. Cancer Topics Added Since Last Status Report: 12 Topics ...... 13 Table 2.2. Currently Monitored Cancer Topics: 72 Topics ...... 25 Table 2.3. Cancer Topics Archived Since Last Status Report: 8 Topics ...... 75 Section 3. Cardiovascular Diseases: 28 Topics ...... 82

Table 3.1. Cardiovascular Diseases Topics Added Since Last Status Report: 1 Topic ...... 82 Table 3.2. Currently Monitored Cardiovascular Diseases Topics: 22 Topics ...... 83 Table 3.3. Cardiovascular Diseases Topics Archived Since Last Status Report: 5 Topics ...... 99 Section 4. Mental and Behavioral Health: 18 Topics ...... 104

Table 4.1. Mental and Behavioral Health Topics Added Since Last Status Report: 1 Topic ...... 104 Table 4.2. Currently Monitored Mental and Behavioral Health Topics: 15 Topics ...... 105 Table 4.3. Mental and Behavioral Health Topics Archived Since Last Status Report: 2 Topics ...... 118 Section 5. Rare Diseases: 119 Topics ...... 120

Table 5.1. Rare Diseases Topics Added Since Last Status Report: 15 Topics ...... 120 Table 5.2. Currently Monitored Rare Diseases Topics: 90 Topics ...... 133 Table 5.3. Rare Diseases Topics Archived Since Last Status Report: 14 Topics ...... 211 Section 6. Potentially Disruptive Trends: 47 Trends ...... 225

Table 6.1. Trends Added Since Last Status Report: 19 Trends ...... 225 Table 6.2. Currently Monitored Trends: 15 Trends ...... 235 Table 6.3. Trends Archived Since Last Status Report: 13 Trends ...... 243 Appendix. Abbreviations and Acronyms ...... 249

HORIZON SCANNING STATUS REPORT ● JUNE 2020 iii

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 2 to 3 tables, depending on the topics or trends contained in that section: (1) topics or trends added since the last Status Report, (2) currently monitored topics or trends, and (3) topics or trends archived since the last Status Report. If no topics or trends fall into a given category (ie, added, monitored, archived), no table will be included for that category in that section. For sections 1 through 5 (priority areas), tables for newly added and currently monitored topics summarize information in each row, as shown in the following columns: Potential patient population; Intervention description (including names and locations of developers/manufacturers); Potential comparators; Patient-oriented outcome measures (limited to those reported in clinical trials); and Regulatory information. Information in the first 4 columns is collectively referred to as PICO (ie, patient population, intervention, comparators, and outcomes) information. In the tables of archived topics, the Regulatory information column is replaced with a Archive reason column. Within each table, topics are sorted alphabetically by intervention name (ie, the second column, Intervention description). Potentially disruptive trends are summarized in section 6. Tables for newly added, currently monitored, and recently archived trends summarize information in each row, as shown in the following columns: Title, Description, Threats, and Opportunities. Trends are sorted alphabetically by title. Trends listed in the table of archived trends are those that ECRI internal stakeholders agreed were unlikely to significantly disrupt health care in the United States within the next 3 years.

HORIZON SCANNING STATUS REPORT ● JUNE 2020 1

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 one of 2 types of records. Topic records encompass PICO (intended patient population, intervention, comparators to the intervention, and patient-oriented outcomes of interest) information and key regulatory information (if the topic is subject to a regulatory pathway). Trend records include a description of the trend, potential clinical areas affected, and lists of potential threats and opportunities posed by the trend. Analysts present potential topics and trends at nomination meetings. After a brief presentation and discussion, HCHSS team members vote in blinded fashion to include or exclude the topic or trend based on criteria described in the Protocol. All included topics and trends are reported in the quarterly Status Report.

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

HORIZON SCANNING STATUS REPORT ● JUNE 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 the it is unlikely to cause significant disruption in US health care in the next 3 years. An included topic may also be archived for one of the following reasons: (1) development of the intervention has ceased; or (2) the intervention has been clinically available outside the clinical research environment for longer than 1 year.

Reporting Period Summary The PCORI HCHSS began operating in December 2018. Since then, review of about 4000 leads has led to the identification of about 550 potential topics across the 5 PCORI priority areas and 100 high-level trends occurring in all areas of health care. After subjecting the potential topics to our inclusion criteria and nomination process, 268 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, 47 trends have been selected and are being actively monitored or were being monitored but have been archived within the past 3 months. These 268 topics and 47 trends are reported in this Status Report.

HORIZON SCANNING STATUS REPORT ● JUNE 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 product. 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: 11 topics (4%) • Cancer: 92 topics (34%) • Cardiovascular diseases: 28 topics (10%) • Mental and behavioral health: 18 topics (7%) • Rare diseases: 119 topics (44%) Note: Total does not equal 100% because of rounding.

Figure 1. Percentage of Topics by Priority Area

HORIZON SCANNING STATUS REPORT ● JUNE 2020 4 Across all priority areas, topics in this report represent the following therapeutic classes (also see Figure 2): • Cell therapy: 21 topics (8%) • Device (nonimplantable): 12 topics (4%) • Gene therapy: 17 topics (6%) • Immunotherapy: 3 topics (1%) • Implant: 8 topics (3%) • Monoclonal antibody: 12 topics (4%) • Other biotechnology: 22 topics (8%) • Pharmaceutical: 161 topics (61%) • Procedure (nonsurgical): 1 topic (0.4%) • Procedure (surgical): 1 topic (0.4%) • RNA interference: 3 topics (1%) • Viral vector therapy: 7 topics (3%) Note: Total does not equal 100% because of rounding.

Figure 2. Percentage of Topics by Therapeutic Class

HORIZON SCANNING STATUS REPORT ● JUNE 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 47 trends presented in this report, 6 themes have emerged (also see Figure 3): • Artificial intelligence and machine learning: 13 trends (28%) • Health information technology, apps, and smart devices: 9 trends (19%) • Innovative treatment models: 13 trends (28%) • Preventive measures: 2 trends (4%) • Proteomics, genomics, and personalized medicine: 8 trends (17%) • Screening and diagnostics: 2 trends (4%)

Figure 3. Percentage of Trends by Theme

HORIZON SCANNING STATUS REPORT ● JUNE 2020 6 Section 1. Alzheimer’s Disease and Other Dementias: 11 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 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 enzyme p38 alpha mitogen-activated protein kinase (MAPK) music therapy, pet therapy) Quality of life Clinical trial(s): Phase 2 AscenD- dementia and have received under study to treat Lewy body dementia. Chronically active Cholinesterase inhibitors LB primary completion June cholinesterase inhibitor p38 alpha purportedly plays a role in the alpha synuclein– (off-label) 2020 therapy for more than 3 associated toxicity observed in the brains of patients with Parkinson disease months Lewy body dementia. Neflamapimod purportedly improves medications (eg, carbidopa- synaptic dysfunction by inhibiting chronically activated p38 levodopa) alpha, which may slow or reverse cognitive impairment associated with Lewy body dementia. In clinical trials, neflamapimod is given orally at a dosage of 40 mg twice or thrice daily with food for 16 weeks. Developer(s): EIP Pharma, Inc (Boston, 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 Clinical trial(s): Phase 3b who have prodromal to mild antibody against amyloid beta (Aβ) intended as a disease- donepezil, galantamine, Overall survival 221AD304 primary completion Alzheimer’s disease (AD) modifying therapy for AD. According to the manufacturer, rivastigmine) Quality of life September 2023; phase 3 aducanumab preferentially binds neurotoxic oligomeric forms Supportive care EMERGE terminated August of Aβ, inhibits new Aβ aggregation, and promotes the 2019, topline data presented disaggregation of existing Aβ aggregates, including plaques. December 2019; phase 3 In clinical trials, aducanumab was given intravenously at one of ENGAGE primary terminated 2 unspecified doses. August 2019, topline data Developer(s): presented December 2019 Biogen (Cambridge, Massachusetts), in collaboration with Note(s): This topic had been Neurimmune AG (Schlieren-Zurich, Switzerland) and Eisai Co, archived in the June 2019 Ltd (Tokyo, Japan) 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 91 years Brexpiprazole (Rexulti) is an atypical antipsychotic medication 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 condition, they carry an increased risk of death in patients with Atypical antipsychotics (eg, Note(s): Brexpiprazole is FDA dementia. Brexpiprazole might have a better safety profile aripiprazole) approved to treat than other antipsychotics. According to the manufacturer, schizophrenia and as adjunctive Beta-adrenergics brexpiprazole is a partial agonist (ie, activator) of serotonin 1A treatment for major depressive (5-HT1A) and dopamine 2 (D2) receptors and an antagonist of Caregiver intervention and disorder (MDD) serotonin 2A (5-HT2A) receptors. Brexpiprazole might also bind environmental modification to noradrenaline α1B/2C receptors. In clinical trials, (eg, removed or alleviated brexpiprazole is given orally at a dosage of 1 to 3 mg once stressors) daily for 10 to 14 weeks. Synthetic Developer(s): tetrahydrocannabinol Otsuka Holdings Co, Ltd (Tokyo, Japan), in collaboration with H Lundbeck A/S (Valby, Denmark)

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 80 years COR388 is a bacterial protease inhibitor that targets the Cholinesterase inhibitors (eg, Cognitive performance, Clinical trial(s): Phase 2/3 GAIN who have mild to moderate infectious pathogen Porphyromonas gingivalis gingipains, a donepezil, galantamine, measured by Alzheimer’s primary completion December Alzheimer’s disease (AD) bacterium purportedly linked to periodontal disease and AD rivastigmine) Disease Assessment 2021 and linked to the production of amyloid beta (Aβ) in preclinical Memantine (off-label) Scale-Cognitive Subscale and clinical models. P gingivalis gingipains is found in the 11 brain tissue and cerebral spinal fluid of people with AD. Progression of AD COR388 purportedly could be the first disease-modifying Quality of life treatment to reduce brain infection, block Aβ production, reduce neuroinflammation, and impart neuroprotection for patients with mild to moderate AD. In clinical trials, COR388 is given by mouth in 40- or 80-mg capsules twice daily. Developer(s): Cortexyme, Inc (San Francisco, California)

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 modify disease in AD. It is intended to slow or donepezil, galantamine, Morbidity COGNITE primary completion Alzheimer’s disease (AD) reverse cognitive and functional decline in patients with early- rivastigmine) Mortality December 2020, designed stage AD. Cromolyn acts as an amyloid beta (Aβ) under Special Protocol Supportive care Quality of life polymerization inhibitor to purportedly block the development Assessment and spread of Aβ plaques. The ibuprofen component is intended to reduce neuronal inflammation caused by existing plaques. In clinical trials, cromolyn is inhaled and ibuprofen is given orally (dosage and treatment duration are unspecified for both components). Developer(s): AZTherapies, Inc (Boston, Massachusetts)

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 the progression of AD. No such treatments rivastigmine) Quality of life completion June 2020; phase are available, and current treatments address only symptoms. Memantine (off-label) 1/2 primary completion January PGRMC1 is a cell-surface protein expressed in brain synapses 2021 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)

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 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 proteins 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): TauRx Pharmaceuticals, Ltd (Singapore, Republic of Singapore)

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, topline data reported exchanging the patient’s albumin with Albutein solution. October 2018, data reported Memantine (off-label) Quality of life Investigators theorize that, because most amyloid beta (Aβ) December 2019 protein is bound to albumin and circulating in plasma, plasma Note(s): FDA approved a exchange might “flush“ Aβ from the brain into the circulation, Biologics License Application mitigating cognitive decline. In clinical trials, treatment groups for Albutein in 1978 as were assigned to receive either a high dose (total plasma adjunctive therapy for patients exchange once weekly, 2.5 to 3.0 L plasma removal with with hypovolemia, albumin replacement for 6 weeks) or a low dose (low-volume cardiopulmonary bypass plasma exchange monthly, 650-880 mL plasma removal with a procedures, hypoalbuminemia, low dose of albumin or immunoglobulin for 12 months). and plasma exchange Developer(s): Grifols SA (Barcelona, Spain)

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 50 to 90 years Pimavanserin (Nuplazid) is a selective serotonin inverse Supportive care Psychosis symptom Submission date: Supplemental who have dementia-related agonist that is intended to treat dementia-related psychosis. severity New Drug Application psychosis No medications are FDA approved for dementia-related Frequency of submission planned for 2020 psychosis. Pimavanserin is intended to improve patient health hospitalizations FDA designation(s): outcomes and quality of life by reducing hallucinations and Quality of life Breakthrough Therapy delusions, which are experienced by about 30% of dementia Clinical trial(s): Phase 3 patients. Pimavanserin purportedly preferentially inhibits the HARMONY completed October activity of serotonin 2A (5-HT2A) receptor that is associated 2019, pivotal data presented with dementia-related psychosis. The exact mechanism of December 2019 action is unknown. In a clinical trial, pimavanserin was given by Note(s): FDA approved mouth at a dosage of 20 or 34 mg once daily, and patients pimavanserin to treat were followed for up to 26 weeks or until a relapse of hallucinations and delusions psychosis occurred. associated with Parkinson Developer(s): disease psychosis in April 2016 Acadia Pharmaceuticals, Inc (San Diego, California)

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 12 Section 2. Cancer: 92 Topics

Table 2.1. Cancer Topics Added Since Last Status Report: 12 Topics

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

Adults aged 18 years or older Belantamab mafodotin (GSK2857916) is an immunoconjugate Various regimens including Progression-free survival Submission date: Biologics who have relapsed or targeting B-cell maturation antigen (BCMA) under study to one or more of the Overall survival License Application submitted refractory multiple myeloma treat relapsed MM or MM that has not responded to following: Quality of life January 21, 2020; Priority (RRMM) treatment. A number of agents have been approved in recent Anti-CD38 monoclonal Review years to treat MM, but the disease is considered incurable and antibodies (eg, FDA designation(s): Orphan most patients develop progressive disease. Effective novel daratumumab) Drug, Breakthrough Therapy treatments are needed that have potential to improve Corticosteroids (eg, Clinical trial(s): Phase 2 outcomes when used in combination with existing treatments dexamethasone) DREAMM-2 primary or after patients have exhausted existing treatment options. Cytotoxic drugs (eg, completion June 2019, data Belantamab mafodotin consists of a humanized, anti-BCMA bendamustine, published February 2020; phase monoclonal antibody conjugated to the cytotoxic drug cyclophosphamide) 3 DREAMM-3 primary monomethyl auristatin F. BCMA has been proposed as a completion July 2021; phase 3 biomarker for targeting MM because it is highly expressed in Histone deacetylase inhibitors (eg, DREAMM-9 primary malignant plasma cells. Binding of BCMA by belantamab completion June 2025 mafodotin purportedly triggers cell take-up and release of the panobinostat) cytotoxic drug, targeting delivery of the drug to MM cells. In Immunomodulatory drugs clinical trials, belantamab mafodotin is given intravenously at a (eg, lenalidomide, dosage of 2.5 or 3.4 mg/kg once every 3 weeks until disease pomalidomide) progression or unacceptable toxicity. Nuclear export inhibitors Developer(s): (eg, selinexor) GlaxoSmithKline (Brentford, United Kingdom) Proteasome inhibitors (eg, bortezomib, carfilzomib) SLAMF7 stimulatory antibodies (eg, elotuzumab)

Section 2. Cancer 13

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

Adults aged 55 years or older CC-486 is a hypomethylating agent under study as a Hypomethylating agents Overall survival PDUFA date: September 3, who have acute myeloid maintenance treatment for AML. Treatments for AML (eg, azacitidine, decitabine) Progression-free survival 2020; Priority Review leukemia (AML) that is in frequently achieve complete remission, which is characterized Quality of life Clinical trial(s): Phase 3 remission after first-line by normalized blood counts and no evidence of leukemic QUAZAR AML-001 primary induction chemotherapy blasts in the bone marrow. However, even with subsequent completion July 2019, data therapy after remission, AML frequently recurs. In particular, reported December 2019 older patients ineligible for intensive consolidation therapy (eg, allogeneic hematopoietic stem cell transplantation [HSCT]) experience relapse at a rate as high as 70% to 80%. Therefore, novel, less intensive therapies are needed. CC-486 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, CC-486 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 14

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

Adults aged 18 years or older Eryaspase (ERY001) consists of L-asparaginase encapsulated One or more of the Overall survival Clinical trial(s): Phase 2/3 who have locally advanced or inside donor-derived red blood cells to treat metabolically following: Progression-free survival TRYbeCA-2 primary completion metastatic triple-negative active tumors. TNBC is a metabolically active cancer associated Alkylating agents (eg, Quality of life December 2020 breast cancer (TNBC) and have with a poorer prognosis when compared with other breast cyclophosphamide) had no previous systemic cancer subtypes because of a lack of effective treatment Anthracyclines (eg, therapy options. L-asparaginase is an enzyme that hydrolyzes the doxorubicin) amino acid asparagine into aspartic acid and ammonia, which Antimetabolites (eg, inhibits protein synthesis. Eryaspase-mediated depletion of capecitabine, gemcitabine) asparagine purportedly arrests cell proliferation and induces programmed cell death (ie, apoptosis). Encapsulating L- Immune checkpoint asparaginase in donor red blood cells purportedly prolongs inhibitors (eg, activity and decreases adverse events. In clinical trials, atezolizumab) for patients eryaspase is given as an intravenous infusion at a dosage of with tumors expressing 100 units/kg on days 1 and 8 of a 3-week cycle until disease programmed cell death progression or unacceptable toxicity, in combination with ligand 1 (PD-L1) gemcitabine (1000 mg/m2) plus carboplatin (AUC 2). Poly adenosine Developer(s): diphosphate-ribose polymerase (PARP) Erytech Pharma SA (Lyon, France) inhibitors (eg, niraparib, olaparib) for patients with BRCA1/2 mutations Taxanes (eg, docetaxel, paclitaxel) Vinca alkaloid (eg, vinorelbine)

Section 2. Cancer 15

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

Adults aged 18 years or older Galinpepimut-S is a therapeutic cancer vaccine under study Hypomethylating agents Overall survival FDA designation(s): Orphan who have relapsed acute that targets the WT1 antigen to treat AML. Treatments for (eg, azacitidine, decitabine) Progression-free survival Drug, Fast Track myeloid leukemia (AML) in AML frequently achieve complete remission, which is Quality of life Clinical trial(s): Phase 3 REGAL complete remission after characterized by normalized blood counts and no evidence of primary completion December second-line induction therapy, leukemic blasts in the bone marrow. However, even with 2021 who are ineligible to receive an subsequent therapy after remission, AML frequently recurs. In allogeneic stem cell transplant, particular, older patients ineligible for intensive consolidation and whose leukemic cells therapy (eg, allogeneic hematopoietic stem cell express the Wilms tumor transplantation [HSCT]) experience relapse at a rate as high as protein (WT1) antigen 70% to 80%. Therefore, novel, less intensive therapies are needed. 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-positive and CD8-positive T-cell responses against WT1-expressing cancer cells. In clinical trials, galinpepimut-S is administered 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 16

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

Adults aged 18 years or older JNJ-4528 is a chimeric antigen receptor (CAR) T-cell therapy One or more of the Overall survival FDA designation(s): Orphan who have relapsed and that has been engineered to target B-cell maturation antigen following: Progression-free survival Drug, Breakthrough Therapy refractory multiple myeloma (BCMA) using T cells isolated from a patient’s own blood Alkylating agents (eg, Quality of life Clinical trial(s): Phase 3 (RRMM) that has been treated sample. BCMA has been proposed as a potential target for bendamustine, CARTITUDE-4 primary with 2 or more lines of therapy CAR-T in MM because BCMA expression is limited to cyclophosphamide) completion April 2026; phase including a protease inhibitor, malignant plasma cells and nonessential normal cells (eg, Anthracyclines (eg, 1/2 CARTITUDE-1 primary immunomodulatory agent, or normal plasma cells, some mature B cells). To produce JNJ- doxorubicin) completion September 2021, anti-CD38 antibody 4528, autologous (ie, self-donated) T cells are transduced with Glucocorticoids (eg, data presented November 2019 a lentiviral vector encoding CARs with 2 unique binding dexamethasone) domains for BCMA. The BCMA CAR-transduced T cells are expanded in culture and then reintroduced into the patient. Immunomodulatory agents JNJ-4528 is intended to target malignant BCMA-expressing (eg, lenalidomide, plasma cells in patients with MM and to promote a robust pomalidomide) cellular immune response against these cells. In clinical trials, Monoclonal antibodies (eg, JNJ-4528 is given as a single intravenous infusion containing daratumumab, elotuzumab) 7.5 x 105 BCMA CAR-T cells/kg. Proteasome inhibitors (eg, Developer(s): bortezomib, ixazomib) Janssen Pharmaceutical, LLC (Titusville, New Jersey), a Topoisomerase inhibitors subsidiary of Johnson & Johnson, Inc (New Brunswick, New (eg, etoposide) Jersey)

Section 2. Cancer 17

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

Children aged 12 years or KD025 is an inhibitor of rho-associated coiled-coil kinase 2 Extracorporeal Mortality Submission date: New Drug older and adults who have (ROCK2) under study for treating chronic GVHD. GVHD is a photopheresis Quality of life Application planned for fourth chronic graft-versus-host life-threatening immune disorder that is a frequent Hydroxychloroquine Treatment response rate quarter of 2020 disease (GVHD) that has been complication of allogeneic hematopoietic stem cell Ibrutinib FDA designation(s): Orphan treated with 2 prior systemic transplantation (HSCT). It arises when donor T cells recognize Imatinib drug, Breakthrough Therapy GVHD therapies host cells as foreign because of their expression of Clinical trial(s): Phase 2 KD025- alloantigens and mount an immune response against host mTor inhibitors (eg, sirolimus) 208 primary completion tissues, leading to inflammation and fibrosis in multiple body October 2020, data presented Mycophenolate mofetil tissues. The standard treatment for chronic GVHD is February 2020; phase 2 KD025- corticosteroids; however, patients whose disease no longer Pentostatin 213 primary completion responds to steroids have poor long-term outcomes, with a Rituximab September 2020, interim data mortality rate of 70% to 80%, indicating the need for novel Ruxolitinib presented February 2020 treatments. ROCK2 has been shown to be involved in regulating proinflammatory cytokines such as interleukin (IL)- 17 and IL-21, which are involved in the pathogenesis of chronic GVHD. KD025 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, KD025 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 18

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

Adults aged 18 years or older Luspatercept-aamt (Reblozyl) is a red blood cell (ie, Hypomethylating agents Red blood cell transfusion Approval date: April 3, 2020 who have very low to erythrocyte) maturation agent under development to treat (eg, azacitidine, decitabine) dependence Clinical trial(s): Phase 3 intermediate risk anemia associated with MDS. Luspatercept-aamt is intended Lenalidomide Overall survival MEDALIST primary completion myelodysplastic syndrome to restore production of normal red blood cells, thus obviating June 2019, data published (MDS) with ring sideroblasts the need for repeat red blood cell transfusions and the January 2020; phase 3 and anemia that has not accompanying iron chelation therapy. Luspatercept-aamt is a COMMANDS primary responded to an first-in-class biologic that purportedly stimulates maturation completion April 2021; phase 3 erythropoiesis-stimulating of erythrocyte precursor cells differently from the body’s extension trial primary agent and requires transfusion natural erythropoietin, thereby increasing erythrocyte completion January 2028 of 2 or more red blood cell production. Luspatercept-aamt is a modified activin receptor Note(s): FDA has approved units over 8 weeks type IIB fusion protein that acts as a ligand trap for members luspatercept-aamt to treat of the transforming growth factor beta (TGF-beta) superfamily anemia in patients with β- involved in late-stage erythrocyte production. The thalassemia who require recommended dosage in the FDA-approved label is 1 mg/kg 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 19

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

Adults aged 18 years or older 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 survival Drug small cell lung cancer (SCLC) but eventually develops resistance. RRx-001 is intended to Alkylating agents (eg, Quality of life Clinical trial(s): Phase 3 that has progressed after 2 or overcome the disease’s resistance to platinum-based cyclophosphamide, REPLATINUM primary more lines systemic therapy chemotherapy and might improve health outcomes of patients temozolomide) completion November 2020 including prior platinum with limited treatment options. SCLC cells activate an innate Antimetabolites (eg, doublet chemotherapy immune checkpoint pathway in macrophages by gemcitabine) overexpressing the protein CD47, which interacts with signal Antitumor antibiotics (eg, regulatory protein-α (SIRPα) to prevent macrophage anthracyclines, mitomycin- phagocytosis and render tumor cells less sensitive to innate C) immune surveillance. Through an unknown mechanism of action, RRx-001 decreases the expression of both CD47 on Microtubule inhibitors (eg, tumor cells and SIRPα on macrophages. By reducing paclitaxel, vinorelbine) 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 20

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 survival Approval date: April 13, 2020 who have neurofibromatosis of the mitogen-activated protein kinase (MAPK) signaling Radiation therapy Quality of life FDA designation(s): Orphan type 1 (NF1) with symptomatic, pathway, which is often overactive in several types of cancers. Systemic chemotherapy (eg, Drug, Breakthrough Therapy inoperable plexiform It was recently approved by FDA. About 50% of patients with carboplatin, vincristine) Clinical trial(s): Phase 1/2 Sprint neurofibromas (PNs) NF1 develop PNs, benign tumors found in peripheral nerve 1 primary completion sheaths that can cause substantial complications, which September 2022, data include airway, bladder, bowel and/or motor dysfunction, published March 2020; phase disfigurement, pain, and visual impairment. Patients who have 1/2 INSPECT primary inoperable NF1-related PNs have no approved treatment completion August 2020 options. Selumetinib specifically targets the MAPK kinases 1 Note(s): This Accelerated and 2 (MEK1/2) to prevent activation of the downstream Approval requires the conduct extracellular signal-related kinase (ERK), which is associated of a further clinical trial to verify with cell growth and proliferation. Selumetinib purportedly and describe selumetinib’s prevents the uncontrolled proliferation of PNs and may clinical benefit 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 21

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

Adults aged 18 years or older Tazemetostat (Tazverik) is a first-in-class, small-molecule Bendamustine plus CD20 Progression-free survival PDUFA date: June 18, 2020; who have relapsed or enhancer of zeste homolog 2 (EZH2) inhibitor under study to antibody (eg, Overall survival Priority Review refractory follicular lymphoma treat follicular lymphoma, an indolent B-cell non-Hodgkin obinutuzumab, rituximab) Health-related quality of life FDA designation(s): Fast Track lymphoma. The disease typically responds well to initial CD20 monoclonal antibody Clinical trial(s): Phase 1/2 chemoimmunotherapy, but if disease progresses within 24 Ibritumomab tiuxetan primary completion November months of diagnosis and treatment, patients have limited Lenalidomide plus CD20 2019, data presented effective options and poor prognosis. EZH2 is an epigenetic antibody December 2019; phase 3 regulator of gene expression that affects histone methylation. primary completion June 2022 Methylation patterns promoted by EZH2 activity promote cell Phosphoinositide 3 kinase Note(s): Tazemetostat is FDA proliferation as well as growth and development of a (PI3K) inhibitor (eg, approved for treating lymphoma (ie, lymphomagenesis). Therefore, tazemetostat copanlisib, idelalisib) metastatic or locally advanced inhibition of EZH2 purportedly has therapeutic potential in epithelioid sarcoma not eligible follicular lymphoma. In particular, about 20% of follicular 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. In clinical trials, tazemetostat is taken by mouth at a dosage of 800 mg twice daily. Developer(s): Epizyme, Inc (Cambridge, Massachusetts)

Section 2. Cancer 22

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

Adults aged 18 years or older Trilaciclib (G1T28) is a small-molecule inhibitor of cyclin- One or more of the Overall survival Submission date: Rolling New who develop dependent kinases 4 and 6 (CDK4/6) intended to prevent following: Myelosuppression Drug Application Initiated myelosuppression during chemotherapy-induced myelosuppression. A common side Blood transfusion Quality of life December 2019 chemotherapy for extensive- effect of chemotherapy for many types of cancer is Bone marrow FDA designation(s): stage small cell lung cancer suppression of the blood-producing cells in the bone marrow. transplantation Breakthrough Therapy (SCLC) Termed myelosuppression, this condition decreases the Red blood cell growth Clinical trial(s): Phase 2 G1T28- number of red and white blood cells and platelets in the body factors (eg, darbepoetin, 05 primary completion July as chemotherapy continues. Ongoing myelosuppression can erythropoietin) 2018, data presented lead to serious complications. No preventive options are September 2019 available—the only options available treat myelosuppression White blood cell growth after it has occurred. These approaches include blood factors (eg, filgrastim, transfusions and growth factors intended to restore blood lenograstim, pegfilgrastim, cells. Trilaciclib purportedly makes blood-producing cells less sargramostim) 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 23

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

Adults aged 18 years or older Venetoclax (Venclexta) is a first-in-class, potent, selective One or more of the Overall survival Clinical trial(s): Phase 3 who have relapsed or inhibitor of the B-cell lymphoma-2 (BCL-2) protein. BCL-2 following: Progression-free survival CANOVA primary completion refractory multiple myeloma prevents programmed cell death (ie, is antiapoptotic). The Alkylating agents (eg, Quality of life January 2021 (RRMM) that has been treated chromosomal t(11;14) is among the most common and bendamustine, Note(s): FDA approved with 2 or more therapies that routinely tested genetic abnormalities in patients with MM; cyclophosphamide) venetoclax to treat many other included a protease inhibitor about 15% to 20% of patients with MM have it. Although this Anthracyclines (eg, cancers. See FDA-approved and an immunomodulatory molecular subtype is associated with poor prognosis with doxorubicin) labeling and prescribing agent and who harbor a available treatments, t(11;14)-positive MM may be particularly Glucocorticoids (eg, document for all approved translocation between sensitive to venetoclax because t(11;14)-positive MM cells dexamethasone) indications. chromosomes 11 and 14, purportedly depend on BCL-2 for survival. Therefore, BCL-2 t(11;14) inhibition by venetoclax purportedly induces programmed cell Immunomodulatory agents death of t(11;14)-positive MM cells. In clinical trials, venetoclax (eg, lenalidomide, is taken by mouth at a dosage of 800 mg once daily in pomalidomide) combination with dexamethasone taken by mouth at a dosage Monoclonal antibodies (eg, of 20 mg once every week of each 28-day cycle until disease daratumumab, elotuzumab) progression or intolerable toxicity. Proteasome inhibitors (eg, Developer(s): bortezomib, carfilzomib) AbbVie, Inc (North Chicago, Illinois), in collaboration with Topoisomerase inhibitors Genentech, Inc (South San Francisco, California), a subsidiary (eg, etoposide) of F Hoffman-La Roche AG (Basel, Switzerland)

Section 2. Cancer 24 Table 2.2. Currently Monitored Cancer Topics: 72 Topics

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

Adults aged 18 years or older Atezolizumab (Tecentriq) is a monoclonal antibody that One or more of the following: Overall survival Submission date: Supplemental who have locally advanced or targets programmed cell death ligand-1 (PD-L1), an inhibitory Anthracyclines (eg, Progression-free survival Biologics License Application metastatic hepatocellular surface molecule expressed by cells to modulate immune doxorubicin) Quality of life January 27, 2020 carcinoma (HCC) and have had responses. HCC, an aggressive cancer, has limited treatment Antimetabolites (eg, 5- FDA designation(s): Orphan no previous systemic therapy options and is a major cause of cancer deaths, so more fluorouracil, gemcitabine) Drug, Breakthrough Therapy effective treatment options are needed. A hallmark of cancer is Multikinase inhibitors (eg, Clinical trial(s): Phase 3 its ability to evade an immune response. Several types of lenvatinib, sorafenib) IMbrave150 primary cancer cells, including HCC, activate an immune checkpoint Platinum agents (eg, cisplatin, completion November 2020, pathway in T cells by overexpressing PD-L1, which binds to the data presented November 2019 programmed cell death-1 (PD-1) coinhibitory receptor and oxaliplatin) Note(s): FDA has approved limits the activation of cancer-specific T cells. Atezolizumab atezolizumab to treat many purportedly prevents the interaction between PD-1 and PD-L1 other cancers. See FDA- to release the brake on the immune checkpoint pathway. approved labeling and Atezolizumab treatment in combination with bevacizumab is prescribing document for all intended to restore anticancer immunity by inhibiting vascular approved indications. endothelial growth factor (VEGF)–related immunosuppression. In clinical trials, atezolizumab is given as an intravenous infusion at a dosage 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 25

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

Adults aged 18 years or older Avapritinib (BLU-285) is purportedly a potent and selective Tyrosine kinase inhibitors (eg, Progression-free survival Submission date: Supplemental who have advanced systemic oral type 1 kinase inhibitor of mutated kinases KIT and imatinib, midostaurin) Overall survival New Drug Application planned mastocytosis that includes platelet-derived growth factor receptor alpha (PDGFRA). It also Quality of life for second half of 2020 aggressive, indolent, or binds and inhibits the KIT D816V variant, the primary driver of FDA designation(s): smoldering systemic disease in up to 95% of patients with systemic mastocytosis. Breakthrough Therapy mastocytosis Because no FDA-approved treatments exist for this patient Clinical trial(s): Phase 2 population, patients need new treatment options. Avapritinib PATHFINDER primary broadly inhibits activating mutations in KIT and PDGFRA, completion May 2022; phase 2 which drive tumor cell division. Avapritinib is designed to act PIONEER primary completion against activation loop mutations in KIT and PDGFRA, which May 2021, data reported approved multikinase inhibitors do not inhibit. In clinical trials, December 2019, data avapritinib 300 mg is given orally once daily until disease presented March 2020; phase 1 progression or intolerable toxicity. EXPLORER primary completion Developer(s): November 2021, topline data Blueprint Medicines Corp (Cambridge, Massachusetts) reported December 2018, updated data reported June 2019

Adults aged 18 years or older Avasopasem manganese (GC4419) is intended to treat One or more of the following: Incidence of severe FDA designation(s): who are at risk for oral patients who are likely to develop OM. No effective treatments Localized therapy (eg, low- mucositis Breakthrough Therapy, Fast mucositis (OM) after are available for OM, a common side effect of anticancer level laser therapy, oral Cancer treatment Track chemoradiation therapy with therapies (eg, chemotherapy, radiation). GC4419 is a small- cryotherapy) adherence Clinical trial(s): Phase 3 ROMAN cisplatin and intensity- molecule superoxide dismutase mimetic drug intended to Supportive care (eg, oral Quality of life primary completion October modulated radiation therapy detoxify reactive oxygen species (ROS). ROS are overproduced hygiene protocols) 2020 for locally advanced, during chemoradiation therapy, overwhelming the body’s nonmetastatic head and neck superoxide dismutase enzymes and resulting in oxidative cancer 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 26

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

Adults aged 18 years or older Avatrombopag (Doptelet) is an oral thrombopoietin (TPO) Platelet transfusion Proportion of patients FDA designation(s): Orphan undergoing chemotherapy receptor agonist (ie, activator) intended for treating severe TPO agonists (eg, who did not require a Drug who develop severe thrombocytopenia that occurs as a side effect of eltrombopag, romiplostim; platelet transfusion or Clinical trial(s): Phase 3 primary thrombocytopenia, defined as chemotherapy. About 10% of patients undergoing off-label) reduction in completion November 2020; 2 platelet counts below chemotherapy develop chemotherapy-induced chemotherapy phase 3 trial topline data 9 50 × 10 /L measured at least 24 thrombocytopenia (CIT), and no drugs are approved to treat it. Proportion of patients expected in second half of 2020 hours apart CIT can complicate surgical procedures and chemotherapy who achieved platelet Note(s): FDA approved treatment and increases the likelihood of serious bleeding counts of more than avatrombopag in May 2018 for 9 events, which might require hospitalization. Avatrombopag 50 × 10 /L after treatment treating thrombocytopenia in purportedly stimulates the division and maturation of cells Proportion of patients adults with chronic liver disease responsible for platelet production (ie, megakaryocytes) from without major or (CLD) who are scheduled to bone marrow precursor cells. Avatrombopag activates the TPO nonmajor clinically undergo a procedure and in receptor by binding to a site distinct from the TPO binding site relevant bleeding June 2019 for treating chronic (ie, an allosteric site) and, therefore, does not compete with immune thrombocytopenia naturally occurring TPO. The agent could be used in combination with nonallosteric TPO agonists (eg, romiplostim). Avatrombopag is taken at an initial dosage of 20 mg (one 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 27

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

Adults aged 18 years or older Canakinumab (Ilaris) is a human monoclonal antibody that One or more of the following: Overall survival Clinical trial(s): Phase 3 who have locally advanced or binds and neutralizes the immune mediator activity of human ALK inhibitors (eg, alectinib, Progression-free survival CANOPY-2 primary completion metastatic non–small cell lung interleukin-1β (IL-1β), a member of the interleukin-1 (IL-1) crizotinib if ALK Quality of life February 2021; phase 3 cancer (NSCLC) of squamous family of cytokines. Canakinumab is intended as an addition to rearrangement positive; CANOPY-1 primary completion or nonsquamous origin that the standard of care and is designed to be a selective antibody ceritinib, crizotinib if ROS1 June 2022 has not been treated or that that binds with high affinity to IL-1β, but not to any other rearrangement positive) Note(s): FDA has approved has been previously treated member of the IL-1 family or IL-1β from another species. Angiogenesis inhibitors (eg, canakinumab to treat many with an immune checkpoint Canakinumab purportedly elicits an anti-inflammatory bevacizumab, ramucirumab) other diseases. See FDA- inhibitor in combination with response in the tumor microenvironment that blocks tumor Anthracyclines (eg, approved labeling and or after platinum-based proliferation and new blood vessel formation (ie, doxorubicin) prescribing document for all chemotherapy angiogenesis). Under specific conditions, IL-1β and other approved indications. inflammatory cytokines, which are produced primarily by Antimetabolites (eg, tumor-associated macrophages, play a role in the growth, gemcitabine, pemetrexed) vascularization, progression, and spread of cancer cells. In EGFR inhibitors (eg, afatinib, clinical trials, canakinumab is given as a subcutaneous erlotinib) if EGFR injection at an unspecified dose in combination with rearrangement positive intravenous docetaxel at a dose of 75 mg/m2 or intravenous Immune checkpoint inhibitors pembrolizumab at a dose of 200 mg plus platinum-based (eg, nivolumab, chemotherapy every 3 weeks until disease progression or pembrolizumab) intolerable toxicity. Platinum-based agents (eg, Developer(s): carboplatin, cisplatin) Novartis AG (Basel, Switzerland) Taxanes (eg, docetaxel, paclitaxel) Tropomyosin kinase inhibitors (eg, larotrectinib) if NTRK rearrangement positive Vinca alkaloids (eg, vinblastine, vinorelbine)

Section 2. Cancer 28

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

Adults aged 18 years or older Capmatinib (Tabrecta, INC280) is a potent and selective, small- One or more of the following: Overall survival Approval date: May 6, 2020 who have locally advanced or molecule inhibitor of the hepatocyte growth factor (HGF) Angiogenesis inhibitors (eg, Progression-free survival FDA designation(s): Orphan MET metastatic non–small cell lung receptor. A receptor tyrosine kinase encoded by the gene, bevacizumab, ramucirumab) Quality of life Drug, Breakthrough Therapy cancer (NSCLC) harboring an the HGF receptor is typically required for tissue and organ Anthracyclines (eg, Clinical trial(s): Phase 2 MET exon 14–skipping mutation in regeneration and damage repair. The incidence of gene doxorubicin) GEOMETRY mono-1 primary the mesenchymal-epithelial alterations in patients with NSCLC, including MET exon 14– Antimetabolites (eg, completion May 2021, data transition gene, MET skipping mutation and MET amplification, is about 2% to 4%. gemcitabine, pemetrexed) presented October 2019 MET-driven NSCLC is an aggressive disease with a poor Note(s): This Accelerated prognosis and limited treatment options. Approved by FDA, Immune checkpoint inhibitors Approval requires the conduct capmatinib is a novel targeted therapy intended to treat (eg, nivolumab, of a further clinical trial to verify patients harboring a MET exon 14–skipping alteration. pembrolizumab) and describe capmatinib’s Capmatinib is designed to interact with tyrosine 1230 and a Platinum agents (eg, clinical benefit hinge motif in the HGF receptor’s kinase domain, which causes carboplatin, cisplatin) it to adopt a unique autoinhibitory shape that prevents access Taxanes (eg, docetaxel, to its ATP binding site. Because capmatinib is highly specific paclitaxel) for the HGF receptor, it purportedly has fewer off-target Vinca alkaloids (eg, effects. In NSCLC cells, capmatinib purportedly blocks new vinblastine, vinorelbine) blood vessel formation (ie, angiogenesis), 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 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 29

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

Females aged 18 years or older Cediranib plus olaparib (Lynparza) is a combination drug One or more of the following: Overall survival Clinical trial(s): Phase 2b who have platinum-resistant, regimen under study for treating platinum-resistant, recurrent Angiogenesis inhibitors (eg, Progression-free survival CONCERTO primary completion recurrent ovarian cancer with ovarian cancer. Poly adenosine diphosphate-ribose bevacizumab) Quality of life August 2019 no evidence of a deleterious polymerase (PARP) inhibitors (eg, olaparib, rucaparib) have Anthracyclines (eg, germline variant in the breast been approved as monotherapies for recurrent ovarian cancer; doxorubicin, pegylated BRCA1 BRCA2 cancer genes or however, their use is limited to patients with deleterious liposomal doxorubicin) BRCA1 or BRCA2 variants, which sensitize cancer cells to PARP Taxanes (eg, docetaxel, inhibition. Research has demonstrated that cediranib, a small- paclitaxel) molecule tyrosine kinase inhibitor with activity against multiple receptor tyrosine kinases, can also sensitize cancer cells to PARP inhibition by suppressing the homologous recombinational repair pathway. Therefore, clinical trials are investigating whether the combined use of cediranib and olaparib is effective in treating ovarian cancer in patients who lack deleterious BRCA1/2 variants. In clinical trials, patients receive an oral dose of 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 30

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

Adults aged 18 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 survival drug multiforme (GBM) that has DCVax-L is a self-donated (ie, autologous) immunotherapy One or more of the following: Quality of life Clinical trial(s): Phase 3 GBM been surgically resected and comprising activated dendritic cells loaded with tumor Alkylating agents (eg, primary completion November treated with adjuvant radiation antigens derived from the patient’s own tumor. It is intended cyclophosphamide, lomustine, 2016, interim data published therapy and chemotherapy to improve outcomes by promoting an immune response procarbazine) May 2018, 3-year survival data against residual glioblastoma cells after surgical resection. Angiogenesis inhibitors (eg, reported November 2018, final DCVax-L is manufactured using monocytes obtained from the bevacizumab) top-line data to be reported patient through a leukapheresis process. The monocytes are end of July 2020 differentiated into dendritic cells in a laboratory and then mTOR inhibitors (eg, activated and loaded with patient-derived antigens from the everolimus) patient’s tumor tissue after surgical resection. The purified Platinum agents (eg, DCVax-L is then given to elicit adaptive immunity from T cells carboplatin, cisplatin) and B cells. Treatment begins at least 2 weeks before the first Vinca alkaloids (eg, vincristine) course of DCVax-L is given and involves total or near total tumor resection followed by conventional external beam radiation therapy and concurrent temozolomide chemotherapy. In clinical trials, DCVax-L containing 2.5 × 106 tumor lysate–pulsed dendritic cells is given as an intradermal injection in the upper arm at days 0, 10, and 20 and at weeks 8, 16, 32, 48, 72, 96, and 120. Developer(s): Northwest Biotherapeutics, Inc (Bethesda, Maryland)

Section 2. Cancer 31

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

Adults aged 18 to 75 years Devimistat (CPI-613) is intended as a first-line treatment for One or more of the following: Overall survival FDA designation(s): Orphan who have pancreatic pancreatic cancer because only about 5% of these patients Antimetabolites (eg, 5- Progression-free survival Drug adenocarcinoma with distant respond to the standard of care (ie, gemcitabine fluorouracil, gemcitabine) Quality of life Clinical trial(s): Phase 3 metastases that have not been chemotherapy). Devimistat is a small-molecule lipoate Chemoprotectant (eg, AVENGER 500 primary treated analogue drug intended to target the altered energy leucovorin) completion October 2021 metabolism of many cancers, including pancreatic DNA synthesis inhibitor (eg, adenocarcinomas. The altered energy metabolism of cancer irinotecan) cells frequently depends on the activity of the pyruvate dehydrogenase complex and the α-ketoglutarate EGFR inhibitor (eg, erlotinib) dehydrogenase complex. Devimistat purportedly Platinum-based agents (eg, downregulates metabolic pathways in cancer cells that depend cisplatin, oxaliplatin) on α-ketoglutarate and acetyl-CoA. In clinical trials, devimistat Taxanes (eg, docetaxel, is given by intravenous injection at a dosage of 500 mg/m2 on paclitaxel) days 1 and 3 of a 14-day cycle, followed 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)

Section 2. Cancer 32

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

Adults aged 18 years or older Dianhydrogalactitol (VAL-083) is a small-molecule drug that One or more of the following: Overall survival FDA designation(s): Orphan who have recurrent malignant causes N7 DNA alkylation. It is intended to treat recurrent Alkylating agents (eg, Progression-free survival Drug, Fast Track glioma (eg, glioblastoma malignant gliomas, which often become resistant to the carmustine, Quality of life Clinical trial(s): Phase 2 DLM- multiforme [GBM]) standard-of-care temozolomide therapy because the tumor cyclophosphamide, 16-001 primary completion 6 expresses high levels of an enzyme (O -methylguanine-DNA- procarbazine) September 2020, data methyltransferase [MGMT]) that helps repair DNA. Patients Angiogenesis inhibitors (eg, published December 2019 need better treatment options, and VAL-083’s novel N7 DNA bevacizumab) alkylation activity is intended to overcome MGMT-mediated mTOR inhibitors (eg, resistance. In clinical trials, VAL-083 is given as an intravenous everolimus) infusion at a dosage of 30 mg/m2 on days 1, 2, and 3 of a 21- day treatment cycle, for up to twelve 21-day treatment cycles. Platinum-based drugs (eg, carboplatin, cisplatin) Developer(s): Vinca alkaloids (eg, vincristine) DelMar Pharmaceuticals, Inc (San Diego, California)

Section 2. Cancer 33

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

Adults aged 18 years or older Dusquetide (SGX942) is intended to treat OM, which has no One or more of the following: Duration of severe FDA designation(s): Orphan who are at risk for oral effective treatments and is a common side effect of anticancer Analgesics (eg, lidocaine, mucositis Drug, Fast Track mucositis (OM) during therapies (eg, chemotherapy, radiation). It affects about 80% narcotics) Incidence of severe Clinical trial(s): Phase 3 DOM- chemoradiation therapy with of patients with oropharyngeal cancer. Dusquetide is a novel, Localized therapy (eg, low- mucositis INNATE primary completion cisplatin and image-modulated synthetic, water-soluble, 5-amino-acid peptide with anti- level laser therapy, oral Pain June 2020, topline data radiation therapy for locally inflammatory and anti-infective properties. It is a member of a cryotherapy) Cancer treatment expected fourth quarter of advanced, nonmetastatic drug class called innate defense regulators. Dusquetide targets Supportive care (eg, oral adherence 2020 squamous cell carcinoma of the innate immune system and binds to an intracellular hygiene protocols) Note(s): National Institutes of the oral cavity or oropharynx adaptor protein, sequestosome-1. Also called p62, this protein Incidence of bacterial infection Health selected SGX942 for its has a pivotal function in signal transduction during activation Small Business Innovation Quality of life and control of the innate immune system. In clinical trials, Research/Small Business dusquetide is given as a 4-minute intravenous infusion at a Technology Transfer dosage of 1.5 mg/kg twice weekly, starting within 3 days after Commercialization Accelerator initiating radiation therapy and continuing through 2 weeks Program in September 2018 after completing radiation therapy. Developer(s): Soligenix, Inc (Princeton, New Jersey)

Adults aged 18 years or older Encorafenib (Braftovi) plus cetuximab (Erbitux) is a Checkpoint inhibitors (eg, Overall survival Approval date: April 8, 2020 who have metastatic colorectal combination therapy for treating metastatic BRAF V600E nivolumab with or without Progression-free survival FDA designation(s): Priority cancer (CRC) that has mutation–positive CRC. This type of cancer is associated with ipilimumab, pembrolizumab) Quality of life Review (BRAFTOVI Doublet) progressed after one or 2 poor prognosis, and patients have a median overall survival of FOLFIRI (ie, leucovorin [folinic Clinical trial(s): Phase 3 previous regimens and has a 4 to 6 months after failure of initial therapy. Unlike treatments acid], 5-fluorouracil, and BEACON CRC completed BRAF- mutation at V600E in the B-Raf for other mutated cancers (eg, melanoma), BRAF irinotecan) with or without February 2019, data published proto-oncogene inhibitor monotherapy and BRAF/MEK inhibitor combination VEGF inhibitor (eg, October 2019 serine/threonine kinase gene, therapy have limited activity in BRAF V600E CRC due to bevacizumab, ziv-aflibercept, Note(s): In June 2018, FDA BRAF mitogen-activated protein kinase (MAPK) pathway reactivation ramucirumab) approved the combination through epidermal growth factor receptor (EGFR) signaling. FOLFOX (ie, leucovorin [folinic therapy of encorafenib and Therefore, combining BRAF/MEK inhibitors with an EGFR acid], 5-fluorouracil, and binimetinib (Braftovi and inhibitor might improve patients’ overall survival. DNA testing oxaliplatin) with or without Mektovi, respectively) for for somatic BRAF V600E mutation will be needed to determine bevacizumab unresectable or metastatic the patient’s eligibility before starting this combination Regorafenib melanoma with a BRAF V600E treatment. The recommended dosage in the FDA-approved or V600K mutation, as detected label is 300 mg of oral encorafenib once daily and standard Trifluridine plus tipiracil by an FDA-approved test weekly dosing of cetuximab by infusion. Developer(s): Array BioPharma, Inc (Boulder, Colorado), a subsidiary of Pfizer, Inc (New York, New York)

