- PCORI Health Care Horizon Scanning System Volume 2 Issue 2

High Potential Disruption Report November 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 5200 Butler Pike Plymouth Meeting, PA 19462

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

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

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

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

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

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

All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of PCORI or its Board of Governors. This publication was developed through a contract to support PCORI’s work. Questions or comments may be sent to PCORI at [email protected] or by mail to 1828 L St, NW, Suite 900, Washington, DC 20036. ©2020 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org.

Suggested citation: Hulshizer R, Lynch M, De Lurio J, et al. PCORI Health Care Horizon Scanning System High Potential Disruption Report Volume 2 Issue 2. Patient-Centered Outcomes Research Institute; November 2020. Prepared by ECRI under Contract No. MSA-HORIZSCAN- ECRI-ENG-2018.7.12.

HIGH POTENTIAL DISRUPTION REPORT • November 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 the outset of this project—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 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 High Potential Disruption Report is the second of 2 editions planned for 2020 and includes topics (ie, interventions intended for a specific use within a specific patient population) and trends (ie, high-level disruptions occurring within or across clinical areas from a combination of factors that, taken together, create a paradigm shift) that have been identified by stakeholders and the horizon scanning team as having high potential to cause disruption to health care. 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].

HIGH POTENTIAL DISRUPTION REPORT • November 2020 ii

Contents

Introduction ...... 1 Background ...... 1 System Overview...... 1 Broad Scanning to Identify Topics and Trends ...... 1 Developing Topic and Trend Profiles ...... 2 Archiving Topics and Trends ...... 2 Report Methods ...... 2 Selecting Topics and Trends for the High Potential Disruption Report ...... 3 High Potential Disruption Report Topic Selection Meeting ...... 3 Producing the High Potential Disruption Report ...... 3 Reporting Period Summary ...... 4

Chapter 1. Alzheimer’s Disease and Other Dementias ...... 10 Chapter Summary ...... 10 Topic Summaries ...... 10 Aducanumab (BIIB037) to Treat Early Alzheimer’s Disease ...... 10 Periodic Therapeutic Plasma Exchange (Alzheimer’s Management by Albumin Replacement Protocol) to Treat Mild to Moderate Alzheimer’s Disease ...... 14

Chapter 2. Cancer ...... 17 Chapter Summary ...... 17 Topic Summaries ...... 19 Atezolizumab (Tecentriq) Plus Bevacizumab (Avastin) as First-Line Treatment for Locally Advanced or Metastatic Hepatocellular Carcinoma ...... 19 Axicabtagene Ciloleucel (Yescarta) to Treat Indolent B-Cell Non-Hodgkin Lymphomas 23 Capmatinib (Tabrecta) to Treat Metastatic, MET-Altered Non–Small Cell Lung Cancer .. 27 Idecabtagene Vicleucel to Treat Relapsed and Refractory Multiple Myeloma ...... 31 Lifileucel (LN-144) as Second-Line Treatment for Locally Advanced or Metastatic Melanoma ...... 35 MDNA55 to Treat First Recurrence of Recurrent Glioblastoma Multiforme ...... 39 Nanoparticle Albumin-Bound Sirolimus (ABI-009) to Treat Locally Advanced or Metastatic Perivascular Epithelioid Cell Sarcoma ...... 41

HIGH POTENTIAL DISRUPTION REPORT • November 2020 iii

Omidubicel to Treat Hematologic Malignancies Eligible for Hematopoietic Stem Cell Transplantation ...... 45 Onureg to Treat Acute Myeloid Leukemia (Maintenance Setting) ...... 48 Oraxol to Treat Locally Advanced or Metastatic Breast Cancer ...... 52 Pemigatinib (Pemazyre) to Treat Locally Advanced or Metastatic Cholangiocarcinoma Harboring Fibroblast Growth Factor Receptor-2 Fusions or Rearrangements ...... 55 Selumetinib (Koselugo) to Treat Symptomatic, Inoperable Plexiform Neurofibromatosis Type 1 ...... 59 Tazemetostat (Tazverik) to Treat Locally Advanced or Metastatic Epithelioid Sarcoma 62 Tazemetostat (Tazverik) to Treat Relapsed or Refractory Follicular Lymphoma ...... 67

Chapter 3. Cardiovascular Diseases ...... 72 Chapter Summary ...... 72 Topic Summary ...... 73 Organ Care System Heart to Treat End-Stage Heart Failure Requiring Transplantation 73

Chapter 4. Mental and Behavioral Health Conditions ...... 78 Chapter Summary ...... 78 Topic Summaries ...... 79 3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy to Treat Severe Posttraumatic Stress Disorder ...... 79 SEP-363856 to Treat Schizophrenia ...... 83

Chapter 5. Rare Diseases...... 87 Chapter Summary ...... 87 Topic Summaries ...... 88 ABO-102 to Treat Sanfilippo Syndrome Type A ...... 88 Arimoclomol (BRX-345) to Treat Niemann-Pick Disease Type C ...... 92 Betibeglogene Autotemcel to Treat Transfusion-Dependent β-Thalassemia ...... 96 CAP-1002 to Treat Duchenne Muscular Dystrophy ...... 102 Casimersen (Amondys 45) to Treat Duchenne Muscular Dystrophy ...... 106 Fenfluramine Hydrochloride Low-Dose (Fintepla) to Treat Dravet Syndrome ...... 110 Fosdenopterin (BBP-879, ORGN001) to Treat Molybdenum Cofactor Deficiency Type A ...... 115 Golodirsen (Vyondys 53) to Treat Duchenne Muscular Dystrophy ...... 117

HIGH POTENTIAL DISRUPTION REPORT • November 2020 iv

Mepolizumab (Nucala) to Treat Hypereosinophilic Syndrome ...... 122 MT1621 to Treat Thymidine Kinase 2 Deficiency ...... 125 Olipudase Alfa (GZ402665) to Treat Acid Sphingomyelinase Deficiency ...... 128 Palovarotene to Treat Fibrodysplasia Ossificans Progressiva ...... 133 PTC-AADC to Treat Aromatic l-Amino Acid Decarboxylase Deficiency ...... 137 RVT-802 to Treat Pediatric Congenital Athymia (DiGeorge Syndrome Immunodeficiency, CHARGE Syndrome, FOXN1 Deficiency) ...... 142 Setmelanotide (RM-493) to Treat Proopiomelanocortin Deficiency Obesity ...... 144 Teprotumumab-trbw (Tepezza) to Treat Thyroid Eye Disease ...... 148 Voxelotor (Oxbryta) to Treat Sickle Cell Disease ...... 151

Chapter 6. Potentially Disruptive Trends ...... 156 Chapter Summary ...... 156 Trend Summaries ...... 156 Artificial Intelligence to Predict Antidepressant Treatment Response ...... 157 Comprehensive Genomic Profiling in Patients Who Have Cancer to Identify Personalized Targeted Therapy ...... 158 Direct-to-Consumer Genetic Testing Collaborations With Pharmaceutical Companies to Facilitate Drug Development and Treatment ...... 160 Identifying Drug Synergies With Artificial Intelligence to Optimize Regimens ...... 162 Proteomic Profiling to Diagnose Cancer and Guide Personalized Targeted Therapy .. 163 Psychedelic Drugs to Treat Mental Health Conditions ...... 165 Smartphone-Guided Medical Examinations and Diagnostics for Use by Patients and Caregivers ...... 167 Telehealth to Treat Mental Health Conditions ...... 168

References ...... 171

HIGH POTENTIAL DISRUPTION REPORT • November 2020 v

Introduction

Background Horizon scanning identifies technology and systems innovations that could disrupt or cause significant shifts in health care. In health care, horizon scanning can identify new (and new uses of existing) diagnostic tests and procedures, health care delivery innovations, medical devices, mental and behavioral health interventions, pharmaceuticals, public health and health promotion activities, rehabilitation interventions, and therapeutic interventions. Health care horizon scanning has typically informed strategic planning activities. Public and private entities around the world have long used formal or informal health care horizon scanning programs for purposes including commercial planning; health services research prioritization; financial or operational planning; controlled diffusion of technologies; and provision of information to policymakers, purchasers, and health care providers.

System Overview 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 and likely to cause significant disruption (ie, change or shift) in one or more key dimensions of health care in the United States. Examples of these dimensions include patient health outcomes, access to care, care settings and delivery processes, disparities, and costs of care. The HCHSS monitors topics for up to 1 year after initial clinical availability. PCORI currently defines its project scope as interventions with high potential for disruption in 5 priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health conditions, and rare diseases. In addition, the system captures high-level disruptive trends across all clinical areas, which may lead PCORI to expand the project scope to include other priority areas in the future.

Broad Scanning to Identify Topics and Trends We scan information sources broadly within each priority area to detect leads for potential topics that meet criteria as described above. Analysts review leads to discover potential topics or trends and, if they meet inclusion criteria, create topic records—encompassing 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)—or trend records, which 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 PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. All included topics and trends are reported in the quarterly Status Report (see the most recent volume, Horizon Scanning Status Report, Volume 2, Issue 3, September 2020).

HIGH POTENTIAL DISRUPTION REPORT • November 2020 1

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), ideally including at least one patient, patient representative, or caregiver. 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 PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual for more details about ECRI’s conflict-of-interest policy. Included trends are developed into trend profiles, revised based on comments from the nomination meeting (if needed) and edited before being sent to internal ECRI stakeholders for comment. Each trend profile is posted to an internal ECRI online bulletin board, and a pool of about 50 ECRI internal stakeholders—representing health care business and finance, clinical engineering, health systems, health care generalist, information technology, nursing, physician, physician assistant, and research perspectives—is invited to provide input on each trend. Any stakeholder from the pool may self-select to review a trend, based on his or her 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, he or she reads a trend summary and then completes a brief online survey to elicit his or her perspectives on the trend’s potential to disrupt health care, the expected timing of the disruption, and the likelihood of the trend to cause disruption.

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

Report Methods The purpose of the stakeholder survey process is to help determine which topics and trends have the highest potential to significantly disrupt patient care in some manner, such as patient outcomes, access to care, health disparities, care delivery, staffing, and costs. 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

HIGH POTENTIAL DISRUPTION REPORT • November 2020 2

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.

Selecting Topics and Trends for the High Potential Disruption Report To be considered for inclusion in the High Potential Disruption Report, topics and trends must be active (ie, not archived) and must have received a minimum of 5 stakeholder surveys within the past 12 months. Topics and trends selected for inclusion are those that stakeholders generally agreed have high potential to significantly disrupt health care in the United States. Topics and trends selected for inclusion are assigned to analysts to draft topic summaries. Analysis of stakeholder comments must generally support conclusions suggested by ratings. Topics with borderline ratings, high variance, or questionable comments are scheduled for discussion at the High Potential Disruption Report topic selection meeting (see below). Each scheduled topic is reviewed by the analyst assigned to the applicable clinical priority area. The analyst rereads the topic profile and reviews each survey received for the topic, paying particular attention to stakeholder comments. The analyst prepares a summary of stakeholder comments to present at the topic selection meeting. Trends with borderline ratings, high variance, or questionable comments are reviewed by a 3- member panel of senior horizon scanning team members to determine inclusion or exclusion. A majority affirmative vote by this panel selects the trend for inclusion. See the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual for a more complete description of the topic and trend selection processes.

High Potential Disruption Report Topic Selection Meeting For some topics, consensus in stakeholder ratings is unclear (ie, there is wide variation among stakeholder opinions about whether the topic will be highly disruptive). The horizon scanning team meets to discuss and vote on whether to include these topics in the High Potential Disruption Report. The assigned analyst for each topic presents a summary of stakeholder comments and ratings received for the topic. A brief discussion then takes place, during which team members may ask questions or provide perspectives regarding the topic’s disruptive potential. After the discussion, a blinded vote determines whether the topic should be included in the High Potential Disruption Report. The topic must receive a majority affirmative vote to be included. Topics selected for inclusion are assigned to analysts to draft topic summaries.

Producing the High Potential Disruption Report After topic and trend selection, the project manager creates a production schedule and assigns the selected topics and trends to the appropriate analysts for topic summary drafting. Analysts draft an analysis of each topic, which includes highlights, PICO information, an evidence development summary, manufacturer and regulatory information, cost information (if available), and a summary of key stakeholder perspectives. Likewise, analysts draft an analysis for each trend, which includes a trend description, a list of clinical areas potentially disrupted, lists of potential opportunities (ie, pros) and threats (ie, cons), and a summary of key stakeholder perspectives.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 3

Topic Summaries Each topic summary begins with a brief paragraph highlighting key takeaways for the reader, followed by a description of the patient population likely affected by the intervention, a description of the intervention, an evidence development summary listing selected ongoing and/or recently completed clinical trials, a brief summary of manufacturers and regulatory status, cost information, and a summary of key stakeholder perspectives. For concision, we generally limit the number of clinical trials reported in each of the evidence development summary tables to 3 trials, although we may make exceptions. We normally report the latest, most complete, and/or largest trials relevant to the specific patient population, but we may apply different selection criteria when appropriate. In a case in which more than 3 trials are ongoing or more than 3 trials have recently been completed, we include a brief note explaining our selection criteria, and we provide references to relevant trials not included in the tables. In the table of recently completed trials in the evidence development summary, we present results as written in abstracts of published studies, conference abstracts, or news releases. The reader should note that abstracts and news releases may not fully reflect the methods and findings of research presented in full published articles. We do not analyze the quality of the study designs, the reliability of the data reported on the outcomes assessed, or whether study investigators used appropriate statistical methods to analyze their data. In addition, we cannot warrant the validity of these results in the absence of such evaluations and analysis; therefore, the reader should review this information cautiously. Trend Summaries Potentially disruptive trends can occur across or within clinical areas and arise from a combination of factors that, taken together, create a paradigm shift in health care. Identification of these trends goes beyond the 5 priority areas PCORI initially defined as a focus. Each trend summary begins with a brief paragraph highlighting key takeaways for the reader, followed by a description of the nature and importance of the trend, a listing of clinical areas potentially affected by the trend, and a brief discussion of opportunities and threats (ie, potential positive and negative disruptions) posed by the trend. Report Compilation Topic summaries are compiled into chapters: 1 for each of the 5 PCORI-defined priority areas and 1 for potentially disruptive trends. After a chapter has been compiled, the project manager reviews all content and writes a chapter summary, which provides basic information and statistics about topics or trends included in the chapter and currently monitored or recently archived in the HCHSS. Each chapter is reviewed carefully by the medical copyeditor, senior technical reviewer, and project director before compilation into the final report. After compilation, the project manager reviews the content and writes the overall reporting period summary, which provides basic information and statistics about topics or trends included in the report and currently monitored or recently archived in the HCHSS.