Section 2. Cancer 34

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

Adults aged 18 years or older Enfortumab vedotin (Padcev), approved by FDA, provides an One or more of the following: Overall survival Approval date: December 18, who have locally advanced or option for patients whose cancer has not responded to Alkylating agents (eg, Progression-free survival 2019 metastatic urothelial cancer standard of care. These patients have limited options and poor ifosfamide) Quality of life FDA designation(s): (mUC) and have previously outcomes. Enfortumab is a monoclonal antibody conjugated Antimetabolites (eg, Breakthrough Therapy, Priority received a programmed cell to a chemotherapy drug (ie, vedotin), designed to bind the gemcitabine, pemetrexed) Review death-1 (PD-1) or programmed surface receptor nectin 4. Vedotin is a synthetic auristatin with Immune checkpoint inhibitors Clinical trial(s): Phase 3 EV-301 cell death ligand-1 (PD-L1) cytotoxic activity that blocks the formation of microtubules. (eg, atezolizumab, primary completion September inhibitor and a platinum- The adhesion protein nectin 4 is highly expressed in various durvalumab) 2021; phase 2 EV-201 primary containing chemotherapy in types of solid tumors, including urothelial cancer. Enfortumab completion November 2020, the neoadjuvant/adjuvant, vedotin purportedly triggers internalization of the drug into Platinum agents (eg, carboplatin, cisplatin) data presented September locally advanced, or metastatic the cells. This increases vedotin’s likelihood of targeting and 2019; single-arm clinical trial Taxanes (eg, docetaxel, setting killing malignant cells while minimizing cytotoxicity on normal data presented in FDA- paclitaxel) cells. The recommended dosage in the FDA-approved label is approved labeling and 1.25 mg/kg (up to a maximum dose of 125 mg) given as an prescribing document intravenous infusion over 30 minutes on days 1, 8, and 15 of a Note(s): This Accelerated 28-day cycle until disease progression or unacceptable Approval requires the conduct toxicity. of a further clinical trial to verify Developer(s): and describe Padcev’s clinical Seattle Genetics, Inc (Bothell, Washington), in collaboration benefit with Astellas Pharma, Inc (Tokyo, Japan)

Section 2. Cancer 35

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

Adults aged 18 years or older Eprenetapopt (APR-246) is a small-molecule anticancer drug. It Azacitidine Overall survival FDA designation(s): Orphan who have myelodysplastic purportedly restores and reactivates wild-type p53 Decitabine Progression-free survival Drug, Fast Track, Breakthrough syndrome (MDS) with at least conformation and function in myelodysplastic cells, causing Erythropoiesis-stimulating Quality of life Therapy one genetic variant in the initiation of programmed cell death (ie, apoptosis) in cancer agents (eg, darbepoetin alfa, Clinical trial(s): Phase 3 primary TP53 tumor protein p53 gene, cells. Triggering programmed cell death of myelodysplastic epoetin alfa, filgrastim) completion June 2020 cells might restore proper bone marrow function, including Luspatercept-aamt blood cell production and function. MDSs represent a spectrum of blood stem cell malignancies in which the bone marrow fails to produce sufficient quantities of 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)

Adults aged 18 years or older Etirinotecan pegol (Onzeald) is a novel drug-polymer form of One or more of the following: Overall survival FDA designation(s): Fast Track who have advanced breast the topoisomerase I inhibitor irinotecan. The drug-polymer Alkylating agents (eg, Progression-free survival Clinical trial(s): Phase 3 cancer with stable brain form is intended to reduce treatment-related adverse events cyclophosphamide) Quality of life BEACON completed June 2016, metastases that has been in patients with breast cancer and brain metastases. Anthracyclines (eg, pivotal data published treated with one or 2 cytotoxic Etirinotecan pegol links to a macromolecule core. This linkage doxorubicin) November 2015, quality-of-life regimens purportedly renders the drug inert in the bloodstream and Antimetabolites (eg, data published May 2017; allows its slow release as the patient’s body metabolizes the fluorouracil, gemcitabine, phase 3 ATTAIN primary linkages. Slow release extends the time the cancer is exposed pemetrexed) completion July 2020 to therapeutic levels of the drug and limits high levels of drug exposure during infusion. Additionally, the large drug-polymer Poly adenosine diphosphate- conjugate might preferentially accumulate in tumor tissues ribose polymerase (PARP) because of the increased permeability of tumor vasculature. In inhibitors (eg, niraparib, clinical trials, etirinotecan pegol is given as an intravenous olaparib, rucaparib) infusion at a dosage of 145 mg/m2 once every 21 days until Taxanes (eg, docetaxel, nab- disease progression or intolerable toxicity. paclitaxel, paclitaxel) Developer(s): Vinca alkaloid (eg, vinorelbine) Nektar Therapeutics, Inc (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 aged 18 years or older Fam-trastuzumab deruxtecan-nxki (Enhertu) is a monoclonal One or more of the following: Overall survival Clinical trial(s): Phase 3 who have locally advanced or antibody conjugated with a chemotherapy drug (ie, Alkylating agents (eg, Progression-free survival DESTINY-Breast04 primary metastatic, hormone receptor deruxtecan) designed to bind the surface receptor HER2, a cyclophosphamide) Quality of life completion January 2023 (HR)–positive or HR-negative, protein commonly associated with certain subtypes of breast Anthracyclines (eg, Note(s): FDA approved fam- human epidermal growth cancer. Front-line therapy for breast cancers expressing low doxorubicin, epirubicin, trastuzumab deruxtecan-nxki to factor receptor 2 (HER2)–low HER2 levels relies on single-agent chemotherapy, but no liposomal doxorubicin) treat HER2-positive breast breast cancer that has therapies are approved specifically for low HER2–expressing Antimetabolites (eg, cancer in December 2019 progressed or recurred after tumors, and fam-trastuzumab deruxtecan-nxki might provide capecitabine, 5-fluorouracil, one or 2 lines of systemic a new option for these patients. Deruxtecan inhibits the gemcitabine, methotrexate, therapy activity of topoisomerase I, an enzyme that relieves DNA pemetrexed) supercoiling, leading cells to cease their cell cycle and die because of replication-dependent, site-selective, DNA double- Immune checkpoint inhibitors strand breaks. Fam-trastuzumab deruxtecan-nxki purportedly (eg, atezolizumab) binds to HER2 and triggers internalization of the drug into the Microtubule inhibitors (eg, cells. This increases the likelihood that deruxtecan will target eribulin, ixabepilone) and kill malignant cells while minimizing toxicity on normal Platinum agents (eg, cells. In clinical trials, fam-trastuzumab deruxtecan-nxki is carboplatin, cisplatin) given intravenously at a dosage of 5.4 mg/kg once every 21 Poly adenosine diphosphate- days until disease progression or intolerable toxicity. ribose polymerase (PARP) Developer(s): inhibitors (eg, olaparib, Daiichi Sankyo Co, Ltd (Tokyo, Japan), in collaboration with talazoparib) AstraZeneca (Cambridge, United Kingdom) Taxanes (eg, docetaxel, nab- paclitaxel, paclitaxel) Vinca alkaloids (eg, vinorelbine)

Section 2. Cancer 37

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

Adults aged 18 years or older Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor One or more of the following: Overall survival Submission date: Biologics who have relapsed and (CAR) T-cell therapy that has been engineered to target B-cell Alkylating agents (eg, Progression-free survival License Application March 2020 refractory multiple myeloma maturation antigen (BCMA) using autologous T cells isolated bendamustine, Quality of life FDA designation(s): Orphan (RRMM) that has been treated from a patient’s blood sample. Patients whose disease has cyclophosphamide) Drug, Breakthrough Therapy with 3 or more lines of progressed after 3 prior treatment lines have a very poor Anthracyclines (eg, Clinical trial(s): Phase 2 KarMMa chemotherapy that included a prognosis and no options, so they need new and better doxorubicin) primary completion November protease inhibitor, an treatments. The collected T cells are genetically modified with Glucocorticoids (eg, 2024, data reported December immunomodulatory agent, and a lentiviral vector (ie, transduction) encoding CARs with a dexamethasone) 2019; phase 3 KarMMa-3 an anti-CD38 antibody unique anti-BCMA single-chain variable fragment (ie, BB2121) primary completion June 2025 fused to the hinge and transmembrane domains of CD8α, the Immunomodulatory agents costimulatory domain (ie, 4-1BB) of CD137, and the signaling (eg, lenalidomide, domains of CD3ζ. The BB2121 CAR-transduced T cells that pomalidomide, thalidomide) compose idecabtagene vicleucel are proliferated and then Monoclonal antibodies (eg, reintroduced into the patient. The treatment purportedly daratumumab, elotuzumab) targets malignant BCMA-expressing plasma cells in patients Proteasome inhibitors (eg, with multiple myeloma cells and promotes robust cellular bortezomib, carfilzomib, activity against these cells to treat the disease. BCMA has been ixazomib) proposed as a biomarker for targeting multiple myeloma Topoisomerase inhibitors (eg, because it is highly expressed in malignant plasma cells. In etoposide) clinical trials, idecabtagene vicleucel is given as a single intravenous infusion at a dose ranging from 1.5 × 108 to 4.5 × 108 anti-BCMA CAR-T cells. Developer(s): bluebird bio, Inc (Cambridge, Massachusetts), in collaboration with Bristol-Myers Squibb Co (New York, New York)

Section 2. Cancer 38

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

Adults aged 18 years or older Infigratinib (BGJ398) is a novel, highly selective, small- One or more of the following: Overall survival FDA designation(s): Orphan who have locally advanced or molecule inhibitor of 3 members of the fibroblast growth Antimetabolites (eg, Progression-free survival Drug, Fast Track metastatic, recurrent factor receptor (FGFR) family (ie, 1, 2, and 3). gemcitabine) Quality of life Clinical trial(s): Phase 3 PROOF cholangiocarcinoma that Cholangiocarcinoma is a rare cancer that forms in bile ducts, Platinum agents (eg, cisplatin, primary completion September harbors fusions or which carry fluid between the liver, the gallbladder, and the oxaliplatin) 2023 translocations in the fibroblast small intestine. Because about 20% of cholangiocarcinoma growth factor receptor 2 gene, cases contain FGFR2 genetic alterations, using infigratinib to FGFR2 target only FGFRs has the potential to improve outcomes of patients with 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 schedule of 3 weeks on, 1 week off, 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 39

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 following: Overall survival FDA designation(s): Orphan who have active, relapsed, or conjugate composed of the CD45-specific monoclonal Anthracyclines (eg, Progression-free survival Drug refractory acute myeloid antibody apamistamab linked to the radioisotope iodine-131. daunorubicin, idarubicin) Quality of life Clinical trial(s): Phase 3 SIERRA leukemia (AML) with leukemic AML is the most common type of acute leukemia, and patients Antibody-drug conjugates primary completion December cells expressing CD45 with relapsed or refractory AML have limited treatment (eg, gemtuzumab ozogamicin) 2020, preliminary data reported options and poor outcomes. Iomab-B is under study for use as Antimetabolites (eg, October 2019, data presented an induction and conditioning agent before hematopoietic cytarabine, fludarabine) December 2019, midpoint data stem cell transplantation (HSCT) or other cellular therapies. presented February 2020 Apamistamab binding to CD45, a receptor purportedly B-cell lymphoma-2 (BCL-2) involved in promoting AML cell proliferation, leads to Iomab-B inhibitors (eg, venetoclax) cell internalization and leukemic cell death through targeted DNA synthesis inhibitors (eg, radiation delivery. In clinical trials, Iomab-B is administered as etoposide, mitoxantrone) a component of a reduced-intensity conditioning regimen FLT3 inhibitors (eg, gilteritinib, containing fludarabine and low-dose total body irradiation sorafenib) before allogeneic HSCT. Hypomethylating agents (eg, Developer(s): azacitidine, decitabine) Actinium Pharmaceuticals, Inc (New York, New York) IDH inhibitors (eg, enasidenib, ivosidenib)

Adults aged 18 years or older KTE-X19 is a chimeric antigen receptor (CAR) T-cell therapy One or more of the following: Overall survival PDUFA date: August 10, 2020; who have relapsed or consisting of genetically modified autologous (ie, self- Cyclophosphamide Progression-free survival Priority Review refractory mantle cell donated) T cells intended to generate specific immune Cytarabine Quality of life FDA designation(s): Orphan lymphoma (MCL) that has responses against the CD19 antigen expressed on the Dexamethasone Drug, Breakthrough Therapy failed to respond to or surface of B cells. MCL is a rare form of non-Hodgkin Doxorubicin Clinical trial(s): Phase 2 ZUMA-2 relapsed after at least one prior lymphoma that arises from cells originating in the mantle primary completion July 2019, Methotrexate regimen zone of the lymph node and typically affects males older data published April 2020 than 60 years of age. KTE-X19 uses the same construct as the Platinum agents (eg, existing CAR-T 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 therapy. In clinical trials, KTE-X19 is given as a single intravenous infusion at a dose of 1 x 106 cells/kg. Developer(s): Kite Pharma, a Gilead company (South San Francisco, California)

Section 2. Cancer 40

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

Adults aged 18 years or older Lifileucel (LN-144) is a self-donated (ie, autologous) cell One or more of the following: Overall survival Submission date: Biologics who have locally advanced or therapy that uses T cells isolated from the patient’s melanoma Alkylating agents (eg, Progression-free survival License Application planned for metastatic melanoma that has tumor. Lifileucel uses a personalized therapy strategy that dacarbazine, temozolomide) Quality of life fourth quarter of 2020 progressed after one or more relies on naturally occurring T cells, called tumor-infiltrating BRAF inhibitors (eg, FDA designation(s): Orphan lines of standard systemic lymphocytes (TILs), that can penetrate cancerous tumors. The dabrafenib, vemurafenib) Drug, Fast Track, Regenerative therapy extracted TILs are expanded in culture until reaching a count Immunotherapy (eg, Medicine Advanced Therapy of billions of cells. Lifileucel is intended as a tumor-specific ipilimumab, nivolumab, Clinical trial(s): Phase 2 C-144- therapy to overcome the tumor’s immune-suppressive pembrolizumab) 01 primary completion July environment and promote its elimination. In clinical trials, MEK inhibitors (eg, trametinib) 2020, safety and efficacy data lifileucel is given as an intravenous infusion followed by up to presented May 2019, data Platinum-based agents (eg, 6 doses of interleukin-2 (IL-2) to support growth and reported November 2019 activation of TILs. carboplatin) Developer(s): Taxane agents (eg, paclitaxel) Iovance Biotherapeutics, Inc (San Carlos, California), in collaboration with the National Institutes of Health’s National Cancer Institute (Bethesda, Maryland)

Females aged 18 years or older LN-145 is a self-donated (ie, autologous) T-cell therapy that One or more of the following: Overall survival Submission date: Biologics who have recurrent, metastatic, uses cells isolated from the patient’s cervical cancer. LN-145 Alkylating agents (eg, Disease-free survival License Application planned for or persistent cervical cancer relies on naturally occurring T cells called tumor-infiltrating ifosfamide) Quality of life second half of 2020 that is unsuitable for surgical lymphocytes (TILs) that can penetrate cancerous tumors. TILs Angiogenesis inhibitors (eg, FDA designation(s): resection and/or radiation isolated from a patient’s tumor are expanded in culture until bevacizumab) Breakthrough Therapy, Fast therapy. Patients must have reaching a count of billions of cells. LN-145 is intended as a Antimetabolites (eg, 5- Track received at least one and no tumor-specific therapy that can overcome the tumor’s fluorouracil, gemcitabine, Clinical trial(s): Phase 2 more than 3 prior systemic immune-suppressive environment and promote its pemetrexed) innovaTIL-04 primary therapy regimens. elimination. In clinical trials, LN-145 is given as an intravenous DNA synthesis inhibitors (eg, completion December 2021, infusion followed by up to 6 doses of interleukin-2 (IL-2) to data presented May 2019 support growth and activation of TILs. mitomycin-C) Developer(s): Immune checkpoint inhibitor (eg, pembrolizumab) Iovance Biotherapeutics, Inc (San Carlos, California) Taxanes (eg, albumin-bound paclitaxel, docetaxel) Topoisomerase inhibitors (eg, irinotecan)

Section 2. Cancer 41

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

Males aged 18 years or older 177Lu-PSMA-617 is a novel small-molecule radioligand therapy Supportive care Overall survival Clinical trial(s): Phase 3 VISION who have progressive made up of a high-affinity targeting ligand specific to PSMA Progression-free survival primary completion August prostate-specific membrane that is chemically linked with a radionucleotide called Time to first symptomatic 2020; phase 2 primary 177 177 antigen (PSMA)–positive, lutetium-177 ( Lu). Lu-PSMA-617 is intended to deliver skeletal event completion August 2020, data metastatic, castration-resistant systemic and targeted radiation, causing cell death to prostate presented May 2019 Quality of life prostate cancer (mCRPC) cancer cells. PSMA protein is highly expressed on the surface of most prostate cancer cells but absent on most normal cells. Eligibility for treatment requires a positive result from a 68Ga- PSMA-11 positron emission tomography/computed tomography (PET/CT) scan. After 177Lu-PSMA-617 purportedly attaches to prostate cancer cells via binding to PSMA, the 177Lu component emits beta-particle radiation intended to induce cytotoxic DNA damage to the tumor cells. In clinical trials, 177Lu-PSMA-617 is given intravenously at a dosage of 7.4 GBq (±10%) every 6 weeks for a maximum of 6 cycles. Developer(s): Endocyte, Inc (West Lafayette, Indiana), a subsidiary of Novartis AG (Basel, Switzerland)

Adults aged 18 years or older Lurbinectedin (Zepsyre) is a synthetic, marine-derived Chemoradiation therapy Overall survival PDUFA date: August 16, 2020; who have extensive-stage compound that selectively inhibits transactivated RNA Platinum-based agents (eg, Progression-free survival Priority Review small cell lung cancer (SCLC) polymerase II transcription. Patients with SCLC that no longer carboplatin, cisplatin) Quality of life FDA designation(s): Orphan refractory to a single platinum- responds to platinum chemotherapy have limited treatment Topoisomerase inhibitors (eg, Drug containing regimen options and a poor prognosis, and they need new therapy etoposide, topotecan) Clinical trial(s): Phase 3 options. Lurbinectedin selectively inhibits RNA polymerase ATLANTIS primary completed (Pol) II activity during the elongation phase of messenger RNA February 2020; phase 2 (mRNA) synthesis. Although lurbinectedin interacts with RNA PM1183-B-005-14 primary Pol II, it does not affect the activity of RNA Pol I, mitochondrial completion January 2021, data RNA Pol, or basal transcription machinery. Lurbinectedin’s presented June 2019 binding to RNA Pol II and inhibition of mRNA synthesis Note(s): New Drug Application purportedly induces cancer cell death by reducing the filed under Accelerated expression of cellular factors involved in tumor progression. In Approval regulations clinical trials, lurbinectedin is given intravenously at a dosage of 4 mg once every 3 weeks in combination with doxorubicin until disease progression or intolerable toxicity. Developer(s): Pharma Mar SA (Madrid, Spain), in collaboration with Jazz Pharmaceuticals plc (Dublin, Ireland)

Section 2. Cancer 42

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

Adults aged 18 years or older MDNA55 is a cytokine that specifically targets the interleukin- One or more of the following: Overall survival FDA designation(s): Orphan who have a recurrent 4 receptor (IL-4R). A surface receptor, IL-4R is reported to be Alkylating agents (eg, Progression-free survival Drug, Fast Track malignant glioma (eg, overexpressed in different types of cancer stem cells, including cyclophosphamide, Quality of life Clinical trial(s): Phase 2 astrocytoma, glioblastoma those in GBM tumors. MDNA55 offers a novel approach for temozolomide) MDNA55-05 completed multiforme [GBM]) treating IL-4R-expressing tumors because GBM does not Angiogenesis inhibitors (eg, October 2019, data reported respond well to standard therapy, and patients need better bevacizumab) January 2020 therapy options. MDNA55 is a genetically engineered fusion mTOR inhibitors (eg, protein composed of a circularly permuted interleukin-4 everolimus) molecule fused to the catalytic domain of the bacterial Pseudomonas aeruginosa exotoxin A (PE) protein. The fusion Platinum agents (eg, protein functions as a molecular decoy by binding IL-4R and carboplatin, cisplatin) triggering receptor-mediated cell take-up (ie, endocytosis) to Vinca alkaloids (eg, vincristine) deliver the cytotoxic PE payload into the cytoplasm. MDNA55 purportedly has high specificity and affinity for IL-4R- expressing tumors to deliver cell-killing payloads to cancer stem cells and immunosuppressive cells of the tumor microenvironment. MDNA55 has the potential to not only kill the tumor cells, but also “unblind“ the immune system to cancer. MDNA55 is given as an infusion via convection- enhanced delivery (CED). Purportedly providing a safer, targeted delivery, CED uses a pressure gradient at the infusion catheter’s tip to push the therapeutic agent across the blood- brain barrier, through the brain’s interstitial spaces, and to the delivery site. In clinical trials, MDNA55 is infused at a single, unspecified dose. Developer(s): Medicenna Therapeutics Corp (Toronto, Ontario, Canada)

Section 2. Cancer 43

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

Adults aged 18 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 with might benefit patients with breast cancer because surgical resection and 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 be antineoplastic 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)

Adults aged 18 years or older Mitomycin gel (Jelmyto) is a proprietary form of the small- Endoscopic management Overall survival Approval date: April 15, 2020 with low-grade, noninvasive, molecule drug mitomycin-C (MMC) intended to treat low- Surgery (ie, Progression-free survival FDA designation(s): Orphan upper-tract urothelial cancer grade upper-tract urothelial cancer. No treatments are nephroureterectomy; might Quality of life Drug, Breakthrough Therapy, approved for this cancer type, and patients need effective require ongoing dialysis or Fast Track options. Approved by FDA, this hydrogel-based form is organ transplantation) Clinical trial(s): Phase 3 intended to enable longer exposure of MMC to urinary tract One or more of the following: OLYMPUS primary completion tissue to enable nonsurgical treatment of tumors. Mitomycin Alkylating agents (eg, April 2019, pivotal data gel purportedly kills bladder cell tumors by inhibiting DNA ifosfamide) reported May 2019, final synthesis, which is required for the cells to divide and tumors analysis of primary end point to grow. The recommended dosage in the FDA-approved label Antimetabolites (eg, gemcitabine, methotrexate) data reported September 2019, is mitomycin gel 4 mg/mL with a maximum dose of 15 mL in data published April 2020; Immune checkpoint inhibitors weekly instillations given a total of 6 times using a standard phase 3 primary completion (eg, atezolizumab, avelumab) urethral catheter or nephrostomy tube. March 2020 Developer(s): Platinum agents (eg, UroGene Pharma, Ltd (New York, New York) carboplatin, cisplatin) Taxanes (eg, docetaxel, paclitaxel)

Section 2. Cancer 44

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

Adults aged 18 to 78 years Motixafortide (BL-8040) is a high-affinity antagonist for the Stem cell transplantation after Overall survival Clinical trial(s): Phase 3 GENESIS who have newly diagnosed CXC chemokine receptor 4 (CXCR4). This receptor is high-dose chemotherapy with Progression-free survival primary completion April 2019, multiple myeloma (MM) and overexpressed in about 70% of cancers, including MM, and is one or more of the following: Quality of life data reported March 2019 are eligible for autologous associated with disease severity. Motixafortide is intended to Alkylating agents (eg, stem cell transplantation mobilize hematopoietic stem cells (HSCs) for autologous (ie, bendamustine, (ASCT) self-donated) transplantation and delay MM progression after cyclophosphamide) primary high-dose therapy. Motixafortide is a biostable, Anthracyclines (eg, synthetic, cyclic peptide with 14 amino acid residues that binds doxorubicin) CXCR4 with high affinity. Expression of CXCR4 in CD34+ HSCs Glucocorticoids (eg, is directly involved in their retention in the bone marrow via dexamethasone) binding to the CXCL12 chemokine protein. However, in MM, CXCR4 expression is also involved in tumor progression, Immunomodulatory agents angiogenesis, metastasis, and cell survival. As a CXCR4 (eg, lenalidomide, antagonist, motixafortide purportedly leads to the pomalidomide, thalidomide) mobilization of CD34+ HSCs, MM cells, and immune cells into Proteasome inhibitors (eg, peripheral blood. Although mobilized CD34+ HSCs can be bortezomib, carfilzomib, collected through apheresis for autologous transplantation, ixazomib) mobilized MM cells are no longer protected in the bone Topoisomerase inhibitors (eg, marrow and are sensitive to maintenance therapy after etoposide) transplantation. In clinical trials, motixafortide is given as a single under-the-skin injection at a dosage of 1.25 mg/kg on day 1 in combination with granulocyte colony-stimulating factor (G-CSF) injected at a dosage of 10 µg/kg/day 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 (Tel Aviv, Israel), in collaboration with Biokine Therapeutics, Ltd (Rehovot, Israel)

Section 2. Cancer 45

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

Adults aged 18 years or older N-803 (formerly ALT-803) is a novel interleukin-15 (IL-15) One or more of the following: Overall survival FDA designation(s): Fast Track, who have bacillus Calmette- superagonist complex. NMIBC is unresponsive to standard Anthracyclines (eg, epirubicin, Progression-free survival Breakthrough Therapy Guérin (BCG)–unresponsive, BCG treatment in about half of affected patients, whose valrubicin) Quality of life Clinical trial(s): Phase 2 QUILT- high-grade, non–muscle disease then progresses. N-803 is intended to provide an Antimetabolites (eg, 3.032 primary completion invasive bladder cancer option after BCG treatment has failed. N-803 purportedly gemcitabine) January 2023, preliminary data (NMIBC) generates rapid and durable immune responses against DNA synthesis inhibitors (eg, presented May 2019 NMIBC by simultaneously mobilizing both innate and mitomycin-C) adaptive immune cells to infiltrate the tumor. While IL-15 and IL-15α enhance cytotoxic T-cell proliferation, Taxanes (eg, docetaxel) immunoglobulin G1 Fc domain (IgG1 Fc) activates NK (natural killer) cell-specific, antibody-dependent, cell- mediated cytotoxicity. In clinical trials, N-803 is mixed with BCG and given as an intravesical (ie, within the bladder) instillation at an unspecified dose weekly for 6 consecutive weeks. At month 3, patients receive either a 3-week maintenance course or a 6-week reinduction course. Subsequently, patients receive 3-week maintenance treatment at 6, 9, 12, and 18 months. Developer(s): ImmunityBio (Miramar, Florida), in collaboration with AGC Biologics, Inc (Bothell, Washington)

Adults aged 18 years or older Nadofaragene firadenovec (Instiladrin) is a gene therapy Cystectomy Overall survival Submission date: Biologics who have recurrent non– intended to treat high-grade NMIBC that does not respond to Immune checkpoint inhibitors Progression-free survival License Application November muscle invasive bladder cancer bacillus Calmette-Guérin (BCG) therapy. About half of patients (eg, pembrolizumab) Time to cystectomy 25, 2019; Priority Review (NMIBC) and confirmed with NMIBC will have recurrent disease after BCG induction Intravesical chemotherapy (surgery) FDA designation(s): Fast Track, carcinoma in situ (CIS) only, therapy, and these patients are more likely to progress to a with one or more of the Quality of life Breakthrough Therapy Ta/T1 high-grade disease with more advanced disease stage. Nadofaragene firadenovec is an following: Clinical trial(s): Phase 3 primary concomitant CIS, or Ta/T1 adenovirus vector gene therapy containing the gene Anthracyclines (eg, epirubicin, completion May 2019, data high-grade disease without interferon alfa-2b. After its administration into the bladder, it valrubicin) reported December 2019 concomitant CIS transduces cells in the bladder cell wall, causing them to produce and secrete interferon alfa-2b protein, a naturally Antimetabolites (eg, occurring protein the body uses to fight cancer. In clinical gemcitabine) trials, nadofaragene firadenovec is administered through a DNA synthesis inhibitors (eg, catheter into the bladder every 3 months for 12 months, and mitomycin-C) patients were followed for 48 months. Taxanes (eg, docetaxel) Developer(s): FKD Therapies Oy (Kuopio, Finland), licensed to FerGene, a company of Ferring Pharmaceuticals (Saint-Prex, Switzerland)

Section 2. Cancer 46

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

Adults aged 18 years or older Nanoparticle albumin-bound sirolimus (nab-sirolimus; ABI- One or more of the following: Overall survival Submission date: New Drug who have locally advanced or 009) is an mTOR inhibitor associated with human albumin Alkylating agents (eg, Progression-free survival Application planned for second metastatic perivascular nanoparticles through noncovalent hydrophobic interactions. dacarbazine, temozolomide, Quality of life quarter of 2020 epithelioid cell tumor Nab-sirolimus has been developed to block the mTOR trabectedin) FDA designation(s): Orphan (PEComa) pathway, which is involved in cell proliferation frequently Anthracyclines (eg, Drug, Fast Track, Breakthrough activated in PEComas by genetic mutations in the TSC doxorubicin, epirubicin, Therapy TSC1 TSC2 complex subunit 1 and/or 2 genes, and/or . PEComa liposomal doxorubicin) Clinical trial(s): Phase 2 AMPECT is a rare type of sarcoma originating from the soft tissues Antimetabolites (eg, primary completion September lining organs such as the intestines, lungs, and stomach. gemcitabine, ifosfamide) 2020, data reported November PEComas are malignant in rare cases and have potential to 2019 spread to other body parts. No approved treatments exist for Microtubule inhibitors (eg, PEComas, and standard sarcoma cytotoxic chemotherapies eribulin, vinorelbine) have minimal survival benefit. Nab-sirolimus purportedly mTOR inhibitors (eg, enters proliferating tumor cells via endocytosis and everolimus, sirolimus, macropinocytosis to have higher accumulation and better temsirolimus) efficacy than other mTOR inhibitors. Testing for TSC1/2 Multikinase inhibitors (eg, mutation status will require use of a companion diagnostic. In imatinib, pazopanib, clinical trials, nab-sirolimus is given by intravenous infusion at regorafenib, sorafenib, a weekly dosage of 100 mg/m2 in a 2-week-on, 1-week-off sunitinib) schedule until disease progression or intolerable toxicity. Developer(s): Aadi Bioscience, Inc (Pacific Palisades, California)

Section 2. Cancer 47

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

Adults aged 18 years or older Napabucasin (BBI608) is a small-molecule inhibitor of the One or more of the following: Overall survival Clinical trial(s): Phase 3 who have metastatic colorectal mitogenic signal transducer and activator of the transcription Angiogenesis inhibitors (eg, Progression-free survival CanStem303C primary cancer (CRC) that has been 3 (STAT-3) pathway. Napabucasin’s novel mechanism of action bevacizumab, ramucirumab) Quality of life completion June 2020; phase 3 treated with a single systemic is intended to treat CRC that does not respond to second-line Antimetabolites (eg, primary completion November chemotherapy regimen based chemotherapy, by purportedly targeting and killing cancer capecitabine, 5-fluorouracil) 2021 on fluoropyrimidine and stem cells in tumors. Cancer stem cells are associated with EGFR antibodies (eg, oxaliplatin treatment resistance, metastasis, and poor prognosis. In cetuximab, panitumumab) clinical trials, napabucasin is given by mouth at a dosage of 240 mg twice daily in combination with the multiagent FOLFIRI cytotoxic chemotherapy regimen FOLFIRI (ie, leucovorin FOLFOX (ie, leucovorin [folinic acid], 5-fluorouracil, and irinotecan), with or without [folinic acid], 5-fluorouracil, the addition of bevacizumab, until disease progression or and oxaliplatin) intolerable toxicity. Immune checkpoint Developer(s): inhibitors (eg, nivolumab, Boston Biomedical, Inc (Cambridge, Massachusetts), a pembrolizumab) for patients subsidiary of Sumitomo Dainippon Pharma Co, Ltd (Osaka, with defects in mismatch Japan) repair or microsatellite instability Multikinase inhibitors (eg, regorafenib) Platinum agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)

Adults aged 22 years or older NovoTTF-100L is a device intended to treat solid tumors by One or more of the following: Overall survival Clinical trial(s): Phase 3 LUNAR who have metastatic non–small exposing them to low-intensity, intermediate-frequency, Immune checkpoint inhibitors Progression-free survival primary completion December cell lung cancer (NSCLC) that alternating electric fields (ie, tumor-treating fields [TTFs]). (eg, atezolizumab, nivolumab) Quality of life 2021 has progressed after first-line, TTFs purportedly disrupt cell division through effects on Taxanes (eg, docetaxel) platinum-based therapy charged macromolecules and organelles within cancer cells, potentially limiting tumor growth. NovoTTF-100L is a battery-powered field generator coupled to an electrode array that is attached to the skin of the patient’s torso as a noninvasive device. The patient applies TTF therapy in the home setting 24 hours a day, 7 days a week. The therapy is intended for use in combination with standard systemic therapies for metastatic NSCLC. Developer(s): Novocure, Ltd (St Helier, Jersey, United Kingdom)

Section 2. Cancer 48

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

Adults aged 18 years or older NovoTTF-100M is a device intended to treat solid tumors by Radiation therapy (eg, Overall survival Clinical trial(s): Phase 3 METIS who have metastatic non–small exposing them to low-intensity, intermediate-frequency, stereotactic radiosurgery, Progression-free survival primary completion December cell lung cancer (NSCLC) and alternating electric fields (ie, tumor-treating fields [TTFs]). TTFs whole-brain radiotherapy) Quality of life 2020 newly diagnosed brain purportedly disrupt cell division through effects on charged In lieu of upfront radiation metastases that have been macromolecules and organelles within cancer cells, potentially therapy, systemic therapy with treated with stereotactic limiting tumor growth. The NovoTTF-100M device is a battery- one of the following: radiosurgery powered field generator coupled to 4 electrically insulated ALK inhibitors (eg, alectinib, electrode arrays attached to the skin of the patient’s head. In brigatinib, ceritinib) if ALK clinical trials, TTF therapy is given in the home setting 24 hours rearrangement positive a day, 7 days a week and is intended for use in combination EGFR inhibitors (eg, with the best supportive treatment available until disease osimertinib) if EGFR variant progression or intolerable toxicity. positive Developer(s): Immune checkpoint inhibitors NovoCure, Ltd (St Helier, Jersey, United Kingdom) (eg, nivolumab, pembrolizumab) if programmed cell death ligand-1 (PD-L1)–positive

Children aged 4 years or older NY-ESO-1 SPEAR T cells (GSK3377794) are an autologous cell One or more of the following: Overall survival FDA designation(s): and adults who have locally therapy engineered from T cells collected from a patient’s Alkylating agents (eg, Progression-free survival Breakthrough Therapy advanced or metastatic peripheral blood. Patients with synovial sarcoma have limited dacarbazine, temozolomide) Quality of life Clinical trial(s): phase 2 IGNYTE- synovial sarcoma that has not treatment options, and NY-ESO-1 SPEAR T cells could Anthracyclines (eg, ESO primary completion been previously treated or has represent a new option. In this therapy, T cells are genetically doxorubicin, epirubicin) January 2022 progressed or recurred after modified with a retroviral vector (ie, transduction) encoding a Antimetabolites (eg, one line of chemotherapy T-cell receptor that recognizes a specific antigen in NY-ESO-1 gemcitabine, ifosfamide) (New York esophageal squamous cell carcinoma-1), a protein with restricted expression in testis and ovaries that is DNA synthesis inhibitors (eg, reexpressed in up to 80% of synovial sarcomas. Successfully mitomycin-C) transduced cells are activated, expanded, and then frozen until Microtubule inhibitors (eg, use. NY-ESO-1 SPEAR T cells purportedly strengthen the eribulin, vinorelbine) patient’s natural T-cell responses against cancer cells Multikinase inhibitors (eg, expressing NY-ESO-1. In clinical trials, after thawing, NY-ESO-1 pazopanib, sorafenib) SPEAR T cells are given as an intravenous infusion at an initial Tropomyosin receptor kinase 9 9 dose ranging from 1 × 10 to 6 × 10 cells. Patients who have a inhibitor (eg, larotrectinib) confirmed response or stable disease for 3 or more months might receive a second NY-ESO-1 SPEAR T-cell infusion. Developer(s): GlaxoSmithKline plc (Brentford, United Kingdom)

Section 2. Cancer 49

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

Females aged 18 years or older Ofranergene obadenovec (VB-111) is an adeno-associated viral One or more of the following: Overall survival FDA designation(s): Orphan who have recurrent, platinum- vector therapy intended for recurrent platinum-resistant ovarian Angiogenesis inhibitors (eg, Progression-free survival Drug resistant ovarian cancer cancer. It is intended to induce programmed cell death in bevacizumab) Quality of life Clinical trial(s): Phase 3 OVAL angiogenic endothelial cells in the tumor microenvironment as Anthracyclines (eg, primary completion December well as induce cellular immune responses against the tumor. doxorubicin, pegylated 2022, interim data reported Patients with recurrent platinum-resistant ovarian cancer have a liposomal doxorubicin) March 2020 poor prognosis and need more effective treatment options. VB- Taxanes (eg, docetaxel, Note(s): European Commission 111 purportedly penetrates and introduces a propriety paclitaxel) has granted ofranergene angiogenesis-specific promoter that specifically induces cell obadenovec Orphan Drug death in angiogenic endothelial cells in the tumor milieu. VB- designation 111 also purportedly recruits CD8+ T cells capable of inducing tumor-specific cellular immune responses. In clinical trials, VB- 111 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)

Males aged 18 to 99 years who Olaparib (Lynparza) is a small-molecule drug intended to inhibit Abiraterone alone Progression-free survival Clinical trial(s): Phase 3 PROpel have metastatic, castration- poly adenosine diphosphate-ribose polymerase (PARP), which Docetaxel Overall survival primary completion April 2021 resistant prostate cancer functions in a DNA repair pathway. Olaparib might provide a Enzalutamide Quality of life Note(s): FDA approved olaparib (mCRPC) that is being treated novel and potentially synergistic mechanism of action when to treat ovarian cancer in with androgen-deprivation used with abiraterone to treat newly diagnosed mCRPC. Cancers December 2014 and to treat therapy but has not yet been are often deficient in a DNA repair pathway, and when PARP is breast cancer in January 2018 treated with chemotherapy or also inhibited the loss of 2 types of DNA repair results in cancer a newer hormonal agent (ie, cell death in response to DNA damage. Preclinical studies have abiraterone or enzalutamide) indicated that cross-talk might exist between androgen receptor at the mCRPC stage signaling 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 50

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

Children aged 12 years or Omidubicel (NiCord) is a donor (ie, allogeneic) stem cell Allogeneic bone marrow Bone marrow FDA designation(s): Orphan older and adults aged up to 65 therapy derived from umbilical cord blood that has been transplantation engraftment rate Drug, Breakthrough Therapy years who have a hematologic multiplied in a laboratory using proprietary nicotinamide Pooled unexpanded cord Neutrophil recovery rate Clinical trial(s): Phase 3 primary malignancy (ie, acute (NAM) technology. Omidubicel is intended as a curative blood transplantation Platelet recovery rate completion December 2019, lymphoblastic leukemia, acute approach for high-risk blood cancers in patients who have Unexpanded cord blood Overall survival topline data announced May myelogenous leukemia, no fully matched donor available. The therapy is intended to transplantation 2020 chronic myelogenous efficiently and quickly restore blood and immune cells and Note(s): Gamida Cell expects to leukemia, or myelodysplastic improve resistance to infections and related complications. report topline phase 3 data in syndrome) NAM purportedly prevents umbilical cord blood cells from the second quarter of 2020 differentiating rapidly in culture, resulting in increased stem cells (CD34+CD38–Lin–). NAM works outside the genetic coding region in the DNA (ie, epigenetic) and purportedly increases the migration, bone marrow homing, and engraftment efficiency of allogeneic blood progenitor cells. In clinical trials, omidubicel is given as a single intravenous infusion at an unspecified dose. Developer(s): Gamida Cell, Ltd (Jerusalem, Israel), in collaboration with Be The Match BioTherapies, LLC (Minneapolis, Minnesota), a subsidiary of the National Marrow Donor Program/Be The Match (Minneapolis, Minnesota)

Section 2. Cancer 51

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 following: Overall survival FDA designation(s): Fast Track and adults who have a compounds) that acts as an antagonist of the G-protein Alkylating agents (eg, Progression-free survival Clinical trial(s): Phase 2 ONC013 recurrent high-grade glioma coupled receptor dopamine 2 (D2) receptor. ONC201 has a carmustine, temozolomide) Quality of life primary completion December that harbors a K27M novel mechanism of action intended to provide an option for Angiogenesis inhibitors (eg, 2020; phase 2 ONC006 primary rearrangement in the histone patients who have few effective treatment options and poor bevacizumab) completion December 2020, gene, H3 prognosis after recurrence. ONC201-mediated antagonism Vinca alkaloids (eg, vincristine) data published January 2020; of D2 receptor purportedly inactivates the ras pathway, a unphased Expanded Access driver of cell growth and proliferation, and activates the Program, data published integrated stress response, which can activate cell death October 2019 pathways. Patients with gliomas harboring K27M variants in the H3 gene have a poor prognosis, and preclinical data have 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 aged 18 years or older Oportuzumab monatox (Vicinium) is an antibody-drug Cystectomy Time to cystectomy Submission date: Rolling who have non–muscle invasive conjugate comprising a humanized monoclonal antibody Transurethral resection of Overall survival Biologics License Application bladder cancer (NMIBC) that is fragment specific for the epithelial cell adhesion molecule bladder tumor (TURBT) Disease-free survival initiated December 2019 Pseudomonas refractory to, or has relapsed (EpCAM) linked to a truncated form of Intravesicular chemotherapy FDA designation(s): Fast Track aeruginosa Quality of life after, at least 2 intravesicular exotoxin A (PE). PE is a cytotoxic agent that inhibits with one or more of the Clinical trial(s): Phase 3 VISTA treatments with bacillus protein synthesis through inactivation of elongation factor-2. following: primary completion December Calmette-Guérin (BCG) EpCAM is highly expressed by bladder cancer cells. Anthracyclines (eg, valrubicin) 2020, preliminary data reported Oportuzumab monatox is intended to preferentially deliver the August 2019 linked exotoxin to these cells and delay the time to major Antimetabolites (eg, surgery (ie, cystectomy) and surgery’s associated side effects gemcitabine) (eg, urinary diversion). In clinical trials, oportuzumab monatox DNA synthesis inhibitors (eg, is given intravesically (ie, into the bladder) at a dose of 30 mg mitomycin-C) in an office setting. In a clinical trial, treatment involves a 12- 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 52

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

Females aged 18 years or older Oraxol is a novel combination therapy composed of a One or more of the following: Overall survival Submission date: New Drug who have locally advanced or paclitaxel capsule and an encequidar tablet that is taken orally Anthracyclines (eg, Progression-free survival Application planned for first metastatic breast cancer for rather than given intravenously. Paclitaxel is a taxane that doxorubicin, liposomal Quality of life quarter of 2020 whom treatment with inhibits cell division, but it is formulated only as an intravenous doxorubicin) FDA designation(s): Orphan intravenous paclitaxel has been infusion that contains additives, which increase the risk of Antimetabolites (eg, Drug recommended neuropathy and hypersensitivity. These adverse reactions capecitabine, gemcitabine) Clinical trial(s): Phase 3 KX- often prevent patients from completing the chemotherapy Microtubule inhibitors (eg, ORAX-001 primary completion regimen, thereby reducing efficacy and adversely affecting eribulin, vinorelbine) July 2019, data presented health outcomes. Paclitaxel has been limited to intravenous December 2019 administration because the drug is a substrate of P- Poly adenosine diphosphate- glycoprotein (P-gp), an active transport protein on the ribose polymerase (PARP) gastrointestinal (GI) tract’s surface that is capable of pumping inhibitors (eg, olaparib, BRCA1/2 paclitaxel back into the GI tract. This limits systemic exposure talazoparib) for - to paclitaxel taken by mouth. Encequidar is a P-gp inhibitor mutated breast cancer that prevents P-gp-mediated efflux of paclitaxel. As an orally Taxanes (eg, docetaxel, administered taxane, oraxol has the potential to decrease the paclitaxel) burden of infusion clinic 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 53

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

Adults aged 18 years or older OSE2101 (Tedopi) is a therapeutic cancer vaccine designed to One or more of the following: Overall survival Clinical trial(s): Phase 3 who have locally advanced or stimulate T-cell responses against NSCLC. Patients with NSCLC Angiogenesis inhibitors (eg, Progression-free survival ATALANTE 1 primary metastatic non–small cell lung that does not respond to immune checkpoint inhibitors have bevacizumab, ramucirumab) Quality of life completion December 2021, cancer (NSCLC) that expresses limited treatment options and a poor prognosis, and new Antimetabolites (eg, data reported April 2020 HLA-A2 and has been therapy options are needed. OSE2101 is based on a collection gemcitabine, pemetrexed) previously treated with an of neo-epitopes, which are short peptides derived from Taxanes (eg, docetaxel) immune checkpoint inhibitor mutant versions of proteins expressed by genes mutated in and platinum-based cancer cells, acting as antigens. Because neo-epitopes are chemotherapy expressed only in the clonal cancer lineage, they are not recognized by the immune system as “self“ antigens and, therefore, might elicit a strong immune response against tumor cells expressing these antigens. 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)

Adults aged 18 or older who Pamiparib (BGB-290) is a small-molecule inhibitor of 2 One or more of the following: Overall survival Clinical trial(s): Phase 3 have inoperable, locally enzymes involved in DNA repair, the poly adenosine Anthracyclines (eg, epirubicin) Progression-free survival PARALLEL 303 primary advanced, or metastatic gastric diphosphate-ribose polymerases I and II (PARP1/2). Antimetabolites (eg, 5- Quality of life completion June 2020 cancer or gastroesophageal Pamiparib’s inhibition of PARP1/2 causes mitotic defects fluorouracil, capecitabine) junction cancer that has such as centrosome amplification, multipolar spindles, HER2 antibodies (eg, responded to a previous line of chromosome misalignment, premature loss of cohesion, trastuzumab) platinum-based chemotherapy metaphase arrest, anaphase DNA bridges, lagging chromosomes, and micronuclei. Patients with advanced Platinum-based agents (eg, gastric cancer usually experience recurrence and need carboplatin, cisplatin, effective options to delay progression. Maintenance therapy oxaliplatin) with pamiparib purportedly mediates death of gastric cancer Taxanes (eg, docetaxel, cells that survived platinum-based chemotherapy regimens paclitaxel) by inhibiting PARP1/2’s DNA repair. In clinical trials, pamiparib 60 mg is given orally twice daily until disease progression or intolerable toxicity. Developer(s): BeiGene, Ltd (Shanghai, China)

Section 2. Cancer 54

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

Adults aged 18 years or older Patidegib (BBP-009) is a hedgehog pathway inhibitor Radiation therapy Overall survival FDA designation(s): Orphan with Gorlin-Goltz syndrome, intended to treat basal cell carcinomas and reduce disease Surgical resection Progression-free survival Drug, Breakthrough Therapy also known as basal cell burden and symptoms in patients with BCCNS. Basal cell Systemic chemotherapy (eg, Quality of life Clinical trial(s): Phase 3 Pelle- carcinoma nevus syndrome carcinoma is usually treated with surgery, radiation, or vismodegib) 926-301 primary completion (BCCNS), who have developed chemotherapy (topical or systemic), all of which have limited Topical chemotherapy (eg, 5- May 2020 basal cell 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)

Adults aged 18 years or older Pegargiminase (ADI-PEG 20) is a pegylated preparation of the One or more of the following: Overall survival FDA designation(s): Orphan who have malignant pleural enzyme arginine deiminase, which catalyzes the hydrolysis of Antimetabolites (eg, Progression-free survival Drug mesothelioma that has not arginine, depleting the supply of this essential amino acid pemetrexed) Quality of life Clinical trial(s): Phase 2/3 been treated with systemic from the bloodstream. Cells of many tumor types cannot Platinum agents (eg, cisplatin) ATOMIC primary completion therapies and exhibits low autonomously synthesize arginine and, therefore, might be October 2020 expression of the sensitive to arginine depletion. In particular, tumor cells that argininosuccinate synthase 1 express low levels of ASS1 (involved in cellular arginine gene, ASS1 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 dose of 36 mg/m2 weekly in combination with standard chemotherapy with cisplatin and pemetrexed until disease progression or intolerable toxicity. Developer(s): Polaris Group (San Diego, California)

Section 2. Cancer 55

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

Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that BCG monotherapy Overall survival Approval date: January 8, 2020 who have bacillus Calmette- targets the programmed cell death-1 (PD-1) coinhibitory Cystectomy Progression-free survival Clinical trial(s): Phase 3 Guérin (BCG)–unresponsive, receptor expressed by activated T cells. About half of patients Intravesical chemotherapy Quality of life KEYNOTE-676 primary high-risk, non–muscle invasive with NMIBC will have recurrent disease after BCG induction with one or more of the completion May 2022; phase 2 bladder 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, epirubicin, completion June 2022, data without papillary tumors and and it is approved by FDA. A hallmark of cancer is its ability to valrubicin) presented February 2019 who are ineligible for or have 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 T Antimetabolites (eg, gemcitabine) pembrolizumab to treat many cystectomy 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 56

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

Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the following: Overall survival FDA designation(s): who have stage IV colorectal targets the programmed cell death-1 (PD-1) coinhibitory Angiogenesis inhibitors (eg, Progression-free survival Breakthrough Therapy cancer (CRC) that is receptor expressed by activated T cells. Pembrolizumab is bevacizumab) Quality of life Clinical trial(s): Phase 3 microsatellite instability–high intended to provide a targeted option for patients with MSI-H Antimetabolites (eg, 5- KEYNOTE-177 primary (MSI-H) or mismatch repair– or dMMR colorectal cancers, which make up 15% to 20% of fluorouracil, capecitabine) completion December 2021, deficient (dMMR) and has not nonhereditary cases and most hereditary cases. A hallmark of EGFR antibodies (eg, data reported April 2020 been previously treated cancer is its ability to evade an immune response. Several cetuximab, panitumumab) Note(s): FDA has approved types of cancer cells, including colorectal cancer cells, activate FOLFIRI (ie, leucovorin [folinic pembrolizumab to treat many an immune checkpoint pathway in T cells by overexpressing other cancers. See the FDA- the programmed cell death ligand-1 (PD-L1), which binds to acid], 5-fluorouracil, and irinotecan) approved labeling and PD-1 and limits the activation of cancer-specific T cells. prescribing document for all FOLFOX (ie, leucovorin [folinic Pembrolizumab purportedly prevents the interaction between approved indications. PD-1 and PD-L1 to overcome CRC’s immune tolerance by acid], 5-fluorouracil, and enhancing cancer-specific T-cell responses. Tumors with MSI- oxaliplatin) H or dMMR are also purportedly more susceptible to Platinum-based agents (eg, pembrolizumab than tumors with low MSI. In clinical trials, oxaliplatin) pembrolizumab is given as an intravenous infusion at a Topoisomerase inhibitors (eg, dosage of 200 mg once every 3 weeks for up to 24 months. irinotecan) Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 57