Reporting Period Summary The PCORI HCHSS began operating in December 2018. Since then, review of about 5000 information leads has led to the identification of about 570 potential topics across the 5 PCORI priority areas and 100 high-level trends occurring in all areas of health care. As of October 2, 2020, after subjecting the potential topics to our inclusion criteria and nomination process, 395 topics have been selected. Of these, 252 topics are being actively

HIGH POTENTIAL DISRUPTION REPORT • November 2020 4

monitored in the system; 143 topics have been archived. These 252 topics represent 140 diseases/conditions and span the PCORI-defined priority areas as follows (see also Figure 1): • Alzheimer’s disease and other dementias: 11 topics (4%) • Cancer: 85 topics (34%) • Cardiovascular diseases: 17 topics (7%) • Mental and behavioral health conditions: 18 topics (7%) • Rare diseases: 121 topics (48%)

Figure 1. Percentage of All Actively Monitored Topics by Priority Area

Across all priority areas, the 252 monitored topics represent the following therapeutic classes (also see Figure 2): • Cell therapy: 18 topics (7%) • Device (nonimplantable): 10 topics (4%) • Gene therapy: 17 topics (7%) • Immunotherapy: 3 topics (1%) • Implant: 4 topics (1.6%) • Monoclonal antibody: 12 topics (5%) • Other biotechnology: 24 topics (10%) • Pharmaceutical: 157 topics (62%) • Procedure (nonsurgical): 1 topic (0.4%) • Viral vector therapy: 6 topics (2%)

HIGH POTENTIAL DISRUPTION REPORT • November 2020 5

Figure 2. Percentage of All Currently Monitored Topics by Therapeutic Class

Of these 252 actively monitored topics, we have selected—based on the procedures described in Report Methods—36 topics for inclusion in this report, distributed across the PCORI priority areas as follows (see also Figure 3): • Alzheimer’s disease and other dementias: 2 topics (6%) • Cancer: 14 topics (39%) • Cardiovascular diseases: 1 topic (3%) • Mental and behavioral health conditions: 2 topics (6%) • Rare diseases: 17 topics (47%) * Total does not equal 100% because of rounding

HIGH POTENTIAL DISRUPTION REPORT • November 2020 6

Figure 3. Percentage of Topics Selected for Report by Priority Area

Likewise, as of October 2, 2020, after subjecting potential trends to our inclusion criteria and nomination process, we have selected 62 trends occurring across clinical areas or within a clinical area that can potentially create a paradigm shift in health care (ie, large, high-level disruptions). Of these trends, 24 are being actively monitored in the system and 38 have been archived. Among these 24 trends, 6 themes have emerged (also see Figure 4): • Artificial intelligence and machine learning: 6 trends (25%) • Health information technology, apps, and smart devices: 4 trends (17%) • Innovative treatment models: 8 trends (33%) • Preventive measures: 1 trend (4%) • Proteomics, genomics, and personalized medicine: 4 trends (17%) • Screening and diagnostics: 1 trend (4%)

HIGH POTENTIAL DISRUPTION REPORT • November 2020 7

Figure 4. Percentage of All Currently Monitored Trends by Theme

Of these 24 actively monitored trends, we have selected—based on the procedure described in Report Methods—8 trends for inclusion in this report, distributed by theme as follows (see also Figure 5): • Artificial intelligence and machine learning: 2 trends (25%) • Health information technology, apps, and smart devices: 1 trend (12.5%) • Innovative treatment models: 2 trends (25%) • Proteomics, genomics, and personalized medicine: 3 trends (37.5%)

HIGH POTENTIAL DISRUPTION REPORT • November 2020 8

Figure 5. Percentage of Trends Selected for Report by Theme

HIGH POTENTIAL DISRUPTION REPORT • November 2020 9

Chapter 1. Alzheimer’s Disease and Other Dementias

Chapter Summary For the Alzheimer’s disease and other dementias priority area, we considered for inclusion 2 topics for which (1) preliminary phase 3 data for drugs, phase 2 (or equivalent) data for devices and procedures, or some human data for off-label uses or programs were available; (2) information was compiled and sent for stakeholder comment before September 8, 2020; and (3) we received at least 5 sets of comments and ratings from stakeholders between September 19, 2019, and September 18, 2020. As of September 8, 2020, we were monitoring 11 topics in this priority area, including the 2 topics considered for inclusion in this report. These 11 topics will be listed in the December 2020 PCORI Health Care Horizon Scanning System: Horizon Scanning Status Report. We also archived one topic in August 2020. A description of that topic and the reason it was archived can be found in the September 2020 Status Report. The 11 monitored topics encompass pharmaceuticals and biotechnologies for treating Alzheimer’s disease and/or related symptoms (eg, agitation). Of these, 9 topics are too early in development to meet criteria (as outlined above) for eligibility for this report. Topics Considered for Inclusion in This Report Table 1.1 lists 2 topics selected for inclusion in this report based on stakeholder ratings and comments and available data. Topics are listed and discussed alphabetically by topic title. Table 1.1. Included Topics for Priority Area: Alzheimer’s Disease and Other Dementias Topic title Aducanumab (BIIB037) to treat early Alzheimer’s diseasea Periodic therapeutic plasma exchange (Alzheimer’s management by albumin replacement protocol) to treat mild to moderate Alzheimer’s disease a Topic appears for the first time in this edition of the High Potential Disruption Report.

Topic Summaries We present below 2 summaries on topics deemed to have high potential for disruption.

Aducanumab (BIIB037) to Treat Early Alzheimer’s Disease Highlights • Aducanumab is a recombinant human monoclonal antibody that is intended to reduce cognitive decline and the progression of Alzheimer’s disease (AD) in early and mild stages. • AD affects millions of Americans, particularly adults aged 55 and older, and a significant unmet need exists for treatments.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 10

• Stakeholders commenting on this topic thought aducanumab could be the first disease- modifying treatment for early AD that might improve patient-oriented health outcomes, including quality of life. • Most stakeholders thought that both the cost (depending on insurance reimbursement) and delivery of the treatment (which occurs in infusion centers) would increase disparities in access and add to the burden of care for these patients and caregivers. • Stakeholders recommended further research to evaluate the treatment’s long-term clinical effectiveness and address any drug safety issues in this high-risk patient population. Patient Population Aducanumab is intended for adults aged 50 years or older who have mild cognitive impairment or mild AD. Intervention AD causes up to 80% of dementia cases, has no cure, and has limited options for effective symptom management. No disease-modifying treatments are available, despite decades of research.1 The Alzheimer’s Association offers more information on AD. The amyloid hypothesis of AD disease development suggests that the accumulation and deposition of oligomeric or fibrillary amyloid beta (Aβ) peptides is the primary cause of AD. However, no Aβ-targeted therapy has demonstrated improved outcomes in patients with AD. Aducanumab is a recombinant human monoclonal antibody that preferentially binds aggregated forms of Aβ (ie, soluble oligomers and insoluble fibrils) that are hypothesized to cause the neurotoxic effects linked with AD.2,3 Aducanumab’s high degree of selectivity for aggregated forms of Aβ may differentiate it from other Aβ-targeting antibodies that failed to demonstrate clinical improvement in clinical trials.3 Although aducanumab’s exact mechanism of action is unclear, animal models suggest that the drug binds with aggregated Aβ isoforms, leading to their clearance by microglia.4 This might reduce cognitive decline in patients with early AD and improve their quality of life.5 A neurologist refers a patient to an infusion center for aducanumab therapy. In clinical trials, aducanumab is given intravenously at a dosage of 10 mg/kg every 4 weeks for 100 weeks.6

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified one late-stage ongoing trial for this topic. We present it in Table 1.2.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 11

Table 1.2. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date of National Clinical Trials planned enrollment completion identifier A Study to Evaluate Safety Adults aged 50 to 90 Phase 3b randomized, open- Primary and study and Tolerability of years (n = 2400) who have label trial to evaluate the long- completion September Aducanumab in AD and participated in an term safety and tolerability of 2023 Participants With AD Who earlier trial of aducanumab in patients with Had Previously aducanumab AD who had previously Participated in the participated in aducanumab Aducanumab Studies studies 221AD103, 221AD301, Primary outcome measures: 221AD302 and 221AD205 • AEs and serious AEs up to NCT04241068 week 118 • Number of participants with ARIA up to week 102 Abbreviations: AD, Alzheimer’s disease; AEs, adverse events; ARIA, amyloid-related imaging abnormalities. Recently Completed and Ongoing Trials With Available Results Our searches identified 2 recently completed late-phase trials with published results.7 We summarize the results of the most recent of these studies, as written in a news release. The following abbreviations are used in this section: AD, Alzheimer’s disease; ADAS-Cog 13, Alzheimer’s Disease Assessment Scale—cognitive subscale, 13 tasks; ADCS-ADL-MCI, Alzheimer’s Disease Cooperative Study—Activities of Daily Living inventory (mild cognitive impairment version); ARIA-E, amyloid-related imaging abnormalities—edema; CDR-SB, clinical dementia rating—sum of boxes; CSF, cerebrospinal fluid; MMSE, mini-mental state examination; P, probability.

Two phase 3 studies, 221AD302 EMERGE (NCT02484547) and 221AD301 ENGAGE (NCT02477800), of aducanumab (BIIB037) in early Alzheimer’s disease. Biogen 2020.7

• Patient population/planned enrollment: Adults aged 50 to 85 years with early AD enrolled in 2 cohorts, receiving either a low or high dose of aducanumab; EMERGE (n = 1638), ENGAGE (n = 1647) • Study design: Two phase 3, randomized, double-blind, placebo-controlled studies to evaluate the efficacy and safety of aducanumab in patients with early AD • Primary outcome: Change from baseline in CDR-SB score up to week 78 • Secondary outcomes: Change from baseline in MMSE score up to week 78, change from baseline in ADAS-Cog 13 score up to week 78, and change from baseline in ADCS-ADL-MCI score up to week 78 • Results presented by study authors: “In EMERGE, which met its pre-specified primary endpoint in the new analysis, patients treated with high dose aducanumab showed a significant reduction of clinical decline from baseline in CDR-SB scores at 78 weeks (23% versus placebo, P=0.01). In EMERGE, patients treated with high dose aducanumab also showed a consistent reduction of clinical decline as measured by the pre-specified secondary endpoints: the MMSE; 15% versus placebo, P=0.06, the AD ADAS-Cog 13; 27% versus placebo, P=0.01, and the ADCS-ADL-MCI; 40% versus placebo, P=0.001. Imaging of amyloid plaque deposition in EMERGE demonstrated that amyloid plaque burden was reduced with low and high dose aducanumab compared to placebo at 26 and 78 weeks (P<0.001). Additional biomarker data of tau levels in the CSF supported these clinical findings. Biogen believes that data from patients in ENGAGE who achieved sufficient exposure to high dose aducanumab supported the findings of EMERGE.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 12

• “In both studies, the most commonly reported adverse events were amyloid-related imaging abnormalities-edema (ARIA-E) and headache. The majority of patients with ARIA-E did not experience symptoms during the ARIA-E episode, and ARIA-E episodes generally resolved within 4 to 16 weeks, typically without long-term clinical sequelae.” Cost Information Cost information is unavailable for this topic. Manufacturers and Regulatory Status In July 2020, Biogen submitted a Biologics License Application (BLA) to FDA for aducanumab to treat AD.5 FDA has accepted the BLA and will review it under the agency’s priority review program with a Prescription Drug User Fee Act (PDUFA)-prescribed decision date of March 7, 2021.8 The BLA was largely supported by data from the 2 phase 3 trials, EMERGE and ENGAGE (see above). In March 2019, the developers had stopped these trials after the preliminary results from futility analysis showed that the trials were unlikely to meet their primary end point of decrease in cognitive decline.9 However, in December 2019, the manufacturers presented additional data from the 2 phase 3 trials showing that a higher dose of the drug might clinically benefit patients with mild to moderate AD.2 Aducanumab is also being evaluated in a phase 3 long-term extension study for treatment of early AD.6 FDA has also granted aducanumab Fast Track designation to treat AD.10 Key Stakeholder Perspectives Between August 19, 2020, and September 14, 2020, ten stakeholders, reflecting caregiver, clinical, health systems, nursing, patient, and research perspectives, provided comments and ratings on this treatment. The list below provides a summary of key stakeholder perspectives. • Given the absence of any other effective treatments addressing slow cognitive decline, aducanumab has potential to be the first treatment to reduce the amyloid burden and alter the paradigm of current care for adults with early AD. • Aducanumab would disrupt costs for patients, payers, and health care facilities, depending on insurance reimbursement and copayments required of patients. The treatment would save overall costs because of decreased needs for home health aides or long-term care facilities. • Aducanumab might disrupt health care delivery with additional clinic visits needed during the treatment period and increase the need for caregiver support in the short term. It might provide significant relief to caregivers by improving patients’ quality of life over the long term. • If effective, aducanumab would increase health care disparities, given the large target population needing to visit infusion centers, which patients in rural areas might find difficult to reach. • Concerns exist regarding aducanumab’s potential to be misused or overused. Longer-term studies are needed to evaluate its clinical effectiveness with comorbid medical conditions associated with aging.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 13

Periodic Therapeutic Plasma Exchange (Alzheimer’s Management by Albumin Replacement Protocol) to Treat Mild to Moderate Alzheimer’s Disease Highlights • Periodic therapeutic plasma exchange is an investigational therapy intended to slow cognitive decline and the progression of mild to moderate Alzheimer’s disease (AD). • AD affects millions of Americans, particularly adults aged 55 years or older, and a significant unmet need exists for treatments. • Although the use of human albumin in plasma exchange has been researched for more than 10 years, results from a recent clinical trial have generated renewed interest in this therapy. • Stakeholders commenting on this topic thought this treatment could address the unmet need and improve patient-oriented health outcomes, including quality of life. • Most stakeholders thought that the cost and delivery of the treatment (eg, infusion center resources, intravenous immunoglobulin [IVIG] shortages) would create disparities in access to care and/or add to the burden of care for these patients and caregivers. • Stakeholders recommended further research to address the treatment’s long-term effectiveness and validate its purported mechanism of action. Patient Population Periodic therapeutic plasma exchange (Alzheimer’s management by albumin replacement [AMBAR] protocol) is intended for adults aged 55 to 85 years with mild to moderate AD. Intervention AD causes up to 80% of dementia cases, has no cure, and has limited options for effective symptom management. No disease-modifying treatments are available despite decades of research.1 The Alzheimer’s Association website offers more information about AD. AMBAR is a therapeutic approach under study that involves performing plasma exchange, using albumin to replace the plasma volume that is removed.11 Researchers theorize that such replacement can lead to a shift of the dynamic equilibrium that exists between brain cerebrospinal fluid (CSF) and plasma amyloid beta peptide (Aβ; most of it is bound to albumin). This equilibrium shift might improve symptoms and delay progression of cognitive decline in the intended population.11,12 Albumin infused as volume replacement would theoretically bind and capture additional free- circulating Aβ. These processes purportedly reduce levels of free Aβ in plasma, resulting in a diffusion gradient that draws Aβ from the CSF and slows the progression of Aβ-driven AD pathogenesis.11 A neurologist refers a patient to an infusion center for the plasma exchange. During a 6-week intensive period, patients undergo weekly total plasma exchange (2.5-3 L plasma removal) and volume replacement with a 5% albumin solution (Albutein). A 12-month maintenance phase follows, during which patients undergo monthly low-volume plasma exchange (650-880 mL plasma removal) and volume replacement with a 20% albumin solution or IVIG.13