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

Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the following: Overall survival Clinical trial(s): Phase 3 who have locally advanced or targets the programmed cell death-1 (PD-1) coinhibitory Anthracyclines (eg, epirubicin) Progression-free survival KEYNOTE-590 primary metastatic esophageal receptor expressed by activated T cells. Front-line therapy for Antimetabolites (eg, Quality of life completion May 2022 carcinoma or esophagogastric esophageal carcinoma relies on platinum-based capecitabine, 5-fluorouracil) Note(s): FDA has approved junction (EGJ) carcinoma that is chemotherapy, but response rates are low and no second-line HER2 antibodies (eg, pembrolizumab to treat many unsuitable for surgery and has therapies exist. Pembrolizumab is intended to provide an trastuzumab) other cancers. See the FDA- not been previously treated option for these patients. A hallmark of cancer is its ability to approved labeling and Platinum agents (eg, evade an immune response. Several types of cancer cells, prescribing document for all carboplatin, cisplatin, including esophageal and EGJ carcinomas, activate an immune approved indications. checkpoint pathway in T cells by overexpressing the oxaliplatin) programmed cell death ligand-1 (PD-L1), which binds to PD-1 Taxanes (eg, docetaxel, and limits the activation of cancer-specific T cells. paclitaxel) Pembrolizumab purportedly prevents the interaction between PD-1 and PD-L1 to overcome the immune tolerance of esophageal and EGJ carcinomas by enhancing cancer-specific T-cell responses. In clinical trials, pembrolizumab is given as an intravenous infusion at a dosage of 200 mg once every 3 weeks for up to 24 months. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 58

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

Adults aged 18 years or older Pemigatinib (Pemazyre) is a novel, highly potent, and selective Fluoropyrimidine-based Overall survival Approval date: April 17, 2020 who have locally advanced or small-molecule inhibitor of FGFR isoforms 1, 2, and 3, which chemotherapy Progression-free survival FDA designation(s): Orphan metastatic cholangiocarcinoma play an important role in cell proliferation, survival, migration, Pembrolizumab (for patients Quality of life Drug, Breakthrough Therapy harboring gene mutations, and angiogenesis (ie, formation of new blood vessels). The with microsatellite instability– Clinical trial(s): Phase 3 FLIGHT- fusions, or translocations in the drug is approved by FDA. Cholangiocarcinoma is a rare cancer high [MSI-H] or mismatch 302 primary completion fibroblast growth factor that forms in bile ducts, which carry fluid between the liver, the repair–deficient [dMMR] October 2023; phase 2 FLIGHT- FGFR2 receptor 2 gene, , whose gallbladder, and the small intestine. About 20% of tumors) 202 primary completion June FGFR2 disease has previously been cholangiocarcinomas harbor a genetic alteration in , 2020, data published March treated with at least one line of which typically involves a gene fusion/translocation that leads 2020 systemic therapy to constitutive FGFR2 activity. By targeting this aberrant FGFR Note(s): This Accelerated signaling, pemigatinib purportedly prevents the growth and Approval requires the conduct spread of cholangiocarcinoma tumors, potentially improving of a further clinical trial to verify outcomes of patients who have limited treatment options. and describe pemigatinib’s Although pemigatinib specifically binds to FGFRs 1, 2, and 3, it clinical benefit 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-week-on, 1-week-off schedule until disease progression or intolerable toxicity. Developer(s): Incyte Corp (Wilmington, Delaware)

Section 2. Cancer 59

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

Adults aged 18 years or older Pexidartinib (Turalio) is a small-molecule multikinase inhibitor. Imatinib (off-label) Response rate Approval date: August 2, 2019 who have a symptomatic It exhibits activity against several receptor tyrosine kinases, Radiation therapy Patient-reported physical FDA designation(s): Orphan tenosynovial giant cell tumor including colony-stimulating factor 1 receptor (CSF1R), FMS- function (ie, PROMIS Drug, Breakthrough Therapy (TGCT) that is associated with like tyrosine kinase 3, and KIT. No FDA-approved interventions [Patient-Reported Clinical trial(s): Phase 3 severe morbidity or functional are available to treat TGCT, and patients need effective Outcomes Measurement ENLIVEN primary completion limitations and is not amenable options. TGCTs typically overexpress colony-stimulating factor Information System] March 2017, data published to improvement with surgery 1 (CSF1), which is an activating ligand for CSF1R. TGCT- physical function scale) August 2019 expressed CSF1 leads to recruitment of CSF1R-expressing Patient-reported pain cells, such as osteoclasts, macrophages, and mast cells, which and stiffness initiate an inflammatory reactive process that contributes to Quality of life TGCT pathogenesis. Therefore, inhibiting CSF1R by pexidartinib might limit CSF1-/CSF1R-driven attraction via chemotaxis of inflammatory cells and limit the proinflammatory process underlying TGCT. The recommended dosage in the FDA-approved label is 200 mg taken twice daily for a total of 400 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)

Adults aged 18 years or older Plinabulin is a marine fungus–derived microtubule inhibitor Myelosuppressive Neutropenia Submission date: New Drug who have advanced or intended to prevent chemotherapy-induced neutropenia (ie, chemotherapy with adjunctive Thrombocytopenia Application planned for fourth metastatic cancer (eg, breast loss of neutrophils), which occurs in most patients with cancer long-lasting G-CSF (eg, Infection incidence quarter of 2020 cancer, non–small cell lung who are receiving myelosuppressive chemotherapy. pegfilgrastim) Quality of life Clinical trial(s): Phase 3 cancer [NSCLC], prostate Neutropenia renders patients susceptible to complications, Protective-1 primary cancer) that has progressed including infection, because the cytotoxic regimens they completion June 2020, data after at least one previous line receive also deplete blood-forming cells in the bone marrow. reported November 2019; of treatment Unlike granulocyte colony-stimulating factor (G-CSF), which phase 3 Protective-2 primary promotes growth of white blood progenitor cells to restore completion March 2020, data neutrophils, plinabulin’s novel mechanism of action (ie, targets presented February 2020 microtubules differently from taxanes and vinca alkaloids) purportedly facilitates the release of cytokines that protect neutrophils from programmed cell death (ie, apoptosis). In clinical trials, plinabulin is given as an intravenous infusion at a dose from 5 to 40 mg/m2. Treatment with plinabulin continues until completion of systemic chemotherapy. Developer(s): BeyondSpring Pharmaceuticals, Inc (New York, New York)

Section 2. Cancer 60

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

Adults aged 18 years or older Pracinostat is an oral histone deacetylase (HDAC) inhibitor. Antibody-drug conjugate (eg, Complete remission rate FDA designation(s): Orphan who have newly diagnosed HDACs act as epigenetic regulators (ie, functioning gemtuzumab ozogamicin) Overall survival Drug, Breakthrough Therapy acute myeloid leukemia (AML), peripherally to the genetic code) that chemically modify the Glasdegib in combination with Quality of life Clinical trial(s): Phase 3 cannot tolerate intensive DNA structure or its associated chromosomal proteins (eg, low-dose cytarabine PRIMULA primary completion remission induction histones). Abnormal activity of epigenetic regulators is Low-dose cytarabine May 2021 chemotherapy, and have thought to contribute to upregulating the accessibility and Low-intensity therapy (eg, Eastern Cooperative Oncology expression of tumor-promoting genes, contributing to the azacitidine and decitabine) Group (ECOG) performance pathogenesis of AML, the most common type of acute status of 2 with significant leukemia. AML has a poor prognosis, and patients who cannot Venetoclax alone or in cardiovascular disease or are tolerate high doses of chemotherapy need other options. combination with azacitidine older than 75 years Pracinostat might improve patient health outcomes in the or low-dose cytarabine first-line setting for AML by restoring normal 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 61

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

Males aged 18 years or older ProstAtak is a gene-mediated cytotoxic immunotherapy. It Radiation therapy with or Disease-free survival Clinical trial(s): Phase 3 PrTK03 who have localized prostate consists of an adenovirus vector containing a herpes simplex without androgen-deprivation Overall survival primary completion December cancer that is deemed to be virus thymidine kinase gene (ie, aglatimagene besadenovec) therapy Quality of life 2022, designed under Special intermediate or high risk based that is injected into tumors and leads infected cells to express Protocol Assessment; phase 2 on one factor and has been thymidine kinase. After viral injection, a low dose of a synthetic ULYSSES primary completion treated with radiation guanosine analogue (eg, valacyclovir) activated by thymidine September 2020 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 by dying tumor cells purportedly leads to an antitumor immune response. ProstAtak is given as 3 rounds of intratumoral aglatimagene besadenovec injection coupled with systemic valacyclovir administration in addition to standard radiation therapy with or without androgen- deprivation therapy. Developer(s): Advantagene, Inc (Auburndale, Massachusetts)

Adults aged 18 years or older ProTmune is a next-generation allogeneic (ie, from a donor), Standard HSCT Progression-free survival FDA designation(s): Orphan who have a hematologic off-the-shelf hematopoietic peripheral blood cell transplant Overall survival Drug, Fast Track malignancy (ie, acute (HPBCT). It is developed from donor-sourced, mobilized, Quality of life Clinical trial(s): Phase 1/2 lymphoblastic leukemia, acute peripheral blood T cells that have been cultured in the PROTECT primary completion myeloid leukemia, chronic laboratory in the presence of 2 small-molecule stem cell April 2020, initial data reported myelogenous leukemia, or modulators (ie, FT1050 and FT4145) that guide cell March 2018, expanded myelodysplastic syndrome) differentiation. Many patients with hematologic malignancies enrollment May 2019 that will be treated with seek curative therapy through hematopoietic stem cell allogeneic hematopoietic transplantation (HSCT), but about 50% of patients undergoing peripheral blood cell HSCT die or experience disease recurrence within the transplantation 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 62

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

Adults aged 18 years or older PVSRIPO is a Sabin type 1 strain of poliovirus genetically Fractionated external beam Overall survival FDA designation(s): Orphan who have recurrent malignant engineered to not harm or kill normal cells. PVSRIPO uses a radiation therapy Progression-free survival Drug, Breakthrough Therapy glioma (eg, glioblastoma novel oncolytic virus approach intended for patients whose One or more of the following: Quality of life Clinical trial(s): Phase 2 multiforme [GBM], anaplastic cancer has recurred and who have limited options after Alkylating agents (eg, Pro00077024 primary astrocytoma) that has been standard therapy. It selectively infects and replicates tumor carmustine, completion August 2023 treated with surgery, adjuvant cells that express the poliovirus receptor nectin-like protein 5 cyclophosphamide, lomustine, radiation, and temozolomide (CD155), which is expressed in most types of solid-tumor procarbazine, temozolomide) cancers and in other immune cells, including dendritic cells Angiogenesis inhibitors (eg, and macrophages. In tumor cells, PVSRIPO infection causes bevacizumab) neuronal incompetence that results in cytotoxicity and death. In contrast, PVSRIPO infection of immune cells facilitates mTOR inhibitors (eg, induction of an antitumor immune response that does not kill everolimus) or limit immune function of dendritic cells and macrophages. Platinum agents (eg, Although immune cells infected by PVSRIPO initiate a type I carboplatin, cisplatin) interferon-mediated response, this will not destroy the Vinca alkaloids (eg, vincristine) oncolytic virus. PVSRIPO purportedly targets and destroys cells in brain tumors and activates tumor-specific immune responses by stimulating dendritic cell activity and immune function. In clinical trials, PVSRIPO is given as a single injection into the tumor at a dose from 7 × 106 to 7 × 109 plaque- forming units. Developer(s): Istari Oncology, Inc (Durham, North Carolina), in collaboration with the Preston Robert Tisch Brain Tumor Center at Duke University (Durham, North Carolina)

Section 2. Cancer 63

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

Children aged 12 years or Relatlimab (BMS-986016) is a novel human immunoglobulin One or more of the following: Overall survival Clinical trial(s): Phase 2/3 older and adults who have G4 (IgG4) monoclonal antibody against lymphocyte-activator Alkylating agents (eg, Progression-free survival primary completion January melanoma that is unsuitable gene-3 (LAG-3), a coinhibitor receptor primarily expressed on dacarbazine, temozolomide) Quality of life 2021 for surgery or is metastatic and exhausted tumor-infiltrating lymphocytes (TILs). Relatlimab is BRAF inhibitors (eg, has not been previously intended to enhance activity of immune checkpoint inhibitors dabrafenib, encorafenib, treated with systemic therapy by stimulating TILs. As an adjunct to a checkpoint inhibitor, vemurafenib) relatlimab might also increase treatment-related costs. Immune checkpoint inhibitors Relatlimab’s binding to LAG-3 prevents inhibitory T-cell (eg, ipilimumab, nivolumab, responses of TILs via interaction with major histocompatibility pembrolizumab) complex molecule class II (MHC-II) on dendritic cells and melanoma cells. Relatlimab purportedly promotes innate MEK inhibitors (eg, immune responses and FAS-mediated programmed cell death binimetinib, cobimetinib, (ie, apoptosis) in melanoma cells expressing high MHC-II. trametinib) Relatlimab also synergizes with programmed cell death-1 (PD- Platinum agents (eg, 1) immune checkpoint inhibitors that might encourage carboplatin) melanoma-specific immune responses. In clinical trials, Taxane agents (eg, paclitaxel) relatlimab is given intravenously at a dose of 160 mg in 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 64

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

Infants and children aged 2 Remestemcel-L (Ryoncil) is an allogeneic mesenchymal Photopheresis alone or Overall survival PDUFA date: September 30, months to 17 years who have precursor cell therapy that uses donor bone marrow and combined with 8- Progression-free survival 2020; Priority Review acute graft-versus-host disease selectively expands mesenchymal stem cells. It is intended for methoxypsoralen Quality of life 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 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 April transplantation (HSCT) and affects many organ systems. It cyclophosphamide) 2018, data reported February arises when donor T cells recognize host cells as foreign by Antibodies (eg, alemtuzumab, 2020 virtue of their expression of alloantigens and mount an antithymocyte globulin) immune response. Remestemcel-L purportedly secretes growth factors and anti-inflammatory cytokines that facilitate Calcineurin inhibitors (eg, tissue repair by downregulating immune and inflammatory cyclosporine, tacrolimus) responses of immunocompetent T cells contained in the graft. Corticosteroids (eg, In clinical trials, remestemcel-L is given by intravenous infusion methotrexate, mycophenolate at a dosage of 2 × 106 cells/kg twice weekly for 4 consecutive mofetil, prednisone) weeks. mTOR inhibitors (eg, Developer(s): sirolimus) Mesoblast, Ltd (Melbourne, Australia, and New York, New York)

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 (PLK1). Quality of life Clinical trial(s): Phase 3 INSPIRE primary resistance to No effective treatment is available for resistant primary completion March hypomethylating agents (ie, myelodysplastic syndrome, and patients generally have a poor 2019, designed under Special disease progression without prognosis when the syndrome has not responded to Protocol Assessment attaining a complete or partial treatment with a hypomethylating agent. Inhibiting PI3K is response or hematologic intended to disrupt cell signaling 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 65

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

Females aged 18 years or older Robotic-assisted nipple-sparing mastectomy using the da Open surgical mastectomy Patient satisfaction Clinical trial(s): Phase 2 MARCI who have invasive breast Vinci system has been pioneered by a few European Tissue necrosis (nipple- primary completion November cancer or ductal carcinoma in investigators as an alternative to open surgery. Compared with areola complex) 2019, data reported April 2019; situ and are undergoing total open surgery, da Vinci robotic-assisted mastectomy Local tumor recurrence unphased IEO 562 primary mastectomy with immediate purportedly facilitates the performance of technically completion March 2022 Distant tumor recurrence breast reconstruction challenging laparoscopic procedures, enhances cosmesis, Note(s): FDA issued a safety Overall survival reduces length of stay, and improves patient satisfaction. In communication on February 28, clinical trials, surgeons performing the surgery avoid the Disease-free survival 2019. nipple-areola tissue by removing the target breast cancer Quality of life tissue through a small incision under the arm (ie, 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)

Adults aged 18 years or older Sacituzumab govitecan-hziy (Trodelvy; IMMU-132) is an One or more of the following: Overall survival Approval date: April 22, 2020 who have locally advanced or antibody-drug conjugate consisting of a monoclonal antibody Alkylating agents (eg, Progression-free survival FDA designation(s): Fast Track, metastatic triple-negative coupled via a cleavable linker to an active metabolite of the cyclophosphamide) Quality of life Breakthrough Therapy breast cancer (TNBC) and have chemotherapy drug irinotecan. It is approved by FDA. The Anthracyclines (eg, Clinical trial(s): Phase 3 ASCENT received at least 2 prior monoclonal antibody is specific for trophoblast cell-surface doxorubicin) primary completion April 2020; systemic therapy regimens for antigen 2 (Trop-2), and the irinotecan metabolite is called SN- Antimetabolites (eg, phase 1/2 IM-T-IMMU-132-01 locally advanced or metastatic 38. Trop-2 is a cell-surface protein overexpressed by several fluorouracil, gemcitabine) primary completion June 2020, disease epithelial cancers, including TNBCs. Upon binding to Trop-2, data published October 2019 sacituzumab govitecan-hziy is internalized and the linker is Microtubule polymerization Note(s): This Accelerated cleaved, releasing the chemotherapy drug. By targeting inhibitors (eg, eribulin) Approval requires the conduct delivery of SN-38 to Trop-2-expressing cells, sacituzumab Poly adenosine diphosphate- of a further clinical trial to verify govitecan-hziy purportedly delivers therapeutic doses of the ribose polymerase (PARP) and describe sacituzumab drug to cancer cells while limiting exposure of noncancer cells. inhibitors (eg, olaparib) govitecan-hziy’s clinical benefit The recommended dosage in the FDA-approved label is an Taxanes (eg, docetaxel, intravenous infusion of 10 mg/kg on days 1 and 8 of each 21- paclitaxel) day treatment cycle, until disease progression or intolerable Vinca alkaloid (eg, vinorelbine) toxicity. Developer(s): Immunomedics, Inc (Morris Plains, New Jersey)

Section 2. Cancer 66

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

Children aged 12 years or Selpercatinib (LOXO-292) is a novel, highly selective, ATP- One or more of the following: Overall survival PDUFA date: Third quarter of older and adults who have competitive small-molecule RET inhibitor intended to provide Anthracyclines (eg, Progression-free survival 2020; Priority Review locally advanced or metastatic a targeted treatment option to patients with recurrent doxorubicin) Quality of life FDA designation(s): RET medullary thyroid cancer that medullary thyroid cancer and a gene alteration. The Antimetabolite agents (eg, 5- Breakthrough Therapy harbors an alteration in the receptor tyrosine kinase RET can be oncogenically activated by fluorouracil) Clinical trial(s): Phase 3 rearranged during transfection gene fusions or point rearrangements, and activating RET Tyrosine kinase inhibitors (eg, LIBRETTO-531 primary gene, RET, and has progressed point rearrangements affect about 60% of metastatic cabozantinib, vandetanib) completion February 2023; after treatment with medullary thyroid cancers. Unlike multikinase inhibitors that phase 1/2 LIBRETTO-001 cabozantinib and/or target specific alterations, selpercatinib has been designed to primary completion March RET vandetanib inhibit diverse fusions, activating gene variants, and 2022, data presented acquired-resistance variants with nanomolar potency. September 2019 Selpercatinib targets and purportedly inhibits RET-variant tumor cells. Eligibility for the therapy will require testing for a RET gene alteration. In clinical trials, selpercatinib is given orally at an undetermined dose and time frame. Developer(s): Loxo Oncology, Inc (Stamford, Connecticut), a subsidiary of Eli Lilly and Co, Inc (Indianapolis, Indiana)

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

Section 2. Cancer 67

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

Adults aged 18 years or older Synthetic hypericin (SGX301) is a photosensitizing agent for Chemotherapy Overall survival FDA designation(s): Orphan who have newly diagnosed use with visible light to treat CTCL. Standard care for CTCL Ultraviolet A phototherapy Damage to tumor- Drug, Fast Track patch/plaque-phase cutaneous often requires photodynamic therapy with ultraviolet light, with psoralen adjacent tissue Clinical trial(s): Phase 3 FLASH T-cell lymphoma (CTCL) that which can damage surrounding tissue and lead to skin burns, Ultraviolet B phototherapy Progression-free survival primary completion December has not been treated with increased pigmentation, or secondary skin cancer. SGX301 Quality of life 2019, data reported April 2020 systemic therapy purportedly clears CTCL lesions without increasing the patient’s risk for 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)

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

Section 2. Cancer 68

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 following: Overall survival Approval date: January 23, 2020 older and adults who have enhancer of zeste homolog 2 (EZH2) inhibitor intended to Alkylating agents (eg, Progression-free survival FDA designation(s): Orphan locally advanced or metastatic treat epithelioid sarcoma, a rare and aggressive type of soft dacarbazine, temozolomide, Quality of life Drug epithelioid sarcoma not tissue sarcoma. Most epithelioid sarcoma cases exhibit trabectedin) Clinical trial(s): Phase 3 EZH- eligible for complete resection increased EZH2 activity that results in many genes being Anthracyclines (eg, 301 primary completion turned off, in particular those involved in differentiation and doxorubicin, epirubicin, September 2020; phase 2 EZH- cell cycle arrest. Approved by FDA, tazemetostat purportedly liposomal doxorubicin) 202 primary completion May improves health outcomes in patients with limited treatment Antimetabolites (eg, 2023, safety and efficacy data options by restoring antitumorigenic gene expression that gemcitabine, ifosfamide) presented June 2019 prevents epithelioid sarcoma cells from proliferating. The Note(s): This Accelerated recommended dosage in the FDA-approved label is 800 mg Microtubule inhibitors (eg, Approval requires the conduct taken orally twice daily with or without food, until disease eribulin, vinorelbine) of a further clinical trial to verify progression or intolerable toxicity. mTOR inhibitors (eg, and describe tazemetostat’s Developer(s): everolimus, sirolimus, temsirolimus) clinical benefit Epizyme, Inc (Cambridge, Massachusetts) Multikinase inhibitors (eg, imatinib, pazopanib, regorafenib, sorafenib, sunitinib)

Section 2. Cancer 69

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

Adults aged 18 years or older Tesetaxel is being developed as the only oral form in the One or more of the following: Overall survival Clinical trial(s): Phase 3 who have human epidermal taxane drug class (eg, docetaxel, nab-paclitaxel, paclitaxel). Anthracyclines (eg, Progression-free survival CONTESSA primary completion growth factor receptor 2 Taxanes inhibit mitosis (ie, duplicative cell division) and are doxorubicin, liposomal Quality of life September 2020 (HER2)–negative, hormone frequently used to treat breast cancer. However, available doxorubicin) receptor (HR)–positive, locally taxanes are formulated only as intravenous infusions and are Antimetabolites (eg, advanced or metastatic breast frequently associated with hypersensitivity reactions because capecitabine, gemcitabine) cancer previously treated with of additives needed as part of the taxane infusion solution. Microtubule inhibitors (eg, a taxane in the neoadjuvant or These reactions can prevent completion of a taxane regimen, eribulin, vinorelbine) adjuvant setting potentially reducing efficacy. Breast cancer also develops resistance over time to these infused taxanes, but oral Poly adenosine diphosphate- tesetaxel has demonstrated anticancer activity in tumors that ribose polymerase (PARP) have previously been exposed to other taxanes and developed inhibitors (eg, olaparib, BRCA1/2 resistance. Thus, oral tesetaxel might provide a more talazoparib) for - convenient and comfortable administration route that mutated breast cancer improves treatment adherence, as well as a treatment option Taxanes (eg, docetaxel, when other taxanes become ineffective. In clinical trials, paclitaxel) tesetaxel (27 mg/m2 once every 21 days on day 1 of each cycle) is being used in an all-oral regimen in combination with low-dose capecitabine until disease progression or intolerable toxicity. Developer(s): Odonate Therapeutics, Inc (San Diego, California)

Females aged 18 years or older Trametinib (Mekinist) is a kinase inhibitor intended to treat One or more of the following: Overall survival Clinical trial(s): Phase 2/3 GOG- who have recurrent low-grade low-grade serous ovarian or peritoneal cancer, a rare subtype Anthracyclines (eg, pegylated Progression-free survival 0281 completion April 2019, serous ovarian or peritoneal of serous cancer characterized by changes in the mitogen- liposomal doxorubicin) Quality of life data presented September cancer that has been treated activated protein kinase (MAPK) signaling pathway. Recurrent Hormone therapies (eg, 2019, data reported April 2020 with one or more lines of low-grade serous ovarian or peritoneal cancer responds poorly letrozole, tamoxifen) Note(s): FDA has approved chemotherapy to treatment with cytotoxic chemotherapy, and better Taxanes (eg, paclitaxel) trametinib (Mekinist) to treat treatment options are needed. Trametinib purportedly shrinks advanced melanoma with BRAF Topoisomerase inhibitors (eg, tumors by blocking the activity of the protein MEK, a molecule V600E or V600K mutation that functions in the MAPK signaling pathway to regulate cell topotecan) growth. In a clinical trial, trametinib was given as an oral dosage of 2 mg daily until disease progression or unacceptable toxicity. Developer(s): NRG Oncology (Philadelphia, Pennsylvania), in collaboration with the National Institutes of Health’s National Cancer Institute (Bethesda, Maryland)

Section 2. Cancer 70

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

Adults aged 18 years or older TT10 is an autologous cell therapy developed from EBV- One or more of the following: Overall survival Clinical trial(s): Phase 3 VANCE who have locally advanced or specific T cells (EBVSTs) collected from a patient’s peripheral Antimetabolites (eg, Progression-free survival primary completion February metastatic, Epstein-Bar virus blood. It is under study for treating EBV-associated NPC, which capecitabine, 5-fluorouracil, Quality of life 2021 (EBV)–associated, recurrent has limited treatment options; TT10 T cells could represent a gemcitabine, methotrexate) nasopharyngeal carcinoma new option in appropriately selected cases. In some NPC EGFR inhibitor (eg, cetuximab) (NPC) that has not been cases, EBV infection reprograms the nasopharyngeal epithelial Platinum-based drugs (eg, previously treated with cells to drive cellular transformation and proliferation and, carboplatin, cisplatin) systemic therapy therefore, may be amenable to treatments targeting EBV. To create TT10, autologous EBVSTs are enriched and expanded in Taxanes (eg, docetaxel, the presence of EBV antigen-expressing dendritic cells and paclitaxel) cytokines to generate large numbers of T cells that recognize 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 71

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

Section 2. Cancer 72

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

Females aged 18 years or older Veliparib (ABT-888) is a small-molecule inhibitor of poly For a first-line treatment Overall survival Clinical trial(s): Phase 3 VELIA who have stage III or IV, high- adenosine diphosphate-ribose polymerase (PARP), an enzyme setting, combination regimens Progression-free survival M13-694 primary completion grade, epithelial ovarian, involved in DNA repair. Veliparib is the first PARP inhibitor with the following agents: Quality of life May 2019, data published fallopian tube, or primary studied in the first-line treatment setting and is intended to Angiogenesis inhibitors (eg, September 2019, data reported peritoneal carcinoma not delay disease progression in the maintenance setting. By bevacizumab) March 2020 previously treated with inhibiting PARP’s DNA repair, veliparib might potentiate the Anthracyclines (eg, systemic therapy anticancer activity of cytotoxic chemotherapy drugs whose doxorubicin, pegylated mechanism of action induces DNA damage. Additionally, PARP liposomal doxorubicin) inhibition might exhibit synthetic lethality with cells harboring Platinum agents (eg, loss-of-function genetic rearrangements in the breast cancer 1 carboplatin, cisplatin) gene, BRCA1, and/or the breast cancer 2 gene, BRCA2 (an ovarian cancer predisposition gene that is also involved in Taxanes (eg, docetaxel, DNA repair); ovarian cancers frequently harbor such genetic paclitaxel) variants. Eligibility for treatment will require testing for BRCA For a maintenance treatment variant status. In clinical trials, veliparib is given orally at an setting, the recommended unspecified dose each day in combination with carboplatin options include the following: and paclitaxel for 6 cycles of 21 days. Veliparib maintenance Bevacizumab for patients who therapy is given for up to 30 additional 21-day cycles. received bevacizumab as part Developer(s): of primary first-line therapy AbbVie, Inc (North Chicago, Illinois) Observation Olaparib for patients with germline or somatic BRCA1/2 mutations

Section 2. Cancer 73

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

Females aged 18 years or older VGX-3100 is a DNA-based immunotherapy vaccine containing Colposcopy followed by one Incidence of cervical HSIL Clinical trial(s): Phase 3 REVEAL who have cervical high-grade plasmids that include expression cassettes for HPV proteins E6 of the following procedures to Incidence of cervical 1 primary completion April squamous intraepithelial lesion and E7. It is intended to offer a nonsurgical approach to treat remove cervical lesions: cancer 2020; phase 3 REVEAL 2 (HSIL) and confirmed infection certain precancerous cervical lesions that are typically treated Carbon dioxide laser ablation Incidence of infection primary completion April 2021 with human papillomavirus surgically. As a noninvasive intervention, VGX-3100’s Cold knife cone biopsy with HPV-16 and/or HPV- (HPV) type 16 and/or 18 optimized DNA is delivered into cells, where it is translated Laser cone biopsy 18 into the E6 and E7 proteins that act as antigens to induce Quality of life targeted T-cell and antibody responses. VGX-3100 purportedly Loop electrosurgical excision 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 74 Table 2.3. Cancer Topics Archived Since Last Status Report: 8 Topics

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

Adults aged 18 years or older Calmangafodipir (PledOx) is a first-in-class drug candidate Oxaliplatin-based CIPN In April 2020, PledPharma who have untreated locally designed to prevent chemotherapy-induced peripheral chemotherapy (eg, FOLFOX) Touch sensitivity announced it would advanced or metastatic neuropathy (CIPN), a common and problematic toxicity caused alone, without adjunct Vibration sensitivity discontinue the POLAR phase 3 colorectal cancer (CRC) and are by chemotherapy-induced cell death of peripheral nerves. preventive therapy program, with data cut off in Pain in the extremities considering combination Among the chemotherapy agents known to induce CIPN is the third quarter of 2020. chemotherapy containing oxaliplatin, which is a component of combination Quality of life leucovorin (folinic acid), 5- chemotherapy regimens commonly used for patients with fluorouracil, and oxaliplatin (ie, CRC. Although the exact mechanism of oxaliplatin-induced FOLFOX) peripheral neuropathy is unclear, it purportedly involves oxaliplatin metabolite generation of reactive oxygen species (ROS) that kill cells via oxidative stress. No treatment options to prevent oxaliplatin-related CIPN are available. Calmangafodipir purportedly acts to degrade ROS, limiting the extent of oxidative stress to cells. In clinical trials, calmangafodipir is given to patients as an intravenous infusion at a dosage of 2 or 5 µmol/kg on day 1 of each 2-week cycle, 10 minutes before receiving FOLFOX. Treatment with calmangafodipir continues until FOLFOX treatment completes. Developer(s): PledPharma AB (Stockholm, Sweden), in collaboration with Solasia Pharma KK (Tokyo, Japan)

Section 2. Cancer 75

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

Adults who have locally Erdafitinib (Balversa) is a novel, highly selective, small- One or more of the Overall survival Erdafitinib to treat locally advanced or metastatic molecule inhibitor of 4 members of the fibroblast growth following: Progression-free survival advanced or metastatic urothelial carcinoma that has factor receptor (FGFR) family (ie, 1, 2, 3, and 4). Erdafitinib is Antimetabolites (eg, Quality of life urothelial cancer was FDA susceptible FGFR3 or FGFR2 intended to treat unresectable, urothelial, FGFR-positive gemcitabine, pemetrexed) approved in April 2019. genetic alterations and has cancer after first- and second-line treatments have failed. Immune checkpoint Because it has been clinically progressed during or after at Approved by FDA, erdafitinib is designed to target FGFRs and inhibitors (eg, nivolumab, available for more than 1 year, least one line of platinum- not bind to similar signaling domains in the vascular pembrolizumab) it is no longer within the time containing chemotherapy, endothelial growth factor receptor (VEGFR) and the platelet- scope for the PCORI Health Platinum agents (eg, including within 12 months of derived growth factor receptor (PDGFR). Erdafitinib Care Horizon Scanning System. carboplatin, cisplatin) neoadjuvant or adjuvant purportedly blocks blood vessel formation, cell proliferation, The time scope is defined as 3 platinum-containing and cell survival pathways in urothelial cancer cells by Taxanes (eg, docetaxel, years before an intervention chemotherapy inhibiting constitutive ligand-independent FGFR signaling. In paclitaxel) becomes clinically available some urothelial cancers, the presence of activating alterations outside of the research setting in the fibroblast growth factor receptor gene, FGFR, including to 1 year after an intervention point mutations and gene rearrangements, leads to becomes clinically available. uncontrolled cell proliferation. Eligibility for treatment requires patients to undergo an FDA-approved genetic test (ie, a companion diagnostic) to determine FGFR status. The initial recommended dosage in the FDA-approved label is 8 mg by mouth once daily with a dose increase to 9 mg daily if criteria are met. The medication comes in 3-, 4-, and 5-mg tablets. Developer(s): Janssen Pharmaceutical, LLC (Titusville, New Jersey), a subsidiary of Johnson & Johnson, Inc (New Brunswick, New Jersey), in collaboration with Astex Pharmaceuticals, Inc (Cambridge, United Kingdom)

Section 2. Cancer 76

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

Adults aged 18 years or older Idasanutlin (RG7388) is a nutlin-class small-molecule drug that One or more of the Progression-free survival In April 2020, Roche reported who have relapsed/refractory blocks interactions between the mouse double minute 2 following: Overall survival that the phase 3 MIRROS trial acute myeloid leukemia (AML) homolog (MDM2) protein and p53, a tumor suppressor Anthracyclines (eg, Quality of life failed to meet its primary end that has not responded to or protein thought to be involved in up to half of AML cases. No daunorubicin, idarubicin) point and removed the has relapsed after one or 2 FDA-approved agents exist for restoring p53 activity. Standard Antibody-drug conjugate relapsed/refractory AML induction regimens AML chemotherapy lacks specificity, leading to a range of side (eg, gemtuzumab indication from its pipeline. effects and disease relapse over time, as well as poor ozogamicin) responses in elderly patients. In some AML cases, MDM2 is Antimetabolites (eg, thought to reduce the amount of p53 by promoting its cladribine, fludarabine) destruction through the ubiquitin-proteasome system and by turning off p53’s transcriptional activation. Idasanutlin Cytokine (eg, granulocyte purportedly targets a small hydrophobic pocket on MDM2 colony-stimulating factor that normally binds to p53. Idasanutlin purportedly stabilizes [G-CSF]) p53 by blocking the MDM2-p53 interaction, potentially DNA synthesis inhibitors activating downstream transcriptional targets that keep AML (eg, etoposide, cells from dividing, and initiates programmed cell death. In mitoxantrone) clinical trials, idasanutlin is taken by mouth at a dosage of 300 FLT3 inhibitor (eg, mg twice daily in combination with cytarabine (1000 mg/m2) gilteritinib) for the first 5 days of a 28-day cycle, until complete remission Hypomethylating agents or disease progression. (eg, azacitidine, decitabine) Developer(s): IDH inhibitors (eg, Genentech, Inc (South San Francisco, California), a subsidiary enasidenib, ivosidenib) of F Hoffman-La Roche, Ltd (Basel, Switzerland) Multikinase inhibitor (eg, sorafenib)

Section 2. Cancer 77

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

Adults aged 18 years or older Ivosidenib (Tibsovo) is a small-molecule inhibitor of a mutant One or more of the Overall survival Stakeholder commenters who have locally advanced or form of the enzyme isocitrate dehydrogenase 1 (IDH1) that following: Progression-free survival agreed that reported overall metastatic cholangiocarcinoma occurs in about 25% of intrahepatic cholangiocarcinomas. Fluoropyrimidine-based Quality of life survival and progression-free that harbors a rearrangement Cholangiocarcinoma is a rare cancer that forms in bile ducts, chemotherapy survival rates for ivosidenib in the isocitrate which carry fluid between the liver, the gallbladder, and the Pembrolizumab (for were incremental and did not IDH1 dehydrogenase 1 gene, , small intestine. IDH1’s mutant form causes a tumor-inducing patients with microsatellite have the potential to improve and has been treated with at metabolite (ie, D-2-hydroxyglutarate) to accumulate while instability–high [MSI-H) or health outcomes. Therefore, its least one previous line of decreasing levels of IDH1’s normal metabolite (ie, α- mismatch repair–deficient disruption potential is low. systemic therapy ketoglutarate). This metabolite imbalance causes histone [dMMR] tumors) modification and DNA methylation that makes cells lose specialized characteristics (ie, dedifferentiate) and might lead to cells that divide more than normal (ie, a neoplastic state). By inhibiting IDH1’s mutant form, ivosidenib purportedly prevents uncontrolled cell division by leading cholangiocarcinoma cells to differentiate. Ivosidenib is given orally at a dose of 500 mg each day until disease progression or intolerable toxicity. Developer(s): Agios Pharmaceuticals, Inc (Cambridge, Massachusetts)

Males aged 18 years or older Olaparib (Lynparza) is a small-molecule drug intended to Abiraterone Overall survival Stakeholder commenters who have metastatic, inhibit poly adenosine diphosphate-ribose polymerase (PARP), Cabazitaxel Progression-free survival agreed that reported patient castration-resistant prostate which functions in a DNA repair pathway. Olaparib might Docetaxel Quality of life health outcomes (eg, cancer (mCRPC) that harbors a improve patients’ overall survival as a single agent and, when progression-free survival, Enzalutamide mutation in one of 15 genes used in a combination, by potentially providing a synergistic overall survival) were involved in homologous mechanism of action for treating prostate cancer in patients Pembrolizumab (for incremental. Commenters recombination repair and has with poor overall outcomes. Cancers are often deficient in a microsatellite instability– agreed that the high incidence been treated with one or more DNA repair pathway, and with the addition of PARP inhibition, high [MSI-H] or mismatch of adverse events would slow newer hormonal agents (ie, the loss of 2 types of DNA repair results in cancer cell death in repair–deficient [dMMR] or prevent adoption of abiraterone and/or response to DNA damage. Olaparib purportedly induces cell tumors) olaparib. Therefore, its enzalutamide) death in prostate tumors that harbor germline mutations in Radium 223 (for bone- disruption potential is low. one of several genes involved in the homologous predominant disease with recombination repair (HRR) pathway, providing a way to treat no organ involvement) tumors for patients with limited options. Treatment eligibility will require testing for specific germline gene mutations. In clinical trials, olaparib is given orally at a dosage of 300 mg twice daily 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 78

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

Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Pembrolizumab was approved who have locally advanced or targets the programmed cell death-1 (PD-1) coinhibitory following: Progression-free survival for treating HNSCC in the first- metastatic, recurrent head and receptor expressed by activated T cells. It is approved by FDA. Antimetabolites (eg, Quality of life line setting in June 2019. neck squamous cell carcinoma Because most patients with HNSCC have disease recurrence capecitabine, 5-fluorouracil, Because it has been clinically (HNSCC) after treatment with standard platinum-based chemotherapy, gemcitabine, methotrexate) available for more than 1 year, pembrolizumab is intended to provide an option for these EGFR inhibitor (eg, it is no longer within the time patients. A hallmark of cancer is its ability to evade an immune cetuximab) scope for the PCORI Health response. Several types of cancer cells, including HNSCC, Care Horizon Scanning System. Platinum-based drugs (eg, activate an immune checkpoint pathway in T cells by The time scope is defined as 3 carboplatin, cisplatin) overexpressing programmed cell death ligand-1 (PD-L1), years before an intervention which binds to PD-1 and limits the activation of cancer- Taxanes (eg, docetaxel, becomes clinically available specific T cells. Pembrolizumab purportedly prevents the paclitaxel) outside of the research setting interaction between PD-1 and PD-L1 in an effort to overcome to 1 year after an intervention the immune tolerance of HNSCC by enhancing cancer-specific becomes clinically available. T-cell responses. 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. Pembrolizumab is also given in combination with intravenous cisplatin (100 mg/m2) or carboplatin (AUC 5) plus 5- fluorouracil (1000 mg/m2). Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)

Section 2. Cancer 79

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

Females aged 18 years or older Pembrolizumab (Keytruda) plus lenvatinib (Lenvima) is a One or more of the Overall survival Stakeholder commenters who have advanced combination therapy consisting of an anti-PD-1 (programmed following: Progression-free survival agreed that, although this endometrial carcinoma (EC) cell death-1) monoclonal antibody (ie, pembrolizumab) and a Anthracyclines (eg, Quality of life combination therapy has some that is not microsatellite multikinase inhibitor (ie, lenvatinib). The combination drug is doxorubicin) potential to improve patient instability–high (MSI-H) or approved by FDA. Pembrolizumab purportedly inhibits cancer mTOR inhibitors (eg, health outcomes, because of mismatch repair–deficient growth and/or survival by inhibiting immune checkpoint everolimus, temsirolimus) the adverse events and 19% (dMMR), who have disease signaling, and lenvatinib purportedly does so by inhibiting discontinuation rate due to Platinum agents (eg, progression after systemic receptor tyrosine kinase–mediated neoplastic signaling. treatment-related adverse carboplatin, cisplatin) therapy and are not candidates Neither drug has shown high levels of efficacy as a single events, it will not likely be a for curative surgery or agent when used in patients with EC who are not selected for Taxanes (eg, docetaxel, preferred regimen. Therefore, radiation biomarkers by genetic testing. However, investigators paclitaxel) its disruptive potential is small. hypothesize that combined use of these agents might improve outcomes. This hypothesis is based not only on the additive nature of the 2 agents, but also on lenvatinib’s purported inhibition of vascular endothelial growth factor receptor (VEGFR)–mediated immunosuppression, which might induce a pembrolizumab immune response. An oncologist prescribes the combination therapy. The recommended regimen in the FDA-approved label is an intravenous infusion at a dosage of 200 mg once every 3 weeks until disease progression or unacceptable toxicity or up to 24 months without disease progression, in combination with oral lenvatinib at a dose of 20 mg daily. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey), in collaboration with Eisai Co, Ltd (Tokyo Japan)

Section 2. Cancer 80

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

Children aged 12 years or Ruxolitinib phosphate (Jakafi) inhibits the Janus kinases (JAKs) One or more of the Treatment response rate Ruxolitinib phosphate was older and adults with steroid- JAK1 and JAK2, which mediate signaling for several cytokines following: Mortality approved to treat steroid- refractory acute graft-versus- and growth factors involved in white blood cell formation and α1-Antitrypsin Quality of life refractory acute graft-versus- host disease (GVHD) after immune function. JAK1 and JAK2 are implicated in GVHD, a Alemtuzumab host disease on May 24, 2019. allogeneic stem cell life-threatening complication of ASCT for cancer. Patients Because it has been clinically Antithymocyte globulin transplantation (ASCT) to treat receiving ASCT are at high risk of GVHD; steroids are a first- available for more than 1 year, cancer line therapy but do not work in some patients. Effective Calcineurin inhibitors (eg, it is no longer within the time options are needed. Ruxolitinib, approved by FDA, provides a cyclosporine, tacrolimus) scope for the PCORI Health new option by inhibiting JAK1 and JAK2 and purportedly Cyclophosphamide Care Horizon Scanning System. decreasing production of inflammatory cytokines and Etanercept The time scope is defined as 3 reducing immune cell migration to the gastrointestinal tract, Extracorporeal years before an intervention which is frequently involved in GVHD. For GVHD, the FDA- photopheresis becomes clinically available approved label states the recommended starting dosage is a outside of the research setting Methotrexate 5-mg tablet taken by mouth twice daily. to 1 year after an intervention Mycophenolate mofetil Developer(s): becomes clinically available. Pentostatin Incyte Corp (Wilmington, Delaware) Sirolimus

Section 2. Cancer 81 Section 3. Cardiovascular Diseases: 28 Topics

Table 3.1. Cardiovascular Diseases 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 18 years or older Nerinetide (NA-1) is a neuroprotective drug in development to Standard-of-care ischemic Stroke-induced disability Clinical trial(s): Phase 3 ESCAPE- who have had an acute reduce brain damage caused by ischemic stroke. When a clot stroke treatment (ie, tissue Survival NA1 completed November ischemic stroke (ie, caused by a blocks an artery supplying the brain, brain cells can be plasminogen activator Quality of life 2019, data published February blood clot) damaged by restricted blood flow (ischemia). When blood [alteplase] thrombolysis, 2020; phase 3 FRONTIER flow is restored, brain cells can also be harmed by reperfusion mechanical thrombectomy) primary completion May 2021 injury, which results from an inflammatory cascade including without nerinetide oxygen-free radicals and proinflammatory cytokines. neuroprotection 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 82 Table 3.2. Currently Monitored Cardiovascular Diseases Topics: 22 Topics

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 uses a Enhanced external Angina incidence Clinical trial(s): Phase 3 who have Canadian patient’s own bone marrow–derived mononuclear cells to counterpulsation Coronary adverse events CardiAMP CMI primary Cardiovascular Society class III transplant into damaged heart muscle to improve heart Guideline-directed drug Exercise tolerance completion December 2022 or IV chronic refractory angina function and exercise capacity. The developer asserts that therapy (eg, aspirin, beta- Survival from obstructive coronary improving heart function could also reduce angina incidence blockers, calcium channel Quality of life artery disease that is 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 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 83

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 class Clinical trial(s): Phase 3 who have New York Heart transplants a patient’s own bone marrow–derived (ie, Barostim neo implant) Exercise tolerance CardiAMP primary completion Association (NYHA) functional mononuclear cells into damaged heart muscle. It is intended Cardiac contractility HF-related June 2020 class II or III heart failure (HF) to improve heart function and exercise capacity through 2 modulation (ie, Optimizer hospitalizations with chronic ischemic left mechanisms: direct and indirect regeneration. In direct implant) Survival ventricular dysfunction regeneration, the transplanted cells purportedly travel to Guideline-directed optimal Quality of life secondary to myocardial injured heart muscle (ie, myocardium) and transform into new drug therapy (eg, angiotensin- infarction and ventricular functional heart cells. In indirect regeneration, the converting enzyme [ACE] ejection fraction between 20% transplanted cells purportedly secrete stimulatory cytokines to inhibitors, diuretics, and 40% that is stable and instruct resident stem cells to regenerate heart tissue. hydralazine, ivabradine, being treated with guideline- Clinicians first collect about 15 cc of bone marrow and send it sacubitril/valsartan) directed medical and device to a partner laboratory for proprietary molecular analysis to 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 84

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 microvasculature counterpulsation Exercise capacity Regenerative Medicine Cardiovascular Society class III (ie, angiogenesis) in ischemic myocardial tissue. CLBS14 is Guideline-directed optimal Major adverse Advanced Therapy or IV chronic refractory angina intended to improve medical therapy for patients with drug- drug therapy (eg, aspirin, cardiovascular events Clinical trial(s): Phase 3 RENEW and obstructive coronary resistant angina for whom conventional revascularization is beta-blockers, calcium (MACE) completed November 2015, disease unsuited for ineffective or unsuitable. During the proprietary process, channel blockers, nitrates, Survival pivotal data published August conventional revascularization patients receive granulocyte colony-stimulating factor (G-CSF; ranolazine) 2016 5 mg/kg subcutaneous injection) for about 4 days to mobilize Quality of life their own CD34+ cells before apheresis (ie, plasma exchange) on day 5 to collect cells from peripheral blood. Clinicians ship peripheral blood to a processing laboratory to isolate CD34+ cells and prepare the cell therapy product for transport back to the treating facility. After about 3 to 4 days, clinicians administer the cell product into ischemic heart muscle via catheter-based intramyocardial injection. Developer(s): Caladrius Biosciences, Inc (Basking Ridge, New Jersey), which acquired exclusive worldwide license from Shire plc (Dublin, Ireland), now part of Takeda Pharmaceutical Co, Ltd (Osaka, Japan)

Section 3. Cardiovascular Diseases 85

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 dal- who have a confirmed AA (CETP), a plasma protein responsible for lipid transport. drug therapy (eg, angiotensin- cardiovascular events GenE primary completion polymorphism at the Dalcetrapib was originally intended to raise high-density converting enzyme [ACE] (MACE), including January 2021 rs1967309 location in the lipoprotein levels by modulating CETP activity. It is also inhibitors, aspirin, beta- cardiovascular death, adenylate cyclase type 9 gene, intended to lower cardiovascular risk by helping lower levels of blockers, calcium channel myocardial infarction, ADCY9, and were recently harmful low-density lipoproteins. However, although blockers, statins) and stroke hospitalized for acute coronary dalcetrapib failed to reduce cardiovascular events in large Proprotein convertase syndrome phase 3 trials, patients treated with dalcetrapib who carried subtilisin kexin type 9 (PCSK9) the AA polymorphism at the rs1967309 location of the ADCY9 inhibitors gene showed a 39% drop in cardiovascular adverse events. DalCor licensed dalcetrapib and the AA allele genetic marker from Roche for use in a genetically defined subpopulation that has an increased cardiovascular risk. Roche is developing a companion diagnostic 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 Clinical trial(s): Phase 3 ORION- who have atherosclerotic to target and reduce the expression of proprotein convertase Ezetimibe cardiovascular events 10 primary completion October cardiovascular disease subtilisin kexin type 9 (PCSK9) to treat high cholesterol (ie, Fibrates (MACE) 2019, data published April (coronary, peripheral, or other hypercholesterolemia). Inhibiting PCSK9 production 2020; phase 3 ORION-8 Niacin Survival arteries) and elevated low- purportedly increases the number of LDL receptors that are primary completion August density lipoprotein (LDL) recycled and are available on cell surfaces to remove LDL PCSK9-inhibiting monoclonal 2023 cholesterol (ie, greater than 70 particles from extracellular fluid. Inclisiran is intended to antibodies mg/dL) despite an optimal simplify the dosing regimen as a subcutaneous (ie, under-the- Statins dose of statins or other lipid- skin) injection every 3 to 6 months rather than an injection of lowering therapies if statin- alirocumab or evolocumab every 2 to 4 weeks. In clinical trials, intolerant 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 subsidiary of Novartis AG (Basel, Switzerland), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)

Section 3. Cardiovascular Diseases 86

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

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 ORION- and an elevated low-density hypercholesterolemia). Inhibiting PCSK9 production Niacin Survival 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-the- Statins 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 subsidiary of Novartis AG (Basel, Switzerland), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)

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 common modulation (ie, Optimizer Exercise tolerance Breakthrough Device York Heart Association (NYHA) feature of HF that causes a backup of blood in the lungs, implant) HF-related Clinical trial(s): Unphased class III or ambulatory class IV leading to pulmonary congestion and breathing difficulty. Guideline-directed optimal hospitalization pivotal REDUCELAPHF-II heart failure (HF), left IASD implantation would disrupt management for patients drug therapy (eg, angiotensin- Survival primary completion December ventricular ejection fraction with HF with preserved left ventricular ejection fraction (ie, converting enzyme [ACE] 2020; phase 2 REDUCELAPHF-I Quality of life greater than 40%, and elevated greater than 40%), which relies on drug therapy prescribed in inhibitors, diuretics, primary completion December left atrial pressure despite an outpatient office setting. IASD implantation might also hydralazine, ivabradine, 2016, data published October stable guideline-directed compete with implantation of the recently introduced sacubitril/valsartan) 2018; REDUCELAPHF-III optimal drug therapy Optimizer electronic implant in a subset of patients with left European postmarket ventricular ejection fraction between 40% and 45%. To implant observational primary the IASD, a physician inserts a specialized catheter in the completion July 2021 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 87