HIGH POTENTIAL DISRUPTION REPORT • November 2020 14

Three regimens are being tested that use some combination of albumin with or without IVIG as the replacement13: • Three 4-month cycles consisting of 20 g IVIG in month 1 and 40 g albumin in months 2 to 4 • Three 4-month cycles consisting of 10 g IVIG in month 1 and 20 g albumin in months 2 to 4 • Twelve 1-month cycles consisting of 20 g albumin

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified no ongoing trials for this topic. Recently Completed and Ongoing Trials With Available Results Our searches identified a single recently completed late-phase trial with published results.14 We summarize this most recent study with results as written in the abstract of the published study. The following abbreviations are used in this section: AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale—cognitive subscale; ADCS-ADL, Alzheimer’s Disease Cooperative Study—Activities of Daily Living; ADCS-CGIC, Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change; AMBAR, Alzheimer’s management by albumin replacement; CDR-sb, Clinical Dementia Rating Scale—sum of boxes; MMSE, Mini-Mental State Examination; P, probability; PE, plasma exchange.

A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer’s disease: Primary results of the AMBAR study. NCT01561053. Boada et al 2020.14

• Patient population/planned enrollment: Adults (n = 347) aged 55 to 85 years with mild to moderate, probable AD • Study design: A phase 2b/3, randomized controlled, parallel-assignment study to evaluate the efficacy and safety of short-term PE, followed by long-term plasmapheresis with human albumin infusion combined with intravenous immunoglobulin in patients with mild to moderate AD • Primary outcome: Cognitive performance from baseline to 14 months • Secondary outcomes: Quality of life from baseline to 14 months and changes in cognitive function from baseline to 14 months Results presented by study authors: “PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS- Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales.” Manufacturers and Regulatory Status The Albutein and IVIG (Flebogamma 5% DIF) treatment protocol (Grifols, SA, Barcelona, Spain) was evaluated in a phase 2/3 clinical trial for treating mild to moderate AD.15 FDA has not approved Albutein to treat AD, but it has been commercially available since 1978, and FDA has approved it for use in several other indications.16 IVIG also is not labeled for use in AD but is indicated for treating primary (inherited) immunodeficiency in adults and pediatric patients aged 2 years or older.17 Albutein and IVIG, as used in the AMBAR protocol, could be administered as an off-label treatment for mild to moderate AD.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 15

In a December 6, 2019, news release, the company announced that it would discuss the next steps for the AMBAR clinical development program with FDA.18 As of early October 2020, the company had not announced any updates, although positive data from the phase 2/3 clinical trial were published in July 2020.14 Cost Information According to ECRI’s PriceGuide database, member hospitals reported a median price paid of about $34 for 250 mL of 5% Albutein, $36 for 50 mL of 25% Albutein, and $836 for 10 g of 5% Flebogamma IVIG (as of August 29, 2019).19-21 Using these figures, the drug cost for 14 months would range from $5474 to $8501, depending on the prescribed dosing regimen.13,19-21 These costs do not include the costs of administration and other fees associated with an infusion procedure. Key Stakeholder Perspectives Between September 29, 2019, and October 7, 2019,* ten stakeholders, reflecting caregiver, clinical, and health systems perspectives, provided comments and ratings on this periodic plasma exchange treatment. The list below provides a summary of key stakeholder perspectives. • AMBAR protocol has the potential to slow AD progression, with high potential to disrupt the paradigm of care because it is an infusion-based treatment rather than an oral drug. • AMBAR might disrupt costs for payers and health care facilities, depending on insurance reimbursement and copayments required of patients. The treatment would save overall costs because of decreased needs for home health aides or long-term care facilities. • Concerns exist regarding AMBAR’s long-term effectiveness (beyond 14 months) as well as its purported mechanism of action of lowering cerebral amyloid. • Given the absence of any other effective treatments addressing slow cognitive decline, this intervention might provide significant relief to caregivers by improving patients’ quality of life. * Five additional stakeholders representing caregiver, clinical, and research perspectives commented on an updated version of this topic between October 1, 2020, and October 9, 2020. Because these comments were received after the comment submission deadline of September 18, 2020, they were not analyzed for inclusion in this report. However, a preliminary review of these ratings and comments confirmed that they were in general agreement with those reported above.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 16

Chapter 2. Cancer

Chapter Summary For the cancer priority area, we considered for inclusion 24 topics for which (1) preliminary phase 3 data for drugs, phase 2 (or equivalent) data for devices and procedures, or some human data for off-label uses or programs were available; (2) information was compiled and sent for stakeholder comment before September 8, 2020; and (3) we received at least 5 sets of comments and ratings from stakeholders between September 19, 2019, and September 18, 2020. As of September 8, 2020, we were monitoring 91 topics in this priority area, including the 24 considered for inclusion in this report. These 91 topics will be listed in the December 2020 PCORI Health Care Horizon Scanning System: Horizon Scanning Status Report. We archived 5 topics in August 2020. Descriptions of these topics and the reasons they were archived can be found in the September 2020 Status Report. We archived an additional 8 topics in September 2020 and 4 topics in October 2020. A description of these 12 topics and the reasons they were archived will be included in the December 2020 Status Report. The 91 monitored topics encompass pharmaceuticals, gene and cellular therapies, viral vector therapies, monoclonal antibodies, and devices intended to treat 39 cancers and/or related conditions. Two topics were developed as topic profiles to be sent for stakeholder comment; however, fewer than 5 sets of stakeholder comments were received for these topics before September 18, 2020, so they were not considered for inclusion in this report. The remaining 65 topics are too early in development to meet criteria (as outlined above) for eligibility for this report. Topics Considered for Inclusion in This Report Table 2.1 lists 14 topics selected for inclusion in this report based on stakeholder ratings and comments and available data. Topics are listed and discussed alphabetically by title. Table 2.1. Included Topics for Priority Area: Cancer

Topic title Atezolizumab (Tecentriq) plus bevacizumab (Avastin) as first-line treatment for locally advanced or metastatic hepatocellular carcinomaa Axicabtagene ciloleucel (Yescarta) to treat indolent B-cell non-Hodgkin lymphomasa Capmatinib (Tabrecta) to treat metastatic, MET-altered non–small cell lung cancer Idecabtagene vicleucel (ide-cel) to treat relapsed and refractory multiple myelomaa Lifileucel (LN-144) as second-line treatment for locally advanced or metastatic melanoma MDNA55 to treat first recurrence of recurrent glioblastoma multiforme Nanoparticle albumin-bound sirolimus (ABI-009) to treat locally advanced or metastatic perivascular epithelioid cell sarcoma Omidubicel to treat hematologic malignancies eligible for hematopoietic stem cell transplantationa Onureg to treat acute myeloid leukemia (maintenance setting)a Oraxol to treat locally advanced or metastatic breast cancera Pemigatinib (Pemazyre) to treat locally advanced or metastatic cholangiocarcinoma harboring fibroblast growth factor receptor-2 fusions or rearrangements

HIGH POTENTIAL DISRUPTION REPORT • November 2020 17

Topic title Selumetinib (Koselugo) to treat symptomatic, inoperable plexiform neurofibromatosis type 1a Tazemetostat (Tazverik) to treat locally advanced or metastatic epithelioid sarcoma Tazemetostat (Tazverik) to treat relapsed or refractory follicular lymphomaa a Topic appears for the first time in this edition of the High Potential Disruption Report.