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

Adults aged 18 years or older Neovasc Reducer is a stent-like implant intended to treat Enhanced external Angina incidence Submission date: Premarket who have Canadian chronic angina by improving blood flow to ischemic heart counterpulsation Exercise tolerance Approval Application Cardiovascular Society class III tissue. This implanted device could provide an option for Guideline-directed medical Device-related adverse December 31, 2019 or IV chronic angina from patients whose angina persists despite optimal medical therapy for ischemic heart events FDA designation(s): obstructive coronary artery therapy and who are unable to undergo conventional bypass disease (eg, aspirin, beta- Survival Breakthrough Device disease that is resistant to surgery. Physicians implant the Neovasc Reducer in the blockers, calcium channel Quality of life Clinical trial(s): Unphased optimal medical therapy and coronary sinus, the large vein that drains blood from heart blockers, nitrates, ranolazine) REDUCER-1 primary who are unsuitable for muscle, to create a pressure backflow that purportedly completion December 2022, conventional revascularization modulates blood flow through the coronary sinus and preliminary data presented redistributes blood to areas of heart muscle with poor October 2019; unphased circulation. To implant the balloon-expandable, hourglass- primary completion December shaped device, a physician inserts the delivery catheter at the 2028 jugular vein in the neck and advances it into the coronary sinus, located on the external heart wall between the left atrium and left ventricle. Implantation purportedly takes about 20 minutes with patients under local anesthesia. Developer(s): Neovasc, Inc (Richmond, British Columbia, Canada)

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

Section 3. Cardiovascular Diseases 88

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

Adults aged 18 years or older Organ Care System (OCS) is intended to maintain a donor Conventional cold storage Graft organ survival Submission date: April 14, 2014 who are candidates for heart organ in a warm, functioning state outside the body for an Overall survival Clinical trial(s): Unphased transplantation extended period to optimize donor organ health and allow for Quality of life EXPAND Heart completed continuous clinical evaluation before transplantation. The OCS December 2019, preliminary Heart is optimized for preserving donor hearts. Many donor data published April 2019; hearts are never transplanted because their condition unphased HEART EXPAND degrades quickly after harvesting; thus, fewer patients receive continued access protocol the heart transplant they need. OCS Heart would represent a primary completion November substantial change to pretransplant procedures for potential 2020; unphased Donors After donor organ assessment, procurement, and transport Circulatory Death primary compared with static cold storage, which is the current completion August 2021; standard. OCS Heart purportedly could increase the volume of unphased observational clinical heart transplantations, enabling longer-distance transport and use cohort primary completion giving clinicians more clinical data to better assess donor December 2021 organ suitability. The manufacturer has developed similar Note(s): On March 16, 2020, technology to preserve lung and liver grafts. The OCS device FDA postponed an advisory comprises 2 principal components: a portable battery- panel meeting to discuss the powered console and an organ-specific perfusion kit that OCS Heart, originally scheduled function together as an integrated system. The system for April 16, 2020, until a future perfuses donor organs with a proprietary blood-based undetermined date because of solution to replenish oxygen and essential nutrients. When issues related to the COVID-19 physicians harvest the donor heart, they place it in the pandemic. FDA approved OCS perfusion module and revive it to a beating state. The self- Lung for standard-criteria lung contained perfusion module maintains the proper temperature preservation in March 2018 and and humidity, protects the organ from external contaminants, for expanded-criteria lung and allows sterile ultrasound assessment of heart function and preservation in June 2019. sterile blood sampling for laboratory analysis. A wireless monitor allows clinicians to assess the organ’s status and control system functions. Developer(s): TransMedics, Inc (Andover, Massachusetts)

Section 3. Cardiovascular Diseases 89

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

Adults aged 18 to 75 years Paradise Renal Denervation System is a catheter-based device Guideline-directed optimal Blood pressure Clinical trial(s): RADIANCE-HTN who have essential intended to ablate the sympathetic nerves that line the main antihypertensive drug therapy Cardiovascular adverse primary completion June 2020, hypertension controlled on renal arteries connecting the kidneys to the aorta. Deactivating with one or more agents (eg, events interim data published March one or 2 medications or the renal sympathetic nerves can purportedly help reduce angiotensin-converting Survival 2019; RADIANCE-II pivotal uncontrolled hypertension on difficult-to-manage, treatment-resistant high blood pressure enzyme [ACE] inhibitors, primary completion December Quality of life zero to 2 medications (average (ie, hypertension). An interventional procedure would shift angiotensin-receptor blockers 2020 office blood pressure between care away from standard office-based medical management [ARBs], calcium channel 140/90 and 180/110 mm Hg) for most patients with uncontrolled high blood pressure. A blockers, thiazide diuretics) physician inserts the proprietary 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 ischemia (PLX-PAD) are mesenchymal-like adherent stromal cells drug therapy (eg, angiotensin- treated leg Expanded Access Program and ischemic lesions with derived from full-term human placentas and cultured in a converting enzyme [ACE] Ischemic pain (EAP), EAP Cost Recovery minor tissue loss up to the proprietary bioreactor. PLX-PAD cells purportedly release inhibitors, aspirin, cilostazol, Major amputation Clinical trial(s): Phase 3 PACE ankle level (Rutherford cytokines, chemokines, and growth factors to promote new clopidogrel, statins) primary completion May 2020 category 5) and are deemed blood vessel growth (ie, angiogenesis) and increase circulation Proprotein convertase unsuitable for peripheral artery in ischemic tissue, induce muscle tissue regeneration, and subtilisin kexin type 9 (PCSK9) revascularization by any modulate inflammation to reduce connective tissue deposition inhibitors conventional method and scarring. The cell product is given by intramuscular injection to the affected leg. Developer(s): Pluristem Therapeutics, Inc (Haifa, Israel)

Section 3. Cardiovascular Diseases 90

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

Adults aged 18 to 90 years Pressure-controlled intermittent coronary sinus occlusion Standard percutaneous Change in size/volume of FDA designation(s): who have ST-segment (PiCSO) system consists of a proprietary catheter, console, and coronary intervention (ie, myocardial infarct (ie, Breakthrough Device elevation myocardial infarction monitor intended to be used to preserve at-risk heart muscle balloon angioplasty with dead heart muscle) Clinical trial(s): Unphased (STEMI) during an acute heart attack. PiCSO is intended to be used as stenting) Heart function randomized PiCSO-AMI-I an adjunct to the standard percutaneous coronary primary completion September intervention for STEMI, balloon angioplasty plus stenting. It 2020; phase 2 nonrandomized could disrupt current management by adding procedural steps OxAMI-PICSO primary and capital equipment. During a percutaneous coronary completion October 2020 intervention procedure, PiCSO therapy is initiated after blood flow has been restored. Physicians insert the 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 91

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 class Clinical trial(s): Phase 3 DREAM who have chronic (at least 6- made from human bone marrow–derived, allogeneic (ie, from drug therapy (eg, ACE Exercise tolerance HF-1 primary completion May month duration) ischemic or a donor) adult mesenchymal precursor cells. Standard medical inhibitors, diuretics, HF-related 2020 nonischemic New York Heart therapy for HF attempts to slow disease progression and hydralazine, ivabradine, hospitalizations Note(s): FDA granted Association (NYHA) functional relieve symptoms. Rexlemestrocel-L purportedly releases a sacubitril/valsartan) Survival rexlemestrocel-L Orphan Drug class II or III heart failure (HF) range of factors that induce functional recovery within designation in June 2019 for Quality of life while being treated with damaged heart tissue by activating multiple pathways to preventing mucosal bleeding maximally tolerated doses of a induce new blood vessel growth, reduce inflammation, reduce after implantation of a left beta-blocker, an angiotensin- fibrosis and scar tissue formation, and regenerate heart ventricular assist device (LVAD) converting enzyme (ACE) muscle. Rexlemestrocel-L is isolated from bone mononuclear in adults with end-stage HF inhibitor or angiotensin- cells with antistromal precursor antigen (STRO)-3 antibodies, receptor blocker (ARB), and/or expanded in a laboratory, and cryopreserved until it is given to an aldosterone antagonist, plus the patient. The product is intended to be an off-the-shelf a diuretic 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 92

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

Adults aged 18 years or older Rexlemestrocel-L (Revascor) is a regenerative cellular therapy LVAD implantation alone Mucosal and GI bleeding FDA designation(s): Orphan who have New York Heart made from human bone marrow–derived, allogeneic (ie, from Functional capacity Drug, Regenerative Medicine Association (NYHA) functional a donor) adult mesenchymal stem cells. Patients who have Treatment-related Advanced Therapy class IIIB or IV heart failure (HF) end-stage HF and require LVAD implantation face a high risk adverse events Clinical trial(s): Phase 2 that has been unresponsive to of serious GI bleeding and repeated hospitalizations. A phase Survival randomized completed August optimal medical management 2 trial of patients who received an LVAD found that adding 2019, data published March Quality of life and who are at risk of rexlemestrocel-L significantly reduced the incidence of major 2019 gastrointestinal (GI) bleeding GI bleeding by about 76% compared with a control group, Note(s): Future confirmatory after implantation of a left although it did not increase the rate of successfully weaning phase 3 is planned (no date ventricular assist device (LVAD) patients from LVAD therapy (the trial’s primary outcome). For stated) to support a future patients with end-stage HF requiring an LVAD, rexlemestrocel- Biologics License Application L given immediately after LVAD implantation is intended to for end-stage HF in patients reduce the risk of GI bleeding and related hospitalization. with an LVAD implant 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 93

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 class 2019 to reevaluate product and left ventricular ejection underexpressed in heart muscle cells of patients with HF. RT- device) Survival development strategy fraction between 10% and 35% 100 is an adenovirus vector (ie, human adenovirus 5 encoding Guideline-directed optimal Quality of life despite guideline-directed human AC6 [Ad5.hAC6]) modified to prevent it from drug therapy (eg, angiotensin- optimal medical therapy replicating. It is designed to enter heart cells to deliver the converting enzyme [ACE] gene encoding for AC6. A physician uses standard cardiac inhibitors, diuretics, catheterization techniques to administer a single dose of RT- hydralazine, ivabradine, 100 into the coronary arteries using an infusion catheter. In a sacubitril/valsartan) phase 2 trial, patients received one of 5 ascending doses from 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 94

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

Adults aged 18 years or older Stereotactic body radiotherapy (SBRT) is an established No comparators exist VT episode incidence Clinical trial(s): Phase 1/2 who have sustained ventricular treatment for several solid-tumor cancers (eg, breast, prostate, Survival ENCORE-VT primary tachycardia (VT) refractory to liver, kidney) that is designed to deliver high-dose radiation Quality of life completion July 2018, or unsuitable for conventional noninvasively to precise targets in the body while avoiding preliminary data published catheter ablation of damage to healthy adjacent tissue. Investigators have begun January 2019, additional data arrhythmias or additional evaluating whether SBRT could offer a noninvasive therapeutic presented November 2019; medical management and alternative for VT, a potentially fatal irregular heartbeat, that phase 1/2 NIRA-VT primary documented, recurrent VT has not responded to conventional treatments. Although completion December 2019; episodes despite an existing several radiation therapy systems are FDA cleared for SBRT for unphased RAVENTA primary implantable cardioverter- various tumors, SBRT for VT would be an off-label use. SBRT completion June 2021; phase defibrillator (ICD) for refractory VT would represent a dramatic shift in 1/2 STRA-MI-VT primary arrhythmia treatment that would require substantial completion September 2022; collaboration among clinicians in different clinical service lines phase 1/2 SABR for refractory (eg, interventional cardiology and radiation physics) who do VT primary completion not typically have reason to 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 less SBRT for VT would not be than 15 minutes. VT episodes may occur within the first 6 subject to FDA approval or weeks after treatment due to radiation-induced inflammation; clearance. US investigators however, VT episodes are expected to decline substantially typically perform the procedure after radiation-associated inflammation resolves. off-label using radiotherapy Developer(s): systems that have FDA Washington University School of Medicine in St Louis (St Louis, clearance to perform SBRT for Missouri) solid-tumor cancers. University of California at Los Angeles (Los Angeles, California) Varian Medical Systems, Inc (Palo Alto, California)

Section 3. Cardiovascular Diseases 95

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 ablate Guideline-directed optimal Blood pressure Clinical trial(s): SPYRAL HTN- who have 24-hour average the sympathetic nerves that line the main renal arteries antihypertensive drug therapy Cardiovascular adverse OFF MED pivotal primary ambulatory systolic blood connecting the kidneys to the aorta. Deactivating the renal with one or more agents (eg, events completion June 2020, pressure of at least 140 mm Hg sympathetic nerves purportedly can help reduce difficult-to- angiotensin-converting Mortality preliminary proof-of-concept and less than 170 mm Hg manage high blood pressure (ie, hypertension). An enzyme [ACE] inhibitors, data published November Quality of life interventional procedure would shift care from standard angiotensin-receptor blockers 2017, further preliminary data office-based medical management for most patients with [ARBs], calcium channel published January 2019, data uncontrolled high blood pressure. A physician inserts the blockers, thiazide diuretics) presented September 2019, helical ablation catheter into the femoral artery in the groin post hoc data presented and advances it into the left and right renal arteries, November 2019, data alternately, to deliver radiofrequency energy in a spiral pattern, published March 2020; SPYRAL about 1 minute per application, to one or more sections of HTN-ON MED primary each artery. The physician removes the catheter using completion November 2020, standard interventional techniques after treating both renal preliminary data published arteries. June 2018; SPYRAL DYSTAL Developer(s): primary completion March Medtronic plc (Dublin, Ireland) 2021

Adults aged 18 years or older Therapeutic Intra-Vascular Ultrasound (TIVUS) System is Atrial septostomy (for drug- Exercise capacity FDA designation(s): who have pulmonary arterial intended to treat PAH by destroying (ie, ablating) the nerves in resistant PAH) PAH worsening Breakthrough Device hypertension (PAH) the pulmonary arteries in a process called pulmonary artery Guideline-directed medical Survival Clinical trial(s): Unphased denervation. As an interventional procedure to treat PAH, therapy (eg, ambrisentan, Quality of life single-arm TROPHY II primary TIVUS would disrupt standard PAH treatment, which relies riociguat, tadalafil, treprostinil) completion July 2020; primarily on medical management (ie, drugs). Studies have Lung transplantation (for unphased single-arm suggested that baroreceptors and sympathetic nerve fibers advanced drug-resistant PAH) TROPHY1-US primary near the branching (ie, bifurcation) of the main pulmonary completion April 2019, artery might contribute to the elevated blood pressures seen preliminary data published in PAH. Therefore, ablating the nerves embedded in the main, April 2019; unphased single- left, and right pulmonary arteries might reduce high blood arm TROPHY1 primary pressure in the pulmonary arteries and lungs in patients with completion October 2018, PAH. To perform pulmonary artery denervation, a physician preliminary data published inserts a proprietary catheter into the jugular vein in the neck April 2019 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 96

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

Adults aged 18 years or older Vitaria is an implant intended to treat HF by electrically Cardiac contractility NYHA HF functional class FDA designation(s): who have symptomatic New stimulating the vagus nerve in the neck. This approach, called modulation (ie, Optimizer Exercise tolerance Breakthrough Device York Heart Association (NYHA) autonomic regulation therapy, purportedly treats HF by implant) HF-related Clinical trial(s): Unphased functional class III heart failure correcting an imbalance in the autonomic nervous system Guideline-directed optimal hospitalizations ANTHEM-HFrEF pivotal primary (HF), or NYHA class II HF with caused by overactive sympathetic nerves and underactive drug therapy (eg, diuretics, Survival completion December 2021, an HF-related hospitalization in parasympathetic nerves. Vagal nerve stimulation (VNS) could angiotensin-converting data presented March 2020 Quality of life the past 6 months, and whose disrupt standard-of-care drug therapy for many patients with enzyme [ACE] inhibitors, heart is in normal sinus rhythm HF. VNS therapy could also compete with the recently hydralazine, ivabradine, with left ventricular ejection introduced Optimizer implantable device for treating some sacubitril/valsartan) fraction of 35% or less despite subsets of patients with HF. To deploy the device, a surgeon stable, guideline-directed places a pacemaker-like stimulator under the skin in the right optimal 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 18 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 device modulation (ie, Optimizer hospitalization randomized RELIEVE-HF failure (HF) despite guideline- implantation would disrupt patient management for HF, which implant) Survival primary completion October directed optimal drug therapy traditionally relies on office-based drug therapy. V-Wave 2021 Guideline-directed optimal Quality of life and regardless of left implantation might also compete with implantation of 2 drug therapy (eg, angiotensin- ventricular ejection fraction recently introduced electronic devices for HF: the Barostim neo converting enzyme [ACE] and Optimizer implants. To implant the V-Wave shunt, a inhibitors, diuretics, physician inserts a specialized catheter into the femoral vein at hydralazine, ivabradine, the groin and threads it up to the right atrium to create an sacubitril/valsartan) opening in the septum, the wall separating the left and right atrial chambers. The stent-like scaffold is designed to keep the transseptal puncture open. This new opening purportedly lowers left atrial pressure and helps reduce pulmonary congestion by allowing blood to cross into the low-pressure right atrium. Developer(s): V-Wave, Ltd (Caesarea, Israel, and Agoura Hills, California)

Section 3. Cardiovascular Diseases 97

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 class FDA designation(s): who have heart failure (HF) and Resynchronization Therapy (WiSE-CRT) is a system that pacing/CRT with epicardial left Exercise tolerance Breakthrough Device New York Heart Association purportedly improves on conventional CRT devices. It replaces ventricular lead HF-related Clinical trial(s): IDE pivotal (NYHA) class I or IIa guideline epicardial left ventricular pacing stimulation from an electrode Guideline-directed optimal hospitalizations (SOLVE CRT) primary indication for conventional lead placed within the coronary sinus vein along the left drug therapy (eg, angiotensin- Survival completion September 2019; cardiac resynchronization ventricular wall with endocardial left ventricular pacing from a converting enzyme [ACE] CT Guided WiSE-CRT primary Quality of life therapy (CRT) and whose wireless electrode implanted inside the left ventricle. A inhibitors, diuretics, completion December 2020; disease has not responded to conventional pacemaker implanted under the skin in the chest hydralazine, ivabradine, WiCS-LV postmarket registry CRT or was previously senses and paces the right ventricle with a conventional right sacubitril/valsartan) primary completion September untreatable (ie, had an atrial lead and a right ventricular lead. A wireless electrode 2019, data published March implanted CRT system turned (2.7 × 16.3 mm) anchored in the left ventricular wall paces the 2020 off due to electrode lead left ventricle. A wireless transmitter placed under the skin in failure or relative the chest senses the right ventricular pacing and sends contraindications to an ultrasound energy to the implant to generate endocardial left implanted lead) 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 98 Table 3.3. Cardiovascular Diseases Topics Archived Since Last Status Report: 5 Topics

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

Adults aged 18 to 85 years Bempedoic acid (Nexletol; previously called ETC-1002) is a Bile acid–binding resins Major adverse Stakeholders reviewing this who have heterozygous small-molecule prodrug converted to an active drug primarily Ezetimibe cardiovascular events topic thought bempedoic acid familial hypercholesterolemia in the liver and designed to inhibit ATP citrate lyase (ACL), a Fibrates (MACE) lacks significant disruptive or established atherosclerotic key enzyme involved in cholesterol and fatty acid synthesis in potential because it will likely Niacin Survival cardiovascular disease who the liver. FDA-approved, bempedoic acid might be more cost- be used as a second- or third- require additional lowering of effective and more widely accepted than injectable proprotein PCSK9-inhibiting line alternative to existing, low-density lipoprotein (LDL) convertase subtilisin kexin type 9 (PCSK9) inhibitors for monoclonal antibodies generic nonstatin alternatives cholesterol managing disease in patients who cannot tolerate statins or such as ezetimibe. who do not achieve sufficiently low cholesterol levels. By inhibiting ACL, bempedoic acid purportedly reduces cholesterol synthesis, thereby upregulating LDL receptors and increasing clearance of LDL cholesterol from the bloodstream. The FDA-approved label is a dosage of 180 mg orally once daily, taken with or without food as an adjunct to diet and maximally tolerated statin therapy. Developer(s): Esperion Therapeutics, Inc (Ann Arbor, Michigan), in collaboration with Otsuka Pharmaceutical Co, Ltd (Tokyo, Japan)

Section 3. Cardiovascular Diseases 99

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

Adults aged 18 years or older Optimizer is a cardiac implant that uses a process called Guideline-directed optimal NYHA HF functional class Optimizer received FDA who have New York Heart cardiac contractility modulation (CCM) to deliver nonexcitatory drug therapy (eg, Exercise tolerance approval on March 21, 2019. Association (NYHA) class III electrical pulses during the myocardial absolute refractory angiotensin-converting HF-related hospitalization Because it has been clinically heart failure (HF) and remain period to improve systolic contraction. The FDA-approved enzyme [ACE] inhibitors, available for more than 1 year, Survival symptomatic despite label states the device is indicated to improve 6-minute hall diuretics, hydralazine, it is no longer within the time guideline-directed medical walk distance, quality of life, and functional status. CCM ivabradine, Quality of life scope for the PCORI Health therapy, are in normal sinus purportedly normalizes phosphorylation of regulatory proteins sacubitril/valsartan) Care Horizon Scanning System. rhythm, are not indicated for to improve calcium handling—ultimately interrupting the The time scope is defined as 3 cardiac resynchronization remodeling cascade (ie, changes in size and shape) to reverse years before an intervention therapy, and have a left enlargement of the left ventricle—and to improve left becomes clinically available ventricular ejection fraction ventricular pumping (ie, contractile) strength. The Optimizer outside of the research setting ranging from 25% to 45% Smart model replaced all earlier Optimizer versions (ie, II, III, to 1 year after an intervention IV) used in clinical trials since 2016. Physicians implant the becomes clinically available. pulse generator under the skin in the right pectoral region similarly to standard pacemaker or defibrillator implantation. Two standard pacemaker leads are placed through major blood vessels into the right ventricle on the right ventricular septum to sense local electrical activity and deliver CCM. An improved, second-generation device (FDA supplemental approval in October 2019) purportedly no longer requires an optional atrial lead placed in the right atrium for additional electrical sensing. The device delivers pulses at regular intervals during the day, purportedly unnoticed by patients. Patients recharge the pulse generator at home for 60 to 90 minutes once weekly using a noninvasive charging system placed over the implant. Developer(s): Impulse Dynamics (Mt Laurel, New Jersey)

Section 3. Cardiovascular Diseases 100

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

Adults aged 18 to 80 years Revivent TC Transcatheter Ventricular Enhancement System is Baroreflex activation NYHA HF functional class Stakeholder commenters who have symptomatic New intended to improve cardiac function in patients with HF by therapy (ie, Barostim neo Exercise tolerance thought that, although the York Heart Association (NYHA) restoring a more normal shape to an enlarged left ventricle. device) HF-related hospitalization concept of improving heart functional class III or IV heart The procedure, called transcatheter ventricular restoration, function by restoring a more Cardiac contractility Survival failure (HF) despite optimal offers a less invasive and purportedly safer procedure than modulation (ie, Optimizer natural shape to an enlarged Quality of life guideline-directed medical open surgical ventricular restoration. Transcatheter ventricular device) left ventricle seemed therapy, left ventricular restoration could allow more patients to undergo ventricular Guideline-directed medical theoretically sound, the high ejection fraction less than 45%, restoration than open surgical ventricular restoration, a therapy (eg, angiotensin- rate of serious adverse events and heart attack–induced left procedure that is typically not covered by health insurers. The converting enzyme [ACE] in early trials would likely limit ventricular aneurysm scar Revivent TC system consists of 2 polyester-covered titanium inhibitors, diuretics, use of the Revivent TC device tissue with viable myocardium anchors connected by a tether. To perform the procedure, an hydralazine, ivabradine, and minimize its disruptive (ie, heart muscle) remote from interventional cardiologist inserts a delivery catheter into the sacubitril/valsartan) potential. the area of intended treatment patient’s jugular vein in the neck to access the heart’s right Open surgical ventricular ventricle and implant the internal anchor along the anterior reduction/restoration septum (ie, the wall separating the left and right ventricles). A surgery cardiac surgeon then makes a 4-cm (1.6-inch) incision in the chest to implant the external anchor over the opposite end of the tether, on the left ventricle’s outside wall, before tightening the tether. Physicians typically implant 2 to 3 pairs of tethered anchors to exclude the scar tissue from healthy myocardium (ie, heart muscle) by placing the left ventricular wall in proximity to the anterior septum. Isolating the scar tissue reduces the size of the left ventricle and purportedly allows the remaining healthy myocardium to pump blood more effectively. Developer(s): BioVentrix, Inc (San Ramon, California)

Section 3. Cardiovascular Diseases 101

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

Adults aged 18 years or older Shockwave Intravascular Lithotripsy System is intended to Laser atherectomy Target vessel Stakeholder commenters who have previously untreated, break up hardened calcium deposits within coronary artery Mechanical atherectomy revascularization thought that this intervention’s calcified lesions with at least walls, purportedly making arteries less stiff. Reducing their Major adverse disruptive potential is low 50% narrowing (ie, stenosis) stiffness could make performing balloon angioplasty and stent cardiovascular events because the device and and evidence of restricted placement easier, with a lower risk of complications. Such (MACE; eg, heart attack, procedural techniques are blood flow (ie, ischemia) in the complications include vascular perforation or rupture that can stroke, death) similar to those used in other coronary arteries, which are occur with use of atherectomy catheters that cut or scrape Lithotripsy-related adverse catheter-based cardiac suitable for percutaneous away calcium deposits that line the coronary arteries. The events interventions. coronary intervention (ie, system consists of a rechargeable generator and energy Quality of life balloon angioplasty with stent delivery catheter. To perform intravascular lithotripsy, a implantation) physician uses standard cardiac catheterization techniques to place a proprietary balloon catheter incorporating multiple lithotripsy emitters within the target calcium deposit in the coronary artery. The catheter produces pulsatile sonic pressure waves that purportedly deliver their energy selectively to hardened calcium deposits in the medial and intimal layers of the artery walls and pass through soft tissue without damage. The pressure waves purportedly create microfractures in the calcium embedded within artery walls, thus reducing vessel wall stiffness. After treatment, the calcium deposits remain embedded in the arterial wall. Developer(s): Shockwave Medical, Inc (Santa Clara, California)

Section 3. Cardiovascular Diseases 102

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

Adults aged 18 years or older Tafamidis (Vyndaqel, Vyndamax) is a first-in-class transthyretin Loop diuretics Cardiovascular-related FDA approved tafamidis in May who have hereditary or wild- stabilizer designed to selectively bind to transthyretin. This Supportive care for HF hospitalizations 2019. Because it has been type amyloid transthyretin- binding purportedly stabilizes the tetramer of the transthyretin Survival clinically available for more mediated cardiomyopathy transport protein and slows amyloidosis (amyloid Quality of life than 1 year, it is no longer (ATTR-CM) accumulation) in organs and tissues. In ATTR-CM, amyloidosis within the time scope for the gradually stiffens heart muscle, leading to heart failure (HF). PCORI Health Care Horizon This FDA-approved treatment targets the underlying disease Scanning System. The time process and could provide a disease-modifying option and scope is defined as 3 years slow progression to advanced HF. The FDA-approved label for before an intervention tafamidis states it is intended to treat cardiomyopathy becomes clinically available associated with inherited or wild-type (ie, not linked to a outside of the research setting known genetic mutation) amyloidosis to reduce cardiovascular to 1 year after an intervention death and cardiovascular-related hospitalizations. Tafamidis is becomes clinically available. available in 2 oral formulations that cannot be interchanged, with the following FDA-approved label recommended dosages: tafamidis meglumine 80 mg once daily, taken as four 20-mg capsules, and tafamidis 61 mg once daily, taken as a single capsule (purportedly for patient convenience). Developer(s): Pfizer, Inc (New York, New York)

Section 3. Cardiovascular Diseases 103 Section 4. Mental and Behavioral Health: 18 Topics

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

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

Adults aged 18 to 65 years Dextromethadone (REL-1017), a single isomer of racemic Antidepressants (eg, Depressive symptoms and FDA designation(s): Fast Track who have major depressive methadone, is an N-methyl-D-aspartate (NMDA) receptor monoamine oxidase severity Clinical trial(s): Phase 2 disorder (MDD) that has not antagonist intended to rapidly improve depressive symptoms inhibitors [MAOIs], selective Quality of life completed July 2019, topline responded to one to 3 prior in patients with treatment-resistant MDD. It might change the serotonin reuptake data reported October 2019 antidepressant regimens paradigm of care and improve patient health outcomes by inhibitors [SSRIs], serotonin improving depressive symptoms in a short, 7-day course of and norepinephrine treatment. It might also have fewer side effects than NMDA reuptake inhibitors [SNRIs], receptor antagonist ketamine, which is often used off-label. tricyclic antidepressants Overactivation of NMDA receptors has been associated with [TCAs]) depression and neuropathic pain. It is thought that the Brain stimulation (eg, deep blocking action of dextromethadone at NMDA receptors brain stimulation [DBS], might reduce depressive symptoms. The manufacturer electroconvulsive therapy purports that, unlike methadone, dextromethadone [ECT], transcranial magnetic demonstrates virtually no opioid receptor activity and no stimulation [TMS], vagal ketamine-like toxicities at its therapeutic dose. In a phase 2 nerve stimulation [VNS]) clinical trial, dextromethadone was taken in powder form in Esketamine juice at a loading dose of 75 or 100 mg on day 1 followed by Ketamine (off-label) either 25 or 50 mg daily on days 2 through 7. Psychotherapy (eg, Developer(s): cognitive behavioral Relmada Therapeutics, Inc (New York, New York) therapy [CBT])

Section 4. Mental and Behavioral Health 104 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

Children aged 8 to 14 years AKL-T01 (ENDEAVOR) is a video game digital therapy Behavior therapy (eg, applied ADHD symptoms and Submission date: 510(k) August who have attention- intended to improve attention and related cognitive control behavior analysis [ABA], severity 2018 deficit/hyperactivity disorder processes in children with ADHD. It is a novel intervention that cognitive behavioral therapy Attentional functioning Clinical trial(s): Unphased (ADHD) might provide a nondrug alternative for treating ADHD. A [CBT]) Executive functioning STARS-ADHD completed 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. AKL-T01 Nonstimulant medications STARS-ADHD2 completed is an action video game using proprietary selective stimulus (eg, atomoxetine, clonidine, February 2018; unphased management technology that purportedly targets and guanfacine) STARS-ADHD adjunctive activates the frontoparietal network in the brain, a network Stimulant medications (eg, primary completion September thought to play an important role in cognitive function and dexmethylphenidate, 2019, data reported January attention, to improve attention and related cognitive control lisdexamfetamine, 2020; unphased primary processes in children with ADHD. Users are given tasks such as methylphenidate) completion January 2020; interference management and sensory motor navigation. An unphased CAVES completed embedded algorithm uniquely adapts to each user’s May 2015, data published performance to provide challenging but tolerable game play. January 2018 Progress is indicated by earning rewards and unlocking new Note(s): AKL-T01 was released environments. AKL-T01 is an application that can be for download in April 2020 downloaded on smart devices and used at home. It has been without 510(k) clearance in studied alone and in combination with stimulant medication. accordance with FDA guidance In clinical trials, AKL-T01 was used by the patient at home on a on expanding use of certain smart tablet for 25 minutes (5 sessions of 5 minutes) 5 times a digital health therapeutic week for 4 weeks. devices for psychiatric disorders Developer(s): for the duration of the public Akili Interactive Labs, Inc (Boston, Massachusetts) health emergency related to the COVID-19 pandemic

Section 4. Mental and Behavioral Health 105

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

Children aged 5 years or older Balovaptan (RG7314) is a small-molecule antagonist of the Atypical antipsychotics (eg, Change in adaptive FDA designation(s): and adults who have high- vasopressin 1a (V1A) receptor intended to improve emotional aripiprazole, risperidone) behavior (eg, Breakthrough Therapy functioning (IQ ≥ 70) autism processing and reduce social deficits in patients with ASD. Behavioral therapy (eg, communication and Clinical trial(s): Phase 3 primary spectrum disorder (ASD) Impairments of social interaction and communication are core applied behavior analysis socialization) completion March 2020; phase symptoms of ASD that cause multiple challenges and affect [ABA]) Adverse events 2 primary completion February quality of life. The neuropeptide vasopressin is an endocrine Quality of life 2020; phase 2 VANILLA hormone that is implicated in the regulation of both completed September 2016, aggression and affiliation. Blocking vasopressin might reduce data published May 2019 aggression and anxiety and promote social bonding in patients with ASD. In trials, balovaptan is given orally at dosages from 4 to 10 mg once daily. Developer(s): F Hoffmann-La Roche (Basel, Switzerland)

Adults aged 18 to 75 years External trigeminal nerve stimulation (eTNS) sends electrical Psychotherapy (eg, cognitive PTSD severity and Clinical trial(s): Phase 1 who have posttraumatic stress stimulation to the trigeminal nerve through a patch placed on behavioral therapy [CBT], eye symptoms completed January 2012, data disorder (PTSD) the patient’s forehead to treat PTSD, which has limited movement desensitization Depression severity and published April 2016; unphased effective treatment options. This small, portable device is and reprocessing [EMDR] symptoms pivotal primary completion intended to improve symptom severity and quality of life. The therapy, prolonged exposure Functional capacity September 2020 eTNS system is a cell phone–sized electrical pulse generator therapy [PET]) Quality of life Note(s): FDA approved eTNS in that delivers mild electrical signals via 2 wires connected to a Selective serotonin reuptake 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 106

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

Children aged 5 years or older Full-spectrum microbiota (FSM, FIN-211) therapy, previously Dietary modifications and Autism symptoms and FDA designation(s): Fast Track and adults aged up to 60 years called CP-101, is an oral route of stool transplantation. The nutritional counseling severity Clinical trial(s): Phase 2 SPROUT who have autism spectrum therapy introduces key strains of purportedly beneficial Fecal microbiota Aberrant behavior primary completion May 2020; disorder (ASD) with bacteria to increase microbial biodiversity within the gut using transplantation by other Social responsiveness phase 2 MTT-ASD primary gastrointestinal (GI) symptoms gut bacteria collected from healthy human donors. About half means GI symptoms completion October 2020; of individuals with ASD have chronic GI symptoms, such as phase 2 primary completion constipation, diarrhea, and abdominal pain. This treatment is June 2021; phase 1/2 intended to improve both GI symptoms and core symptoms in completed April 2016, data individuals with ASD. Research has found that individuals with published January 2017, follow- ASD are more likely to have an abnormal gut microbiome than up data published April 2019 healthy controls, 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 107

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

Adults aged 18 to 65 years Ketamine is an N-methyl-D-aspartate (NMDA) receptor Psychotherapy (eg, cognitive PTSD symptoms and Clinical trial(s): Phase 2 who fulfill Diagnostic and antagonist intended to treat PTSD symptoms in adults. behavioral therapy [CBT], eye severity completed September 2013 Statistical Manual of Mental Glutamate, an excitatory neurotransmitter that binds to NMDA movement desensitization Depression symptoms (single dose), data published Disorders, Fifth Edition (DSM-5) receptors, is purported to be highly involved in the stress and reprocessing [EMDR] and severity June 2014; phase 2/3 primary criteria for current civilian or response and formation of traumatic memories in PTSD. By therapy, prolonged exposure Quality of life completed January 2020 combat-related posttraumatic decreasing glutamate’s excitatory activity and thus reducing therapy [PET]) (repeated dose) stress disorder (PTSD) stress-related synaptic activity that contributes to PTSD Repetitive transcranial symptoms, ketamine is intended to improve PTSD symptoms magnetic stimulation (rTMS; and patient quality of life. It is intended to have faster action off-label) than currently approved PTSD therapies, including Selective serotonin reuptake psychotherapy and selective serotonin reuptake inhibitors. inhibitors (SSRIs; eg, Ketamine purportedly provides rapid and sustained paroxetine, sertraline) therapeutic effects for patients with PTSD. Its use for this purpose is off-label. In clinical trials, participants are given 0.2 or 0.5 mg/kg doses of ketamine intravenously for a variable number of infusions (6-8) over 2 to 4 weeks. 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)

Section 4. Mental and Behavioral Health 108

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

Adults aged 18 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 serotonin Lurasidone (monotherapy or Depression symptoms Clinical trial(s): NRX-100/NRX- 2A (5-HT2A) receptor antagonist, and D-cycloserine (DCS), an in combination with lithium or and severity 101: Pivotal phase 2 STABIL-B N-methyl-D-aspartate (NMDA) receptor modulator. This valproate) completed November 2018, 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. The completion March 2019, Quetiapine therapy can be given in the outpatient setting after a single designed under Special dose of ketamine in a clinical setting. Lurasidone, alone or in Supportive care (eg, Protocol Assessment; phase 2/3 combination with lithium or valproate, is an FDA-approved hospitalization) primary completion September treatment for depressive episodes in bipolar depression. DCS, 2020, designed under Special an agent used in tuberculosis therapy, acts as a partial or full Protocol Assessment; NRX-100: agonist of NMDA receptors. Studies of its use as a cognitive phase 3 primary completion enhancer with other psychosocial interventions have had September 2020 mixed results in various psychiatric 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/day for 6 weeks. Patient observation is required after ketamine infusion. Developer(s): NeuroRx, Inc (Wilmington, Delaware)

Section 4. Mental and Behavioral Health 109

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

Adults aged 18 years or older 3,4-Methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy (eg, cognitive PTSD symptoms and FDA designation(s): who have severe posttraumatic psychotherapy involves treatment with MDMA during an 8- behavioral therapy [CBT], eye severity Breakthrough Therapy stress disorder (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 June 2020; MDMA administration is intended to reduce avoidance and therapy, prolonged exposure phase 3 MAPP2 primary hyperarousal, purportedly leading to a desirable psychological therapy [PET]) completion June 2021; phase 2 state that enhances the therapeutic process for patients with Selective serotonin reuptake completed July 2010; phase 2 severe PTSD, which has limited effective treatment options. inhibitors (SSRIs; eg, completed February 2011; MDMA, known by the street names Ecstasy and Molly, is a paroxetine, sertraline) phase 2 completed October psychedelic compound that is known to release serotonin, 2016; phase 2 completed norepinephrine, and dopamine in the brain and to indirectly October 2016; phase 2 increase oxytocin and cortisol levels. MDMA is intended to completed February 2017; reduce anxiety and emotional distress and increase prosocial phase 2 completed July 2017, behaviors, including communication, compassion, and phase 2 pooled data published introspection. According to the Diagnostic and Statistical May 2019; phase 2 open-label Manual of Mental Disorders, Fifth Edition (DSM-5), PTSD’s 4 completed October 2019, data main symptom categories are arousal and reactivity, avoidance published February 2020 of triggers, negative thoughts and feelings, and intrusive thoughts and nightmares. In trials, a flexible dose of MDMA is given orally once a month for 3 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 110

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

Adults aged 18 to 65 years Oxytocin is a naturally occurring hormone in the brain that is Antidepressants (eg, selective Social cognition Clinical trial(s): Unphased who have schizophrenia known for its association with social bonding and, when given serotonin reuptake inhibitors Negative schizophrenia completed August 2012, data intranasally, purportedly improves social cognition in patients [SSRIs], serotonin and symptoms published July 2013; phase 2 with schizophrenia. Studies have shown that patients with norepinephrine reuptake Quality of life CIDAR-3 completed July 2014; schizophrenia have lower oxytocin levels, which has been inhibitors [SNRIs]) phase 2 completed November associated with impaired trust, empathy, and ability to Antipsychotics (oral and 2015, data published April interpret mental states. Current antipsychotic drugs have been injectable) 2016; phase 2 completed used successfully to treat the positive symptoms of patients Combination therapy March 2017 with schizophrenia but have minimal effects on negative Electroconvulsive therapy symptoms and cognitive deficits. Increasing oxytocin levels might reduce negative symptoms and normalize social Mood stabilizers dysfunction associated with schizophrenia. It is being studied Psychotherapy (eg, cognitive as both a standalone and adjunct treatment. In the most behavioral therapy [CBT]) recent clinical trial, oxytocin was used in combination with risperidone. In this study, oxytocin is 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. Developer(s): Emory University (Atlanta, Georgia), in collaboration with Atlanta Veterans Affairs’ (VA’s) Health Care System (Atlanta, Georgia)

Section 4. Mental and Behavioral Health 111

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

Adults aged 18 years or older Pimavanserin (Nuplazid) is a selective serotonin inverse Antidepressants (eg, selective Negative symptoms and Clinical trial(s): Phase 2 who have schizophrenia with agonist and antagonist targeting serotonin 2A (5-HT2A) serotonin reuptake inhibitors symptom severity of ADVANCE (negative symptoms) predominant negative receptors. It is intended to be used as an adjunct to [SSRIs]; off-label) schizophrenia completed October 2019, symptoms antipsychotic medication to treat negative symptoms of Atypical antipsychotics (ie, Quality of life topline data reported schizophrenia. Pimavanserin might improve patient health cariprazine, risperidone) November 2019; phase 3 outcomes and quality of life, because no FDA-approved Psychosocial interventions (eg, ENHANCE-I (positive and treatments exist specifically for negative symptoms of arts therapy, cognitive negative symptoms) completed schizophrenia. Negative symptoms of schizophrenia include behavioral therapy [CBT]) May 2019, topline data loss of interest, lack of expression, emotional withdrawal, and reported July 2019; phase 3 cognitive impairment. Although positive symptoms of extension study (positive and schizophrenia (eg, hallucinations, distorted thinking) are negative symptoms) primary typically seen as more urgent to treat, negative symptoms completion August 2020 more commonly impact patients’ ability to live independently, Note(s): The developer intends hold jobs, and maintain relationships. It is thought that 5-HT2A to commence a second pivotal receptors play an important role in psychosis, schizophrenia, trial with the 34-mg dose in the depression, and other neuropsychiatric disorders. Although first half of 2020. Pimavanserin the exact mechanism of action is unknown, pimavanserin was FDA approved to treat purportedly exerts its effects by acting on 5-HT2A receptors in hallucinations and delusions the brain. Pimavanserin, FDA approved to treat hallucinations associated with Parkinson and delusions associated with Parkinson disease, carries a disease psychosis in April 2016. warning for QT interval prolongation. In clinical trials, FDA responded to safety pimavanserin is taken by mouth at a dosage of 10, 20, or 34 concerns over the use of mg once daily as an adjunct to the patient’s current pimavanserin in patients with antipsychotic medication. hallucinations and delusions Developer(s): associated with Parkinson Acadia Pharmaceuticals, Inc (San Diego, California) disease in September 2018.

Section 4. Mental and Behavioral Health 112

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

Adults aged 18 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 inhibitors and severity Breakthrough Therapy depression When used in combination with psychological support from [MAOIs], selective serotonin Quality of life Clinical trial(s): Phase 2 P-TRD trained therapists, it might improve patient health outcomes reuptake inhibitors [SSRIs], primary completion August and disrupt the paradigm of depression treatment. Recent serotonin and norepinephrine 2020 research has found a link between mental health disorders and reuptake inhibitors [SNRIs], hyperconnected, dysfunctional, neural networks in the brain. tricyclic antidepressants Psilocybin purportedly disrupts those dysfunctional networks [TCAs]) and helps restore healthier connectivity in the brain, thus Brain stimulation (eg, deep improving depression symptoms. Psilocybin is thought to brain stimulation [DBS], 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 marked stimulation [TMS], vagal nerve changes in sensory perception, emotion, thought, and sense of stimulation [VNS]) self. In phase 1 clinical trials, synthetic psilocybin was taken Ketamine (off-label) orally at doses of 10 or 25 mg, before receiving one-on-one Psychotherapy (eg, cognitive psychological support from an assisting therapist throughout behavioral therapy [CBT]) a session of unspecified duration. In phase 2 clinical trials, psilocybin is taken orally at unspecified, differing doses (stated as low dose, medium dose, and high dose) 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 113

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

Adolescents aged 13 years or SEP-363856 is a psychotropic medication intended to treat Antipsychotics (first and Schizophrenia symptoms FDA designation(s): older and adults aged up to 65 schizophrenia through a different mechanism from currently second generation) (positive and negative) Breakthrough Therapy years who have schizophrenia approved antipsychotics by not binding to dopamine 2 (D2) or Psychotherapy (eg, cognitive and severity Clinical trial(s): Phase 3 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 (5- Social functioning phase 3 DIAMOND 2 primary 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; phase and negative symptoms without the serious side effects of 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

Section 4. Mental and Behavioral Health 114

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

Adolescents aged 12 years or Sodium benzoate (NaBen) is a prescription-strength Antidepressants (eg, selective Schizophrenia symptoms FDA designation(s): Orphan older and adults aged up to 55 formulation of the sodium salt used as a common food serotonin reuptake inhibitors (positive and negative) Drug, Breakthrough Therapy years who have a confirmed preservative. Sodium benzoate is a D-amino acid oxidase [SSRIs], serotonin and Efficacy of antipsychotics Clinical trial(s): Phase 2b/3 diagnosis of schizophrenia (DAAO) inhibitor intended to treat schizophrenia’s positive norepinephrine reuptake Quality of life primary completion June 2021; according to criteria of the and negative symptoms. Existing drugs for treating inhibitors [SNRIs]) phase 2b/3 primary completion Diagnostic and Statistical schizophrenia have limited efficacy in reducing both positive Antipsychotics (oral and June 2021; phase 2b/3I primary Manual of Mental Disorders, and negative symptoms, and many are associated with serious injectable) completion June 2021 Fourth or Fifth Edition DSM-IV ( side effects. A key dysfunction related to schizophrenia is the Combination therapy or DSM-5), and are clinically reduced function of the N-methyl-D-aspartate (NMDA) Mood stabilizers stable with residual symptoms; receptor in the brain. NaBen addresses this by inhibiting and adults aged 18 to 55 years DAAO metabolism to increase DAAO activity, leading to Psychotherapy (eg, cognitive who have treatment-refractory production of more d-serine, which increases NMDA activity in behavioral therapy [CBT]) schizophrenia 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 115

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

Adults aged 18 to 65 years Zonisamide (Zonegran) is a sulfonamide anticonvulsant Pharmacotherapy (eg, Alcohol consumption Clinical trial(s): Pilot unphased who have alcohol use disorder demonstrated to modulate gamma-aminobutyric acidergic acamprosate, disulfiram, Alcohol cravings completed March 2009; pilot (AUD) (GABAergic) and glutamatergic neurotransmission. Approved naltrexone) Alcohol withdrawal phase 4 completed May 2009; medications to treat AUD have shown limited effectiveness; Psychotherapy (eg, cognitive symptoms phase 3 primary completion only one-third of patients achieve full remission with available February 2021 behavioral therapy [CBT]) Relapse therapies. Zonisamide is intended to reduce alcohol 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 purportedly Quality of life 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): Department of Veterans Affairs’ (VA’s) Office of Research and Development (Washington, DC)

Section 4. Mental and Behavioral Health 116

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

Adults aged 18 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 and yield benefits in about half the time of inhibitors [SSRIs], serotonin Quality of life Clinical trial(s): Phase 2 standard pharmacotherapies (ie, 2 weeks or sooner versus 4 to and norepinephrine reuptake completed October 2017, data 6 weeks). The manufacturer asserts that zuranolone might inhibitors [SNRIs]) published September 2019; improve symptoms within a few days. Reduced brain Psychotherapy (eg, cognitive phase 3 MOUNTAIN (MDD- concentrations of the inhibitory neurotransmitter GABA as well behavioral therapy [CBT]) 301) primary completion as alterations in the subunit composition of GABAA (ie, deficits September 2019, topline data in GABAergic transmission) are thought to contribute to MDD. reported December 2019; Zuranolone purportedly works by amplifying GABAA receptor phase 3 SHORELINE (MDD-303) activity. Investigators postulate that competing standard-of- primary completion April 2021; care antidepressants might similarly, but more slowly, reduce phase 3 open-label REDWOOD GABAergic deficits due to downstream effects. The (MDD-302) primary completion manufacturer states that zuranolone is given orally once daily December 2021 (dose unspecified), for a target treatment length of 2 weeks. Note(s): The developer released Developer(s): trial updates in March 2020: the Sage Therapeutics, Inc (Cambridge, Massachusetts) REDWOOD study, which was paused in the fourth quarter of 2019, is being reevaluated for timing to reinitiate, and the developer intends to add a new cohort to the SHORELINE study

Section 4. Mental and Behavioral Health 117 Table 4.3. Mental and Behavioral Health Topics Archived Since Last Status Report: 2 Topics

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

Adults aged 18 to 56 years Dasotraline (SEP-225289) is a serotonin, dopamine, and Antiepileptics (off-label) Binge eating frequency and In May 2020, Sunovion who have moderate to severe norepinephrine reuptake inhibitor (SDNRI) intended to treat Lisdexamfetamine severity withdrew its New Drug binge eating disorder (BED) BED by reducing the frequency of binge eating episodes. Norepinephrine reuptake Anxiety symptoms and Application for dasotraline and Unlike comparator lisdexamfetamine, dasotraline does not inhibitors (off-label) severity announced discontinuation of stimulate neuronal release of dopamine and norepinephrine. development, stating additional Psychotherapy (eg, Depression symptoms and BED is a mental health disorder characterized by recurring clinical studies would be cognitive behavioral severity episodes of consuming large amounts of food in a short time needed to support a regulatory therapy [CBT], dialectical Quality of life accompanied by feelings of loss of control, physical discomfort approval. behavior therapy) from overeating, shame, guilt, and/or depressed mood. Dasotraline demonstrates strong inhibition at dopamine and Serotonin norepinephrine norepinephrine transporters and weak inhibition at serotonin reuptake inhibitors (SNRIs; transporters. By increasing the amount of serotonin, off-label) dopamine, and norepinephrine in the brain, dasotraline purportedly helps increase positive mood states and decrease anxiety and other negative mood states, helping prevent binge eating behavior. In clinical trials, dasotraline was taken orally at a dosage of 4, 6, or 8 mg once daily for up to 12 months. Developer(s): Sunovion (Marlborough, Massachusetts), a subsidiary of Sumitomo Dainippon Pharma (Osaka, Japan)