Table 2.2 lists 10 topics considered, but not selected, for inclusion during the High Potential Disruption Report decision meeting. A majority of the voting team agreed that these topics lacked high potential for disruption, based on stakeholder ratings and comments and available data. Each record contains a note explaining the reasons for exclusion. Table 2.2. Topics Considered but Not Included for Priority Area: Cancer

Topic title Exclusion reason(s) and notes based on stakeholder comments Belumosudil (KD025) to treat chronic As another oral agent for treating chronic graft-versus-host disease, graft-vs-host disease belumosudil might complement other orally administered alternatives (eg, ibrutinib, ruxolitinib) but is unlikely to cause substantial disruption of treatment paradigms or health care infrastructure. In addition, phase 2 trials lack control groups. Brexucabtagene autoleucel The overall disruptive potential of brexucabtagene autoleucel will be (Tecartus) to treat relapsed or small because of the low prevalence of mantle cell lymphoma and the refractory mantle cell lymphoma restricted use of the intervention to only patients who have undergone several prior rounds of therapy. DCVax-L to treat glioblastoma Preliminary data suggest that the DCVax-L vaccine might lead to a multiforme (adjuvant setting) slight increase in overall survival. However, long-term results are needed to make a definitive statement on whether DCVax-L has potential to substantially improve health outcomes. Encorafenib (Braftovi) plus Even though encorafenib plus cetuximab showed some improvement cetuximab (Erbitux) to treat BRAF in health outcomes, the treatment has small potential to cause V600E-mutant metastatic colorectal disruption because of the availability of other treatment options in the cancer (second-line setting) same patient population. Iomab-B (apamistamab-I-131) to Initial data for Iomab-B suggest that the intervention might increase treat relapsed or refractory acute the number of patients with acute myeloid leukemia eligible for a myeloid leukemia potentially curative hematopoietic stem cell transplant. However, data on the primary end point of complete durable remission and patient- centered outcomes are lacking. More data are needed to assess disruptive potential. Luspatercept-aamt (Reblozyl) to Although luspatercept-aamt will likely be an additional treatment treat lower risk myelodysplastic option for this patient population, a small percentage of patients will syndrome–associated anemia likely experience substantial clinical benefit. In addition, as another subcutaneously injected drug for treating myelodysplastic syndrome– associated anemia, luspatercept-aamt was seen as unlikely to cause substantial shifts to health care infrastructure or treatment paradigms. Pembrolizumab (Keytruda) to treat Although 6-month follow-up data suggest that pembrolizumab might high-risk non–muscle invasive improve survival and extend time to surgical removal of the bladder, bladder cancer long-term data are needed to assess whether patients treated with pembrolizumab will have sustained benefit beyond 6 months.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 18

Topic title Exclusion reason(s) and notes based on stakeholder comments Pomalidomide (Pomalyst) to treat Although available data from a small clinical trial suggest that Kaposi sarcoma pomalidomide might improve health outcomes in patients with limited treatment options, its disruptive potential is difficult to assess because pomalidomide was not compared with the standard of care. Selpercatinib (Retevmo) to treat Overall, selpercatinib has little potential to disrupt the health care locally advanced or metastatic RET system because of the small size of its intended patient population. In fusion–positive non–small cell lung addition, although preliminary data suggest that selpercatinib might cancer improve patient response rates, it was not compared with the standard of care. Trilaciclib (G1T28) to prevent bone Trilaciclib has little potential to disrupt the health care system because marrow damage during it does not appear to substantially improve chemotherapy-induced chemotherapy for extensive stage bone marrow suppression compared with the current standard of small cell lung cancer care.

Topic Summaries We present below 14 summaries on topics deemed to have high potential for disruption.

Atezolizumab (Tecentriq) Plus Bevacizumab (Avastin) as First- Line Treatment for Locally Advanced or Metastatic Hepatocellular Carcinoma Highlights • Atezolizumab is an immune checkpoint inhibitor given intravenously in combination with bevacizumab, a drug that prevents new blood vessel formation, to prevent tumor cells from downregulating cancer-specific immune responses. FDA approved this combination therapy in June 2020 for treating hepatocellular carcinoma (HCC). • Locally advanced or metastatic HCC is usually treated with multikinase inhibitors, but their benefit is incremental and associated with adverse events. • The cost of atezolizumab plus bevacizumab is about $19 680 per cycle, which does not include administration costs and other fees associated with an infusion procedure. This is 10 times more costly than the oral multikinase sorafenib, a current standard of care. • Stakeholders commenting on this topic thought that atezolizumab plus bevacizumab might have greater potential than multikinase inhibitors to improve patient outcomes and quality of life. • Stakeholders also thought that this treatment combination could become the standard of care in the first-line setting; however, its high cost might increase disparities and be unaffordable for uninsured or underinsured patients. Patient Population Atezolizumab plus bevacizumab is intended for adults who have locally advanced or metastatic HCC and have had no previous systemic therapy.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 19

Intervention HCC is the most common type of liver cancer and often occurs in patients with chronic liver diseases, such as alcoholic cirrhosis, fatty liver disease, and viral hepatitis. HCC accounts for more than 800 000 deaths worldwide each year. Patients with HCC have a 5-year survival rate of 18%.22,23 The American Cancer Society offers more information about HCC. Historically, multikinase inhibitors (eg, sorafenib, lenvatinib) have been the most effective therapies for locally advanced or metastatic HCC. However, these drugs extend median survival by only 3 months and are associated with considerable adverse events.22,24 In the body, programmed cell death 1 (PD-1) is an immune checkpoint protein on T cells and other immune cells that binds to programmed death ligand 1 (PD-L1) to downregulate immune cells and prevent runaway immune responses.25,26 Cancer cells overexpress PD-L1 to avoid detection and destruction by the immune system. Also, vascular endothelial growth factor (VEGF) is often overexpressed in cancer cells. This overexpression promotes blood vessel formation and exerts immunosuppressive effects.24,27 Atezolizumab (Tecentriq) is a humanized monoclonal antibody that selectively binds PD-L1 to prevent its interaction with the coinhibitory receptor PD-1.25,26 This releases the brakes on the PD-1 and PD-L1 immune checkpoint pathway, and by so doing, atezolizumab purportedly enhances cancer-specific T-cell responses against HCC tumors.24,25 Bevacizumab (Avastin) is a humanized monoclonal antibody that blocks the VEGF pathway. This limits blood vessel formation and also helps overcome immune tolerance of HCC by helping cancer-specific T cells infiltrate the tumor.24,27 An oncologist prescribes atezolizumab and bevacizumab to be given at an infusion center. An infusion nurse gives 1200 mg of atezolizumab and 15 mg/kg of bevacizumab to the patient through a vein on day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified a single ongoing trial for this topic. We present this phase 3 trial in Table 2.3.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 20

Table 2.3. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier A Study of Atezolizumab Patients (n = 480) who have Phase 3, randomized, parallel- Primary in Combination With locally advanced or assignment, open-label trial to completion Bevacizumab Compared metastatic HCC and have evaluate the safety and efficacy of February 2021 With Sorafenib in Patients had no previous systemic atezolizumab in combination with Study With Untreated Locally therapy in the locally bevacizumab in patients with HCC completion June Advanced or Metastatic advanced/metastatic Patients will be randomly assigned to 2022 Hepatocellular Carcinoma setting treatment with either combination (IMbrave150) therapy with atezolizumab plus NCT03434379 bevacizumab or monotherapy with sorafenib.

Primary end points: Overall survival and progression-free survival

Secondary end points: Objective response, duration of response, time to progression, and time to deterioration Abbreviation: HCC, hepatocellular carcinoma.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed late-phase trial with published results.28,29 We summarize results as written in the abstract of a published study and a conference abstract. The following abbreviations are used in this section: atezo, atezolizumab; bev, bevacizumab; CI, confidence interval; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer, quality-of-life questionnaire–core module; EORTC QLQ-HCC18, European Organization for Research and Treatment of Cancer, quality-of-life questionnaire–primary liver cancer module; HCC, hepatocellular carcinoma; HR, hazard ratio; mo, month; P, probability; pts, patients; QOL, quality of life; sor, sorafenib; TTD, time to deterioration; tx, treatment; vs, versus.

A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma (IMbrave150). NCT03434379. Finn et al 202028 and Galle et al 2020.29

• Patient population/planned enrollment: Patients (n = 501) with locally advanced or metastatic HCC who had no previous systemic therapy in the locally advanced/metastatic setting • Study design: Phase 3, randomized, parallel-assignment, open-label trial to evaluate the safety and efficacy of atezolizumab in combination with bevacizumab in patients with HCC. Patients were randomly assigned in a 2:1 ratio to receive either intravenous atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) on day 1 of each 21-day cycle or sorafenib (400 mg) taken by mouth twice daily. Patients completed the EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires before treatment, every 3 weeks on treatment, and every 3 months after treatment discontinuation or disease progression. • Primary outcome: Overall survival and progression-free survival • Secondary outcomes: QOL, duration of response, time to progression, time to deterioration, and adverse events

HIGH POTENTIAL DISRUPTION REPORT • November 2020 21

• Results presented by Finn et al: “The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.”

• Results presented by Galle et al: “Questionnaire completion rates were ≥ 92% in both arms from baseline through most of the tx period. Compared with sor, atezo + bev delayed TTD of pt-reported QOL (median TTD, 11.2 vs 3.6 mo; HR, 0.63 [95% CI: 0.46, 0.85]), physical functioning (median TTD, 13.1 vs 4.9 mo; HR, 0.53 [95% CI: 0.39, 0.73]), and role functioning (median TTD, 9.1 vs 3.6 mo; HR, 0.62 [95% CI: 0.46, 0.84]). Atezo + bev also delayed TTD in pt-reported appetite loss, fatigue, pain, and diarrhea vs sor; a lower proportion of pts on atezo + bev experienced clinically meaningful deterioration in each of these symptoms vs sor.” Manufacturers and Regulatory Status Genentech, Inc (South San Francisco, California), a subsidiary of F Hoffman-La Roche AG (Basel, Switzerland), manufactures atezolizumab. On June 2, 2020, FDA approved atezolizumab in combination with bevacizumab, based on results from the IMbrave150 trial, as first-line therapy for adults who have locally advanced or metastatic HCC.30 FDA earlier had granted atezolizumab in combination with bevacizumab Orphan Drug and Breakthrough Therapy designations for treating HCC.31,32 Both atezolizumab and bevacizumab are commercially available because FDA has approved them for multiple indications other than HCC. For a list of FDA-approved indications, see the FDA prescribing information for atezolizumab and bevacizumab. Cost Information An online aggregator of US prescription drug prices, Drugs.com, reported a retail price of $9600 for one vial of 1200 mg of atezolizumab and $210 for one vial of 25 mg of bevacizumab (as of October 5, 2020).33,34 Patients with an average weight of 80 kg would receive 1200 mg of atezolizumab and 1200 mg (15 mg/kg) of bevacizumab once every 21 days. At those prices, the estimated per-cycle cost of this combination regimen would be $19 680. On average, patients in the phase 3 IMbrave trial received about 7 months of treatment.28 Therefore, 10 cycles of this regimen would cost about $200 000. This estimate excludes the costs of administration and other fees associated with an infusion procedure. Key Stakeholder Perspectives Between April 2, 2020, and June 1, 2020, nine stakeholders, reflecting clinical, health systems, patient, and research perspectives, provided comments and ratings on atezolizumab in combination with bevacizumab. The list below provides a summary of key stakeholder perspectives. • Atezolizumab plus bevacizumab might improve patient survival and quality of life compared with multikinase inhibitors, which have been considered the standard of care for more than a decade. • Atezolizumab plus bevacizumab might create disparities because it costs 10 times more than the multikinase sorafenib. This combination therapy could cause a significant financial burden for uninsured or underinsured patients.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 22

• While atezolizumab plus bevacizumab are given at an infusion center, multikinases are taken by mouth. This shift from a home setting to an infusion center might disrupt health care delivery because infusion centers require resources, space, and personnel to offer treatment for patients with HCC. • Most stakeholders thought that atezolizumab and bevacizumab’s potential for disruption is based on data demonstrating superiority over multikinase inhibitors. Therefore, this combination is likely to become standard of care for patients with HCC.

Axicabtagene Ciloleucel (Yescarta) to Treat Indolent B-Cell Non- Hodgkin Lymphomas Highlights • Axicabtagene ciloleucel is an engineered chimeric antigen receptor (CAR) T-cell therapy produced by genetically modifying a patient’s own T cells, programming them to generate an immune response to the patient’s cancer. Given as a single intravenous infusion, the therapy is currently under FDA review for approval to treat indolent B-cell non-Hodgkin lymphomas. • Patients with relapsed or refractory B-cell non-Hodgkin lymphoma that has progressed despite multiple treatments have limited treatment options. In particular, patients who experience early relapse after initial treatment have a poor prognosis with available treatments. • Stakeholders commenting on this topic indicated that the rate and duration of response to axicabtagene ciloleucel observed in clinical trials suggested that the therapy has substantial potential to improve patient health outcomes. However, stakeholders also noted that the treatment was associated with a high burden of adverse events that could negatively impact quality of life. • Stakeholders suggested that axicabtagene ciloleucel would likely substantially increase treatment costs for indolent non-Hodgkin lymphomas, because it costs about $373 000 and the resource-intensive nature of its preparation, administration, and posttreatment monitoring can bring total treatment costs to nearly $1 000 000. Patient Population Axicabtagene ciloleucel is intended for adults aged 18 years or older with relapsed or refractory indolent B-cell non-Hodgkin lymphomas (eg, follicular lymphoma [FL], marginal zone lymphoma [MZL]) that has been treated with at least 2 prior combination systemic therapies. Intervention Indolent B-cell lymphomas account for about 40% of non-Hodgkin lymphomas and are diagnosed in about 30 000 people each year in the United States.35 The most common forms of indolent B-cell lymphomas are FL and MZL, which together account for about three-quarters of cases. Indolent B-cell lymphomas requiring therapy typically respond to available therapies. However, most patients experience disease recurrence, and novel effective therapies are needed for patients who have undergone multiple rounds of therapy and for whom limited effective therapies are available.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 23

Axicabtagene ciloleucel (Yescarta) is a CAR T-cell therapy that consists of patient-derived (ie, autologous) T cells that are genetically modified to express a CAR receptor.36 The CAR receptor in axicabtagene ciloleucel targets CD19, an antigen expressed on the surface of normal and malignant B cells. The CAR protein construct contains an antibody-like region that binds CD19 linked to an intracellular T-cell signaling domain, which produces activating signals that induce CAR T-cell proliferation and tumor cell killing.37 To produce axicabtagene ciloleucel, T cells are obtained from the patient’s blood and sent to the manufacturer’s facility to be genetically modified with the CAR construct. The cells are multiplied in culture and returned to the patient’s treatment facility.36 CAR T-cell therapies are available only at specialist centers equipped to handle administration and manage adverse events associated with the treatment. To prepare for administration, patients undergo a cytotoxic chemotherapy-based conditioning regimen to deplete lymphocytes, which purportedly improves expansion, function, and persistence of CAR T cells through multiple mechanisms.38 After this regiment, patients receive a single infusion of the manufactured CAR T- cell therapy at a dose of about 2 × 106 CAR T cells/kg.39

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified one ongoing trial for this topic. We present this trial in Table 2.4. Our searches also identified, but excluded, an expanded access study (ZUMA-9, NCT03153462) for which patients with FL or MZL are eligible.