Section 4. Mental and Behavioral Health 118

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

Adults aged 18 to 68 years Deep transcranial magnetic stimulation (Deep TMS) is a Psychotherapy (eg, PTSD symptoms and In February 2020, BrainsWay who have moderate to severe noninvasive outpatient treatment that uses directed cognitive behavioral severity announced discontinuation of posttraumatic stress disorder electromagnetic fields to target and stimulate the prefrontal therapy [CBT], eye Change in cognitive Deep TMS to treat PTSD (PTSD) cortex region of the brain to treat PTSD. A new coil design movement desensitization function development because of purportedly allows for deeper stimulation at safe levels to try and reprocessing [EMDR] Quality of life statistically insignificant interim to reduce PTSD symptoms and severity. The manufacturer therapy, prolonged data. asserts that the H1 coil used in the device stimulates deeper exposure therapy [PET]) regions of the prefrontal cortex than the figure-8 coil used in Repetitive transcranial repetitive TMS. The treatment is intended as an adjunct to magnetic stimulation (rTMS; pharmacologic and/or psychologic treatment. In an ongoing off-label) trial, Deep TMS is given in 20-minute sessions, 3 times a week Selective serotonin for 4 weeks, with a booster treatment at week 5 and another reuptake inhibitors (eg, at week 9, totaling 14 treatment sessions. At least 8 sessions paroxetine, sertraline) are required for treatment. Developer(s): BrainsWay, Ltd (Hackensack, New Jersey)

Section 4. Mental and Behavioral Health 119 Section 5. Rare Diseases: 119 Topics

Table 5.1. Rare Diseases Topics Added Since Last Status Report: 15 Topics

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

Children and adults aged up to Adrabetadex (VTS-270, cyclodextrin, 2-hydroxypropyl-β- Glucosylceramide synthase Disability Clinical trial(s): Pivotal phase 21 years who have genetically cyclodextrin) is intended to treat neurologic manifestations of inhibitor (ie, miglustat; off- Disease progression 2/3 (ages 4 to 21) primary confirmed Niemann-Pick Niemann-Pick disease type C (NPC) by regulating intracellular label) Disease symptoms and completion September 2021; disease type C1 (NPC-1) or cholesterol in NPC-1-deficient cells. NPC is a rare, Supportive treatment (eg, severity phase 2/3 open-label extension type C2 (NPC-2) with neurodegenerative, lysosomal storage disorder caused by (ages 4 to 21) primary bowel regimen, Survival neurologic manifestations mutations in the NPC intracellular cholesterol transporter 1 or 2 bronchoalveolar lavage, completion December 2021; Quality of life genes, NPC1 or NPC2. Lack of the encoded NPC1 or NPC2 bronchodilation therapy, phase 2 (up to 4 years of age) protein disrupts intracellular cholesterol and other lipid trafficking, gastrostomy tube, physical primary completion October leading to excessive lipid accumulation in tissues including the therapy) 2022 brain, liver, and spleen. This results in a range of symptoms and complications, including enlarged liver and spleen; eye, liver, and lung disease; feeding difficulties; hearing loss; motor impairment (including cataplexy and dystonia); and cognitive deterioration. About one-third of patients also develop seizures. The disease is most often diagnosed around 10 years of age, and most patients die before 20 years of age. Adrabetadex purportedly promotes cholesterol transport, restores normal cholesterol metabolism and regulation, and slows disease progression in patients with NPC-1. It is injected directly into spinal fluid to better target the neurologic manifestations of NPC-1. In clinical trials of patients younger than 4 years of age, adrabetadex is infused into the spinal canal via lumbar puncture at a dose of 200 mg initially with dose escalation of 100 mg every 2 weeks up to a maximum tolerable dose of 900 mg for up to 3 years. In clinical trials of children and adults aged 4 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 120

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

Adults aged 18 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 to treat liver disease associated with AAT deficiency, a rare (reserved for end-stage Liver function Drug, Fast Track (AAT) deficiency and biopsy- inherited disease affecting mostly the lungs and liver. AAT liver 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 SEQUOIA primary completion member 1 gene, SERPINA1, which codes for production of the or reduce the complications May 2023 AAT protein. In AAT deficiency caused by certain genetic of chronic liver disease variants, misfolded copies of the AAT protein cannot be (CLD; eg, ascites, portal vein secreted normally into the blood, so they build up in the liver, hypertension, causing liver injury. No approved disease-modifying therapies gastrointestinal are available for AAT deficiency–related liver damage; hemorrhage) treatment consists mainly of supportive care. ARO-AAT is designed to block production of AAT protein 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 121

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

Patients aged 7 to 18 years Carbetocin (LV-101) is an analogue of the hormone oxytocin Cognitive behavioral Hyperphagia symptoms FDA designation(s): Fast Track who have Prader-Willi intended to treat nutritional phase 3 hyperphagia in children therapy (CBT) and severity Clinical trial(s): Phase 2 syndrome (PWS) with with PWS. Hyperphagia is abnormally increased appetite Diazoxide (off-label) Rate of comorbidities (eg, completed July 2014, data nutritional phase 3 without feelings of satiety (fullness after eating). PWS is a Diet and food intake cardiovascular disease, published June 2018; phase 3 hyperphagia genetic condition with a loss of function in genes on control diabetes mellitus, obesity) CARE-PWS primary completion chromosome 15 that results in slowed development, Exercise Quality of life June 2020 intellectual disability, behavioral problems, and various Note(s): Phase 3 enrollment physical manifestations. A hallmark symptom is hyperphagia, Glucagon-like peptide 1 (GLP-1) receptor agonist paused in April 2020 because which begins in childhood and often results in morbid obesity of issues related to the COVID- if food intake is not restricted. The exact cause of the (eg, exenatide or liraglutide; off-label) 19 pandemic, not a suspension increased appetite in this population is unknown but might be of institutional review board linked to oxytocin dysregulation in the hypothalamus area of (IRB) approval the brain. Patients have been found to have fewer oxytocin- producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin is thought to play a role in regulating eating behaviors, social interactions, and emotional reactivity. Oxytocin supplementation for treating PWS has been researched but is not FDA approved. Carbetocin, a longer- acting analogue of oxytocin with an improved oxytocin receptor–selectivity profile, purportedly helps suppress appetite. The developer additionally purports it might reduce obsessive-compulsive symptoms and anxiety. In clinical trials, carbetocin (dose unspecified) is given as a nasal spray 3 times a day before meals. Developer(s): Levo Therapeutics, Inc (Skokie, Illinois), which acquired exclusive worldwide license from Ferring Pharmaceuticals (Saint-Prex, Switzerland)

Section 5. Rare Diseases 122

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

Adults aged 18 to 75 years Cilofexor (GS-9674) is a selective, nonsteroidal farnesoid X Endoscopy (ie, Liver fibrosis progression Clinical trial(s): Phase 3 PRIMIS who have large duct primary receptor (FXR) agonist (ie, activator) being developed to treat cholangioscopy) with or Need for liver primary completion January sclerosing cholangitis (PSC) PSC. In PSC, the bile ducts narrow severely for reasons not without stents to widen transplantation 2023; phase 2 primary and stage F0 to F3 liver fibrosis clearly understood, preventing bile acid from leaving the liver narrowed bile ducts Quality of life completion February 2018, data and causing progressive inflammation and scarring (ie, Liver transplantation published January 2019 fibrosis) of liver tissue. Most care is supportive and targets (reserved for advanced liver symptom relief. Liver transplantation is potentially curative but disease) generally reserved for patients with end-stage liver disease. Long-term antibiotics (to Additionally, PSC reportedly recurs often after liver treat and prevent frequent transplantation (in up to 45% of patients in some reports). infections caused by Therefore, therapies are needed that could slow or stop blocked bile ducts) continued liver fibrosis in PSC. Cilofexor purportedly works by Supportive care to reduce multiple mechanisms to regulate bile acid synthesis and itching (eg, bile acid excretion. FXR downregulation by cilofexor in the intestine sequestrants, purportedly leads to release of a hormone that downregulates antihistamines, the rate-limiting enzyme in bile acid synthesis in the liver. ursodeoxycholic acid Additionally, direct activation of FXR in liver cells (ie, [UDCA]) hepatocytes) increases the expression of transporters responsible for moving bile acid out of the liver while inhibiting bile acid synthesis and uptake by liver cells. In a phase 3 trial, cilofexor is 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 123

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 primary (gMG) and test positive for inflammation and destruction of the muscle membrane at the Corticosteroids (eg, 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-AchR antibodies against AchRs, which are necessary to turn nerve methotrexate, antibodies. Eculizumab is also signals into muscle movements. The disorder manifests as mycophenolate mofetil, FDA approved (and available muscle weakness that often begins in the eyes and eyelids and tacrolimus) only under a Risk Evaluation generalizes to more areas of the body, including the head, Thymus gland removal and Mitigation Strategy) to neck, trunk, limbs, and chest. No cure is available for gMG, and treat paroxysmal nocturnal some patients do not respond to standard hemoglobinuria to reduce immunosuppressive therapies. Eculizumab purportedly binds hemolysis, atypical hemolytic with high affinity to the complement protein C5 (a soluble uremic syndrome to inhibit component of the innate immune system) to reduce activation complement-mediated of the complement pathway that causes inflammation and thrombotic microangiopathy, muscle membrane destruction at the neuromuscular junction and relapsing neuromyelitis that contributes to gMG pathology and symptoms. In clinical optica. 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 124

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

Adults aged 18 years or older Mitapivat (AG-348) is a small-molecule allosteric activator of Supportive care, including Need for transfusions FDA designation(s): Orphan with a confirmed diagnosis of the enzyme pyruvate kinase being developed to treat PKD. red blood cell transfusions Quality of life Drug, Fast Track pyruvate kinase deficiency PKD arises from inherited mutations in the PKLR gene that as needed for anemia Clinical trial(s): Phase 3 (PKD) and at least 2 mutant lead to hemolytic anemia (ie, anemia caused by red blood cell ACTIVATE primary completion alleles in the pyruvate kinase destruction). No approved treatments exist for PKD; care is August 2020; phase 3 L/R gene, PKLR supportive, consisting mainly of red blood cell transfusions as ACTIVATE-T primary needed based on the severity and symptoms of anemia. This completion November 2020; drug could reduce the need for transfusions and provide the phase 2 DRIVE-PK primary first disease-modifying treatment for PKD. Mitapivat completion May 2017, purportedly activates pyruvate kinase-R, the form of pyruvate preliminary data published kinase present in red blood cells, which helps convert glucose September 2019, further data (ie, sugar) into energy. Without sufficient pyruvate kinase-R reported December 2019 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)

Section 5. Rare Diseases 125

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

Adults aged 18 years or older Nemolizumab (CD14152) is a novel monoclonal antibody that Antihistamines (eg, Anxiety and depression FDA designation(s): with severe itching (ie, prurigo) blocks signaling of interleukin-31 (IL-31) to treat itching (ie, diphenhydramine, symptoms and severity Breakthrough Therapy associated with moderate to pruritus) associated with prurigo nodularis, a chronic skin hydroxyzine; off-label) Itch frequency and severity Clinical trial(s): Phase 3 pivotal severe prurigo nodularis with disease in which hard lumps (ie, nodules) form on the skin and Immunosuppressants (eg, Sleep quality primary completion August at least 20 nodules on the cause intense itching that often leads to patients scratching cyclosporine, methotrexate; Quality of life 2022; phase 2 completed body the areas until they bleed. Current therapies often do not off-label) September 2018, data provide adequate symptomatic relief. Scratching can cause Over-the-counter lotions published February 2020 more nodules to appear. The disease cause is unknown, (eg, containing calamine, although some patients have underlying skin conditions or camphor, menthol, allergies that are thought to contribute. Prurigo nodularis can pramoxine hydrochloride) be highly disruptive to patients’ daily lives because it can Phototherapy (ie, narrow negatively impact patients’ sleep quality, mental health, band ultraviolet B, psoralen concentration, and body image and confidence. Nemolizumab plus ultraviolet A; off-label) purportedly reduces itching by blocking the binding of the inflammatory cytokine IL-31 to IL-31 alpha receptors that are Topical capsaicin (off-label) thought to play a key role in itch signaling to the brain in Topical corticosteroids (eg, prurigo nodularis. In phase 2 clinical trials, nemolizumab was betamethasone, clobetasol; injected under the skin (ie, subcutaneously) at a dosage of 0.5 off-label) 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 126

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

Children aged 6 months to 18 Odevixibat inhibits the apical sodium-dependent bile acid Cholestyramine Liver function FDA designation(s): Orphan years who have genetically 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 2). Sodium 4-phenylbutyrate Quality of life Clinical trial(s): Phase 3 (PFIC1) or type 2 (PFIC2) In PFIC, inherited alterations in genes that regulate bile acid randomized PEDFIC1, primary UDCA flow cause a buildup of bile acid in the liver, eventually leading completion July 2020; phase 3 to poor growth and progressive liver disease. No drugs are single-arm extension PEDFIC2, FDA approved for treating patients with PFIC, and off-label primary completion December treatments (eg, cholestyramine, rifampicin, ursodeoxycholic 2021 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 127

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

Adults aged 18 years or older QR-1123 is an antisense oligonucleotide under study for Nutritional Best corrected visual acuity FDA designation(s): Orphan who have autosomal-dominant treating adRP caused by a variant (P23H) in the RHO gene. A supplementation (BCVA) Drug, Fast Track retinitis pigmentosa (adRP) rare genetic disease, adRP causes progressive vision loss, Supportive care Retinal sensitivity Clinical trial(s): Phase 1/2 caused by the P23H variant in typically leading to blindness by mid-adulthood. In adRP Peripheral vision AURORA primary completion the rhodopsin gene, 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 intravitreal injections once every 3 months at various dose levels. Developer(s): ProQR Therapeutics (Leiden, the Netherlands)

Section 5. Rare Diseases 128

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

Adults aged 18 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 moderate that is intended as an ongoing therapy to reduce the number Immunosuppressants (eg, Death Clinical trial(s): Pivotal phase 3 to severe pemphigus vulgaris of skin lesions in moderate to severe PV and PF. Complications azathioprine, Pain PEGASUS primary completion (PV) or pemphigus foliaceus with current treatments can be life threatening, and cyclophosphamide, December 2021; phase 2 Quality of life (PF) rilzabrutinib might induce complete disease remission and mycophenolate) completed January 2020, reduce steroid and immunosuppressant use. Pemphigus is an Monoclonal antibody (ie, preliminary data reported autoimmune blistering skin disorder that most often occurs in rituximab) October 2019 middle-aged adults. PV and PF are the 2 most common types of pemphigus. 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 129

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

Adults aged 18 years or older Sutimlimab (BIVV009) is a humanized monoclonal antibody Plasmapheresis Hemoglobin level FDA designation(s): Orphan who have primary cold that purportedly selectively inhibits the C1 complex of the Rituximab with or without Number of blood Drug, Breakthrough Therapy agglutinin disease (CAD) complement system, preventing classical complement fludarabine transfusions required Clinical trial(s): Phase 3 Cardinal activation without affecting the alternative or lectin pathways. Number of acute hemolytic primary completion September CAD is a rare autoimmune hemolytic anemia characterized by crises 2020, interim data reported overactivation of the classical complement pathway in Change in Functional November 2019; phase 3 response to triggers (eg, cold temperatures or viral infections). Assessment of Chronic Cadenza primary completion This overactivation leads to erythrocyte engulfment by Illness Therapy (FACIT)- December 2021 phagocytes (ie, opsonization), extravascular destruction, and fatigue scale score (quality anemia, which can cause severe fatigue, acute hemolytic crisis, of life) from baseline and poor quality of life. CAD also puts patients at increased risk of thromboembolism and early 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 aged 18 years or older Teprotumumab-trbw (Tepezza) is a fully human monoclonal Corticosteroids Vision Approval date: January 21, 2020 who have moderate to severe antibody specific for insulinlike growth factor 1 receptor (IGF- Orbital decompression Light sensitivity FDA designation(s): Orphan active thyroid eye disease 1R) intended to treat TED. It is approved by FDA. TED is a rare surgery Quality of life Drug, Priority Review, (TED) autoimmune condition in which inflammation and increased Breakthrough Therapy, Fast volume of muscles and fatty tissues behind the eye cause the Track eyes to be pushed forward and bulge outward. IGF-1R plays a Clinical trial(s): Phase 3 OPTIC central role in TED pathogenesis, promoting the structural completed February 2019, data changes driving the disease. Teprotumumab-trbw inhibition of published January 2020; phase IGF-1R-mediated signaling might provide a noninvasive 3 OPTIC-X extension primary alternative to surgical treatment for patients with TED. completion September 2020; According to FDA-approved labeling, teprotumumab-trbw is phase 2 RV001 primary given intravenously for 60 to 90 minutes every 3 weeks over completion March 2016, data 21 weeks at a dose of 10 mg/kg for the first dose and 20 published May 2017 mg/kg for the remaining treatment course, for a total of 8 infusions. Developer(s): Horizon Therapeutics plc (Dublin, Ireland)

Section 5. Rare Diseases 130

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

Adults aged 25 to 65 years Tominersen, formerly known as IONIS-HTTRx , RG6042, and Symptomatic care (eg, Disease progression FDA designation(s): Orphan who have genetically RO7234292, is an antisense oligonucleotide intended to treat antipsychotics for chorea or Motor and ambulatory Drug confirmed, symptomatic HD by preventing the production of toxic, mutant, huntingtin agitation [off-label], function Clinical trial(s): Phase 3 Huntington disease (HD) (HTT) protein that leads to neurodegeneration and disease physical therapy, speech Cognitive function GENERATION HD1 primary progression. HD is an inherited (autosomal dominant), therapy, tetrabenazine to Survival completion March 2022; phase progressive, neurodegenerative disease caused by mutations treat chorea) 3 open-label extension primary Quality of life in the huntingtin gene, HTT. Mutant, elongated HTT proteins completion July 2023; phase 2 are cleaved into smaller, neurotoxic fragments that accumulate open-label extension in neurons, causing neurodegeneration that manifests as completed October 2019; uncontrolled movements (ie, chorea), cognitive decline, and phase 1/2 completed mood changes. Symptoms typically begin in the fourth or fifth November 2017, data released decade of life, and typical life expectancy after symptom onset March 2018 is about 20 years. There is no cure or disease-modifying treatment for HD. Tominersen purportedly reduces production of mutant HTT proteins by binding to the messenger RNA (mRNA) that encodes it to prevent harmful HTT accumulation in neurons that contribute to progressive neurodegeneration. It can potentially treat all patients with HD regardless of individual HTT mutation. In phase 3 clinical trials, tominersen is injected into the spinal cord (ie, intrathecally) once every 8 or 16 weeks for 25 months. Developer(s): F Hoffmann-La Roche, Ltd (Basel, Switzerland), which licensed rights from original developer Ionis Pharmaceuticals (Carlsbad, California)

Section 5. Rare Diseases 131

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 gel Behavior-stabilizing Aggression symptoms and Submission date: New Drug who have genetically formulation of cannabidiol (CBD) intended to treat behavioral medications (eg, alpha-2 severity Application planned for second confirmed fragile X syndrome symptoms of FXS, a rare, noninherited, X chromosome–linked agonists, anticonvulsants, Anxiety symptoms and quarter of 2020 (FXS) and moderate to severe neurodevelopmental disorder. In patients with FXS, loss of the antidepressants, beta- severity FDA designation(s): Orphan behavioral symptoms protein Fmrp function purportedly disrupts protein translation, blockers) Hyperactivity symptoms Drug, Fast Track synaptic plasticity, and intracellular signaling, leading to Plant-derived oral CBD and severity Clinical trial(s): Phase 2/3 development of autism-like symptoms, including anxiety, Irritability symptoms and CONNECT-FX primary irritability, aggression, hyperactivity, and restricted and severity completion May 2020; phase repetitive behaviors. Some patients also experience seizures. 2/3 open-label extension The endocannabinoid system, which regulates cellular Repetitive behavior symptoms and severity primary completion February homeostasis, is also disrupted in patients with FXS. These 2022 patients often take behavior-stabilizing medications, which Note(s): Topline data expected cause significant side effects. Patients may also take oral, in the second quarter of 2020 plant-derived CBD, but oral bioavailability of the drug is low (about 6%), and oral CBD administration is associated with liver impairment, nausea, diarrhea, and changes in appetite. Transdermal delivery of Zygel purportedly allows for CBD delivery to the 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 132 Table 5.2. Currently Monitored Rare Diseases Topics: 90 Topics

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

Infants and children aged 6 ABO-101 is a recombinant adeno-associated viral vector Supportive care Cognitive and motor FDA designation(s): Orphan months or older and adults carrying a wild-type copy of the N-acetyl-alpha-D- function, as measured by Drug, Rare Pediatric Disease, who have Sanfilippo syndrome glucosaminidase gene, NAGLU. The therapy is intended for validated clinical ratings Fast Track type B (also called Sanfilippo syndrome type B, a childhood-onset, progressive, and scales Clinical trial(s): Phase 1/2 mucopolysaccharidosis type III inherited metabolic disorder caused by a mutation in NAGLU. NAGLU enzyme activity Transpher B primary 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 data care. Patients with the disorder cannot break down the published 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 133

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

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

Section 5. Rare Diseases 134

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

Adults aged 18 years or older Afamelanotide (Scenesse) is a melanocortin 1 receptor (MC1- Beta-carotene Duration of sunlight Approval date: October 8, 2019 who have a history of R) agonist indicated to increase pain-free light exposure in supplementation tolerated without pain FDA designation(s): Orphan phototoxic reactions from adults who have EPP. A rare genetic metabolic disorder, EPP Lifestyle modification (ie, Number and severity of Drug, Priority Review erythropoietic protoporphyria causes phototoxicity and anaphylactoid reactions when the sunlight avoidance) phototoxic reactions Clinical trial(s): Phase 3 (EPP) patient’s skin is exposed to light. The drug is a chemical Quality of life completed July 2013, data analogue of alpha-melanocyte stimulating hormone (α-MSH), published July 2015; phase 3 a naturally occurring peptide hormone released by skin cells in completed May 2011 response to ultraviolet radiation (UVR). α-MSH 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 135

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

Adults aged 18 years or older Apremilast (Otezla) is a small-molecule anti-inflammatory oral Corticosteroids Pain, frequency, or Approval date: July 19, 2019 who have oral ulcers drug that inhibits phosphodiesterase type 4 (PDE4). Behçet Immunosuppressants (eg, duration of oral ulcers FDA designation(s): Orphan associated with Behçet disease disease is a rare disease caused by blood vessel inflammation azathioprine, cyclosporine) from baseline Drug that can cause skin symptoms, including oral ulcers. Few Nonsteroidal anti- Disease progression Clinical trial(s): Phase 3 primary effective treatment options (ie, immunosuppressant therapy) inflammatory drugs (NSAIDs) Quality of life completion September 2017, exist for affected patients. Investigators have linked Behçet data published November 2019 disease to overactive T helper 17 (Th17) cells and increased Note(s): FDA approved interleukin-17 (IL-17) production. Approved by FDA, apremilast in March 2014 to apremilast’s PDE4 inhibitory activity purportedly increases treat psoriatic arthritis and in cyclic adenosine monophosphate in immune cells, This September 2014 to treat decreases production of proinflammatory mediators, such as plaque psoriasis tumor necrosis factor (TNF)-alpha, IL-17, and IL-23, which purportedly alleviates blood vessel inflammation and symptoms. The FDA-approved label recommends a 5-day 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 136

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 second body myositis (sIBM) shock proteins (HSPs) in damaged muscle cells. A prednisone) Survival 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, can increase the risk of death. Investigators data published March 2016; suspect that sIBM-induced muscle degeneration might be phase 3 open-label extension caused by the accumulation of abnormal and misfolded primary completion May 2022 proteins in muscle cells. Arimoclomol purportedly increases Note(s): Pivotal trial final results the activity of heat shock factor 1, a transcription factor that are expected in the first half of promotes HSP expression in cells experiencing stress or 2021 toxicity. HSPs protect against the accumulation of misfolded proteins and other toxic waste products by restoring functional protein shapes and degrading abnormal protein aggregates. In clinical trials, arimoclomol is given orally at a dosage of 400 mg (two 200-mg pills) 3 times daily, for a daily dose of 1200 mg. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)

Section 5. Rare Diseases 137

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

Patients aged 2 to 18 years Arimoclomol (BRX-345) is a small-molecule drug intended to Glucosylceramide synthase Disability Submission date: New Drug who have Niemann-Pick treat NPC by amplifying the production of reparative heat inhibitor (ie, miglustat [off- Disease progression Application planned for first disease type C (NPC) shock proteins (HSPs) that are purported to slow disease label]) Disease symptoms and half of 2020 progression. NPC is a rare, neurodegenerative, lysosomal Supportive treatment (eg, severity FDA designation(s): Orphan storage disorder caused by mutations in the NPC intracellular bowel regimen, Survival Drug, Fast Track, Breakthrough cholesterol transporter 1 or 2 genes, NPC1 or NPC2. Lack of bronchoalveolar lavage, Therapy Quality of life the encoded NPC1 or NPC2 protein disrupts intracellular bronchodilation therapy, Clinical trial(s): Phase 2/3 cholesterol and other lipid trafficking, leading to excessive gastrostomy tube, physical primary completion June 2018, lipid accumulation in tissues including the brain, liver, and therapy) data reported January 2019, spleen. This results in a range of symptoms and complications, data reported January 2020 including enlarged liver and spleen; eye, liver, and lung disease; feeding difficulties; hearing loss; motor impairment (including cataplexy and dystonia); and cognitive deterioration. About one-third of patients also develop seizures. The disease is most often diagnosed in patients around 10 years of age, and most patients die before 20 years of age. 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 138

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

Adults aged 18 years or older Arimoclomol (BRX-345) is a small-molecule amine intended to Edaravone Disability FDA designation(s): Orphan who have amyotrophic lateral treat ALS by helping regulate proteins involved with the Riluzole Disease progression Drug sclerosis (ALS) 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. While the exact phase 3 ORARIALS-2 open- cause is unknown, it is thought to be caused by accumulations label extension primary of abnormal proteins in neural cells. Arimoclomol might completion August 2022; phase reduce abnormal protein accumulation and help deconstruct 2/3 (patients with SOD1 abnormal proteins, slowing disease progression and improving mutation) completed patient quality of life by prolonging motor function. The exact November 2016, data cause of abnormal protein collection in ALS is unknown, published February 2018 although patients with inherited forms of ALS could have Note(s): Headline results are variants in other genes that might contribute, such as the expected in the first half of SOD1 copper-zinc superoxide dismutase 1 gene, . FDA- 2021 approved drugs to treat the disease (eg, edaravone, riluzole) might decrease symptom severity but do not prevent disease progression. Arimoclomol purportedly increases the activity of heat shock factor 1, a transcription factor that promotes expression of heat shock proteins (HSPs). These proteins are thought to regulate normal protein folding and deconstruct abnormal proteins. In clinical trials, patients take arimoclomol by mouth. One recent trial reported giving a dosage of 200 mg 3 times daily for up to 12 months. The dosage in the ongoing phase 3 trial is unspecified. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)

Section 5. Rare Diseases 139

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

Adults aged 18 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 second confirmed by evidence of patients’ ability to metabolize galactose, a simple sugar found and other sources of Cognitive decline from half of 2020 absent or significantly in foods and produced during normal metabolism. Elevated galactose) baseline FDA designation(s): Orphan decreased galactose-1 circulating galactose is converted by aldose reductase into Cataract formation from Drug phosphate uridyl transferase galactitol, a toxic metabolite that causes long-term baseline Clinical trial(s): Phase 2 (GALT) activity complications including central nervous system damage (eg, Sepsis incidence from ACTION-Galactosemia pivotal convulsions, irritability, lethargy, developmental delays) and baseline primary completion December cataracts. Galactosemia has no cure or approved treatments. 2019, topline data reported AT-007 purportedly penetrates tissues, including the central January 2020, additional data nervous system, to inhibit aldose reductase, thereby reducing reported April 2020 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 140

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

Section 5. Rare Diseases 141

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

Adults aged 18 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 therapy Riluzole Disability Drug, Fast Track amyotrophic lateral sclerosis intended to treat ALS. A rare and fatal neurodegenerative Supportive care Quality of life Clinical trial(s): Phase 3 BCT-002 (ALS) disease, ALS is characterized by the death of nerve cells (ie, primary completion October neurons) in the brain and spinal cord that leads to a loss of 2020, data presented April voluntary muscle function, wasting of muscle mass, and 2020, topline data expected eventual death. In patients with ALS, the presence of abnormal fourth quarter of 2020; phase 2 proteins in the brain and spinal cord causes neuronal death completed September 2015, and contributes to disease progression. The exact cause of data published March 2016, these aggregates is unknown. FDA-approved drugs to treat data published November the disease (eg, riluzole, edaravone) decrease symptom 2017; phase 2 completed July severity in some patients but do not prevent neuronal injury 2016, data published and ALS progression. NurOwn grows the patient’s bone November 2019 marrow cells in a proprietary culture media to differentiate Note(s): BrainStorm Cell mesenchymal stromal cells into astrocyte-like cells. The Therapeutics met with FDA in cultured cells purportedly secrete neurotrophic and growth February 2020 to discuss a factors, including glial-derived neurotrophic factor, brain- regulatory pathway and derived 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 142

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

Adults aged 18 years or older Avacopan (CCX168) is a small-molecule anti-inflammatory Prednisone with Remission FDA designation(s): Orphan who have newly diagnosed or drug that purportedly binds and inhibits the complement cyclophosphamide followed Response time Drug relapsed antineutrophil anaphylatoxin C5a from triggering inflammatory reactions by azathioprine Estimated glomerular Clinical trial(s): Phase 3 cytoplasmic antibody (ANCA)– through C5 receptors, which are associated with AAV Prednisone with rituximab filtration rate (eGFR) ADVOCATE completed associated vasculitis (AAV) pathogenesis. Patients with AAV have limited treatment followed by azathioprine Vasculitis Damage Index November 2019, topline data requiring treatment with options and increased risk of death from inflammatory reported November 2019 cyclophosphamide or vascular complications arising in various organs (often the Quality of life rituximab kidneys). Avacopan might reduce inflammation, 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 the activity of C5 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 143

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

Children aged 12 years or Benralizumab (Fasenra) is a monoclonal antibody that 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 overproduction of eosinophils. These eosinophils infiltrate tissues and may cause damage to organs, such as the heart and lungs, which can negatively affect quality of life and increase risk of death. Treatment options are limited. Benralizumab purportedly binds the IL-5α receptor and attracts natural killer (NK) cells that induce rapid and near- complete eosinophil depletion via programmed cell death (ie, apoptosis). In clinical trials, benralizumab was injected under the skin at a dosage of 30 mg every 4 weeks. Developer(s): AstraZeneca plc (Cambridge, United Kingdom)

Children aged 5 years or older Bercolagene telserpavec (B-VEC) is a herpes simplex virus 1 Supportive care to minimize Wound healing FDA designation(s): Orphan 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 Pediatric dystrophic epidermolysis recurring wounds in patients with DEB. This rare, debilitating Disease, Regenerative Medicine bullosa (DEB) and have at least connective tissue disorder has no approved treatments. Advanced Therapy one wound between 10 and 20 Patients with DEB carry a genetic variant in the collagen type Clinical trial(s): Phase 2 GEM-1 2 cm in size VII alpha 1 chain gene, COL7A1. This variant prevents cells primary completion February from producing type VII collagen, causing severe, painful, 2020, data reported October and/or itchy epidermal wounds that can affect a patient’s 2019 longevity and quality of life. Bercolagene telserpavec is a recombinant, replication-incompetent, HSV-1 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, bercolagene telserpavec purportedly anchors the skin’s dermal and epidermal layers to prevent blistering and promote wound healing without heavy scarring. In clinical trials, bercolagene telserpavec 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 144

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 intended C1 esterase inhibitors (eg, Number of angioedema PDUFA date: December 3, 2020 older and adults who have to treat type I or II HAE. A rare inherited genetic disorder, HAE Cinryze, Haegarda) attacks FDA designation(s): Orphan type I or type II hereditary is caused by a mutation in the gene encoding the C1 esterase Plasma kallikrein inhibitors Quality of life, as Drug, Fast Track angioedema (HAE) inhibitor protein (C1-INH). Berotralstat is intended to prevent (eg, ianadelumab-flyo) measured by accepted Clinical trial(s): Phase 3 APeX-2 the onset of HAE attacks by providing an oral alternative to clinical ratings and scales primary completion April 2019, injectable HAE treatments, which might improve treatment data reported November 2019, adherence. C1-INH normally regulates production and activity data reported March 2020 of the plasma serine protease kallikrein, which in turn regulates production and activity of the inflammatory mediator bradykinin. Unregulated kallikrein 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. Symptoms are triggered by stress, injury, illness, or hormone fluctuations. 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 145

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

Children and adults aged up to Betibeglogene autotemcel (LentiGlobin) is a gene therapy Allogeneic stem cell Transfusion need status FDA designation(s): Orphan 50 years who have transfusion- intended for β-thalassemia, an inherited blood disorder transplantation (ASCT) Organ function Drug, Breakthrough Therapy dependent β-thalassemia, also caused by a mutation in the hemoglobin subunit beta gene, Luspatercept-aamt Level of iron overload Clinical trial(s): Phase 3 HBB known as β-thalassemia major, . This mutation causes ineffective red blood cell Repeated blood transfusions NORTHSTAR-2 primary 0 0 Quality of life with a β /β genotype (ie, no β- production, leading to severe anemia. Standard of care completion February 2022, + 0 globin expression) or a β /β involves use of frequent blood transfusions and supportive interim data reported genotype (ie, little β-globin care. Betibeglogene autotemcel might provide a one-time December 2019; phase 3 expression) functional cure for β-thalassemia. Betibeglogene autotemcel NORTHSTAR-3 primary + consists of bone marrow–derived CD34 hematopoietic stem completion June 2022, cells (HSCs) harvested from the patient and treated with a preliminary data reported lentivirus vector that stably inserts a functional copy of the December 2019 HBB gene into the cells. The cells are then multiplied in culture Note(s): bluebird bio plans to to facilitate uptake. This autologous HSC therapy does not complete a Biologics License require immunosuppressive therapy. In clinical trials, Application submission in the betibeglogene autotemcel is given as a single intravenous fourth quarter of 2020 infusion, at an unspecified dose, after patients are treated with busulfan to destroy β-thalassemia-causing blood cells. Developer(s): bluebird bio, Inc (Cambridge, Massachusetts)

Males aged 10 years or older BIIB112 (NSR-RPGR) is a recombinant adeno-associated viral Supportive care Best corrected visual Clinical trial(s): Phase 2/3 who have retina specialist– vector that delivers a codon-optimized form of the retinitis Vitamin and nutritional acuity (BCVA) XIRIUS primary completion confirmed chromosome X– pigmentosa GTPase regulator-open reading frame 15 gene, supplementation Retinal sensitivity March 2021, preliminary safety RPGR-ORF 15. linked retinitis pigmentosa This gene encodes a full-length functional Peripheral vision and efficacy data reported (XLRP) and RPGR-ORF 15 gene protein intended to treat XLRP. No effective treatments are September 2018, preliminary Recovery time variants approved for this rare condition, and BIIB112 could become the data presented May 2019, data first retinal gene therapy to delay XLRP or reverse vision loss. Quality of life published February 2020 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 146

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

Females aged 18 to 45 years Blarcamesine (ANAVEX2-73) is a small-molecule sigma-1 Supportive care (eg, Behavioral symptom FDA designation(s): Orphan who have genetically receptor activator intended to treat adult females who have anticonvulsants, assistive severity, as measured by Drug, Fast Track, Rare Pediatric confirmed Rett syndrome Rett syndrome, a rare, postnatal, progressive neurologic devices, noninvasive accepted clinical ratings Disease disorder. Rett syndrome is caused by a mutation in the methyl ventilation, nutritional and scales Clinical trial(s): Phase 2 primary CpG binding protein 2 gene, MECP2. Located on the X support, oxygen treatment, Seizure frequency completion September 2020, MECP2 chromosome, encodes the MeCP2 protein that physical and occupational Sleep quality and preliminary (Part A) data normally mediates gene expression in neuronal and glial cells. therapy, speech/language duration presented September 2019; Loss of MeCP2 function results in nerve cell dysfunction, which therapy) phase 2 AVATAR primary is thought to be reversible. Patients with Rett syndrome completion June 2020 develop normally until 6 to 18 months of age and subsequently experience developmental delays and regression of previously learned motor and verbal skills. The disease eventually causes additional symptoms, such as repeated hand movements, impaired gait, slowed head growth, disordered breathing, and seizures. Symptom severity varies by patient and depends on the individual’s specific MECP2 mutation and the amount of mutant MeCP2 protein expression. No cure exists, and treatment generally consists of supportive care for managing 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 19 weeks. Developer(s): Anavex Life Sciences Corp (New York, New York)

Section 5. Rare Diseases 147

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 to Corticosteroids Proteinuria change from FDA designation(s): Orphan who have biopsy-proven 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-stage Clinical trial(s): Phase 3 nephropathy (Berger disease) the kidneys and causes local inflammation that can gradually cyclophosphamide, renal disease Nefigard primary completion and an estimated glomerular affect kidney function. The disease can cause end-stage kidney mycophenolate) Change in eGFR from October 2020 filtration rate (eGFR) between disease within 10 to 20 years in up to 40% of affected patients. baseline 45 and 90 mL/min/1.73 m2 No treatments are approved for IgA nephropathy. The Change in quality of life (stage 2 to 3A chronic kidney standard of care (ie, high-dose systemic corticosteroids) is from baseline disease) and medically controversial because of the increased risks of adverse events controlled blood pressure 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 148

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 muscular rearrangements or deletions in the dystrophin gene, DMD. clinical ratings and scales Regenerative Medicine dystrophy (DMD), are either DMD encodes the dystrophin protein, which helps promote (eg, time to stand, time Advanced Therapy ambulatory or nonambulatory, muscle function. The absence of wild-type dystrophin protein to run/walk/climb; 6- Clinical trial(s): Phase 2 HOPE-2 and are receiving stable doses causes progressive muscle fiber death and eventual minute walk test, North primary completion April 2020, of systemic glucocorticoids widespread muscle weakness. No cure for DMD exists, and Star Ambulatory interim data reported July 2019 first-line corticosteroid treatment addresses symptoms but Assessment) and October 2019 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 149

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 FDA designation(s): Orphan have Duchenne muscular oligomer (PMO; DNA analogue) intended to treat DMD, an deflazacort, prednisone) measured by accepted Drug dystrophy (DMD) with a inherited, X chromosome–linked genetic disorder caused by clinical ratings and scales Clinical trial(s): Phase 3 rearrangement in the rearrangements or deletions in the DMD gene. DMD encodes Quality of life ESSENCE trial primary dystrophin gene, DMD, that the dystrophin protein, which is involved in muscle function, completion May 2022 (children involves exon 45 and who are and the absence of wild-type dystrophin protein causes aged 7 to 13 years), topline on a stable dose of progressive muscle fiber necrosis and eventual widespread data reported March 2019; corticosteroids muscle weakness. Casimersen purportedly binds exon 45 of phase 3 open-label extension dystrophin pre-messenger RNA (mRNA; ie, precursor RNA primary completion August composed of introns and exons) and promotes skipping of 2026 (children aged 7 to 17 exon 45 during mRNA processing. This allows for synthesis of years and adults aged 18 to 23 an internally truncated, but functional, dystrophin protein. years) Casimersen treatment is intended to promote skeletal muscle Note(s): In November 2019, function and prevent or delay disease progression in patients Sarepta Therapeutics DMD with DMD who have exon 45 variants. In clinical trials, announced that it intended to casimersen is given intravenously at a dosage of 30 mg/kg address issues outlined in a once weekly for up to 144 weeks. Complete Response Letter Developer(s): (CRL) from FDA regarding its Sarepta Therapeutics, Inc (Cambridge, Massachusetts) New Drug Application (NDA) for golodirsen, also in development for treating DMD, before pursuing regulatory approval for casimersen. Before receiving the CRL for golodirsen, it had planned to file an NDA for casimersen in the first half of 2020.

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 Crizanlizumab-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 (blood cell– intravenous opioid use 2019 sickle cell disease (SCD) promotes the inflammation and adhesion involved in vaso- generating) stem cell Frequency of VOCs FDA designation(s): Orphan occlusive crises (VOCs). It is approved by FDA. Crizanlizumab- transplantation Hospital length of stay Drug, Breakthrough Therapy, tmca is intended to improve treatment efficacy by blocking P- Hydroxyurea Rehospitalizations within Priority Review selectin to prevent abnormal red blood cell clumping in small Pharmaceutical-grade l- 3 days of discharge Clinical trial(s): Phase 3 STAND blood vessels and maintain blood flow. In SCD, sickled red glutamine (ie, Endari) primary completion May 2022; blood cells are more susceptible to oxidative damage, Quality of life Voxelotor (ie, Oxbryta) 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 been on phase 2 SUSTAIN data a mainstay of treatment for VOC, can reduce its incidence but is ineffective in 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 151

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 PWS/C601 primary increased appetite) in patients with PWS. PWS is a rare genetic Glucagon-like peptide 1 (GLP- disease, diabetes completion May 2020; phase 3 disease (about 8000-11 000 US patients) caused by lack of 1) receptor agonist (eg, mellitus, obesity) C602 open-label extension expression of several genes on chromosome 15. It is often exenatide or liraglutide; off- Mortality primary completion April 2021; managed with off-label diazoxide (Proglycem), which is label) Quality of life phase 3 C603 open-label approved to treat low blood glucose. However, patients with primary completion March PWS require a lower dose of diazoxide than the current 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 152

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

Adults aged 18 years or older Eculizumab (Soliris) is a recombinant humanized monoclonal Azathioprine Functional impairments Approval date: June 27, 2019 who have neuromyelitis optica antibody that binds with high affinity to the complement Hematopoietic stem cell (eg, vision, mobility, and FDA designation(s): Orphan spectrum disorder (NMOSD) protein C5 (ie, a soluble component of the innate immune transplantation (HSCT) bowel or bladder Drug and who test positive for anti- system). It is approved by FDA. Eculizumab is intended to Intravenous corticosteroids incontinence) change Clinical trial(s): Phase 3 aquaporin-4 (AQP4) antibodies relieve the autoimmune and neurodegenerative symptoms from baseline Mycophenolate mofetil PREVENT completed July 2018, and pathology of neuromyelitis optica by binding C5 and Incidence of relapse from Plasmapheresis data published May 2019; inhibiting its cleavage to C5a and C5b. This action prevents the baseline phase 3 open-label extension Rituximab downstream formation and activation of the cell-lysing Quality of life change primary completion June 2020 terminal complement complex C5b-9, which damages cell Thymus transplantation from baseline membranes targeted with the complexes. C5b-9 complex (donor matched) production is thought to directly drive the uncontrolled complement activation that promotes some autoimmune reactions. The FDA-approved label recommends 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, and 1200 mg every 2 weeks thereafter. Developer(s): Alexion Pharmaceuticals, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 153

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

Males aged 4 to 7 years who Edasalonexent (CAT-1004) is a small-molecule inhibitor of Corticosteroids (eg, Ambulatory function (eg, Submission date: New Drug have Duchenne muscular nuclear factor kappa-light-chain-enhancer of activated B cells deflazacort, prednisone) North Star Ambulatory Application anticipated in early dystrophy (DMD) (NF-kB). It is intended to treat DMD, an inherited X Supportive care Assessment, 4-stair climb 2021 chromosome–linked genetic disorder caused by velocity, stand from FDA designation(s): Orphan rearrangements or deletions in the dystrophin gene, DMD. supine velocity, 10-meter Drug, Fast Track, Rare Pediatric DMD encodes the dystrophin protein that helps keep muscle walk/run velocity) Disease cells intact. The absence of wild-type dystrophin protein Muscle strength Clinical trial(s): Pivotal phase 3 causes progressive muscle fiber death and eventual PolarisDMD primary widespread muscle weakness and purportedly leads to the completion June 2020 (boys persistent activation of NF-kB, which contributes to disease aged 4 to younger than 8 progression. DMD has no cure, and first-line corticosteroid years), topline data expected in treatment (eg, deflazacort) manages symptoms but does not fourth quarter of 2020; phase 3 prevent disease progression and has significant side effects. GalaxyDMD open-label FDA approved 2 gene therapies for patients who have a extension primary completion DMD specific mutation in (ie, in exon 51 or exon 53), but June 2022 (boys aged 4 to 12 DMD patients who have other variants are ineligible for these years); phase 2 MoveDMD therapies. Therefore, additional therapies are needed. completed August 2019, data Edasalonexent therapy is intended for all patients with DMD published April 2018, data regardless of genetic variant status. By blocking NF-kB activity, presented March 2020 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/day (divided into 3 equal doses) for up to 104 weeks. Developer(s): Catabasis Pharmaceuticals, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 154

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

Adults aged 18 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 had (PPARα) and PPAR delta (PPARδ) intended to treat PBC. An liver failure Clinical trial(s): Phase 2 an inadequate response to autoimmune disease, PBC damages the liver’s bile ducts, Symptom relief (eg, completed October 2018, data ursodeoxycholic acid (UDCA) causing bile to accumulate in the liver and leading to diarrhea due to fat reported April 2019 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 whom Quality of life 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 is unaddressed by any existing PBC treatments. In a phase 2 clinical trial, elafibranor is taken in 80- or 120-mg tablets twice daily for 12 weeks. Developer(s): GENFIT Corp (Paris, France)

Section 5. Rare Diseases 155

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 symptoms Fatigue Drug, Fast Track, Rare Pediatric confirmed Barth syndrome and energy production. Barth syndrome is a chromosome X–linked (eg, bacterial infection, heart Quality of life Disease a baseline body weight of mitochondrial disorder characterized by degeneration of heart failure) Clinical trial(s): Phase 2/3 more than 30 kg with muscle (ie, dilated cardiomyopathy) and skeletal muscle (ie, TAZPOWER primary completion estimated glomerular filtration myopathy), recurrent infections due to neutropenia (ie, low April 2021, preliminary data rate (eGFR) greater than 90 white cells), and short stature. Barth syndrome is managed reported April 2019, additional 2 mL/min/1.73 m or body primarily with supportive care because no pharmacologic data presented November 2019 weight of more than 40 kg and therapies have yet demonstrated clinical benefits. In Barth eGFR greater than 60 but less syndrome, mutations in the tafazzin gene, TAZ, result in the than 90 mL/min/1.73 m2 production of dysfunctional tafazzin protein. This protein ensures adequate levels of functional cardiolipin, a lipid required for normal mitochondrial structure, function, and energy production. Tissues with the highest energy demands (eg, heart and skeletal muscle) are most affected. Elamipretide purportedly penetrates mitochondrial membranes to bond reversibly to cardiolipin, thereby normalizing the inner mitochondrial membrane structure and improving mitochondrial function. Elamipretide is thought to enhance energy generation through increased production of ATP, a critical component in energy transport, and to potentially lower levels of reactive oxygen species (ROS) 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 156

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 monotherapy Drug, Fast Track, Breakthrough copy of the cystic fibrosis produced by the mutant CFTR gene more effective. This drug (ie, ivacaftor) Therapy, Priority Review 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 cell primary completion September CFTR surface. This results in increased activity, as measured by 2020; phase 3 primary CFTR- mediated chloride transport. Elexacaftor and tezacaftor completion October 2020;

bind to different sites on the CFTR protein and have an phase 3 primary completion additive effect in facilitating the cellular processing and June 2021; phase 3 open-label CFTR trafficking of F508del- to increase the amount of CFTR primary completion May 2022; protein delivered to the cell surface compared with either phase 3 primary completion molecule alone. Ivacaftor potentiates the channel open August 2022 probability (or gating) of the CFTR protein at the cell surface. Note(s): Vertex Pharmaceuticals The recommended dosage in the FDA-approved label is 2 will receive a Rare Pediatric tablets containing elexacaftor 100 mg, tezacaftor 50 mg, and Disease Priority Review voucher ivacaftor 75 mg taken orally in the morning and one ivacaftor for developing this therapy 150-mg tablet taken in the evening; the morning and evening doses are to be taken about 12 hours apart and with fat- containing food. Developer(s): Vertex Pharmaceuticals, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 157

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

Males aged 18 years or older Etranacogene dezaparvovec (AMT-061) gene therapy consists Factor IX replacement therapy Bleeding episodes FDA designation(s): Orphan who have moderate to severe of adeno-associated viral vector serotype 5 (AAV5) containing (human plasma–derived or Treatment-related Drug, Breakthrough Therapy congenital (ie, inherited) a codon-optimized human factor IX Padua gene (AAV5- recombinant) complications Clinical trial(s): Phase 3 HOPE-B hemophilia B and are receiving hFIXco-Padua). The adeno-associated viral vector delivers a Survival primary completion March factor IX prophylaxis with more copy of the Padua variant of the factor IX gene, F9 or FIX. It Quality of life 2020; single-arm phase 2 than 150 days’ exposure to purportedly has an 8-fold increase in activity compared with primary completion October factor IX protein treatment wild-type (ie, not caused by any known genetic variant) factor 2018, data published October IX to provide sustained coagulation. As a single-treatment 2019, further data presented gene therapy, AMT-061 could eliminate the need for repeated December 2019 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 (skin cells) treated to produce a infection risk from baseline Drug, Fast Track, Rare Pediatric dystrophic epidermolysis functional copy of the collagen type VII alpha 1 chain gene, Time to wound closure Disease, Regenerative Medicine bullosa (RDEB) COL7A1. The cell therapy is delivered by injection into the from baseline Advanced Therapy patient’s skin lesions to promote wound healing. RDEB is a Clinical trial(s): Phase 3 FCX-007 rare genetic disease caused by mutations in the collagen primary completion December COL7A1 protein, which is needed for maintaining proper skin 2020; phase 1/2 FI-FCX-007 integrity. Loss of COL7A1 expression in RDEB leads to primary completion June 2020, widespread blistering, resulting in severe scarring, vision loss, interim data reported May disfigurement, and other serious medical problems. FCX-007 is 2018; phase 3 primary intended to prevent blistering and promote wound healing completion December 2020 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), which acquired previous collaborator Fibrocell Technologies, Inc (Exton, Pennsylvania)

Section 5. Rare Diseases 158

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

Children aged 2 years or older Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, clobazam, Frequency of seizures FDA designation(s): Orphan and adults aged up to 35 years amphetamine derivative intended as an adjunctive therapy for stiripentol, topiramate, that result in drops Drug who have Lennox-Gastaut Lennox-Gastaut syndrome. The syndrome is a rare, severe, valproate) Duration of seizures that Clinical trial(s): Pivotal phase 3 syndrome that is being treated infantile- or childhood-onset form of epilepsy. Fintepla might Ketogenic diet result in drops primary completion December with one to 4 antiepileptic improve health outcomes in patients with Lennox-Gastaut Plant-derived CBD Seizure-free interval 2020, topline data reported drugs syndrome, who often experience multiple types of seizures Functional capacity February 2020; phase 2 primary (eg, atonic, tonic, atypical absence, drop attacks) difficult to completion September 2018, Quality of life control with FDA-approved antiepileptic drugs. In addition, data published August 2018; patients typically experience cognitive impairment, intellectual phase 3 long-term follow-up disability, behavioral problems, delayed development, and primary completion April 2023 muscle weakness. FDA has approved cannabidiol (CBD) to treat the disease, but it might cause hepatic impairment, especially when used in conjunction with certain antiepileptics; the drug can also cause sleepiness, sedation, and suicidal behavior. In patients with Lennox-Gastaut syndrome, fenfluramine hydrochloride low-dose purportedly promotes serotonin release and stabilizes nerve activity in the brain, which might decrease seizure frequency and duration. In clinical trials, patients take the drug by mouth at a dosage of 0.2 or 0.8 mg/kg/day (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 159

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

Children aged 2 years or older Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, clobazam, Monthly convulsive PDUFA date: June 25, 2020 and adults aged up to 35 years amphetamine derivative intended as an adjunctive therapy for stiripentol, topiramate, seizure frequency (MCSF) FDA designation(s): Orphan who have Dravet syndrome Dravet syndrome. A rare, severe, infantile-onset form of valproate) Convulsive seizure Drug, Fast Track and are taking one or more epilepsy, Dravet syndrome is usually caused by a variant in the Ketogenic diet duration Clinical trial(s): Phase 3 SCN1A antiepileptic drugs sodium voltage-gated channel alpha subunit 1 gene, . Plant-derived CBD Seizure-free interval completed June 2018, data Fintepla is intended as an option for patients who have Functional capacity published December 2019; prolonged seizures that are difficult to control with available Quality of life phase 3 primary completion antiepileptic drugs. In addition, patients typically experience July 2020; phase 3 primary cognitive impairment, behavioral problems, muscle weakness, completion July 2020, pooled and sleep disorders. FDA has approved cannabidiol (CBD) to data published December 2019; treat the disease, but it can cause hepatic impairment, phase 3 open-label extension especially when used in conjunction with certain antiepileptics; primary completion December the drug also can cause sleepiness, sedation, and suicidal 2020, data presented behavior. In patients with Dravet syndrome, fenfluramine December 2018, data hydrochloride low-dose purportedly promotes serotonin presented October 2019; phase release and stabilizes nerve activity in the brain, which might 3 long-term follow-up primary decrease seizure frequency and duration. In clinical trials, completion April 2023 patients take the drug by mouth or caregivers give it at a Note(s): FDA issued a Refusal to dosage of 0.2, 0.4, or 0.8 mg/kg/day (up to a maximum of 20 File letter on April 8, 2019, mg/day) for the duration of the trial. The drug is intended to citing missing and incorrect be taken daily, on an ongoing basis. data. FDA rescinded Developer(s): Breakthrough Therapy Zogenix, Inc (Emeryville, California) designation because criteria were no longer met with the approval of 2 other drugs for Dravet syndrome. Zogenix resubmitted a New Drug Application in November 2019.

Section 5. Rare Diseases 160

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

Adolescents aged 16 years or Fezagepras (PBI-4050; 3-pentylbenzeneacetic acid sodium salt) Organ transplantation Change from baseline in FDA designation(s): Orphan older and adults who have is a novel, synthetic, medium-chain fatty acid derivative, oral Supportive care skin pathology Drug, Rare Pediatric Disease Alström syndrome antifibrotic (ie, reduces scar tissue formation). It is intended to Change from baseline in Clinical trial(s): Phase 2/3 treat Alström syndrome, a rare genetic syndrome. The fasting plasma glucose primary completion July 2020, syndrome is characterized by obesity in childhood or Change from baseline in preliminary data presented adolescence and type 2 diabetes mellitus (T2DM), often with plasma insulin April 2018; pivotal phase 3 severe insulin resistance; dyslipidemia; high blood pressure; Change from baseline in planned and severe life-threatening multiorgan fibrosis involving the glycated hemoglobin bladder, kidney, liver, and heart. Progressive loss of vision and (HbA1c) hearing, dilated cardiomyopathy, and short stature might also occur. Fezagepras is intended to alleviate development of Change from baseline in insulin resistance, dyslipidemia, and hypertension and severe blood glucose, as multiorgan fibrosis. The drug purportedly has stimulating measured by weekly 4- activity toward the G-protein coupled receptor 40, GPR40, and point profile inhibiting activity toward a related receptor, GPR84. This Change from baseline in activity reduces fibrotic activity in macrophages, fibroblasts liver stiffness 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)

Males aged 18 to 65 years who Fidanacogene elaparvovec (PF-06838435) is an adeno- Factor IX replacement therapy Bleeding episodes FDA designation(s): Orphan have moderate to severe associated viral vector gene therapy under development to (human plasma–derived or Treatment-related Drug, Breakthrough Therapy hemophilia B (factor IX activity treat hemophilia B. As a single-treatment gene therapy, recombinant) complications Clinical trial(s): Phase 3 single- of 2% or less) and have fidanacogene elaparvovec could eliminate the need for Survival arm BENEGENE-2 primary received routine factor IX repeated injections of coagulation-factor replacement. The Quality of life completion November 2021 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 administered as a single intravenous infusion (dose not stated). Developer(s): Pfizer, Inc (New York, New York)

Section 5. Rare Diseases 161

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 completion cascade. This inactivation promotes sufficient thrombin April 2020; phase 3 ATLAS-PPX recombinant; hemophilia A) Quality of life generation to restore hemostasis and prevent bleeding. Factor IX replacement (human primary completion March Fitusiran therapy would replace regular intravenous blood plasma–derived or 2022; phase 2/3 ATLAS-PEDS factor infusions with a monthly subcutaneous injection. In recombinant; hemophilia B) primary completion June 2023; clinical trials, fitusiran is injected under the skin at a dosage of phase 3 ATLAS-OLE primary 80 mg once monthly for up to 20 months. completion January 2026 Developer(s): Note(s): FDA lifted a clinical Alnylam Pharmaceuticals (Cambridge, Massachusetts), in hold on fitusiran studies in collaboration with Sanofi Genzyme (Cambridge, December 2017 Massachusetts)

Infants and children aged up to Fosdenopterin (BBP-870, ORGN001) is a synthetic version of Anticonvulsants Ability to sit upright Submission date: Rolling New 5 years who have molybdenum cyclic pyranopterin monophosphate (cPMP). It is intended to Breathing (ie, ventilator) independently for at least Drug Application initiated cofactor deficiency (MoCD) restore molybdenum cofactor (MoCo) levels and sulfite support 30 seconds at 12 months December 3, 2019 type A oxidase activity to enable clearance of sulfite from patients Supportive care Bayley Scales of Infant FDA designation(s): Orphan with MoCD type A. An ultra-rare genetic metabolic disorder, Development at 12 Drug, Breakthrough Therapy, MoCD type A causes catastrophic and irreversible neurologic months Rare Pediatric Disease damage within the first weeks of life. MoCD type A has no Pediatric Evaluation of Clinical trial(s): Phase 2 primary effective treatments and is caused by a mutation in the Disability Inventory completion December 2020; MOCS1, molybdenum cofactor synthesis 1 gene, which turns (PEDI) at 12 months phase 2/3 primary completion guanosine triphosphate to cPMP, an intermediate in the Survival at 12 months December 2021 body’s production of MoCo. MoCo is a key component of the 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 162

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

Children aged 2 years or older Gaboxadol (OV101), also known as THIP, is a small-molecule Supportive care (eg, Motor function, as FDA designation(s): Orphan and adults aged up to 49 years derivative of muscimol, a compound found in the mushroom anticonvulsants for seizures, measured by accepted Drug, Fast Track who have genetically Amanita muscaria. It is intended to treat Angelman syndrome, assistive devices, clinical ratings and scales Clinical trial(s): Pivotal phase 3 confirmed Angelman a rare, noninherited, X chromosome–linked benzodiazepines for sleep Time to sleep onset NEPTUNE primary completion syndrome neurodevelopmental disorder caused by a mutation in the disturbances, occupational Total sleep time July 2020 (children); phase 2 ubiquitin protein ligase E3a gene, UBE3A. UBE3A encodes the therapy, physical therapy, Behavioral disturbances, completed June 2018 (children UBE3A protein, which mediates cellular protein degradation speech/language therapy) as measured by accepted and adults), data presented and is expressed in both excitatory and inhibitory neurons in clinical ratings and scales October 2018, data reported the brain. Normally, the brain can differentiate between May 2019; phase 2 ELARA excitatory and inhibitory signals, a process called tonic open-label extension primary inhibition, that is partially mediated by gamma-aminobutyric completion July 2020 (children acid (GABA) receptors. In a mouse model of Angelman and adults) syndrome in which the animals lacked UBE3A and UBE3A expression, loss of tonic inhibition disrupted nerve cell function and normal brain activity, resulting in motor dysfunction. Patients with Angelman syndrome experience severe 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. Because the drug is a delta-selective, gamma-aminobutyric acid receptor A (GABAA) receptor agonist (ie, activator) that selectively activates GABAA receptors, it purportedly restores the process of tonic 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 163

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

Males aged 13 to 22 years who Gaboxadol (OV101) is a small-molecule derivative of Supportive care (eg, Aberrant behavior FDA designation(s): Orphan have fragile X syndrome (FXS) muscimol, a compound found in the mushroom Amanita anticonvulsants for seizures incidence and severity, as Drug, Fast Track muscaria. It is intended to treat FXS, a rare, noninherited, X and/or behavior stabilization, measured by accepted Clinical trial(s): Phase 2 ROCKET chromosome–linked neurodevelopmental disorder. This behavior-stabilizing clinical ratings and scales completed February 2020, data syndrome is caused by mutations in the fragile X mental medications [eg, alpha2 reported May 2020 retardation 1 gene, FMR1. Expansion of the cytosine, guanine, agonists, antidepressants, guanine (CGG) trinucleotide repeats in the 5′ untranslated beta-blockers], educational region of FMR1 causes gene hypermethylation, which then interventions, sensory silences expression of the encoded Fmr1 protein (Fmrp). Fmrp, integration techniques) which is expressed in neurons and glial cells, is thought to promote synapse formation and adaptation (ie, synaptic plasticity) in the brain and is thought to be important for learning, memory, and regulating protein synthesis and transport of coding and noncoding RNA in the brain. Normally, the brain can differentiate between excitatory and inhibitory signals, a process called tonic inhibition that is partially mediated by gamma-aminobutyric acid (GABA) receptors. In patients with FXS, loss of Fmrp function purportedly disrupts protein translation, synaptic plasticity, intracellular signaling, and GABA-mediated tonic inhibition. This 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). Because gaboxadol is a delta-selective, GABA A (GABAA) receptor agonist (ie, activator) that selectively activates GABAA receptors, it purportedly restores the process of tonic 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 164

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

Adults aged 18 years or older Galcanezumab-gnlm (Emgality) is a humanized monoclonal Corticosteroids Weekly cluster headache Approval date: June 4, 2019 who have episodic cluster antibody against calcitonin gene–related peptide (CGRP) Topiramate (off-label) frequency FDA designation(s): headache intended to treat episodic cluster headache. Galcanezumab- Verapamil (off-label) Cluster headache Breakthrough Therapy gnlm is the first biologic approved by FDA to treat these severity, as measured by Clinical trial(s): Phase 3 CGAL headaches. CGRP is a neuropeptide thought to contribute to accepted clinical ratings completed February 2018, data pain signaling of the trigeminal sensory nerve, leading to and scales published July 2019; phase 3 headache development. Galcanezumab purportedly prevents CGAR open-label extension CGRP from binding to its receptor, which might reduce cluster primary completion December headache frequency. The FDA-approved label states the 2020 (episodic, chronic cluster recommended dosage is 300 mg (3 consecutive under-the- headache), data presented skin injections of 100 mg each that patients take themselves) September 2019 (abstract IHC- at the onset of the cluster period, and then monthly until the PO-247) end of the cluster period. A missed dose during a cluster Note(s): FDA approved period is recommended to be taken as soon as possible. galcanezumab-gnlm to treat Developer(s): migraine headache in Eli Lilly and Co (Indianapolis, Indiana) September 2018

Section 5. Rare Diseases 165

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

Males aged 6 years or older Givinostat is a small-molecule histone deacetylase (HDAC) Corticosteroids (eg, Ambulatory function (eg, FDA designation(s): Orphan and adults who have Duchenne inhibitor intended to treat DMD, an inherited X chromosome– deflazacort, prednisone) 6-minute walk test Drug, Fast Track muscular dystrophy (DMD), are linked genetic disorder caused by mutations or deletions in distance, time to rise Clinical trial(s): Phase 3 primary ambulatory, and are receiving the dystrophin gene, DMD. DMD encodes the dystrophin from floor, North Star completion March 2022; phase a stable dose of corticosteroids protein, which helps keep muscle cells intact. The absence of Ambulatory Assessment) 2/3 long-term follow-up wild-type dystrophin protein causes progressive muscle fiber Muscle strength primary completion December necrosis and eventual widespread muscle weakness. Patients 2023 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. Therefore, additional therapies are needed. 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 166

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

Adults who have acute hepatic Givosiran (Givlaari) is an RNA interference (RNAi) therapeutic Carbohydrate perfusion Rate of attacks Approval date: November 20, porphyria (AHP) that reduces the expression of aminolevulinic acid synthase 1 (acute) Rate of hemin 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 in Trigger avoidance (acute) baseline Clinical trial(s): Phase 3 the liver and converge in their respective metabolic pathways Nausea score change ENVISION primary completion on the ALAS1 enzyme. This convergence is thought to increase from baseline January 2019, data reported the production of heme intermediates in the liver that are September 2019 toxic to nerves and contribute to developing AHP. The Fatigue score change manifestations include intermittent porphyria, aminolevulinic from baseline 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 FDA- approved label’s recommended dose is 2.5 mg/kg once monthly by injection under the skin. Developer(s): Alnylam Pharmaceuticals, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 167

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

Section 5. Rare Diseases 168

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 second dystrophy (DMD) genetic disorder caused by mutations or deletions in the predicted) 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-type peak expiratory flow Drug, Fast Track, Rare Pediatric dystrophin protein causes progressive muscle fiber necrosis Percentage predicted Disease and eventual widespread muscle weakness. No cure exists for forced expiratory volume Clinical trial(s): Phase 3 DMD, and first-line corticosteroid treatment manages in 1 second SIDEROS primary completion symptoms but does not prevent disease progression and has Muscle strength August 2021; phase 3 SIDEROS- significant side effects. FDA approved 2 gene therapies for E open-label extension primary DMD Quality of life patients who have a specific mutation in (ie, in exon 51 completion December 2023; DMD or exon 53), but patients who have other variants are phase 3 DELOS completed April ineligible for these therapies. Therefore, additional therapies 2014, data published April are needed. Idebenone is similar to coenzyme Q10 and 2015, additional data presented purportedly facilitates electron transport within mitochondria. December 2017, additional According to the manufacturer, maintaining correct electron long-term follow-up data balance is essential for normal energy metabolism, particularly presented March 2020 in nerve and muscle cells, which demand more energy, making them more prone to rapid cell damage or death from mitochondrial dysfunction. In patients with DMD, preserving mitochondrial function and protecting cells from oxidative stress through idebenone treatment might prevent cell 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 169

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

Adults aged 18 to 55 years IMR-687 is a selective inhibitor of the enzyme Blood transfusion Frequency of vaso- FDA designation(s): Orphan who have sickle cell disease phosphodiesterase type 9 (PDE9) in development to treat SCD. Crizanlizumab-tmca occlusive crises (VOCs) Drug, Fast Track, Rare Pediatric (SCD) Donor stem cell transplantation is the only potentially curative Hematopoietic (blood cell– and hospitalization Disease treatment for SCD but is not widely available because of the generating) stem cell Number of blood Clinical trial(s): Phase 2 difficulty of finding a closely matched donor to increase the transplantation transfusions required randomized primary chance of success. IMR-687 could represent a disease- Hydroxyurea Quality of life completion July 2020, initial modifying treatment that is more widely available. The oral data reported June 2019; phase Pharmaceutical-grade l- drug purportedly prevents destruction of and increases levels 2 single-arm extension primary glutamine of cyclic guanosine monophosphate (cGMP). Higher cGMP completion June 2024 levels in turn increase production of fetal hemoglobin while Voxelotor reducing the sickling of red blood cells 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)

Adults aged 18 years or older Inebilizumab (MEDI-551) is a humanized monoclonal antibody Azathioprine Attack rate PDUFA date: June 11, 2020 who have neuromyelitis optica intended to bind to CD19, which is expressed on a broad Eculizumab plus Functional impairments FDA designation(s): Orphan or neuromyelitis optica range of B cells. Inebilizumab is intended to bind to and immunosuppressants (eg, vision, mobility, Drug, Breakthrough Therapy spectrum disorder (NMOSD), deplete autoreactive B cells involved in the neurodegenerative Intravenous corticosteroids bowel or bladder Clinical trial(s): Phase 2/3 N- regardless of aquaporin-4- disease course of NMOSD, for which no cure exists. NMOSD is Mycophenolate mofetil incontinence) change MOmentum primary immunoglobulin G (AQP4-IgG) a rare autoimmune disease that affects myelin in the eyes, from baseline Plasmapheresis completion October 2018, antibody presence, who have spinal cord, and other parts of the body. Patients with NMOSD Hospitalizations pivotal study data published had one relapse requiring can have pain, paralysis, vision loss, and bladder and bowel Rituximab Quality of life change October 2019 rescue therapy in the previous problems. Approved treatments are immunosuppressants from baseline year 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. In clinical trials, regardless of whether they tested positive or negative for AQP4-IgG antibodies, patients received inebilizumab intravenously, and results were followed for 28 weeks. Developer(s): Viela Bio (Gaithersburg, Maryland)

Section 5. Rare Diseases 170

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

Adults aged 18 years or older jCell is an allogeneic (ie, unrelated donor) stem cell therapy Supportive care Best corrected visual FDA designation(s): Orphan who have genetically that uses human retinal progenitor cells that have been Vitamin and nutritional acuity (BCVA) Drug, Regenerative Medicine confirmed retinitis pigmentosa cultured and expanded. No effective treatments are available supplementation Retinal sensitivity Advanced Therapy (RP) for RP, so jCell could be the first nonsurgical therapy for the Peripheral vision Clinical trial(s): Phase 2 JC-02 disease. It is intended to delay RP progression or reverse Recovery time primary completion September vision loss through the release of neurotrophic factors that 2020 might rescue diseased retinal cells and possibly differentiate Quality of life into new rod cells in the retina. In clinical trials, jCell has been given as 3 × 106 or 6 × 106 human retinal progenitor cells suspended in medium. It is injected intravitreally under local anesthesia into the eye with the poorest visual acuity or, if vision is comparable in both eyes, the nondominant eye. Developer(s): jCyte, Inc (Newport Beach, California), in collaboration with California Institute of Regenerative Medicine (Oakland, California)

Section 5. Rare Diseases 171

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

Adults aged 18 years or older Lenabasum (JBT-101) is a novel synthetic anti-inflammatory Combined autologous Disease progression Submission date: New Drug who have diffuse cutaneous and antiscarring (ie, antifibrotic) medication under hematopoietic stem cell Skin fibrosis and Application planned for 2021 systemic sclerosis investigation to treat systemic sclerosis, a rare, incurable, transplantation (HSCT) and inflammation FDA designation(s): Orphan autoimmune, connective tissue disease. Conventional high-dose Mortality Drug, Fast Track immunosuppressive therapy has limited efficacy in preventing immunosuppressive therapy Quality of life Clinical trial(s): Phase 3 disease progression or reducing mortality rates. The disease is Low-dose immunosuppressive (RESOLVE-1) primary marked by vasculopathy, skin thickening due to collagen therapy completion March 2020 accumulation, autoantibody formation, and inflammation, Symptom-based palliative which leads to fibrosis in skin and internal organs. Patients pharmacotherapy (eg, with limited cutaneous systemic sclerosis have fairly high angiotensin-converting survival rates but are at increased risk of pulmonary arterial enzyme [ACE] inhibitors, hypertension (PAH). Patients with diffuse cutaneous systemic nonsteroidal anti- sclerosis have worse survival rates. Preclinical studies suggest inflammatory drugs [NSAIDs]) that lenabasum preferentially 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 172

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 disease Quality of life Application planned for second Leber hereditary optic of mitochondrial DNA that leads to irreversible vision loss. half of 2021 neuropathy (LHON) caused by Lenadogene nolparvovec is intended to restore vision loss and FDA designation(s): Orphan a mutation in the NADH quality of life in patients with LHON caused by a mutation in Drug ND4 ND4 dehydrogenase 4 gene, the gene. Lenadogene nolparvovec is an adeno- Clinical trial(s): Phase 3 REFLECT associated virus serotype 2 (AAV2) vector that delivers a primary completion June 2020, ND4 functional copy of the gene into cells. The therapy uses a developed under Special mitochondrial targeting sequence that carries therapeutic Protocol Assessment; phase 3 messenger RNA (mRNA) transcribed from this transgene from RESCUE completed July 2019, the nucleus of treated cells directly to the mitochondria, where data reported September 2019; functional ND4 proteins are produced and incorporated, phase 3 REVERSE completed treating the deficiency. In clinical trials, lenadogene December 2018, data reported nolparvovec is given as a single intravitreal (ie, into the eye) May 2019 injection at a dose of 9 × 1010 vg in 90 μL of balanced salt solution plus 0.001% Pluronic F68. Developer(s): Gensight Biologics, Inc (New York, New York)

Section 5. Rare Diseases 173

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

Males aged 17 years or Lenti-D is a bone marrow–derived gene therapy product Histocompatible stem cell CALD progression Submission date: Biologics younger who have active intended for adrenoleukodystrophy (ALD). A rare, X transplantation Functional disability License Application expected cerebral adrenoleukodystrophy chromosome–linked, inherited metabolic disorder, ALD is Lorenzo’s oil (4 parts glyceryl Quality of life third quarter of 2021 (CALD) 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-long- Clinical trial(s): Phase 2/3 chain fatty acids in patients’ brains and adrenal cortexes. Starbeam primary completion Cerebral ALD (CALD) is the most severe form and involves April 2021, data reported neurodegeneration, including the breakdown of the protective September 2019; phase 3 myelin sheath of nerve cells in the brain. Symptoms occur in primary completion July 2023 early childhood and progress rapidly, causing severe loss of neurologic function and eventual death. CALD can be treated with bone marrow or stem cell transplants. However, fewer than 30% of patients find matching donors, and allogenic (ie, unrelated donor) transplants can have potentially fatal side effects. 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 174

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

Children aged 2 years or older LentiGlobin (BB305) consists of patient-derived hematopoietic Blood transfusion Frequency of VOCs and FDA designation(s): Orphan and adults aged up to 50 years stem cells transduced with a functional copy of the human Crizanlizumab-tmca hospitalizations Drug, Regenerative Medicine HBB, who have severe sickle cell hemoglobin subunit beta gene, which are then Hematopoietic stem cell Number of blood Advanced Therapy disease (SCD) reintroduced to the patient. In SCD, sickled red blood cells are transplantation (HSCT) transfusions required Clinical trial(s): Phase 3 single- 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 hospitalization. primary completion February glutamine VOC complications can include circulating blood clots, stroke, 2022; interim data reported organ failure, or early death. LentiGlobin has a unique amino Voxelotor June 2019 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 175

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

Adults aged 18 years or older Liposomal cyclosporine A for inhalation (L-CsA-i) is an Immunosuppressants (eg, Disease progression FDA designation(s): Orphan who develop bronchiolitis immunosuppressive treatment intended to reduce the azithromycin, mycophenolate, Lung retransplantation Drug, Fast Track obliterans syndrome (BOS) inflammatory disease burden of BOS, the most common cause tacrolimus) Survival Clinical trial(s): Phase 2/3 after lung transplantation of chronic lung allograft dysfunction after transplantation. No Supportive care (eg, Quality of life completed December 2014 (see treatments are approved for BOS, and no standardized corticosteroids, oxygen) note), data presented March treatment protocols are available. Cyclosporine A is a potent 2019, data presented April immunosuppressive drug for preventing transplant rejection, 2019, data presented May but systemic administration has insufficient penetration into 2019; phase 3 BOSTON-2 the lungs to treat BOS and carries a risk of nephrotoxicity. L- primary completion September CsA-i uses a proprietary inhaled liposomal nanodelivery 2021; phase 3 BOSTON-1 system to administer what researchers believe to be a primary completion December sufficient concentration of cyclosporine A directly to the lung 2021; phase 3 BOSTON-3 parenchyma, mediating immunosuppressive effects. L-CsA-i open-label extension primary purportedly dampens key inflammatory T-cell activity in the completion March 2023 lungs thought to contribute to the chronic inflammation and Note(s): A phase 2/3 trial was irreversible scarring caused by BOS, slowing or preventing terminated early because disease progression. In clinical trials, the drug is inhaled using “interim analysis results the PARI eFlow Nebulizer system at a dosage of 5 mg twice revealed substantial increase of daily for 48 weeks for participants with a single-lung patient number, with unfeasible transplantation or 10 mg twice daily for 48 weeks for study prolongation” participants with a double-lung transplantation. Developer(s): Breath Therapeutics, a Zambon Group company (Menlo Park, California)

Section 5. Rare Diseases 176

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

Infants, children, and adults Lumasiran (ALN-GO1) is an RNA interference (RNAi) Diet management and fluid Change in urinary oxalate Submission date: Rolling New who have primary therapeutic intended to reduce glycolate oxidase (GO) intake excretion from baseline Drug Application completed hyperoxaluria type 1 (PH1) expression in PH1. A rare inherited disorder, PH1 is Organ transplantation (ie, Hospitalizations April 7, 2020 characterized by kidney and bladder stones from the buildup isolated or combined liver and Quality of life for patients FDA designation(s): Orphan of excessive oxalate. Lumasiran is intended to improve health kidney) and caregivers Drug, Breakthrough Therapy outcomes in patients with PH1 by reducing illness from Renal dialysis Clinical trial(s): Phase 3 oxalate crystals accumulating in the kidneys and urinary tract. Shockwave lithotripsy ILLUMINATE-A primary No pharmacologic treatments are available for PH1. Lumasiran completion November 2019, purportedly lowers hepatic levels of GO, which produces the data reported December 2019; substrate necessary for the subsequent production of oxalate. phase 3 ILLUMINATE-B primary Limiting the substrate necessary for oxalate production is completion July 2020; phase 3 intended to limit its buildup. In clinical trials, lumasiran is given ILLUMINATE-C primary subcutaneously by injection at a dosage of 3 mg/kg/month. completion March 2021; phase Developer(s): 1/2 completed January 2019, Alnylam Pharmaceuticals (Cambridge, Massachusetts) data reported February 2019 Note(s): Topline data expected for ILLUMINATE-B in mid-2020

Section 5. Rare Diseases 177

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

Adults aged 18 years or older Luspatercept-aamt (Reblozyl) is a red blood cell (ie, Allogeneic stem cell Blood transfusion Approval date: November 8, who have β-thalassemia that erythrocyte) maturation agent under development to treat β- transplantation (ASCT) dependence 2019 requires 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 need overload Drug, Fast Track for repeat transfusions and the accompanying iron chelation Organ function Clinical trial(s): Phase 3 BELIEVE therapy. β-thalassemia is caused by a rearrangement in the primary completion November HBB. Quality of life hemoglobin subunit beta gene, This prevents normal 2017, data published March erythrocyte maturation, resulting in severe anemia requiring 2020; phase 2 single-arm chronic blood transfusions for survival plus nightly iron completed November 2015, chelation to prevent iron overload. Approved by FDA, data published March 2019 luspatercept-aamt is a first-in-class 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 on 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 178

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 Pediatric genotypically confirmed inherited metabolic disorder caused by a variant in the N- measured by MPS clinical Disease Sanfilippo syndrome type A sulfoglucosamine sulfohydrolase gene, SGSH. Patients with the ratings and scales Clinical trial(s): Phase 2/3 (also called disorder cannot break down the polysaccharide heparan Independence, as AAVance primary completion mucopolysaccharidosis type III sulfate, a process normally mediated by the SGSH-encoded measured by MPS clinical January 2022 A [MPSIIIA]) enzyme heparan-N-sulfamidase. Buildup of heparan sulfate in ratings and scales central nervous system cells causes degeneration that Sleep duration manifests as behavioral problems, sleeplessness, loss of Quality of life speech and cognitive skills, mental retardation, heart problems, seizures, and loss of mobility. No cure exists for Sanfilippo syndrome type A (about 60% of all Sanfilippo syndrome cases), and patients typically do not survive past 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 intracerebrally into both halves of the brain through image-guided tracks, once. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts), in collaboration with Lysogene SA (Paris, France)

Section 5. Rare Diseases 179

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

Children 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 INDIGO with PFIC subtypes PFIC1, PFIC2, PFIC3, and PFIC4. A Quality of life primary completion February progressive disease, PFIC can require surgical intervention or 2020, preliminary data reported liver transplantation and has minimally effective therapy. PFIC April 2019, data presented is characterized by variants in key genes leading to decreased November 2019; phase 3 bile acid flow through the liver. Accumulation of bile acid in MARCH-PFIC primary the liver can lead to jaundice, intense itching, gallstones, completion May 2020; phase 3 abdominal pain, nausea, vomiting, and liver damage, as well as extension primary completion a higher risk for hepatocellular carcinoma. Maralixibat binds to November 2022 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 180

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

Children aged 12 years or Mepolizumab (Nucala) is a monoclonal antibody specific 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 expected 2020 hypereosinophilic syndrome eosinophil activation and inflammatory responses. HES is a cyclophosphamide, Fatigue score from FDA designation(s): Orphan (HES) group of rare inflammatory disorders characterized by the hydroxyurea, vincristine) baseline Drug, Fast Track chronic overproduction of eosinophils. These eosinophils Imatinib Overall survival Clinical trial(s): Phase 3 infiltrate tissues and might damage organs such as the heart Quality of life completed December 2019; and lungs, which can negatively impact quality of life and risk phase 3 completed August of death. Treatment options are limited. Mepolizumab 2019, data reported November purportedly binds to IL-5 and prevents it from binding to the 2019; phase 3 completed IL-5 receptor on the surface of eosinophils, which inhibits September 2010 inflammatory signaling and reduces eosinophil levels in Note(s): FDA approved circulation without completely depleting them from the body. mepolizumab to treat severe In clinical trials, mepolizumab was given as an injection under asthma in November 2015, to the skin of 300 mg every 4 weeks. treat eosinophilic Developer(s): granulomatosis with GlaxoSmithKline plc (Brentford, United Kingdom) 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

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

Section 5. Rare Diseases 181

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 antibody Eculizumab Platelet count change FDA designation(s): Orphan older and adults who have specific for mannan-binding lectin-associated serine protease- Plasma therapy (ie, plasma from baseline Drug, Fast Track primary atypical hemolytic 2 (MASP-2), the effector enzyme of the lectin pathway in the infusion or plasmapheresis) Glomerular filtration rate Clinical trial(s): Phase 3 primary uremic syndrome (aHUS) complement system. An ultra-rare genetic disease, aHUS from baseline completion February 2020 results in chronic uncontrolled complement activation, leading TMA events from to complement-mediated thrombotic microangiopathy (TMA). baseline TMA is characterized by the formation of blood clots in small Disease remission rate 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 182

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

Adults aged 18 years or older Narsoplimab (OMS721) is a fully human monoclonal antibody Corticosteroids Renal function from FDA designation(s): Orphan who have immunoglobulin A that binds mannan-binding lectin-associated serine protease-2 Immunosuppressants (eg, baseline Drug, Breakthrough Therapy (IgA) nephropathy (MASP-2). Narsoplimab is intended to reduce excessive azathioprine, Urine protein excretion Clinical trial(s): Phase 3 primary complement-mediated inflammation and endothelial damage cyclophosphamide, from baseline completion August 2020 characteristic of IgA nephropathy while leaving other immune mycophenolate) system functions intact. IgA nephropathy is a kidney disease Supportive care 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 kidney disease within 10 to 20 years in up to 40% of affected patients. No treatments are approved for IgA nephropathy. The standard of care (ie, high-dose systemic corticosteroids) is controversial because of the increased risks of adverse events and serious infections, high blood pressure, weight gain, diabetes mellitus, and osteoporosis. MASP-2 is a key enzyme for activating the lectin pathway of the body’s complement system in response to tissue damage or microbial infection. Excessive complement activation is a trait of IgA nephropathy. Targeting the lectin pathway is intended to reduce excessive inflammation while leaving other key complement functions intact. In clinical trials, narsoplimab is given as an intravenous infusion at an unspecified loading dose followed by daily under-the-skin injections. Developer(s): Omeros Corp (Seattle, Washington)

Section 5. Rare Diseases 183

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

Adults aged 18 years or older Narsoplimab (OMS721) is a fully human monoclonal antibody Eculizumab (off-label) Inflammation biomarkers Submission date: Rolling who have hematopoietic stem specific for mannan-binding lectin-associated serine protease- Rituximab with from baseline Biologics License Application cell transplantation (HSCT)– 2 (MASP-2), which is being investigated to treat HSCT-TMA. plasmapheresis Red blood cell initiated October 2019 associated thrombotic About 10% to 25% of HSCTs lead to TMA and, in high-risk Supportive care (eg, transfusion requirements FDA designation(s): Orphan microangiopathy (TMA) patients (eg, patients with comorbid graft-versus-host disease antibiotics, antihypertensives, from baseline Drug, Breakthrough Therapy whose TMA has not responded to modified erythropoietin, Platelet requirements Clinical trial(s): Phase 2 primary immunosuppressive therapy), the death rate is more than 90%. thrombopoietin) from baseline completion October 2019, No treatments are FDA approved for HSCT-TMA. TMA is Survival preliminary data reported characterized by the formation of blood clots in small blood December 2019, updated data vessels throughout the body that can progressively damage reported March 2020 organs, including the kidneys, and carries a high risk of serious illness and death. In addition, TMA is characterized by excessive activation of the immune system’s complement system. MASP-2 is a key enzyme in the lectin pathway responsible for activating the complement system in response to tissue damage or microbial infection. By binding and inhibiting MASP-2, narsoplimab purportedly reduces excessive complement-mediated inflammation and endothelial damage characteristic of TMA while leaving other complement system functions intact. In clinical trials, narsoplimab has been given as an intravenous infusion at an unspecified loading dose followed by daily unspecified low, medium, or high doses as under-the-skin injections. Developer(s): Omeros Corp (Seattle, Washington)

Section 5. Rare Diseases 184

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

Adults aged 18 years or older Nintedanib (Ofev) is an oral kinase inhibitor and antifibrotic Azathioprine Breathing function Approval date: September 6, who have systemic sclerosis– drug approved by FDA to treat SSc-ILD. Patients with systemic Cyclophosphamide Disease progression 2019 associated interstitial lung sclerosis, also known as scleroderma, have thickening and Mycophenolate mofetil Survival FDA designation(s): Orphan disease (SSc-ILD) scarring of connective tissue in multiple organs. Most develop Rituximab Quality of life Drug, Fast Track interstitial lung disease (ILD), which is the leading cause of Supportive care Clinical trial(s): Phase 3 SENSCIS death in these patients. No cure exists for SSc-ILD, and before completed November 2018, Ofev’s approval, available treatments only managed symptoms data published May 2019; and did not prevent disease progression. Nintedanib patient subgroup data purportedly binds to and blocks intracellular signaling of the published April 2020; phase 3 following receptor tyrosine kinases (RTKs): platelet-derived open-label extension primary growth factor receptor alpha and beta (PDGFRA and PDGFRB), completion July 2021 fibroblast growth factor receptor 1, 2, and 3 (FGFR1, FGFR2, Note(s): FDA approved FGFR3), and vascular endothelial growth factor receptor 1, 2, nintedanib to treat IPF in and 3 (VEGFR1, VEGFR2, VEGFR3). These RTKs are thought to October 2014 contribute to lung tissue fibrosis in both ILD and a related condition, idiopathic pulmonary fibrosis (IPF). 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 185

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 carry macular ellipsoid zone Clinical trial(s): Phase 3 NTMT- biologics for MacTel type 2, a neurodegenerative disorder that Macular thickness 03-B primary completion March causes gradual central vision loss over a period of 10 to 20 Visual acuity 2022; phase 3 NTMT-03-A years. Therefore, NT-501 might represent a novel treatment Retinal sensitivity primary completion March option for these patients. NT-501 allows controlled release of 2022; phase 2 NTMT-02 Reading speed biologic drugs and is intended to slow retinal degeneration. completed April 2017, data CNTF purportedly diffuses into the retina from the cells published April 2019 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)

Adults aged 18 years or older OCU300 is a proprietary nanoemulsion of brimonidine tartrate Dry eye treatment for Bulbar redness FDA designation(s): Orphan who have ocular graft-versus- eye drop solution intended to treat oGVHD. No FDA-approved symptom management (off- Dry eye symptoms Drug host disease (oGVHD) treatments exist for oGVHD, and patients are sometimes given label) Ocular discomfort Clinical trial(s): Phase 3 primary off-label dry eye treatment to manage symptoms. A Light sensitivity completion July 2020 debilitating immune disorder, oGVHD is a frequent complication of allogeneic bone marrow transplants and Quality of life 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 186

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

Infants and children aged 30 OTL-101 is a bone marrow–derived gene therapy product Bone marrow transplantation Event-free survival FDA designation(s): Orphan days to 17 years who have intended for ADA-SCID, a rare and life-threatening inherited Enzyme replacement Overall survival Drug, Breakthrough Therapy, adenosine deaminase–severe disease of the immune system due to a faulty adenosine Quality of life Rare Pediatric Disease combined immunodeficiency deaminase gene, ADA. This gene is essential for T-cell and B- Clinical trial(s): Phase 2/3 (ADA-SCID) and are ineligible cell (ie, lymphocyte) production. Patients with ADA-SCID primary completion August for 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-101 reported February 2019; phase was designed to restore lymphocyte development and 1/2 primary completion July immunity in patients with ADA-SCID (also known as bubble 2021 boy disease). OTL-101 consists of patient-derived CD34+ stem cells that are harvested from the patient and treated with a lentivirus vector that stably inserts a functional copy of the ADA gene into the cells. The cells are then multiplied in culture to facilitate uptake. In clinical trials, OTL-101 is given as a single intravenous infusion of an unspecified dose. Developer(s): Orchard Therapeutics, Ltd (London, United Kingdom)

Section 5. Rare Diseases 187

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

Children and adults aged up to OTL-103 is a bone marrow–derived gene therapy product Hematopoietic stem cell Frequency of Submission date: Biologics 65 years who have Wiskott- intended for WAS, a rare X chromosome–linked inherited transplantation (HSCT) immunoglobulin or License Application planned for Aldrich syndrome (WAS ) primary immunodeficiency disorder caused by mutations in Immunoglobulin infusion platelet infusions fourth quarter of 2021 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 blood- for infection or bleeding Drug, Regenerative Medicine forming (ie, hematopoietic) cells. WAS deficiency leads to episodes Advanced Therapy eczema, petechiae, thrombocytopenia, reduced blood clotting, Clinical trial(s): Phase 1/2 and susceptibility to infections. A bone marrow transplant TIGET-WAS primary completion from an allogeneic (ie, unmatched) donor can potentially cure October 2018, data published WAS. OTL-103 is intended to relieve WAS symptoms by May 2019; phase 2 primary WAS repopulating the bone marrow with -expressing completion February 2022 hematopoietic stem cells to restore growth, 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 188

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

Children aged up to 7 years OTL-200 is a gene therapy consisting of autologous CD34+ Supportive care (eg, Gross motor function, as Submission date: Biologics who have genetically hematopoietic stem cells transduced in the laboratory with a nutritional therapy; measured by accepted License Application planned for confirmed metachromatic lentiviral vector containing the arylsulfatase A gene, ARSA. It is occupational, physical, and MLD clinical ratings and first half of 2021 leukodystrophy (MLD) intended to treat patients who have MLD, a progressive speech therapy) scales FDA designation(s): Orphan inherited lysosomal storage disorder caused by variants in Neurocognitive function, Drug, Rare Pediatric Disease ARSA. both alleles of The gene normally encodes the enzyme as measured by accepted Clinical trial(s): Phase 1/2 arylsulfatase A, which breaks down sphingolipids. Lack of MLD clinical ratings and primary completion April 2018 arylsulfatase A activity leads to sphingolipid accumulation in scales (fresh cells), data presented the brain, gall bladder, kidneys, liver, and spleen, which in turn Quality of life March 2019, data presented causes myelin loss on nerve fibers of the central nervous September 2019; phase 2 system. Affected patients experience convulsions, motor primary completion August disturbances, paralysis, personality changes, progressive 2022 (cryopreserved cells), data dementia, seizures, spasticity, and visual impairment. No cure presented October 2019; phase exists for MLD, and the disease is fatal; treatment consists of 3 open-label extension primary supportive care to manage symptoms. OTL-200 purportedly completion January 2032 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 189

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

Children older than 14 years of Palovarotene is a selective retinoic acid receptor gamma Supportive care (eg, assistive New HO formation FDA designation(s): Orphan age and adults who have (RARγ) agonist (ie, potentiator) being developed to treat FOP. devices, corticosteroids, Number of body regions Drug, Breakthrough Therapy, fibrodysplasia ossificans A rare connective tissue disorder, FOP leads to the abnormal nonsteroidal anti- with HO Fast Track, Rare Pediatric progressiva (FOP) growth of bone in muscles, tendons, and ligaments, known as inflammatory drugs [NSAIDs], Flare rate Disease heterotopic ossification (HO). Palovarotene treatment might occupational therapy) Range of motion, as Clinical trial(s): Phase 3 MOVE prevent HO in patients with FOP. HO flares can occur measured by accepted primary completion September spontaneously or after physical trauma (eg, injury, infection). clinical ratings and scales 2022; phase 2 completed May Once formed, the heterotopic bone cannot be removed 2016, phase 2 long-term Physical function, as because tissue disruption causes additional HO episodes. HO extension primary completion measured by accepted progressively interferes with normal body functions, including May 2021 clinical ratings and scales walking, bending, breathing, chewing, and swallowing. FOP is Note(s): Palovarotene is under caused by a mutation in the activin A receptor type 1 gene, partial clinical hold in patients ACVR1 , which encodes for the ACVR1/ALK2 receptor. ALK2 younger than 14 years of age 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 palovarotene 10 mg once daily for 8 weeks. Developer(s): Clementia, an Ipsen Company (Montreal, Québec, Canada)

Section 5. Rare Diseases 190

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 deficiency, Nitrogen-scavenging drugs walk test, Functional Drug, Breakthrough Therapy, 1 deficiency a rare, inherited metabolic disorder caused by mutations in the (eg, sodium phenylacetate, Mobility Assessment) Rare Pediatric Disease arginase 1 gene, ARG1. Lack of the ARG1-encoded arginase sodium benzoate) Adaptive behavior (eg, Clinical trial(s): Phase 3 PEACE enzyme, which is part of the cellular urea cycle, leads to Seizure medications (eg, Vineland Adaptive primary completion March excessive nitrogen accumulation in the blood and carbamazepine, Behavior Scale II) 2021, topline data expected in cerebrospinal fluid. Affected patients typically experience phenobarbital) first quarter of 2021; phase 2 seizures, growth impairment, and intellectual disability. primary completion June 2021, According to the manufacturer, pegzilarginase is modified to topline data reported increase enzyme activity and stability compared with native September 2019 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)

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 75 inhibitor. It purportedly prevents most leukocyte subsets from stimulating factor (G-CSF; for Severity of infections Drug years who have a clinical homing in and localizing in the bone marrow, a characteristic infection prevention) Wart control Clinical trial(s): Phase 2/3 diagnosis of WHIM (warts, of WHIM syndrome. A rare primary immunodeficiency, WHIM Imiquimod (to treat warts) Hematologic and primary completion October hypogammaglobulinemia, syndrome is caused by several different mutations in the C-X- Intravenous immunoglobulin immunologic parameters 2020 infections, and myelokathexis) C motif chemokine receptor 4 gene, CXCR4. The mutations (IVIg; for infection prevention) Quality of life Note(s): In December 2008, syndrome with a heterozygous associated with the syndrome cause dysfunction of the FDA approved plerixafor for mutation in the C-tail of the immune system, which increases infection risk and other use in combination with G-CSF CXCR4 gene, documented complications resulting in many types of bacterial infection to mobilize hematopoietic stem neutropenia, and history of that can be mild to severe with serious sequelae. No cure cells (HSCs) to the peripheral severe or recurrent infections exists. Standard treatment involves antibiotic prophylaxis, blood for collection and immune stimulation, and treatment of infections and their subsequent autologous consequences. Plerixafor is intended to reduce infection risk. transplantation in patients with In a clinical trial, it is given by an injection of 0.02 to 0.04 non-Hodgkin lymphoma and mg/kg/day for 6 months. multiple myeloma (MM) Developer(s): Sanofi Genzyme (Cambridge, Massachusetts)

Section 5. Rare Diseases 191

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 a bromocriptine, pramipexole, measured by accepted License Application planned for genetically confirmed, functional copy of the human dopa decarboxylase gene, DDC. ropinirole, rotigotine) clinical ratings and scales second half of 2020 symptomatic aromatic l-amino It is intended to treat patients who have AADCD, a childhood- Monoamine oxidase inhibitors Developmental delays FDA designation(s): Orphan acid decarboxylase deficiency onset, progressive, inherited neurometabolic disorder. AADCD (eg, selegiline, Dyskinesia Drug, Rare Pediatric Disease (AADCD) is caused by a rearrangement in DDC that results in the loss of tranylcypromine) Quality of life Clinical trial(s): Phase 1/2 the gene’s encoded enzyme, aromatic l-amino acid Vitamin B6 primary completion December decarboxylase (AADC). This enzyme is critical for converting 2020, data published December neurotransmitter precursors into dopamine, epinephrine, 2017; phase 2 MIND primary norepinephrine, or serotonin. Patients with AADCD experience completion December 2020; symptoms including severe developmental delays, weak pooled data presented May muscle tone, involuntary movements of the arms and legs, and 2018, pooled data presented seizures. Existing treatments only manage symptoms and do October 2019 (abstracts 207, not prevent disease progression. Delivery of a functional copy 231) 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 192

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 to from baseline primary completion July 2020 promote healing. No cure exists for RDEB, and treatment relies Evidence of collagen 7 on preventing blister formation and managing symptoms. anchoring in tissue 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)

Section 5. Rare Diseases 193

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 rate Clinical trial(s): Phase 3 trial syndrome (aHUS) and evidence terminal complement cascade. An ultra-rare genetic disease, from baseline primary completion November of complement-mediated aHUS results in chronic uncontrolled complement activation, TMA events from 2018, data reported January thrombotic microangiopathy leading to complement-mediated TMA. TMA is characterized baseline 2019; phase 3 primary (TMA) by the formation of blood clots in small blood vessels Disease remission rate completion July 2020 throughout the body that can progressively damage organs, Note(s): Ravulizumab-cwvz was including the kidneys, and carries a high risk of serious illness approved to treat adults with and death. Approved by FDA, ravulizumab-cwvz is intended to paroxysmal nocturnal inhibit C5 activation leading to excessive complement- hemoglobinuria (PNH) in mediated inflammation and endothelial damage characteristic December 2018 of aHUS while leaving other aspects of the 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 194

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

Adults aged 18 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, selective frequency Drug excessive daytime sleepiness cataplexy from narcolepsy, a chronic neurologic sleep serotonin reuptake inhibitors EDS symptoms and Clinical trial(s): Phase 2 (EDS) and cataplexy disorder. Narcolepsy treatments typically address either EDS or [SSRIs], tricyclic severity CONCERT completed cataplexy, whereas reboxetine purportedly addresses both. antidepressants [TCAs]) Wakefulness November 2019, topline data Narcolepsy is caused by impaired production of hypocretin, an Nonamphetamine stimulants Quality of life reported December 2019 excitatory neuropeptide that regulates the sleep-wake cycle. (eg, armodafinil, modafinil) Note(s): More than 40 countries About 60% to 70% of patients with narcolepsy also experience Sodium oxybate outside of the United States cataplexy, a disorder characterized by sudden, uncontrollable Solriamfetol have approved reboxetine to muscle weakness or paralysis that occurs during the daytime treat major depressive disorder and is often triggered by a strong emotion, such as crying, (MDD) excitement, or laughter. Reboxetine purportedly promotes wakefulness and increases the activity of the excitatory neurotransmitter norepinephrine. In clinical trials, patients receive an unspecified dose of reboxetine 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 of Pirfenidone Exercise capacity Drug, Breakthrough Therapy pulmonary fibrosis (IPF) tissue damage and has demonstrated broad antifibrotic Mortality Clinical trial(s): Phase 2 primary activity in preclinical models. Unlike available therapies for IPF Quality of life completion May 2018, data that only slow the rate of disease progression, RG6354 is an published June 2018, data agonist (ie, activator) that purportedly reverses IPF pathology. published May 2019 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 195

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

Adults aged 18 years or older RGN-259 is a sterile and preservative-free eye drop Antibiotic eye drops Visual acuity FDA designation(s): Orphan who have stage 2 or 3 formulation of thymosin beta 4 (Tβ4), a naturally occurring Bandage contact lenses Corneal sensitivity Drug neurotrophic keratopathy in at regenerative peptide. RGN-259 is intended to treat Cenegermin eye drops Quality of life Clinical trial(s): Phase 3 SEER-1 least one eye neurotrophic keratitis (NK), a rare degenerative disease of the Surgery primary completion August corneal epithelium that currently has no effective treatments. 2020 NK is characterized by 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 a day for 4 weeks. Developer(s): RegeneRx Biopharmaceuticals, Inc (Rockville, Maryland), in collaboration with RegenTree, LLC (Princeton, New Jersey)

Section 5. Rare Diseases 196

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, as Drug, Fast Track, Rare Pediatric syndrome (also called is intended to treat Hunter syndrome. This childhood-onset, measured by accepted Disease mucopolysaccharidosis type II progressive, inherited metabolic disorder is caused by a MPSII-specific clinical Clinical trial(s): Phase 1/2 RGX- [MPSII]) mutation in IDS. Patients with the disorder cannot break down ratings and scales 121-101 primary completion the polysaccharides dermatan sulfate and heparan sulfate, the Quality of life December 2020, interim data process of which is normally mediated by the IDS-encoded 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 1.3 × 1010 gc/g of brain mass or 6.5 × 1010 gc/g of brain mass is injected into the cerebrospinal fluid (ie, intracisternally), once. Developer(s): Regenxbio, Inc (Rockville, Maryland)

Section 5. Rare Diseases 197

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 cell structure to a carbohydrate. It is a panselectin inhibitor that acetaminophen, morphine, Frequency of VOCs Drug, Fast Track 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 [NSAIDs]) Rehospitalizations within completed June 2019, designed crisis (VOC) duration of VOC and hospital stays. In SCD, sickled red blood Crizanlizumab-tmca 3 days of discharge under Special Protocol cells are more susceptible to oxidative damage, inappropriate Hydration Assessment, pivotal data adhesion, and vascular obstruction, leading to VOCs that Quality of life Hydroxyurea reported August 2019; phase 3 cause severe pain, requiring hospitalization. VOC extension terminated Voxelotor complications can include circulating blood clots, stroke, November 2019 organ failure, or early death. In clinical trials, rivipansel is given Note(s): The phase 3 RESET trial by intravenous infusion every 12 hours for up to 15 doses. For failed to meet primary and key patients older than 12 years of age and heavier than 40 kg, the secondary end points first dose is 1680 mg and subsequent doses are 840 mg. For patients aged 6 to 12 years or weighing less than 40 kg, the first dose is 40 mg/kg up to 1680 mg and subsequent doses are 20 mg/kg up to 840 mg every 12 hours. Developer(s): GlycoMimetics, Inc (Rockville, Maryland)

Section 5. Rare Diseases 198

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: Rolling primary immune deficiency derived, cell-based therapy intended to restore immune transplantation (HSCT) Survival Biologics License Application from congenital athymia (ie, function in patients with primary immune deficiencies from Supportive care June 2019; Priority Review lack of a thymus), which congenital athymia, which includes complete DiGeorge FDA designation(s): Orphan includes complete DiGeorge genetic anomaly, CHARGE syndrome, and FOXN1 deficiency. Drug, Rare Pediatric Disease, genetic anomaly; coloboma, Patients with congenital athymia have a high risk of death Breakthrough Therapy, heart defects, atresia choanae, (often by 24 months of age) due to chromosomal mutations Regenerative Medicine retarded growth and that disrupt T-cell production. The absence of functional Advanced Therapy development, genital mature T cells or B cells severely compromises immunity. RVT- Clinical trial(s): Phase 2 hypoplasia, and ear 802 is intended to restore the patient’s ability to produce completed April 2009; phase 2 abnormalities and deafness naïve T cells with a broad T-cell receptor repertoire, conferring completed November 2010 (CHARGE) syndrome; and effective immune responses. Isolated thymocytes are cultured Note(s): FDA declined to Forkhead Box N1 (FOXN1) in a manufacturing facility for 14 to 21 days. In clinical trials, approve RVT-802 because of deficiency RVT-802 is given by placing a cultured thymus slice into a manufacturing concerns on small hole in the quadriceps muscle, which is then pulled over December 5, 2019, but on the slice using an insoluble stitch. The dose is 4 to 18 g/m2 of December 27, 2019, the original thymus tissue per patient body weight in kilograms. developer completed a Developer(s): 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 199

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

Adults aged 18 to 75 years Seladelpar (MBX-8025) is an orally administered peroxisome Obeticholic acid Overall survival FDA designation(s): Orphan with a diagnosis of primary proliferator-activated receptor delta (PPARδ) agonist in Rate of progression to Drug, Breakthrough Therapy biliary cholangitis (PBC) who development for treating PBC. An autoimmune disease, PBC liver failure Clinical trial(s): Phase 3 had an inadequate response to damages the liver’s bile ducts, causing bile to accumulate in Symptom relief (eg, ENHANCE suspended ursodeoxycholic acid (UDCA) the liver and leading to irreversible liver scarring and potential diarrhea due to fat November 2019; phase 2/3 treatment or were intolerant to liver failure. Seladelpar is intended to provide a safer malabsorption, fatigue, suspended November 2019; UDCA treatment alternative to obeticholic acid (Ocaliva) for treating PBC in itching) phase 2 suspended November patients for whom initial therapy with UDCA is inadequate or Quality of life 2019, preliminary data who cannot tolerate it. Seladelpar purportedly has presented May 2019 anticholestatic and anti-inflammatory effects that might Note(s): On November 25, reduce itching (ie, pruritus), inflammation, and destruction of 2019, CymaBay Therapeutics the intrahepatic bile ducts. In a phase 3 clinical trial, seladelpar suspended clinical trials for all is taken as a 5- or 10-mg tablet once daily for 52 weeks. indications and halted Developer(s): seladelpar development after CymaBay Therapeutics (Newark, California) identifying abnormal liver findings in some trials. However, the company affirmed in a May 11, 2020, news release its intention to continue development of seladelpar.

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 compound Mobility course Drug, Fast Track, Rare Pediatric congenital amaurosis 10 heterozygous mutations due to aberrant splicing of Full-field light sensitivity Disease (LCA10) centrosome protein 290 (CEP290) messenger RNA (mRNA). Quality of life Clinical trial(s): Phase 2/3 This aberration causes LCA10, the leading genetic cause of ILLUMINATE primary childhood blindness. Sepofarsen is intended to restore vision completion December 2020 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 200

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 Submission date: Rolling New and adults who have receptor agonist (ie, activator) peptide intended to treat diet, exercise) severity Drug Application completed proopiomelanocortin (POMC) patients with POMC deficiency obesity. This is a rare, recessive, Psychotherapy (eg, cognitive Rate of comorbidities March 30, 2020 deficiency genetic obesity genetic disorder in which patients are often severely obese by behavioral therapy [CBT]) (eg, cardiovascular FDA designation(s): Orphan 1 year of age, remain obese for life, and experience a variety of disease, diabetes Drug, Breakthrough Therapy obesity-related complications. Setmelanotide might improve mellitus, obesity) Clinical trial(s): Phase 2/3 patient quality of life and health outcomes by reducing Weight primary completion July 2020, insatiable hunger, obesity, and obesity-related complications. Quality of life topline data reported August POMC deficiency obesity is caused by variants in the 2019, additional data (body POMC, proopiomelanocortin gene, that result in insufficient mass index [BMI] and production of adrenocorticotropic hormone (ACTH), alpha- cardiovascular) reported melanocyte stimulating hormone (α-MSH), and beta- November 2019; phase 2/3 melanocyte stimulating hormone (β-MSH). Normally, α-MSH primary completion May 2021; and β-MSH bind to MC4 receptors in the brain and help phase 2/3 long-term extension suppress appetite. A lack of α-MSH and β-MSH in patients trial primary completion March with POMC deficiency is thought to lead to excessive hunger 2023 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 a companion diagnostic device to determine patient 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 201

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 Pediatric Duchenne muscular dystrophy intended to treat DMD, an inherited, X chromosome–linked Disease (DMD), are on a stable dose of genetic disorder caused by rearrangements or deletions in the Clinical trial(s): Phase 1/2 corticosteroids, and have levels DMD gene. DMD encodes the dystrophin protein, which helps IGNITE DMD primary of anti-AAV9 antibodies below keep muscle cells intact. The absence of wild-type dystrophin completion March 2020 (see a specified threshold protein causes progressive muscle fiber death and eventual note), preliminary data widespread muscle weakness. No cure exists for DMD. First- reported February 2019 and line corticosteroid treatment manages symptoms but does not March 2020 prevent disease progression and has significant side effects. Note(s): FDA placed a clinical FDA approved 2 gene therapies for patients who have a hold on the IGNITE DMD trial in DMD specific mutation in (ie, in exon 51 or exon 53), but November 2019 patients who have other DMD mutations are ineligible for these therapies. Therefore, additional therapies are needed. The synthetic DMD gene in SGT-001 encodes for microdystrophin, a truncated but functional protein surrogate for dystrophin, because the large size of the dystrophin protein prohibits delivery by viral vectors. In patients with DMD, SGT-001 treatment might restore skeletal muscle function and prevent or delay disease progression, independent of the patient’s mutation status. In clinical trials, SGT-001 is given intravenously at one of 3 unspecified doses, once. Developer(s): Solid Biosciences, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 202

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 sarcoglycan Physical therapy test Drug, Rare Pediatric Disease SGCB confirmed, early symptomatic beta gene, . It is intended to treat LGMD2E (also called β- Supportive care Mobility Clinical trial(s): Phase 1/2 limb-girdle muscular dystrophy sarcoglycanopathy), a progressive, inherited neuromuscular Muscle strength IRB17-00253 primary type 2E (LGMD2E) disorder caused by a mutation in SGCB. The gene normally Quality of life completion December 2020, encodes the protein β-sarcoglycan, which is part of a complex interim data reported October involved in muscle function, regulation, and repair. Without β- 2019 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 203

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

Adults aged 18 years or older Tildacerfont (SPR001) is a small-molecule antagonist of the Glucocorticoids (eg, Disease progression FDA designation(s): Orphan who have congenital adrenal corticotropin-releasing factor type 1 (CRF1) receptor. It might dexamethasone, Measures of disease Drug hyperplasia (CAH) due to 21- help improve health outcomes in patients with CAH by hydrocortisone, prednisone) severity (eg, serum levels Clinical trial(s): Phase 2 hydroxylase deficiency reducing symptoms associated with adrenal enlargement and of 17- completed April 2019, data excessive androgen production and reducing chronic hydroxyprogesterone, reported March 2019; phase 2 treatment with high-dose steroids. CAH is a group of genetic androstenedione, and completed September 2019, disorders characterized by abnormal hormone production in ACTH) data reported September 2019 the adrenal gland. Accounting for approximately 95% of cases, Symptom severity CAH due to 21-hydroxylase deficiency occurs when variations Quality of life 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 for 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 204

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

Males aged 18 years or older Timrepigene emparvovec (BIIB111/AAV2-REP1) is an adeno- Low-vision aids (eg, telescopic Best corrected visual FDA designation(s): Orphan who have genetically associated virus serotype 2 (AAV2) vector that delivers a and magnifying lenses) acuity (BCVA) Drug, Regenerative Medicine confirmed choroideremia recombinant human CHM-associated gene. The gene encodes Supportive care Color vision Advanced Therapy (CHM) Rab escort protein 1 (REP1) inside the eye to treat Contrast sensitivity Clinical trial(s): Phase 3 STAR choroideremia, a rare, degenerative, X chromosome–linked Retinal sensitivity primary completion November genetic retinal disorder primarily affecting males, for which no 2020 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 205

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

Adults aged 18 or older who Tofersen (BIIB067) is an antisense oligonucleotide intended to Edaravone Disability Clinical trial(s): Phase 3 VALOR have inherited amyotrophic treat a variation in the SOD1 gene (in SOD1-ALS disease). It Riluzole Disease progression primary completion July 2021; lateral sclerosis (ALS) and a does this by lowering the level of abnormal SOD1 protein that Supportive care Functional capacity phase 3 extension study confirmed variation of the is thought to cause motor neuron death and contribute to ALS primary completion June 2023 Survival superoxide dismutase 1 gene, pathology. ALS is a rare and fatal neurodegenerative disease in SOD1 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 206

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-1) anticonvulsants; assistive severity Drug, Fast Track, Rare Pediatric confirmed Rett syndrome intended to treat Rett syndrome. A rare, postnatal, progressive devices; noninvasive Motor function Disease neurologic disorder, Rett syndrome is caused by a mutation in ventilation; nutritional Quality of life Clinical trial(s): Phase 3 the methyl CpG binding protein 2 gene, MECP2. Located on support; oxygen treatment; LAVENDER primary completion the X chromosome, MECP2 encodes the MeCP2 protein that physical, occupational, and September 2021; phase 3 LILAC normally mediates gene expression in neuronal and glial cells. speech/language therapy) open-label extension primary Loss of MeCP2 function results in nerve cell dysfunction, which completion October 2022; is thought to be reversible. Patients with Rett syndrome phase 2 Rett-001 completed develop normally until 6 to 18 months of age and September 2014, data subsequently experience developmental delays and regression published November 2017; of previously learned motor and verbal skills. The disease phase 2 Rett-002 completed eventually causes additional symptoms, such as repeated hand January 2017, data published movements, impaired gait, slowed head growth, disordered April 2019 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 peptide 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 207

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

Adults aged 18 to 75 years Troriluzole (BHV-4157) is a third-generation, tripeptide- Physical and occupational Ataxia symptom severity, Clinical trial(s): Phase 3 primary who have genetically prodrug conjugate of riluzole being developed to treat certain therapy as measured by accepted completion October 2020; confirmed spinocerebellar autosomal-dominant (ie, inherited) types of SCA. A Supportive care clinical ratings and scales phase 2/3 primary completion ataxia (SCA) type 1, 2, 3, 6, 7, 8, progressive neurodegenerative disease, SCA is generally Use of assistive devices Activities of daily living, August 2017, preliminary post or 10 characterized by loss of balance and motor coordination, as measured by accepted hoc data released March 2019 abnormal speech, vision problems, and cognitive impairment. clinical ratings and scales All autosomal-dominant forms of SCA are caused by repeat Daily functioning expansions in genes normally involved in neuron function, and capacity, as measured by disruption of these genes causes progressive neuronal accepted clinical ratings damage. In patients with SCA or other neurodegenerative and scales disorders, such as amyotrophic lateral sclerosis (ALS), Quality of life 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, hepatotoxicity). 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 208

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

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

Patients aged 5 to 18 years Vosoritide (BMN 111) is a recombinant C-type natriuretic Human growth hormone Health complications Submission date: New Drug who have achondroplasia peptide analogue intended to treat achondroplasia by Limb-lengthening surgery Quality of life Application planned for third 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, but completed October 2017; 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 to October 2019, data reported the overactivity. In clinical trials, vosoritide is given as a daily December 2019; phase 3 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 209

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

Children aged 12 years or Voxelotor (Oxbryta, GBT440) is intended as a disease- Blood transfusions Opioid use for pain Approval date: November 25, older and adults who have modifying agent to treat SCD. Some other recently developed Crizanlizumab-tmca management 2019 sickle cell disease (SCD) drugs may target the root cause of SCD, but they do not work Hematopoietic (blood cell– Frequency of VOCs FDA designation(s): Orphan in all patients and have side effects that many patients cannot generating) stem cell Number of blood Drug, Rare Pediatric Disease, tolerate. In SCD, sickled red blood cells are more susceptible transplantation transfusions required Breakthrough Therapy, Fast to oxidative damage, inappropriate clumping, and vessel Hydroxyurea Hospitalized days Track blockage, leading to vaso-occlusive crises (VOCs) that cause Clinical trial(s): Phase 3 GBT severe pain, requiring hospitalization. Approved by FDA, Pharmaceutical-grade L- Quality of life glutamine HOPE completed October 2019, voxelotor purportedly binds mutated hemoglobin and pivotal data published August prevents it from sickling and aggregating, increasing native 2019, post hoc data reported hemoglobin’s affinity for oxygen. Because oxygenated sickled November 2019; phase 3 hemoglobin does not polymerize, voxelotor purportedly extension primary completion reduces polymerization and the resultant sickling and October 2024 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 disease symptoms. The FDA-approved label states that the drug is intended to treat SCD, based on an increase in hemoglobin. The recommended dosage is 1500 mg (three 500-mg tablets) taken once daily with or without food. Developer(s): Global Blood Therapeutics, Inc (South San Francisco, California)

Section 5. Rare Diseases 210 Table 5.3. Rare Diseases Topics Archived Since Last Status Report: 14 Topics

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

Adults aged 18 years or older ACE-083 is a locally acting, follistatin protein–based therapy Foot surgery Muscle volume In March 2020, Acceleron who have genetically intended for CMT disease types 1 or X. Most patients with Supportive care (eg, Muscle strength Pharma announced confirmed Charcot-Marie- CMT1 overexpress peripheral myelin protein 22 (PMP22) due analgesics, mobility aids, Muscle function (eg, discontinuation of ACE-083 Tooth (CMT) disease type 1 or to an extra copy of the peripheral myelin protein 22 gene, orthotic devices, physical walk/run time, walk development after it failed to PMP22. X Most patients with CMT type X underexpress and occupational therapy) distance) meet its primary end point in connexin-32 protein due to alterations in the gap junction phase 2 clinical trials. Balance and fall risk protein beta 1 gene, GJB1. Disruption of PMP22 or connexin- 32 expression degrades the protective myelin sheath on nerve Quality of life fibers, leading to peripheral nerve dysfunction, eventual nerve conduction loss, and muscle weakness in the hands and lower limbs. No curative or disease-modifying treatments are available for any type of CMT disease, and patients typically receive supportive care to lessen functional disability and neuropathic pain. Therefore, additional therapies are needed. ACE-083 is a recombinant fusion protein consisting of a modified form of human follistatin linked to the human immunoglobulin G2 Fc domain (IgG2 Fc) that purportedly binds to and inhibits specific proteins in the transforming growth factor beta (TGF-beta) protein superfamily that reduce muscle growth, such as activins and myostatin. Thus, ACE-083 is intended to increase muscle mass and strength in the areas where the drug is given. In clinical trials, patients receive up to 250 mg of ACE-083 injected bilaterally into the tibialis anterior (ie, lower leg) muscle once every 3 to 4 weeks up to 24 times. Developer(s): Acceleron Pharma, Inc (Cambridge, Massachusetts)

Section 5. Rare Diseases 211

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

Children aged 6 to 16 years Amifampridine (Ruzurgi), also known as 3,4-diaminopyridine, Acetylcholinesterase Ambulatory function (ie, Stakeholder commenters who have Lambert-Eaton is a potassium channel blocker approved by FDA to treat inhibitors (eg, Triple Timed Up & Go thought that amifampridine’s myasthenic syndrome (LEMS) children who have LEMS, a rare autoimmune neuromuscular pyridostigmine; off-label) [3TUG] test) disruptive potential is low and disorder. About 60% of patients with LEMS also have small cell Immunoglobulins that available data do not lung cancer, but the disorder can occur in patients without Immunosuppressive drugs address patient-oriented cancer. Pediatric onset of LEMS is rare. Patients with LEMS (eg, prednisone) outcomes. In addition, they develop antibodies that attack the body’s own cells and thought that the frequent disrupt normal signaling between nerve cells and muscles. dosing schedule (3-4 times Muscle weakness first develops in the legs and arms and can daily) might be a barrier to progress to the shoulders, feet and hands, and head and medication adherence for throat. Patients may also experience dry mouth and eyes, children. constipation, weight loss, and reduced reflex response. LEMS has no cure, and treatment is intended to relieve symptoms. Ruzurgi purportedly improves muscle function by promoting normal nerve cell-muscle signaling. Its manufacturer formerly made the drug freely available to adults with LEMS through a compassionate use program. In November 2018, FDA approved a competing drug, the phosphate salt of amifampridine (Firdapse), for treating adults with LEMS. Because Firdapse contains the same active ingredient as Ruzurgi, its mechanism of action is likely similar. However, the 2 drugs’ wholesale acquisition costs (WACs) differ significantly: Ruzurgi’s monthly maximum-dose WAC ranges from $12 000 to $24 000 (depending on dosing), while Firdapse’s monthly maximum-dose WAC is about $43 000. According to Ruzurgi’s FDA-approved label, patients take the drug by mouth. Depending on patient weight, patients receive 7.5 to 30 mg initially in 2 to 3 divided doses and gradually increase to a maximum daily maintenance dose of 50 to 100 mg daily in up to 5 divided doses. Developer(s): Jacobus Pharmaceutical Co, Inc (Princeton, New Jersey)

Section 5. Rare Diseases 212

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

Children aged 16 years or Elamipretide is a peptide compound designed to treat PMM Supportive care, especially Exercise tolerance In December 2019, Stealth older and adults aged up to 80 by restoring cellular energy production. No curative or to address cardiovascular, Fatigue Biotherapeutics announced it years who have primary disease-modifying treatments exist for the disease. In PMM, neurologic, or respiratory Quality of life would halt further development mitochondrial myopathy DNA mutations impair the mitochondria’s ability to produce complications of elamipretide for primary (PMM) energy by metabolizing lipids, especially cardiolipin. The mitochondrial myopathy after impaired energy production causes muscle degeneration. the MMPOWER trial failed to Tissues composed of cells with the highest energy meet primary end points. requirements (eg, skeletal muscle, heart, brain) are most affected. Prognosis worsens if disease onset is early and depends on the number of organs 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 (ROS) that can damage cardiolipin. In clinical trials, patients receive elamipretide as under-the-skin (ie, subcutaneous) injections at a dosage of 40 mg (0.5 mL) once daily for up to 168 weeks. Developer(s): Stealth Biotherapeutics, Inc (Newton, Massachusetts)

Section 5. Rare Diseases 213

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

Infants, children, and adults Epidiolex (cannabidiol oral solution) is the first prescription Anticonvulsants (eg, Change in seizure Stakeholder commenters aged 1 to 65 years who have drug approved by FDA that is based on plant-derived levetiracetam) frequency thought that Epidiolex’s inadequately controlled cannabidiols, and it is intended to treat seizures caused by Chemotherapy (eg, Cognitive and mechanism of action is unclear seizures associated with TSC. This intervention purportedly reduces seizure frequency, everolimus) developmental effects and that whether it might work tuberous sclerosis complex which is a significant cause of illness and death in this patient Epilepsy surgery Hospitalizations independently of antiepileptic (TSC) population. TSC is a rare autosomal-dominant genetic drugs is yet to be determined. Vagal nerve stimulation Survival condition that is caused by mutations in either subunit of the They also thought long-term (VNS) TSC complex gene, TSC1 or TSC2. The disease is characterized Quality of life data are needed beyond the by noncancerous tumor growth in many different organs, 16-week treatment period in including the brain, and is the leading cause of genetic clinical trials. Also, Epidiolex is epilepsy and autism in children. Although the exact taken orally, which is not a mechanism of action is unknown, Epidiolex might impart an departure from the current overall anticonvulsant effect by modulating several neuronal paradigm of care. pathways when used in combination with antiepileptic drug treatment. In clinical trials, Epidiolex is given at a low (25 mg/kg/day) or high (50 mg/kg/day) dose; the drug is split into a twice-daily dose taken in an oral solution. Developer(s): GW Pharmaceuticals plc (Wiltshire, United Kingdom)

Section 5. Rare Diseases 214

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

Pregnant females with a In utero percutaneous endoscopic repair is a surgical Fetoscopic repair with Successful repair of spine Stakeholder commenters singleton fetus of gestational procedure to repair myelomeningocele, the most severe form laparotomy and uterine defects agreed that the technique has age 19 to 26 weeks who has a of spina bifida, in a fetus. The procedure uses cameras and externalization Developmental status low disruptive potential diagnosis of specialized instruments inserted through a few small incisions Open surgical repair Survival because it would be limited to myelomeningocele (including in the woman’s womb without surgically opening the a few centers already Quality of life myeloschisis) that occurs at abdomen or uterus. Although this approach is technically experienced in high-risk fetal vertebral level T1 through S1 more difficult than open surgical in utero myelomeningocele surgery. Further, stakeholders with hindbrain herniation repair, it purportedly reduces surgical risks for both mother thought the high rates of and fetus while offering outcomes similar to open surgery. The prematurity and fetal death MOMS trial in 2011 established prenatal surgery for would severely limit adoption. myelomeningocele as superior to postnatal surgical repair for improving quality of life and reducing long-term disability for mother and fetus. However, prenatal surgery increased short- term risks for both fetus and mother. Prenatal open surgery involved a large abdominal incision and opening the uterus (ie, hysterotomy) to access the fetal spine, which increased risk of uterine rupture. Selected centers then developed fetoscopic surgery with uterine externalization in which surgeons partially removed and exposed the uterus (temporarily) to improve surgeons’ access to the fetus. Surgeons inflated the uterus with inert gas, repaired the fetal spine defects with endoscopic tools inserted through several small incisions in the uterus, and replaced the intact uterus back in the woman’s abdomen. With this new percutaneous (ie, through the skin) approach, a few centers now seek to improve on fetoscopic surgery that would have required uterine externalization by testing whether they can safely and effectively perform the spinal repair without large abdominal incisions and without removing the uterus. Developer(s): Joint research collaboration among University of Southern California (Los Angeles, California), Children’s Hospital Los Angeles (Los Angeles, California), Huntingdon Hospital (Pasadena, California), Wellington Regional Medical Center (Wellington, Florida), and USFetus Consortium

Section 5. Rare Diseases 215

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

Children aged 4 years or older Livoletide (AZP-531) is a first-in-class analogue of unacylated Cognitive behavioral Hyperphagia symptoms In April 2020, Millendo and adults aged up to 65 years ghrelin, a naturally occurring hormone intended to treat therapy (CBT) and severity Therapeutics announced who have Prader-Willi hyperphagia (ie, abnormally increased appetite) in patients Diazoxide (off-label) Rate of comorbidities (eg, discontinuation of livoletide syndrome (PWS) with with PWS. Unacylated ghrelin is thought to counteract the Diet and food intake cardiovascular disease, development after the ZEPHYR hyperphagia effects of acylated ghrelin, commonly called the “hunger control diabetes mellitus, obesity) trial failed to show hormone,” which stimulates food-seeking behavior. No improvement in hyperphagia or Exercise Mortality effective treatments are approved for PWS-associated food-related behaviors. Quality of life abnormal eating behaviors. If livoletide effectively treats Glucagon-like peptide 1 abnormal eating in PWS, it might reduce obesity-related (GLP-1) receptor agonist complications and improve quality of life for patients. (eg, exenatide or liraglutide; Livoletide is under development to treat hyperphagia off-label) associated with PWS, a rare genetic disease (about 8000- 11 000 US patients) caused by lack of expression of several genes on chromosome 15. In addition to having intellectual disability and short stature, patients with PWS often die by about 40 years of age, mainly from obesity-related comorbidities, including cardiovascular and respiratory (eg, sleep apnea) complications and type 2 diabetes mellitus (T2DM). In clinical trials, patients receive subcutaneous injections at dosages between about 60 and 120 µg/kg daily. Developer(s): Millendo Therapeutics (Ann Arbor, Michigan)

Section 5. Rare Diseases 216

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

Children aged 2 years or Onasemnogene abeparvovec-xioi (AVXS-101, Zolgensma) is Manual chest physiotherapy Breathing (ie, ventilator) Zolgensma to treat spinal younger who have spinal an adeno-associated viral vector (AAV) approved by FDA for for ineffective cough (eg, support use muscular atrophy was FDA muscle atrophy (SMA) with patients 2 years of age or younger with SMA (type Cough Assist or VitalCough) Nutritional support use approved May 24, 2019. biallelic mutations in the unspecified). Onasemnogene abeparvovec-xioi contains a Noninvasive positive Motor function, as Because it has been clinically SMN1, survival motor neuron 1 gene, functional copy of and delivery of this functional gene pressure ventilation measured by accepted available for more than 1 year, SMN1 copy by the drug might delay or halt SMA disease Nusinersen clinical ratings and scales it is no longer within the time progression. Patients receiving the treatment are likely to have scope for the PCORI Health Muscle strength, as SMA types I or II because onset of these types typically occurs Care Horizon Scanning System. measured by accepted before 2 years of age. SMA is a neuromuscular disorder The time scope is defined as 3 clinical ratings and scales caused by a genetic defect in SMN1. This defect results in loss years before an intervention of the gene’s encoded SMN protein, which is critical for motor Developmental milestone becomes clinically available neuron function and transmission of signals from the brain to achievement outside of the research setting skeletal muscles. Patients with SMA experience motor neuron Death to 1 year after an intervention loss, resulting in progressive muscle weakness and eventual Hospitalization rates becomes clinically available. paralysis. The related gene, survival of motor neuron 2, centromeric, or SMN2, can also produce low levels of SMN protein. SMA disease severity generally correlates with the number of SMN2 copies the patient has (ie, the more copies of SMN2, the less severe the disease). SMA is classified into one of 4 types (ie, I, II, III, or IV), with type I being the most severe and having the earliest onset, at about 0 to 6 months. The FDA-approved label’s recommended dose of Zolgensma is 1.1 × 1014 vg/kg, delivered intravenously via peripheral vein, once. Because patients can experience immune reactions to the viral vector and/or transient changes in liver enzyme function after onasemnogene abeparvovec-xioi treatment, patients also receive systemic corticosteroids equivalent to oral prednisolone at 1 mg/kg of body weight per day, starting 1 day before onasemnogene abeparvovec-xioi is given and continuing for a total of 30 days. After 30 days, clinicians assess patients’ liver function. Patients with normal follow-up results taper the corticosteroid dose over the next 28 days. If liver function abnormalities persist, patients continue systemic corticosteroid treatment until laboratory findings are normal and then taper the corticosteroid dose over the next 28 days. Developer(s): AveXis, Inc (Bannockburn, Illinois), a wholly owned subsidiary of Novartis AG (Basel, Switzerland)

Section 5. Rare Diseases 217

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

Adults aged 18 years or older Pitolisant (Wakix) is a selective histamine 3 (H3) receptor Amphetamines (eg, EDS symptoms and severity Stakeholder commenters who have excessive daytime antagonist/inverse agonist that is intended to treat patients dextroamphetamine, Sleep attack frequency thought that pitolisant is likely sleepiness (EDS) from with EDS from narcolepsy. A rare sleep disorder, EDS from lisdexamfetamine, mixed Functional capacity to be cost-prohibitive and, narcolepsy narcolepsy is characterized by overwhelming daytime amphetamine salts) because is taken orally, it is not Quality of life sleepiness and sudden sleep attacks throughout the day. Methylphenidate a departure from the current Pitolisant has a novel mechanism of action compared with Modafinil paradigm of care. Therefore, its currently approved therapies and is the first treatment for the disruptive potential is low. Solriamfetol disorder that is not scheduled as a controlled substance by the US Drug Enforcement Administration. Pitolisant purportedly works by increasing the synthesis and release of histamine, a wakefulness-promoting neurotransmitter in the brain. The exact mechanism of action is unknown. Pitolisant is taken by mouth at a dosage of 17.8 or 35.6 mg once daily in the morning. The FDA-approved label recommends patients titrate up to 17.8 mg by taking 8.9 mg the first week and increasing to 17.8 mg the second week. The dose may be increased to a maximum recommended dosage of 35.6 mg once daily in the third week if therapeutic effect is not reached. Developer(s): Harmony Biosciences, LLC (Plymouth Meeting, Pennsylvania), with license to develop, manufacture, and commercialize pitolisant in the United States from Bioprojet Pharma (Paris, France)

Section 5. Rare Diseases 218

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

Children aged 16 years or PXT3003 is a proprietary combination of 3 FDA-approved Analgesics Functional mobility Stakeholder commenters older and adults aged up to 67 pharmaceuticals (ie, [RS]-baclofen, naltrexone hydrochloride, Foot surgery Pain agreed that the reported data years who have genetically and D-sorbitol) intended to treat CMT1A. Patients with CMT1A Mobility aids Quality of life for patient outcomes in trials of confirmed Charcot-Marie- overexpress peripheral myelin protein 22 (PMP22) because of PXT3003 was of insufficient Orthotic devices Tooth disease type 1A an extra copy of the peripheral myelin protein 22 gene, magnitude to substantially (CMT1A) PMP22. PMP22 overexpression degrades the protective myelin Physical and occupational improve health outcomes or sheath on nerve fibers, leading to peripheral nerve dysfunction therapy disrupt the care paradigm for and eventual nerve conduction loss. No curative or disease- patients with CMT1A. modifying treatments exist, and patients typically receive supportive care to address functional disability and neuropathic pain. Additional therapies for CMT1A are needed. The 3 drugs in PXT3003 are all involved in modulation of cellular activity in the central nervous system: (RS)-baclofen is a gamma-aminobutyric acid (GABA) receptor agonist (ie, activator) that blocks excitatory neurotransmitter release; naltrexone hydrochloride is an opioid receptor antagonist; and D-sorbitol purportedly is a muscarinic acetylcholine receptor activator that might promote expression of genes involved in myelin production. Thus, PXT3003 might improve myelination, protect nerve and muscle cell function, and prevent disease progression in patients with CMT1A. In clinical trials, patients drink a solution of PXT3003 twice daily with food, for 15 months. Developer(s): Pharnext SA (Paris, France)

Section 5. Rare Diseases 219

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

Children aged 4 years or older Sarizotan is a full serotonin 1A (5-HT1A) receptor agonist (ie, Supportive care (eg, Apnea incidence and In May 2020, Newron Phama and adults who have Rett activator) and a dopamine 2 (D2) receptor-like agonist/partial anticonvulsants; assistive severity announced discontinuation of syndrome and breathing agonist being developed to treat breathing dysfunction (eg, devices; noninvasive Hyperventilation incidence sarizotan development after dysfunction apnea [halted breathing], hyperventilation) in patients with ventilation; nutritional and severity the drug failed to meet primary Rett syndrome. A rare, postnatal, progressive neurologic support; oxygen treatment; Quality of life or secondary end points in the disorder, Rett syndrome is caused by a mutation in the methyl physical, occupational, and phase 2/3 STARS trial. CpG binding protein 2 gene, MECP2. Located on the X speech/language therapy) chromosome, MECP2 encodes the MeCP2 protein that normally mediates gene expression in neuronal and glial cells. Loss of MeCP2 function results in nerve cell dysfunction, which is thought to be reversible. Patients with Rett syndrome typically develop normally until 6 to 18 months of life but then experience developmental delays and regression of previously learned motor and verbal skills. The disease eventually causes additional symptoms, such as repeated hand movements, impaired gait, slowed head growth, breathing dysfunction, and seizures. Symptom severity varies by patient and depends on the individual’s specific MECP2 mutation and the amount of mutant MeCP2 protein expression. In patients with Rett syndrome who are experiencing breathing dysfunction, sarizotan purportedly stimulates serotonin activity in the brain, which is intended to restore breathing rhythm and decrease apnea and hyperventilation incidence or severity. In clinical trials, patients receive sarizotan orally at a dosage of 2 to 10 mg (depending on age and weight) twice daily for 24 weeks. Developer(s): Newron Pharmaceuticals SpA (Milan, Italy)

Section 5. Rare Diseases 220

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

Adults aged 18 years or older Serlopitant (VPD-737) is a small-molecule selective neurokinin- Antihistamines (eg, Anxiety and depression In April 2020, Menlo with itchiness (ie, prurigo) 1 (NK1) receptor antagonist intended to alleviate itching hydroxyzine, symptoms and severity Therapeutics announced associated with prurigo associated with prurigo nodularis. Current therapies often fail diphenhydramine; off-label) Itch frequency and severity discontinuation of serlopitant nodularis with at least 10 to provide adequate symptom relief. Prurigo nodularis is a Immunosuppressants (eg, Sleep quality development after 2 phase 3 nodules on at least 2 different chronic skin disease in which hard lumps (ie, nodules) form on trials (NCT03546816 and methotrexate, cyclosporine; Quality of life body surface areas the skin and cause intense itching that often leads to patients off-label) NCT03677401) failed to meet scratching the areas until they bleed. Scratching can cause Over-the-counter lotions their primary end points of more nodules to appear. The exact cause of the disease is (eg, containing calamine, pruritus (itch) reduction. unknown, although some patients have underlying skin camphor, menthol, or conditions or allergies that are thought to contribute. Prurigo pramoxine hydrochloride) nodularis can be highly disruptive to patients’ daily lives, Phototherapy (ie, negatively impacting patients’ sleep quality, mental health, narrowband ultraviolet B, concentration, and body image/confidence. Serlopitant psoralen plus ultraviolet A; purportedly reduces itching by blocking the NK1 receptor, off-label) which is thought to be a key mediator of sensory nerve signaling, including the itch-scratch reflex and vomiting reflex. Topical capsaicin (off-label) Other NK1 receptor antagonists are currently approved only Topical corticosteroids (eg, for chemotherapy-induced nausea and vomiting. In clinical betamethasone, clobetasol; trials serlopitant is taken by mouth once daily at a dose of 5 off-label) mg. Developer(s): Menlo Therapeutics (Redwood City, California)

Section 5. Rare Diseases 221

Potential patient Intervention description Potential comparators Patient-oriented Archive reason 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 Stakeholder commenters and adults who have leptin receptor agonist (ie, activator) peptide intended to treat diet, exercise) severity agreed that the small evidence receptor (LEPR) deficiency patients with LEPR deficiency obesity. Setmelanotide might Psychotherapy (eg, Rate of comorbidities (eg, base, anticipated high costs for genetic obesity improve patient quality of life and health outcomes by cognitive behavioral cardiovascular disease, yet another obesity drug with reducing insatiable hunger, obesity, and obesity-related therapy [CBT]) diabetes mellitus, obesity) uncertain insurance coverage, complications. LEPR deficiency obesity is a rare, recessive, Weight and the need for daily genetic disorder in which a variation in the leptin receptor injections will likely limit patient Quality of life gene, LEPR, results in inadequate leptin receptors. Leptin acceptance and, therefore, the receptors normally signal a feeling of fullness (ie, satiety) when intervention’s overall disruptive leptin binds to them in the hypothalamus area of the brain. potential. Patients with LEPR deficiency do not receive those signals of satiety, due to a lack of functional leptin receptors, and subsequently experience insatiable hunger that leads to obesity and obesity-related complications. Patients are born of normal weight but often become obese in the first few months of life. It is thought that MC4 receptors function downstream of leptin receptors in controlling satiety. Setmelanotide purportedly activates MC4 receptors in the paraventricular nucleus and lateral hypothalamic nuclei areas in the brain, thereby suppressing appetite. It also purportedly increases resting energy expenditure. Setmelanotide might require a companion diagnostic device to determine patient eligibility. In clinical trials, setmelanotide is administered as an injection underneath the skin once daily at an unspecified dose. Developer(s): Rhythm Pharmaceuticals, Inc (Boston, Massachusetts)

Section 5. Rare Diseases 222

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

Children aged 4 to 6 years who Vamorolone (VBP15) is a dissociative steroid (ie, a steroid Corticosteroids (eg, Muscle function, as Stakeholder commenters have genetically confirmed lacking gene transactivation activity) intended to treat DMD, deflazacort, prednisone) measured by Time to Stand thought that vamorolone is Duchenne muscular dystrophy an inherited, X chromosome–linked genetic disorder caused Test incremental to corticosteroids (DMD) by mutations or deletions in the dystrophin gene, DMD. DMD Ambulatory function, as and has not demonstrated encodes the dystrophin protein, which helps keep muscle cells measured by accepted significant efficacy over intact. The absence of wild-type dystrophin protein causes clinical ratings or scales (eg, corticosteroids to reduce progressive muscle fiber death and eventual widespread time to run/walk/climb, 6- further muscle breakdown, an muscle weakness. No cure exists for DMD, and while FDA minute walk test, North Star important outcome for patients approved 2 dystrophin-replacement gene therapies for Ambulatory Assessment) with DMD. patients who have a specific mutation in DMD (eg, in exon 51 or exon 53), patients with other mutations are ineligible for these therapies. First-line corticosteroid treatment (eg, deflazacort) decreases inflammation but does not prevent disease progression. Corticosteroids typically cause severe side effects, such as hyperglycemia, muscle breakdown, and impaired hormone production. These side effects result from increased gene transactivation that is distinct from corticosteroids’ anti-inflammatory properties. Because dissociative steroids, such as vamorolone, purportedly lack gene transactivation activity while retaining anti-inflammatory function, they might have improved safety profiles versus typical corticosteroids. In clinical trials, patients receive vamorolone orally at 2 or 6 mg/kg/day for up to 48 weeks. Developer(s): ReveraGen BioPharma, Inc (Rockville, Maryland), in collaboration with the National Institutes of Health (Bethesda, Maryland), US Department of Defense (Washington, DC), and European Commission’s Horizon 2020 program (Brussels, Belgium)

Section 5. Rare Diseases 223

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

Males aged 4 to 10 years who Viltolarsen (NS-065/NCNP-01) is a morpholino antisense Corticosteroids (eg, Muscle strength A similar drug (golodirsen) in have Duchenne muscular oligonucleotide intended to treat DMD, an inherited, X deflazacort, prednisone) 6-minute walk test distance the same class has been dystrophy (DMD) with a chromosome–linked genetic disorder caused by mutations or Golodirsen Time to climb 4 stairs approved for this patient deletion in the DMD gene deletions in the dystrophin gene, DMD. DMD encodes the population. Therefore, the Time to run/walk 10 meters involving exon 53 who are on a dystrophin protein, which helps keep muscle cells intact. The subsequent approval of stable dose of corticosteroids absence of wild-type dystrophin protein causes progressive Time to stand viltolarsen for this patient muscle fiber death and eventual widespread muscle weakness. Ambulatory function, as population would no longer be No cure exists for DMD, and first-line corticosteroid treatment measured by accepted considered disruptive. (eg, deflazacort) manages symptoms but does not prevent clinical ratings and scales 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. Therefore, additional therapies are needed. Viltolarsen purportedly binds exon 53 of dystrophin pre-mRNA (ie, precursor messenger RNA composed of introns and exons) and promotes skipping of exon 53 during mRNA processing, which allows for synthesis of an internally truncated but functional dystrophin protein. Therefore, viltolarsen treatment might promote skeletal muscle function and prevent or delay disease progression in patients who have mutations in DMD exon 53. In clinical trials, viltolarsen is given intravenously at a dosage of 40 or 80 mg/kg once weekly for up to 144 weeks. Developer(s): NS Pharma, Inc (Paramus, New Jersey), a subsidiary of Nippon Shinyaku Co, Ltd (Kyoto, Japan), in collaboration with the Cooperative International Neuromuscular Research Group (CINRG; Washington, DC) and TRiNDS (Washington, DC)

Section 5. Rare Diseases 224 Section 6. Potentially Disruptive Trends: 47 Trends

Table 6.1. Trends Added Since Last Status Report: 19 Trends

Title Description Threats Opportunities

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

Section 6. Potentially Disruptive Trends 225

Title Description Threats Opportunities

Artificial intelligence (AI) AI algorithms that analyze cardiovascular imaging scans, electrocardiograms Might create physician resentment Might improve patient outcomes by to predict cardiovascular (ECGs), and other cardiovascular tests have the potential to highlight short-term regarding loss of diagnostic automatically combining multiple events and health health risks and improve predictions of patients’ cardiovascular health outcomes. autonomy data sources into cardiovascular risk outcomes Mayo Clinic researchers have applied AI to ECG analysis to estimate physiologic Might prompt medico-legal concerns assessment age. The PERFORM machine learning model might predict pulmonary embolism for centers that have not adopted AI Might leverage existing patient data risk. AI-augmented computed tomography (CT) angiography assessment of 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 allowing possible HF. One developer offers an AI algorithm for a digital stethoscope that Might create risk of cardiovascular primary providers to detect subtle allows primary care providers to screen patients for cardiac arrhythmias (atrial disease overdiagnosis if patient data arrhythmias and refer to cardiologists fibrillation, murmur). Some researchers have suggested AI analysis of chest CT for collected for other indications (eg, lung cancer screening might detect undiagnosed heart conditions. Abbott has an chest CT scans for lung cancer AI algorithm that purportedly provides individualized heart attack detection and screening) are overanalyzed confirmation in the emergency department. Cleveland Clinic uses AI-augmented patient monitoring in the hopes of identifying impending cardiac events up to 1 hour in advance, based on clinical data.

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

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Bioanalytical services for The typical screening for evaluating central nervous system disorders uses Might increase disparities for some Might be less costly for patients, neurodegenerative positron emission tomography (PET) imaging and lab tests of spinal fluid, which is who do not have access to these caregivers, and health insurers than disorders invasive and expensive. Biomarker analysis using a simple blood test might services current brain imaging scans provide an easier way to assess any neurologic damage to help inform treatment Might lead to overtreatment or Might be less invasive than spinal decisions. C2N Diagnostics (St Louis, Missouri), a diagnostic company, is inappropriate treatment due to fluid tests, which require lumbar measuring concentrations of biomolecules such as neurofilament light protein possible false positives in the analysis punctures using sensitive stable isotope labeling to provide novel insights into the normal 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 to Might address the unmet need of peptide (CGRP) inhibitors episodic migraine headaches and treat acute migraine headaches. They are give themselves under-the-skin patients with migraine headache to to prevent and treat monoclonal antibodies that work by preventing CGRP, a protein found in injections of CGRP inhibitors at home, reduce headache frequency and migraine headache trigeminal nerve ganglia, from binding to CGRP receptors, either by blocking the and there is a risk for infection and severity, thus improving patient receptor or CGRP itself. These actions purportedly block trigeminal nerve pain 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 2018), inhibitors cost about $7000 per year medications, including fremanezumab (approved September 2018), galcanezumab (approved September antidepressants, antiepileptics, and 2018), and eptinezumab (approved February 2020). Others are in clinical antihypertensives, which might development. In addition, CGRPs are in clinical development as a nasal spray for improve patient outcomes, overall the acute treatment of migraine. As monoclonal antibodies, CGRP inhibitors are health, and quality of life highly targeted against CGRP and have demonstrated a more favorable side effect Might improve the understanding of profile than traditional migraine medications, including antiepileptics, migraine pathophysiology and antidepressants, and antihypertensives. A 2018 Institute for Clinical and Economic change the standard of care 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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Title Description Threats Opportunities

Closed-loop glucose Patients with type 1 diabetes mellitus (T1DM) need to continually monitor and Might pose health risks if algorithms Might improve patient quality of life monitoring (artificial adjust their blood glucose levels to avoid extreme high or low levels that can are not precise or can be hacked by allowing more freedom in diet, pancreas) systems for cause serious immediate and/or long-term health problems. Glucose monitoring, destructively physical activity, and sleep type 1 diabetes historically a time-consuming, manual task, is moving toward continuous, Might increase health disparities if the Might improve patient health automated systems. FDA approved the first “artificial pancreas” in 2016. The technology is cost-prohibitive outcomes by minimizing periods of closed-loop system consisted of a sensor underneath the skin and an insulin Might decrease patient knowledge harmful low or high blood glucose pump. In automated mode, the system measured blood glucose every 5 minutes and competency of manual blood that contribute to health to automatically administer or withhold insulin according to its measurements glucose monitoring and insulin dosing complications (insulin lowers blood glucose). Among its limits, it did not accommodate large meals or exercise, which strongly 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. Since that time, patients and researchers have worked to improve continuous glucose monitoring systems. At one point, patients began hacking old insulin pumps to sync them with new smartphone apps that had algorithms for controlling blood glucose. Newer closed-loop glucose monitoring systems now integrate with smartphone apps that contain algorithms for more precise blood glucose control and have additional features, including predictive alerts (ie, impending highs or lows 10 to 60 minutes beforehand). Research is demonstrating that closed-loop systems help patients spend more time in target glycemic ranges, thus lowering risk of health complications. One developer 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.

COVID-19-driven The COVID-19 pandemic caused by severe acute respiratory syndrome Might limit access and increase Might improve patient health telehealth coronavirus 2 (SARS-CoV-2) infection has increased the development and use of disparities for those who are not outcomes telehealth visits. Several companies are heavily promoting existing HIPAA- comfortable with technology and/or Might alleviate the strained health compliant telehealth platforms to provide medical care for patients. Examples do not have a stable broadband care system due to COVID-19 include PlushCare by Fitbit, Teledoc by Aetna, and Aveanna Teletherapy by connection pandemic. Aveanna Healthcare. The Federal Communications Commission (FCC) is also Might lead to overdiagnosis and Might reduce costs of treating funding new telehealth program applications to help patients receive medical prescribing for treating upper critically ill patients care at their homes or mobile locations. respiratory infections Might lead to misdiagnosis due to incomplete information or inability to perform a physical exam Might increase privacy concerns due to destructive hacking

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Disease-modifying The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that Might limit access to therapies due to Might improve patient health agents causes coronavirus disease (COVID-19) has generated substantial interest in the the need for global scale-up to outcomes (immunomodulators) for rapid development of effective treatments to manage severe immune produce sufficient quantity for new Might reduce costs of treating mitigating severe complications from infection. These complications can lead to organ damage, uses for effective treatments critically ill patients COVID-19 symptoms sepsis, and death. Investigators are examining the use of established Might uncover new adverse events by immunomodulatory agents that might hold potential to dampen some patients’ repurposing existing agents for severe immune reactions to SARS-CoV-2 infection, which are linked with poor treating COVID-19 outcomes. Three small-molecule immunomodulators are under investigation. Might incur substantial cost by Thalidomide, an antineoplastic agent investigated for anti-inflammatory, treating patients with expensive antifibrotic, and antiangiogenesis properties, is in a phase 2 trial, with primary therapies for other chronic conditions completion expected May 30, 2020. Fingolimod, a multiple sclerosis therapy, is in a phase 2 trial, with primary completion expected in July 2020. Tetrandrine, a Chinese plant–derived alkaloid and calcium channel blocker that purportedly inhibits mast cell degranulation, has phase 4 data expected in March 2021. Finally, investigators are examining a combination therapy with anti-PD-1 (programmed cell death-1) monoclonal antibodies and thymosin. This therapy might deplete T cells and reduce the risk of sepsis and severe pneumonia in patients with SARS- CoV-2 infection. PD-1 protein is expressed on the surface of T cells and acts as a negative regulator of T-cell function. Preclinical studies suggest that blocking PD- 1 or its ligand programmed cell death ligand-1 (PD-L1) might regulate cytokine production, reduce organ dysfunction, and reduce mortality from sepsis. Thymosin also purportedly regulates cellular immunity in sepsis patients, but the mechanism is unclear. A phase 2 trial for the combination therapy has primary completion expected in April 2020.

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Title Description Threats Opportunities

Emerging antiviral The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that Might limit access to new therapies Might improve patient health therapies for COVID-19 causes coronavirus disease (COVID-19) has generated substantial interest in the due to the need for global scale-up outcomes rapid development of effective therapies for targeting the infection. Investigators for new treatments Might reduce costs of treating are pursuing novel agents and repurposing existing agents. One of 2 novel agents Might uncover new adverse events by critically ill patients is remdesivir (Gilead Sciences), a small-molecule nucleotide polymerase inhibitor, repurposing existing agents for originally developed to treat Ebola and Marburg virus infections. Remdesivir is in treating COVID-19 phase 3 development for treating SARS-CoV-2 infection, with primary data for Might incur substantial cost by severe cases expected in April 2020 and moderate cases in May 2020. The second treating patients with expensive HIV novel therapy, meplazumab, is a humanized anti-CD147 monoclonal antibody therapies that purportedly inhibits the binding of the SARS-CoV-2 Spike protein with CD147

on host cells, preventing binding or cell entry. Meplazumab is in phase 1/2 development, with primary completion expected in December 2020. Various combination regimens that repurpose established antiviral agents for other clinical indications include the viral protease inhibitors lopinavir/ritonavir (HIV treatments), the viral RNA polymerase inhibitor favipiravir (approved in Japan for influenza), the neuraminidase inhibitor oseltamivir (influenza), and the immunomodulator chloroquine, with a phase 3 trial’s primary completion expected in October 2020. Additionally, treatment with the antiviral cytokine therapy IFN-α1β is being evaluated, with a phase 1 trial’s primary completion expected in May 2020.

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

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Human microbiome An increasing body of research has proposed using human microbiome analysis Might cause overdiagnosis of certain Might facilitate new understanding of analysis and as a way to predict disease and death risk. Artificial intelligence and machine conditions certain diseases or conditions manipulation to prevent learning techniques will become increasingly important tools for harnessing that Might cause anxiety in some patients, Might allow earlier intervention or or manage disease information and translating it into clinically meaningful new approaches to 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.

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

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Title Description Threats Opportunities

Novel antimicrobial Investigators are developing polymers, alloys, and coating technologies to give Might cause relaxed sanitation efforts Might reduce health care–acquired environmental surface commonly touched surfaces in health care and public health settings inherently Might cause skin irritations or other infection rates coatings to prevent sustained antimicrobial properties to limit the spread of communicable diseases. adverse events not discovered in Might improve overall population health care–acquired Hong Kong researchers developed a Multilevel Antimicrobial Polymer (MAP-1) completed studies health when implemented in public infections coating that purportedly introduces surface moieties that disrupt microbial Might increase infrastructure costs settings envelopes and surface molecules, rendering pathogens (viruses, bacteria, and without substantial impact on Might reduce costs compared with spores) unviable upon contact (up to 99.9% of highly infectious viruses and more infection rates other infection control measures than 98.7% of drug-resistant bacteria on hospital privacy curtains in 3 weeks). It can be used on metals, plastics, concrete, wood, glass, textiles, and leathers and without affecting surfaces’ look and feel for up to 90 days. The European Cooperation in Science & Technology (COST) 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, 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.

Pet therapy using robotic Pet therapy using robotic pets might provide supportive care to patients with Might increase disparities by limiting Might provide a nondrug treatment pets for patients who agitation and depression due to Alzheimer’s disease or dementia. Pet therapy availability to those who can afford to option for some patients have Alzheimer’s disease using robotic pets might reduce caregiver burden by providing a nondrug therapy pay for these robots Might reduce caregiver burden and or dementia option to promote sensory processing and control negative behavioral symptoms. long-term costs of care 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.

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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 and appropriate patients Might lower costs by reducing therapy are excluded from trials. They may respond differently to guideline-directed Might increase inappropriate demand overuse of more-expensive or riskier medical therapy. FDA has noted available data indicate a potential for cardiovascular genetic testing drugs pharmacogenetic association between genetic mutations and several without patient and/or provider Might improve patient adherence to cardiovascular drugs that might affect drug safety or response. Drugs include education therapy if more-effective drugs are CYP2D6 carvedilol, metoprolol, nebivolol, and propranolol ( gene); simvastatin and selected sooner 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 disease Might have limited coverage because Might improve health outcomes by men at high risk of is rare in this group. Most cases of breast cancer in men are diagnosed only when third-party payers are unlikely to detecting early-stage breast cancer breast cancer the disease is symptomatic. Men with breast cancer caused by inherited gene cover male breast cancer screening Might reduce costs associated with mutations usually have poor prognosis compared with outcomes in similar unless it is proved to be cost effective late-stage cancer treatment by patients with cancer caused by acquired gene mutations. Men with a family Might increase disparities by being enabling earlier curative intervention history of breast cancer might harbor inherited gene mutations that increase their available only to patients who are risk of developing the disease. For these men, screening programs that include insured or able to pay for screening clinical examination, family history, genetic testing, and mammography out of pocket purportedly detect occult early-stage breast cancer and guide patient Might lead to overtreatment of some management to improve health outcomes. early-stage cancers that never develop into life-threatening disease

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, or goal. Other groups are embedding sensors in prosthetic legs that purportedly Might increase treatment costs for 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.

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Stem cell therapy to At least 3 biotechnology companies (Athersys, Inc; ReNeuron Group plc; Might increase disparities due to Might reduce stroke-induced reduce stroke-induced Stemedica Cell Technologies, Inc) are pursuing development of allogeneic (ie, potential high cost and limited disability and improve quality of life disability donor) stem cell products intended to reduce chronic disability that develops availability Might lower need for long-term after stroke caused by a blood clot (ie, ischemic stroke). Phase 2 and phase 3 trials Might increase short-term treatment rehabilitation therapy and nursing are under way. Independent investigators at several international sites are also costs, especially if demand or care investigating autologous (ie, a patient’s own) or allogeneic stem cells derived awareness is high Might reduce long-term treatment from various tissue types (eg, adipose [fat] or nerve cells) to treat or reduce costs despite higher short-term existing stroke-induced disability. Treatment approaches and timelines for therapy costs 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.

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 patient manage chronic choose drug administration via self-injections because it requires less-frequent device errors adherence to treatment regimens conditions dosing than taking oral medications. Wearable drug delivery devices are intended Might increase costs for patients who Might boost patient confidence, to provide a simple, easy-to-use system to improve patients’ compliance to the do not have insurance coverage for driving patients to take greater recommended treatment and improve their quality of life. For example, these devices control of their health SmartDose is a preloaded device that allows larger volume on-body drug delivery Might increase ability to deliver high- less frequently and continuous monitoring that can alert clinicians to make volume and high-viscosity drug changes in treatment regimens. Omnipod is another wearable device that products to improve longer-term provides up to 72 hours of insulin delivery for patients with diabetes. health outcomes 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 234 Table 6.2. Currently Monitored Trends: 15 Trends

Title Description Threats Opportunities

Artificial intelligence (AI) In this application of AI, a software program analyzes magnetic resonance Might lead, due to algorithmic Might help detect cancer at earlier analysis of imaging scans imaging (MRI), computed tomography (CT), or ultrasound scans from patients detection errors, to false-negative or stages, thereby enabling earlier to screen for cancer or suspected of having cancer and generates a probability-of-malignancy score. A false-positive reports that could have treatment and potentially improving confirm a cancer standard risk score that could be used, for example, is the Breast Imaging health and/or legal implications patient health outcomes 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 radiologists’ lead to unnecessary treatment or ability to detect abnormal lumps and nodules and to help determine whether they undue negative psychological impact are dangerous. It does this by scanning all dimension slices at once, homing in on on the patient) regions of interest, and providing a cancer risk score. Might be viewed by some radiologists as a threat to their autonomy as clinicians

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

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 scans dependent on the operator’s ultrasound skills. New AI algorithms have been Might elevate data security risks available to more patients in lower- 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 workload of Might allow earlier detection of heart guidance in probe positioning and image capturing from an experienced cardiologists and demand for follow- conditions that could be effectively sonographer. The first AI-assisted echocardiography operator guidance system, up testing if high volumes of patients managed

Caption Guidance, received FDA De Novo marketing authorization on February 7, are referred from primary care 2020. practices

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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 developed a standardized approach to analyze imaging, clinical data, biomarkers, and treatment outcomes across research sites and will help lead clinical trials of TBI treatments in development by matching candidates to investigational interventions.

Bacteriophages to treat Bacteriophages are viruses that infect only bacterial cells and might help treat Might add significant short-term costs Might lead to decreased patient bacterial infections bacterial infections. They were discovered more than a century ago but were not 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 and resistance and better understanding of bacteriophage biology, researchers are about bacteriophage biology 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 urinary tract infections, gastrointestinal tract infections, diabetic foot ulcers, leg ulcers, wound infections, Pseudomonas aeruginosa infections, and Staphylococcus aureus infections. The Center for Innovative Phase Applications and Therapeutics (IPATH) treats patients who have life-threatening multidrug-resistant infections with bacteriophages on a case-by-case basis through FDA’s Compassionate Use program. IPATH intends to conduct phase 1/2 trials for chronic infections in cystic fibrosis and infections associated with implantable hardware such as pacemakers and prosthetic joints.

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Title Description Threats Opportunities

Comprehensive genomic CGP involves sequencing a large panel (ie, thousands) of cancer-associated genes Might lead to overtreatment of some Might improve health outcomes for profiling (CGP) in in DNA and/or RNA isolated from a patient’s tumor tissue or blood sample. CGP is early-stage cancers that could resolve patients who have limited targeted patients who have cancer intended to detect actionable genomic alterations (AGAs) known to be on their own therapy options to identify personalized therapeutic targets. Clinicians are using CGP (in both germline and somatic Might have limited availability of Might strengthen collaborations targeted therapy testing scenarios) to determine the aggressiveness and inheritable factors of insurance coverage because third- between genetic counselors and 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 might pathway (somatic testing; ie, in cells with cancer) to benefit patients with cancers specific indications and are unlikely to be drug targets that harbor AGAs. CGP also is being used to help identify patients who are eligible cover targeted therapies for for clinical trials of investigational therapies for cancers with specific AGAs. unapproved indications Might increase disparities by being available only to patients who are insured or able to pay for treatment out of pocket

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 data disadvantage for drug developers that Might enable effective and less- companies to facilitate sets that might provide insight into new disease targets worth pursuing by drug choose not to partner with DTC expensive identification of patients drug development and 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 personalized 23andMe has established collaborations with GlaxoSmithKline, and another medicines genetic testing company, Nebula Genomics, is collaborating with EMD Serono to use consumer data to drive the drug development process.

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, human genome. The technology allows researchers to permanently modify genes societal threats (eg, unethical curative treatment option 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

Section 6. Potentially Disruptive Trends 237

Title Description Threats Opportunities

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

Section 6. Potentially Disruptive Trends 238

Title Description Threats Opportunities

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.

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

Section 6. Potentially Disruptive Trends 239

Title Description Threats Opportunities

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

Section 6. Potentially Disruptive Trends 240

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

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 conditions being increasingly harnessed to provide psychiatric assessments and treatment to confidentiality if communications are population health outcomes by patients to help address access-to-care issues. A 2017 report found that 77% of not secure allowing patients quicker, more 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 readily mental health care and by allowing health resources, especially in rural areas. Telehealth aims to help narrow the gap able as during face-to-face visits to patients to pick providers who are by improving patient access to providers and helping patients receive mental collect crucial information such as best suited for them health care faster and more conveniently, because communication takes place vital signs for medical decision Might reduce health care costs by online. Telehealth psychiatry is increasingly being used to treat behavioral health making reducing the amount of time patients conditions including anxiety, depression, attention-deficit/hyperactivity disorder, Might be difficult to treat patients are away from work, reducing money and substance use disorders. with serious health issues like active spent traveling to appointments, and suicidal ideation or alcohol withdrawal reducing overall treatment time from a distance, especially if providers are unfamiliar with local inpatient facilities and mental health resources Might impede a health care provider from establishing patient rapport as readily (compared with in-person visits), and providers might not understand a patient’s geographical and/or psychosocial context as well (compared with in-person visits)

Section 6. Potentially Disruptive Trends 241

Title Description Threats Opportunities

Tissue of origin–agnostic, Oncology drugs have traditionally been approved by FDA for cancers arising from Might increase costs by requiring Might provide a pathway to FDA molecularly targeted specific tissues or organs (eg, breast, prostate, lung, blood). With the increasing more widespread testing of tumors approval in instances of indications oncology drugs recognition that some genetic changes drive the development of cancers arising using whole genome sequencing or that might not be suited for across different organs or tissues, investigators began defining patient very large gene panels upon initial traditional clinical trial designs populations in terms of their molecular subtype. These observations were made in diagnosis of a patient to identify all Might create new collaboration so-called basket trials or umbrella trials—the same clinical trial enrolled patients potential therapeutic targets opportunities for laboratories and with cancers originating in different tissues or organs and researchers observed a Might involve a substantial learning companies that offer whole genome signal of efficacy for a molecular target of a drug across those cancers. This led to curve for providers and exome sequencing expansion of cohorts or creation of tissue of origin–specific trials with the intent Might lead to poor outcomes in that the manufacturer seek FDA drug approval for that tissue of origin (eg, ALK certain patients with a molecular receptor tyrosine kinase [ALK] inhibitors for non–small cell lung cancer [NSCLC], driver and tissue-of-origin b-Raf proto-oncogene serine/threonine kinase [BRAF] inhibitors for melanoma or combination for which the targeted Erdheim Chester disease). However, FDA has recently approved 3 drugs for use in therapy is ineffective molecularly defined patient populations. Examples 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 242 Table 6.3. Trends Archived Since Last Status Report: 13 Trends

Title Description Threats Opportunities

Aging treated as a Drugs considered to have antiaging properties can be prescribed off-label for Might stigmatize large segments of Might promote research into aging- disease aging but are not covered by insurance because aging is not considered a the population based on their age related conditions (eg, Alzheimer’s disease. However, a new research paradigm advocates classifying aging as a Might threaten ethical boundaries disease, cancer, diabetes, heart disease instead of the natural consequence of growing older. Some researchers regarding how blood and stem cell disease, stroke) and lead to hope to shift popular notions of aging toward a disease-based model and products for transfusions from downstream benefits for many promote antiaging therapies as a solution to the problem. Some argue that most younger people are obtained and patients of all ages serious diseases today are a function of aging, and they think that research into used Might lead to downstream increases these mechanisms will uncover effective antiaging therapies that will improve the Might increase disparities because of in overall lifespan of patients by independence, quality of life, and productivity of older people while decreasing the high cost of antiaging therapies encouraging research into antiaging burden to health care and social systems. Antiaging treatments under therapies investigation include metformin, rapamycin, resveratrol, and nicotinamide, as well as blood or stem cell transfusions from young people. Researchers in Singapore are purportedly examining between 10 and 15 antiaging agents.

Artificial intelligence (AI) Recent reports show potential for AI and ML to detect or diagnose mental and Might lead, due to algorithmic Might enable more objective, and machine learning behavioral health conditions, including depression, posttraumatic stress disorder detection errors, to inaccurate biologically grounded diagnoses of (ML) for biologically (PTSD), schizophrenia, and bipolar disorder. Data analysis techniques and ML diagnoses that could have health some mental and behavioral health based diagnosis of algorithms can be used to match specific brain patterns, behavior, and genetic and/or legal implications conditions compared with traditional mental and behavioral factors, allowing for biologically based, individualized prediction and diagnosis of Might be more costly in the short methods of diagnosis health conditions mental and behavioral health disorders. term than traditional methods of Might reduce the stigma associated diagnosis with mental illness by supporting a Might be viewed by some clinicians biological basis for some mental and and therapists as a threat to their behavioral health conditions autonomy Might lead to earlier treatment Might reduce or eliminate the trial- and-error nature of current diagnosis methods Might be more cost effective in the long term than traditional methods of diagnosis

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 243

Title Description Threats Opportunities

Artificial intelligence Traditional analysis of brain tumor samples during neurosurgery requires at least Might be costly to implement Might improve outcomes through (AI)–augmented 30 minutes, increasing risks to patients and raising procedural costs. AI- Might require additional information improved detection and classification pathology to improve augmented pathology combines optical imaging and a deep convolutional technology infrastructure to digitize of tumor samples in real time brain cancer diagnosis network to analyze digitized images of brain tumor samples to detect and classify all pathology specimens Might help alleviate shortage of cancerous cells in the operating room in about 3 minutes. The technique uses a Might increase disparities in improved specialist pathologists fiber-laser microscope to perform stimulated Raman scattering microscopy to care at centers without this Might facilitate personalized cancer allow sample analysis without conventional slicing and staining in a pathology lab. technology care by more complete specimen An AI algorithm automatically classifies the brain tumor subtype, purportedly with analysis 90% accuracy, giving surgeons additional near–real time information about how to proceed. Neuropathologists can review digital images to confirm AI-assisted sample analysis, potentially remotely if not available on site. AI algorithms purportedly can also increase their proficiency by learning from larger sample volumes over time. AI-assisted intraoperative analysis of brain tumors can purportedly be readily expanded to other tumor types.

Artificial intelligence Immersive AI virtual reality (AI-VR) is being developed for use anywhere in health Might pose threats to data privacy if Might provide customizable sessions, (AI)–based virtual reality care, including to improve patient experiences, evaluate treatment options, and hackers gain access to patients’ full- so patients can progress at their own therapy model inform treatment of various conditions, including posttraumatic stress disorder body digital tracking data pace, while providing real-time (PTSD), anxiety, and hot flashes, as well as many other disorders. Several Might increase disparities if insurance analytics for clinicians immersive AI-VR algorithms have been designed to adapt to the patient’s does not cover the cost of the VR Might provide a cost-effective, progress in sessions and to be used every day to improve patients’ physical and treatment nonpharmacological therapy model psychological symptoms related to their specific condition. Might improve patient health outcomes and reduce burden for health care providers

Section 6. Potentially Disruptive Trends 244

Title Description Threats Opportunities

Artificial intelligence This application of AI uses machine learning (ML) and natural language Might not be covered by third-party Might improve patient health (AI)–enabled precision processing (NLP) to analyze electronic pathology (e-path) records, comprising payers for genomic/proteomic outcomes by analyzing large amounts medicine for cancer personal and family history, clinical features, and genetic or protein biomarkers. profiling or the targeted therapies if of clinical, genomic, and proteomic prognosis and treatment The intent is to manage patients’ cancer as follows: (1) predict response to FDA has not approved the AI- data, yielding recommendations that decisions treatment; (2) evaluate whether subsequent treatment might be beneficial; (3) recommended therapies for the can help clinicians more quickly guide targeted therapy selection (on- or off-label) for cancers harboring cancers for which they were identify targeted therapies and/or actionable genomic alterations (AGAs); and/or (4) help enroll patients in clinical recommended biomarkers likely to benefit patients trials of investigational therapies. The AI algorithms would need to be adapted to Might increase disparities if off-label Might reduce human error rates in understand treatment paradigms for different types of cancers. The algorithms therapies are available only to cancer detection and diagnosis would also need to learn to recognize and collect information for different e-path patients who have the resources to Might help identify novel prognostic records, which can have different formats and content. AI’s performance is pay for treatments not covered by markers that can be incorporated into compared with the gold standard of clinicians manually reviewing e-path records. their insurance prognosis assessment Clinicians then use this information to establish a management plan that is most Might cause skepticism among some likely to benefit patients with cancer. physicians about using AI-generated treatment recommendations because of prior failed attempts in AI research to yield appropriate and reliable treatment recommendations

Artificial intelligence (AI) About 50% of people with advanced (stage IV) chronic kidney disease are Might lead some health care Might provide an actionable early systems for early unaware of their level of kidney function impairment. This can lead to rapid professionals to rely too much on an warning to clinicians of imminent detection of acute kidney progression to kidney failure and a need for dialysis in the emergency AI system for patient monitoring and declining kidney function injury (AKI) risk in high- department, involve immediate consultation with a nephrologist, and have use less of their own clinical faculties Might improve disease management risk patients generally poor outcomes. Researchers are developing AI-enabled diagnostics Might contribute to clinicians’ alert and patient outcomes intended to monitor patients at high risk of developing AKI to provide early fatigue from all of the clinical care Might substantially reduce clinical and warning alerts to a clinician about a patient’s deteriorating condition. For tools intended to protect patients and financial burdens to patients and the example, DeepMind AI, in collaboration with the US Department of Veterans alert clinicians about potential harms health care system if these systems Affairs, is developing AI that evaluates data from the electronic medical record can provide early warning of AKI that (EMR) that purportedly predicts AKI in patients up to 48 hours earlier than current enables early intervention and averts diagnostic approaches. They are designing the system to provide clinicians with a kidney damage warning through an app called Streams App. This notification indicates that a patient is a candidate for earlier and more-intensive preventive treatment to avoid more-invasive procedures like dialysis. In addition, KidneyIntelX (RenalytixAI plc) is in development for evaluating the long-term risk of AKI in patients with type 2 diabetes mellitus (T2DM). KidneyIntelX purportedly identifies patients with T2DM and fast-progressing kidney disease by using machine learning (ML) algorithms that assess a combination of predictive blood-based biomarkers in combination with EMR information to identify patients at high risk of kidney disease progression.

Section 6. Potentially Disruptive Trends 245

Title Description Threats Opportunities

Artificial intelligence (AI) Digital voice assistants, or conversational agents, have grown into widely used AI Might lead, due to inaccurate NLP, to Might improve patient access to care voice assistants for software programs designed to respond to natural language processing (NLP) providing patients with incorrect by providing convenient, 24-hour patient-oriented health and simulate human conversation. These assistants are being positioned to medical advice, thereby causing medical advice care applications provide patient health care support (eg, LifePod, Nuance, Aiva Health). AI- subsequent adverse events Might improve patient health powered virtual assistants can provide 24-hour support to a wide range of Might pose threats to patient health outcomes and reduce burden for patients who might need access to home care on demand. For example, LifePod is data privacy health care providers designed to help people follow a care plan developed by their provider or to Might decrease costs of care by contact a caregiver. Another patient voice assistant, Aiva, purportedly reduces the reducing doctor’s office visits response time needed to connect with the caregiving team by triaging patient requests to the most appropriate caregiver.

Cannabidiol to treat Cannabidiol (CBD) is a cannabinoid found in cannabis. Although its exact Might pose health risks to patients Might improve patient health brain-related diseases mechanism of action is unknown, its binding to endocannabinoid receptors in the until more is known regarding its outcomes by providing a new and symptoms brain produces sensations of calmness, relaxation, improved mood, reduced pain, mechanism of action, safety, and treatment class and paradigm and sleepiness. CBD has been registered in more than 200 clinical trials to treat a efficacy Might improve understanding of variety of brain-related diseases and symptoms, including anxiety, depression, brain-related disease pathology substance use, posttraumatic stress disorder (PTSD), pain, spasms, and seizures. FDA approved the first and, so far only, CBD-containing drug in June 2018 to treat seizures associated with 2 rare forms of epilepsy: Dravet syndrome and Lennox- Gastaut syndrome.

Complete omics Complete omics monitoring is being marketed as a comprehensive wellness Might increase costs significantly for Might improve patient management monitoring: package that includes whole genome sequencing, microbiome analyses, participants and also for third-party options metabolomics, metabolome analyses, and proteome analyses. Researchers are exploring this payers that would need to cover Might enable clinicians to more easily proteomics, genomics, widely based monitoring as a way to screen for disease risk, detect diseases treatment of identified diseases and identify patients’ risks or early disease and transcriptomics for earlier, and identify effective treatment options for patients. The approach is conditions in their beneficiaries stages to pursue the best treatment disease prevention and intended to improve early treatment, posttreatment, and progression monitoring Might widen health disparities further options in a shorter time than treatment of diseases such as cancers, neurodegenerative diseases, and metabolic diseases. because those who could afford to standard screening and diagnostic For example, Q Bio’s platform uses a 75-minute patient evaluation visit and pay for it (ie, it is unlikely to be processes quarterly omics examinations to gather all the necessary data. The company covered by insurance) would have Might improve identification of new integrates information gained from anatomic, genetic, biochemical, and biometric health information to inform their drug targets and development of measurements for early health intervention and disease prevention. course of action that individuals who effective personalized medicines in could not afford wellness omics the future testing would not Might lead to overdiagnosis and overtreatment for health issues that could be clinically insignificant or that might resolve on their own; this might negatively impact the mental and behavioral health of participants

Section 6. Potentially Disruptive Trends 246

Title Description Threats Opportunities

Fecal microbiota FMT is the transfer of donor stool into the gastrointestinal (GI) tract of a patient Might pose health risks for patients Might improve patient health transplantation (FMT) to with the aim of repopulating a healthier GI tract microbiome. FMT might change from transmissible agents that could outcomes and quality of life as a treat diseases associated treatment paradigms and improve health outcomes for patients with various GI be contained in the donor stool treatment option for many GI, with disturbances in the diseases and other diseases with GI involvement. FMT can be accomplished Might pose legal risks for donor infectious, autoimmune, mental gut microbiome (ie, gut directly through colonoscopy or indirectly through a nasal tube, oral feeding tube, banks if they can be held liable for health, and other health conditions dysbiosis) enema, or capsule. The stool is sourced from volunteers believed to be healthy, FMT-related adverse events and Might improve understanding of the who undergo a variety of formal medical screening processes before donating. health outcomes microbiome and its association with The stool is tested for various pathogens before being deemed safe for Might significantly shift paradigms of various diseases and conditions transplantation. FDA has not approved FMT for any uses, although the agency care and involve clinician learning Might reduce use of other treatments, allows its investigational use. The agency has issued guidance regarding donor curves and changes in treatment such as antibiotics and biologics, screening and stool-testing protections to avoid serious risks of infection models, infrastructure, and care which could help stem antibiotic transmission. Stool banks such as OpenBiome work with clinicians to make FMT settings, depending on the disease or resistance and avert the risk of serious available and safer for use by screening donor stool, preparing the stool for condition for which it is used side effects posed by those therapies implantation, and freezing the stool until it is ready for use. One of the most Might be costly due to the increasing common uses for FMT is in recurrent Clostridium difficile (C diff) infection. FMT number of tests, processing, and has been found, in randomized controlled clinical trials, to resolve 80% to 90% of storage required to ensure safety, and infections caused by recurrent C diff that did not respond to antibiotics. disparities in patient access to FMT might occur

Immuno-positron Immuno-PET imaging is a noninvasive clinical tool that measures the uptake of Might increase costs associated with Might improve patient outcomes and emission tomography radiolabeled monoclonal antibodies to predict their toxicity in normal tissues and equipment, personnel, and quality of life by helping optimize the (PET) to predict response efficacy in tumors. The most common isotopes for labeling monoclonal radiolabeling selection and dosage of therapeutic to cancer-specific antibodies used in immuno-PET include 89-Zr, 124-I, 64-Cu, and 86-Y. In cancer Might have limited access because monoclonal antibodies therapeutic monoclonal cells, the uptake of a therapeutic monoclonal antibody (eg, atezolizumab, immuno-PET may be unavailable at Might decrease off-target adverse antibodies cetuximab, trastuzumab) is associated with the expression levels of its target most infusion centers events biomarker (eg, programmed cell death ligand-1 [PD-L1], epidermal growth factor Might be a process that takes longer Might determine noninvasively the receptor [EGFR], human epidermal growth factor receptor 2 [HER2]). However, than normal and delays treatment for patient’s biomarker status, which therapeutic monoclonal antibodies also accumulate in normal tissues that express patients could reduce the number of biopsies the biomarker, which may lead to off-target toxicity. Immuno-PET imaging purportedly allows clinicians to measure noninvasively and at a whole-body level the distribution, tumor targeting, and accumulation of radiolabeled monoclonal antibodies in patients. Immuno-PET has the potential to improve patient outcomes by guiding selection and dosage of therapeutic monoclonal antibodies and helping in the design of clinical trials of novel monoclonal antibodies. Compared with immunohistochemistry, which shows a biomarker’s expression in a biopsy at a single time point, immuno-PET also has the potential to assess the biomarker expression status of patients over time and throughout the body.

Section 6. Potentially Disruptive Trends 247

Title Description Threats Opportunities

Smart device Mental health apps are intended to relieve symptoms associated with a variety of Might decrease the likelihood that a Might decrease health care disparities applications to improve mental health conditions. They are available as part of curated app libraries or patient seeks a diagnosis and by providing more patients with mental health because of consumer online searching. The apps offer features including appropriate medical care plan access to mental health resources, symptom tracking, self-monitoring, guided meditation, and talk therapy. Authors Might compromise patient health especially if regional access to of a recent study seeking to evaluate quality claims of mental health apps outcomes if patients rely solely on an psychiatrists and psychologists is searched Android and iOS app stores and found 1435 apps for anxiety, app to self-diagnose limited depression, schizophrenia, self-harm, and substance abuse. Of the apps that met Might lead to breaches in personal Might improve patient outcomes, inclusion criteria of purporting to be based on scientific principles (n = 73), about health information, which has legal augmenting existing treatment plans 67% claimed effectiveness at diagnosing a mental health condition or improving and patient-centered ramifications by providing new and additional symptoms, mood, or self-management; 14% provided a description that their Might be difficult to regulate and support that can be accessed outside development was based on lived experience; and only one app had a citation to might require additional infrastructure of the health care setting published literature. FDA has not subjected any mental health apps to regulatory for that process Might raise awareness of mental pathways to treat mental health conditions. A recent meta-analysis and qualitative health conditions and reduce review suggests that mental health apps might be useful adjunctive treatment for associated stigma depression, noting potential benefits of increased patient access and decreased Might enable patients who are costs. More research is needed to determine the safety and efficacy of mental reluctant to reach out for or attend in- health apps and their appropriate clinical context. person therapy to get help, while preserving some discretion

Wearable smart devices ASD is a developmental disorder defined by deficits in social interaction and Might pose threats to patient health Might provide a nonpharmacological to provide social support communication, including difficulty understanding emotions and regulating data privacy treatment option for some patients for patients who have behavior. Several wearable smart devices intended to improve social deficits in Might increase disparities by being Might incentivize positive behaviors autism spectrum autism, such as a wrist-worn biosensor to predict aggression and glasses available only to those who can afford that will improve health outcomes disorder (ASD) equipped with facial recognition that deliver real-time social cues to improve to pay for these expensive devices Might reduce caregiver burden and socialization, are in development. long-term costs of care Might increase patient independence

Section 6. Potentially Disruptive Trends 248 Appendix. Abbreviations and Acronyms

AADC aromatic l-amino acid decarboxylase AGA actionable genomic alteration AADCD aromatic l-amino acid decarboxylase deficiency AHP acute hepatic porphyria AAT alpha-1 antitrypsin aHUS atypical hemolytic uremic syndrome AAV adeno-associated viral vector AI artificial intelligence AAV ANCA-associated vasculitis AI-VR artificial intelligence virtural reality AAV2 adeno-associated virus serotype 2 AKI acute kidney injury AAV5 adeno-associated virus serotype 5 ALAS1 aminolevulinic acid synthase 1 AAV9 adeno-associated virus serotype 9 ALD adrenoleukodystrophy Aβ amyloid beta ALDP adrenoleukodystrophy protein ABA applied behavior analysis ALK ALK receptor tyrosine kinase ABCD1 ATP binding cassette subfamily D member 1 ALK2 activin receptor-like kinase-2; ACVR1 AC6 adenylyl cyclase type 6 ALS amyotrophic lateral sclerosis ACC American College of Cardiology AMBAR Alzheimer Management by Albumin Replacement ACE angiotensin-converting enzyme AML acute myeloid leukemia AchR acetylcholine receptor α-MSH alpha-melanocyte stimulating hormone ACL ATP citrate lyase AMP adenosine monophosphate ACTH adrenocorticotropic hormone ANCA antineutrophil cytoplasmic antibody ACVR1 activin A receptor type 1 Apo E apolipoprotein E AD Alzheimer’s disease AQP4 aquaporin-4 ADA adenosine deaminase AQP4-IgG aquaporin-4-immunoglobulin G ADA-SCID adenosine deaminase/severe combined ARB angiotensin-receptor blocker immunodeficiency ARG1 arginase 1 ADCY9 adenylate cyclase type 9 ARSA arylsulfatase A Ad5.hAC6 adenovirus 5 encoding human AC6 ASBT apical sodium-dependent bile acid transporter ADHD attention-deficit/hyperactivity disorder ASCT allogeneic stem cell transplantation adRP autosomal-dominant retinitis pigmentosa ASD autism spectrum disorder

APPENDIX. ABBREVIATIONS AND ACRONYMS 249

ASMD acid sphingomyelinase deficiency C1 complement component 1 ASS1 argininosuccinate synthase 1 C1-INH C1 esterase inhibitor ATP adenosine triphosphate C5 complement component 5 ATTR-CM amyloid transthyretin-mediated cardiomyopathy C5a complement 5a anaphylatoxin fragment AUC area under the curve C5b complement 5b anaphylatoxin fragment AUD alcohol use disorder C5b-9 complement 5b complex 9 BCCNS basal cell carcinoma nevus syndrome CAD cold agglutinin disease B cell bursa of Fabricius–maturing cell; B lymphocyte CAH congenital adrenal hyperplasia BCG bacillus Calmette-Guérin CALD cerebral adrenoleukodystrophy BCL-2 B-cell lympohma-2 CAR chimeric antigen receptor

BCL-2 BCL2 apoptosis regulator CB2 cannabinoid receptor 2 BCMA B-cell maturation antigen CBD cannabidiol BCVA best corrected visual acuity CBT cognitive behavioral therapy BED binge eating disorder cc cubic centimeters BI-RADS Breast Imaging Reporting and Data System CCM cardiac contractility modulation BMI body mass index CD3ζ cluster of differentiation 3ζ BMP bone morphogenetic protein CD4 cluster of differentiation 4 BMP2 bone morphogenetic protein 2 CD8+ cluster of differentiation 8–positive β-MSH beta-melanocyte stimulating hormone CD8α cluster of differentiation 8α BNP B-type natriuretic peptide CD19 cluster of differentiation 19 BOS bronchiolitis obliterans syndrome CD20 cluster of differentiation 20 BRAF B-Raf proto-oncogene serine/threonine kinase CD34+ cluster of differentiation 34–positive BRCA breast cancer CD38 cluster of differentiation 38 BRCA1 breast cancer 1 CD38– cluster of differentiation 38–negative BRCA2 breast cancer 2 CD45 cluster of differentiation 45 BTK Bruton tyrosine kinase CD47 cluster of differentiation 47

APPENDIX. ABBREVIATIONS AND ACRONYMS 250

CD137 cluster of differentiation 137 CMT Charcot-Marie-Tooth CD147 cluster of differentiation 147 CMT1 Charcot-Marie-Tooth disease type 1 CD155 poliovirus receptor nectin-like protein 5 CMT1A Charcot-Marie-Tooth disease type 1A CDC cardiosphere-derived cell CNTF ciliary neurotrophic factor C diff Clostridium difficile COL7A1 collagen CDK4/6 cyclin-dependent kinases 4 and 6 COL7A1 collagen type VII alpha 1 chain CED convection-enhanced delivery COST Cooperation in Science and Technology cells/kg cells of biologic agent per kilogram of body weight COVID-19 coronavirus disease of 2019 CEP290 centrosome protein 290 CPIC Clinical Pharmacogenetics Implementation CETP cholesteryl ester transfer protein Consortium CF cystic fibrosis cPMP cyclic pyranopterin monophosphate CFTR cystic fibrosis transmembrane conductance CRC colorectal cancer regulator CRF1 corticotropin-releasing factor type 1 CGG cytosine, guanine, guanine CRISPR clustered regularly interspaced short palindromic cGMP cyclic guanosine monophosphate repeats CGP comprehensive genomic profiling CRL Complete Response Letter CGRP calcitonin gene–related peptide CRT cardiac resynchronization therapy CHARGE coloboma, heart defects, atresia choanae, retarded CSF1 colony-stimulating factor 1 growth and development, genital hypoplasia, and CSF1R colony-stimulating factor 1 receptor ear abnormalities and deafness CT computed tomography CHM choroideremia CTCL cutaneous T-cell lymphoma CIPN chemotherapy-induced peripheral neuropathy CTL cytotoxic T lymphocyte CIS carcinoma in situ CXCL12 CXC chemokine ligand 12 CIT chemotherapy-induced thrombocytopenia CXCR4 CXC chemokine receptor 4 CLD chronic liver disease CXCR4 C-X-C motif chemokine receptor 4 2 cm square centimeters CYP2C19 cytochrome P450 family 2 subfamily C member 19

APPENDIX. ABBREVIATIONS AND ACRONYMS 251

CYP2D6 cytochrome P450 family 2 subfamily D member 6 ECG electrocardiogram CYP21A2 cytochrome P450 family 21 subfamily A member 2 ECOG Eastern Cooperative Oncology Group

D2 dopamine 2 ECT electroconvulsive therapy DAAO D-amino acid oxidase EDS excessive daytime sleepiness DBS deep brain stimulation eGFR estimated glomerular filtration rate DCS D-cycloserine EGFR epidermal growth factor receptor DDC dopa decarboxylase EGJ esophagogastric junction DEB dystrophic epidermolysis bullosa EMDR eye movement desensitization and reprocessing DMD Duchenne muscular dystrophy EMR electronic medical record DMD dystrophin e-path electronic pathology dMMR mismatch repair–deficient EpCAM epithelial cell adhesion molecule DMT N,N-dimethyltryptamine EPP erythropoietic protoporphyria DQ developmental quotient ERK extracellular signal-related kinase DSM-IV Diagnostic and Statistical Manual of Mental eTENS external trigeminal nerve stimulation Disorders, Fourth Edition EZH2 enhancer of zeste 2 homolog 2 DSM-5 Diagnostic and Statistical Manual of Mental EZH2 enhancer of the zeste 2 polycomb repressive Disorders, Fifth Edition complex 2 subunit DTC direct-to-consumer F9 coagulation factor IX E6 early expression 6 F9 factor IX E7 early expression 7 FACIT Functional Assessment of Chronic Illness Therapy EAP Expanded Access Program FAI fludarabine, cytarabine, and idarubicin EBV Epstein-Barr virus FAS FS-7-associated surface antigen EBV+PTLD Epstein-Barr virus–associated posttransplant Fc crystallizable fragment lymphoproliferative disorder FCC Federal Communications Commission EBVSTs Epstein-Barr virus–specific T cells FDA US Food and Drug Administration EC endrometrial carcinoma FGFR fibroblast growth factor receptor

APPENDIX. ABBREVIATIONS AND ACRONYMS 252

FGFR2 fibroblast growth factor receptor 2 GBq gigabecquerel FGFR3 fibroblast growth factor receptor 3 gc/g genome copies per gram of target tissue FGFR4 fibroblast growth factor receptor 4 gc/kg genome copies per kilogram of body weight FIX alias for coagulation factor IX gene, F9 G-CSF granulocyte colony-stimulating factor FLT3 fms-like tyrosine kinase 3 GI gastrointestinal FMR1 fragile X mental retardation 1 GJB1 gap junction protein beta 1 Fmrp Fmr1 protein GLP-1 glucagon-like peptide 1 FMT fecal microbiota transplantation g/m2 grams per square meter of body surface area FOLFIRI leucovorin (folinic acid), 5-fluorouracil, and gMG generalized myasthenia gravis irinotecan GO glycolate oxidase FOLFIRINOX leucovorin (folinic acid), 5-fluorouracil, irinotecan, GPR40 G-protein coupled receptor 40 and oxaliplatin GPR84 G-protein coupled receptor 84 FOLFOX leucovorin (folinic acid), 5-fluorouracil, and GTPase (guanosine triphosphate) superfamily of enzymes oxaliplatin GVHD graft-versus-host disease FOP fibrodysplasia ossificans progressiva H3 histamine 3 FOXN1 Forkhead Box N1 H3 histone FT1050 small-molecule stem cell modulator (made by Fate Therapeutics) hAAT human α1-antitrypsin FT4145 small-molecule stem cell modulator (made by Fate HAE hereditary angioedema

Therapeutics) HbA1c glycated hemoglobin FXR fornesoid X receptor HBB hemoglobin subunit beta FXS fragile X syndrome HCC hepatocellular carcinoma GABA gamma-aminobutyric acid HCHSS PCORI Health Care Horizon Scanning System GABAA gamma-aminobutyric acid receptor A HD Huntington disease GABAergic gamma-aminobutyric acidergic HDAC histone deacetylase GALT galactose-1 phosphate uridyl transferase HER2 human epidermal growth factor receptor 2 GBM glioblastoma multiforme HES hypereosinophilic syndrome

APPENDIX. ABBREVIATIONS AND ACRONYMS 253

HF heart failure IDS iduronate-2-sulfatase HGF hepatocyte growth factor IFN-α1β interferon-alpha 1b HIPAA Heath Insurance Portability and Accountability Act IgA immunoglobulin A HLA-A2 human leukocyte antigen serotype A2 IGF-1 insulinlike growth factor 1 HNSCC head and neck squamous cell carcinoma IGF-1R insulinlike growth factor 1 receptor HO heterotopic ossification IgG1 Fc immunoglobulin G1 Fc domain HPBCT hematopoietic peripheral blood cell transplant IgG2 immunoglobulin G2 HPV human papillomavirus IgG2 Fc immunoglobulin G2 Fc domain HPV-16 human papillomavirus type 16 IgG4 immunoglobulin G4 HPV-18 human papillomavirus type 18 IgM immunoglobulin M HR hormone receptor IGNITE Implementing Genomics in Practice HRR homologous recombination repair IL-1 interleukin-1 HSC hematopoietic stem cell IL-1β interleukin-1β HSCT hematopoietic stem cell transplantation IL-2 interleukin-2 HSCT-TMA hematopoietic stem cell transplantation–associated IL-4R interleukin-4 receptor thrombotic microangiopathy IL-5 interleukin-5 HSIL high-grade squamous intraepithelial lesion IL-5α interleukin-5 α chain HSP heat shock protein IL-15 interleukin-15 HSV-1 herpes simplex virus 1 IL-15α interleukin-15α 5-HT1A 5-hydroxytryptamine 1A; serotonin IL-17 interleukin-17 5-HT2A 5-hydroxytryptamine 2A; serotonin IL-21 interleukin-21 HTT huntingtin IL-23 interleukin-23 ICD implantable cardioverter-defibrillator IL-31 interleukin-31 IDE Investigational Device Exemption ILD interstitial lung disease IDH icocitrate dehydrogenase iPATH Center for Innovative Phase Applications and IDH1 icocitrate dehydrogenase 1 Therapeutics

APPENDIX. ABBREVIATIONS AND ACRONYMS 254

IPF idiopathic pulmonary fibrosis MC4 melanocortin-4 IQ intelligence quotient MCI mild cognitive impairment IRB institutional review board MCL mantle cell lymphoma IU international unit mCRPC metastatic, castration-resistant prostate cancer IU/dL international unit per deciliter MCSF monthly convulsive seizure frequency IVIg intravenous immunoglobulin MDD major depressive disorder JAK Janus kinase MDM2 mouse double minute 2 homolog JAK1 Janus kinase 1 MDMA 3,4-methylenedioxymethamphetamine JAK2 Janus kinase 2 MDS myelodysplastic syndrome KIT KIT proto-oncogene receptor tyrosine kinase MEC mitoxantrone, etoposide, and cytarabine LAG-3 lymphocyte-activator gene-3 MeCP2 methyl CpG binding protein 2 LCA10 Leber congenital amaurosis 10 MECP2 methyl CpG binding protein 2 LDL low-density lipoprotein MEK MAPK kinase kinase LEMS Lambert-Eaton myasthenic syndrome MEK1 MAPK kinase 1 LEPR leptin receptor MEK2 MAPK kinase 2 LGMD2E limb-girdle muscular dystrophy type 2E MET mesenchymal-epithelial transition LHON Leber hereditary optic neuropathy µg/kg microgram per kilogram of body weight LSD lysergic acid diethylamide mg/m2 milligram per square meter of body surface area 177Lu lutetium-177 mg/mL milligram per milliliters of solution LVAD left ventricular assist device MGMT O6-methylguanine-DNA-methyltransferase MACE major adverse cardiovascular events MHC-II major histocompatibility complex molecule class II MacTel macular telangiectasia ML machine learning MAOI monoamine oxidase inhibitor μL microliter MAPK mitogen-activated protein kinase MLD metachromatic leukodystrophy MASP-2 mannan-binding lectin-associated serine protease-2 MM multiple myeloma MC1-R melanocortin 1 receptor MMC mitomycin-C

APPENDIX. ABBREVIATIONS AND ACRONYMS 255

mm Hg millimeters of mercury NK neurotrophic keratitis

µmol/kg micromole per kilogram of body weight NK1 neurokinin-1 MoCD molybdenum cofactor deficiency NLP natural language processing MoCo molybdenum cofactor NMDA N-methyl-D-aspartate MOCS1 molybdenum cofactor synthesis 1 NMIBC non–muscle invasive bladder cancer MPS mucopolysaccharidosis NMOSD neuromyelitis optica spectrum disorder MPSII mucopolysaccharidosis type II; Hunter syndrome nNOS neuronal nitric oxide synthase MPSIIIA mucopolysaccharidosis type III A; Sanfilippo NPC nasopharyngeal carcinoma syndrome type A NPC Niemann-Pick disease type C MPSIIIB mucopolysaccharidosis type III B; Sanfilippo NPC1 NPC intracellular cholesterol transporter 1 syndrome type B NPC-1 Niemann-Pick disease type C1 MRI magnetic resonance imaging NPC2 NPC intracellular cholesterol transporter mRNA messenger RNA NPD A/B Niemann-Pick disease type A/B MSI microsatellite instability NPD-B Niemann-Pick disease type B MSI-H microsatellite instability–high NSAID nonsteroidal anti-inflammatory drug mTOR mammalian target of rapamycin NSCLC non–small cell lung cancer mUC metastatic urothelial cancer NTproBNP N-terminal pro B-type natriuretic peptide NADH nicotinamide adenine dinucleotide NTRK neurotrophic tyrosine receptor kinase NAGLU N-acetyl-alpha-D-glucosaminidase NY-ESO-1 New York esophageal squamous cell carcinoma-1 NAM nicotinamide NYHA New York Heart Association ND4 NADH dehydrogenase 4 OCT optical coherence tomography NDA New Drug Application oGVHD ocular graft-versus-host disease NF1 neurofibromatosis type 1 OM oral mucositis NF-kB nuclear factor kappa-light-chain-enhancer of p53 tumor protein 53 activated B cells p62 tumor protein 62; sequestosome-1 NK natural killer PAH pulmonary arterial hypertension

APPENDIX. ABBREVIATIONS AND ACRONYMS 256

PARP poly adenosine diphosphate-ribose polymerase PGRMC1 progesterone receptor member component 1 PARP1/2 poly adenosine piphosphate-ribose polymerases I PH1 primary hyperoxaluria type 1 and II PHI protected health information PBC primary biliary cholangitis PI3K phosphoinositide 3 kinase PCORI Patient-Centered Outcomes Research Institute PICO patient population, intervention, comparators, PCSK9 proprotein convertase subtilisin kexin type 9 outcomes PD-1 programmed cell death-1 PKD pyruvate kinase deficiency PDE4 phosphodiesterase type 4 PKLR pyruvate kinase L/R PDE9 phosphodiesterase type 9 PLK1 polo-like kinase 1 PDGFR platelet-derived growth factor receptor PMM primary mitochondrial myopathy PDGFRA platelet-derived growth factor receptor alpha PMO phosphorodiamidate morpholino oligomer PDGFRB platelet-derived growth factor receptor beta PMP22 peripheral myelin protein 22 PD-L1 programmed cell death ligand-1 PN plexiform neurofibroma PDUFA Prescription Drug User Fee Act PNH paroxysmal nocturnal hemoglobinuria PE Pseudomonas aeruginosa exotoxin A Pol polymerase PEComa perivascular epithelioid cell tumor Pol I polymerase I PEDI Pediatric Evaluation of Disability Inventory Pol II polymerase II PET positron emission tomography POMC proopiomelanocortin PET prolonged exposure therapy PPAR peroxisome proliferator-activated receptor PF pemphigus foliaceus PPARα peroxisome proliferator-activated receptor alpha PFIC progressive familial intrahepatic cholestasis PPARδ peroxisome proliferator-activated receptor delta PFIC1 progressive familial intrahepatic cholestasis type 1 PROMIS Patient-Reported Outcomes Measurement PFIC2 progressive familial intrahepatic cholestasis type 2 Information System PFIC3 progressive familial intrahepatic cholestasis type 3 PSC primary sclerosing cholangitis PFIC4 progressive familial intrahepatic cholestasis type 4 PSD-95 postsynaptic density-95 P-gp P-glycoprotein PSMA prostate-specific membrane antigen

APPENDIX. ABBREVIATIONS AND ACRONYMS 257

PTC1 phosphatase type 2 C rTMS repetitive transcranial magnetic stimulation PTCH1 patched 1 SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 PTSD posttraumatic stress disorder SBRT stereotactic body radiotherapy PUL Performance of Upper Limb SCA spinocerebellar ataxia PV pemphigus vulgaris SCD sickle cell disease PWS Prader-Willi syndrome SCLC small cell lung cancer QT ventricular depolarization interval from the start of SCN1A sodium voltage-gated channel alpha subunit 1 the Q wave to the end of the T wave SDNRI serotonin, dopamine, and norepinephrine reuptake Rab ras genes from rat brains inhibitor RARγ retinoic acid receptor gamma SERPINA1 serpin family A member 1 ras rat sarcoma SGCB sarcoglycan beta rC7 recombinant collagen type VII SGSH N-sulfoglucosamine sulfohydrolase RDEB recessive dystrophic epidermolysis bullosa sIBM sporadic inclusion body myositis REP1 Rab escort protein 1 SIRPα signal regulatory protein-α RET rearranged during transfection SLAMF7 signaling lymphocytic activation molecule family RHO rhodopsin member 7 RNAi RNA interference SLCO1B1 solute carrier organic anion transporter family member 1B1 ROCK2 rho-associated coiled-coil kinase 2 SMA spinal muscle atrophy ROS reactive oxygen species Smad Sma/mothers against decapentaplegic homolog ROS1 ROS proto-oncogene 1 receptor tyrosine kinase Smad1 Sma/mothers against decapentaplegic homolog 1 RP retinitis pigmentosa Smad5 Sma/mothers against decapentaplegic homolog 5 RPGR retinitis pigmentosa GTPase regulator Smad8 Sma/mothers against decapentaplegic homolog 8 RPGR-ORF 15 retinitis pigmentosa GTPase regulator-open reading frame 15 SMN survival of motor neuron RRMM relapsed and refractory multiple myeloma SMN1 survival of motor neuron 1 RTK receptor tyrosine kinase SMN2 survival of motor neuron 2, centromeric

APPENDIX. ABBREVIATIONS AND ACRONYMS 258

Smo Smoothened TMS transcranial magnetic stimulation SN-38 7-ethyl-10-hydroxycamptothecin TNBC triple-negative breast cancer SNRI serotonin and norepinephrine reuptake inhibitor TNF tumor necrosis factor SOD1 superoxide dismutase 1 TP53 tumor protein p53 SSc-ILD systemic sclerosis–associated interstitial lung disease TPO thrombopoietin SSRI selective serotonin reuptake inhibitor TRACK-TBI Transforming Research and Clinical Knowledge in STAT-3 signal transducer and activator of transcription 3 Traumatic Brain Injury STEMI ST-segment elevation myocardial infarction Trop-2 trophoblast cell-surface antigen 2 STRO antistromal precursor antigenTAAR1 trace TSC tuberous sclerosis complex amine-associated receptor 1 TSC1 TSC complex subunit 1 TAZ tafazzin TSC2 TSC complex subunit 2 Tβ4 thymosin beta 4 TTF tumor-treating field TBI traumatic brain injury 3TUG Triple Timed Up & Go TCA tricyclic antidepressant TURBT transurethral resection of bladder tumor T cell thymus-originating cell; T lymphocyte UBE3A ubiquitin protein ligase E3a T1DM type 1 diabetes mellitus UDCA ursodeoxycholic acid T2DM type 2 diabetes mellitus US United States TED thyroid eye disease UVR ultraviolet radiation t(11,14) translocation between chromosomes 11 and 14 V1A vasopressin 1a TGCT tenosynovial giant cell tumor VA US Department of Veterans Affairs TGF-beta transforming growth factor beta VEGF vascular endothelial growth factor Th17 T helper 17 VEGFR vascular endothelial growth factor receptor TIL tumor-infiltrating lymphocyte VEGFR1 vascular endothelial growth factor receptor 1 TK2 thymidine kinase 2 VEGFR2 vascular endothelial growth factor receptor 2 TK2d thymidine kinase 2 deficiency VEGFR3 vascular endothelial growth factor receptor 3 TMA thrombotic microangiopathy vg viral genomes

APPENDIX. ABBREVIATIONS AND ACRONYMS 259

vg/kg viral genomes per kiligram of body weight VKORC1 vitamin K epoxide reductase complex subunit 1 VNS vagal nerve stimulation VOC vaso-occlusive crisis VR virtual reality VT ventricular tachycardia WAC wholesale acquisition cost 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 XLRP X-linked retinitis pigmentosa

APPENDIX. ABBREVIATIONS AND ACRONYMS 260