Table 2.4. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier A Phase 2 Multicenter Patients (n = 160) with FL or Single-arm, phase 2 trial of the safety Primary Study of Axicabtagene MZL that has progressed and efficacy of axicabtagene ciloleucel to completion Ciloleucel in Subjects With after at least 2 lines of treat relapsed or refractory indolent February 2022 Relapsed/Refractory treatment with combination non-Hodgkin lymphomas Study completion Indolent Non-Hodgkin systemic therapy Patients will undergo leukapheresis to February 2037 Lymphoma (ZUMA-5) collect white blood cells to manufacture NCT03105336 axicabtagene ciloleucel. First, patients See preliminary results by will undergo 3 days of treatment with a Jacobson et al 2020 under conditioning regimen of Recently Completed and cyclophosphamide and fludarabine. Ongoing Trials With Then patients will receive an infusion of Available Results. axicabtagene ciloleucel at an unspecified dose. Primary outcome: Objective response rate Selected secondary outcomes: Duration of response, progression-free survival, overall survival, and percentage of patients experiencing adverse events

Abbreviations: FL, follicular lymphoma; MZL, marginal zone lymphoma.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 24

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial with published results.39 We summarize results as written in a conference abstract. The following abbreviations are used in this section: AEs, adverse events; AUC0-28, area under the curve between days 0 and 28; axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; CR, complete response; CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events; d, days; DOR, duration of response; FL, follicular lymphoma, FLIPI, Follicular Lymphoma International Prognostic Index; GELF, Groupe d’Etude des Lymphomes Folliculaires; mAb, monoclonal antibody; mo, months; MZL, marginal zone lymphoma; NE, neurologic event; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; POD24, progression of disease within 24 months of first treatment; pts, patients; y, years.

A Phase 2 Multicenter Study of Axicabtagene Ciloleucel in Subjects With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5). NCT03105336. Jacobson et al 2020.39

• Patient population/planned enrollment: Patients (n = 160) with FL or MZL that had progressed after at least 2 lines of combination systemic therapy • Study design: Single-arm, phase 2 trial of the safety and efficacy of axicabtagene ciloleucel to treat relapsed or refractory indolent non-Hodgkin lymphomas. Patients will undergo leukapheresis to collect the white blood cells needed to manufacture axicabtagene ciloleucel. For treatment, patients will first undergo 3 days of treatment with a conditioning regimen containing cyclophosphamide and fludarabine. Then patients will receive an infusion of axicabtagene ciloleucel at an unspecified dose. • Primary outcome: ORR • Secondary outcomes: DOR, OS, PFS, and percentage of patients experiencing AEs • Results presented by study authors: “As of 8/20/19, 94 pts (80 FL; 14 MZL) received axi-cel with a median follow-up of 11.5 mo (range, 4.2 – 24.9). Median age was 63 y (range, 34 – 79), 47% of pts were male, 52% had stage IV disease, 51% had ≥ 3 FLIPI, and 59% had high tumor bulk (GELF). Pts had a median 3 prior lines of therapy, 66% progressed < 2 y after initial anti-CD20 mAb-containing therapy (POD24), and 73% were refractory to the last prior treatment. Of 87 pts evaluable for efficacy, ORR was 94% (79% complete response [CR] rate). Pts with FL (n = 80) had an ORR of 95% (80% CR rate). Pts with MZL (n = 7) had an ORR of 86% (71% CR rate). Overall, 68% of pts had ongoing responses as of the data cutoff. Updated data, including DOR, PFS, and OS with longer follow-up, will be included in the presentation. Of 94 pts evaluable for safety, 83% experienced Grade ≥ 3 adverse events (AEs), most commonly neutropenia (33%) and anemia (28%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al, Blood 2014) and neurologic events (NEs; per CTCAE v4.03) occurred in 11% and 19% of pts, respectively. Median times to onset of CRS and NEs were 4 and 7 d, with median durations of 6 and 14.5 d. There were 2 Grade 5 AEs: multisystem organ failure in the context of CRS (related to axi-cel) and aortic dissection (unrelated to axi-cel). Median peak

and AUC0-28 CAR T cell levels were 44 cells/µL and 490 cells/µL × d, respectively.”

Updated data were presented in a May 29, 2020, developer news release,40 which stated, “Ninety-five percent of patients with relapsed or refractory FL (n=80) who had received at least two prior lines of systemic therapy responded to Yescarta, including 81 percent of patients achieving a CR and 68 percent of patients in an ongoing response after at least nine months of follow-up as per independent review committee assessment. Of patients with relapsed or refractory MZL (n=16), 81 percent responded to Yescarta, with 75 percent achieving a CR after at least one month of follow-up as per independent review committee assessment. With a median follow-up of 15.3 months in all patients, median duration of response (DOR) was 20.8 months, median progression-free survival (PFS) was 23.5 months and median overall survival (OS) was not reached.

“In the safety analysis of 140 treated patients with FL or MZL, Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 8 percent and 17 percent of patients, respectively. There were two Grade 5 adverse events in patients with FL, including one patient with multisystem organ failure in the

HIGH POTENTIAL DISRUPTION REPORT • November 2020 25

context of CRS related to treatment with Yescarta and one patient with aortic dissection unrelated to Yescarta treatment. The primary analysis with 12 months of follow-up is ongoing.” Manufacturers and Regulatory Status Kite Pharma, a Gilead Company (South San Francisco, California), is developing axicabtagene ciloleucel. On September 4, 2020, the developer submitted a supplemental Biologics License Application to FDA to treat relapsed or refractory FL and MZL after 2 or more prior lines of systemic therapy.41 FDA had previously granted these indications a Breakthrough Therapy Designation. FDA earlier approved axicabtagene ciloleucel for a different indication, to treat relapsed or refractory diffuse large B-cell lymphoma. The prescribing information carries a black box warning for this indication regarding the potential for cytokine release syndrome, which labeling indicates occurred in 94% of patients, and neurologic toxicities, which occurred in 87% of patients.40 Severe instances of these toxicities may threaten life and require supportive care and/or immunosuppressive treatment.42 To mitigate the risk associated with these toxicities, axicabtagene ciloleucel is available only to facilities enrolled in a Risk Evaluation and Mitigation Strategy (REMS).43 The program requires that facilities enroll and comply with the REMS requirements and have onsite “immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of [cytokine release syndrome]. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Yescarta are trained about the management of [cytokine release syndrome] and neurologic toxicities.”43 Cost Information According to an online aggregator of US prescription drug prices, Drugs.com, the list price of axicabtagene ciloleucel is $373 000 per treatment regimen.44 This price excludes additional costs related to hospital care during the preparation and administration of the therapy and costs related to the management of side effects, which can increase the overall cost of treatment to about $1 000 000.45,46 Key Stakeholder Perspectives Between September 9, 2020, and September 16, 2020, five stakeholders, reflecting clinical, health systems, and patient perspectives, provided comments and ratings on axicabtagene ciloleucel for treating indolent non-Hodgkin lymphoma. The list below provides a summary of key stakeholder perspectives. • Axicabtagene ciloleucel has moderate potential to improve health outcomes for patients with relapsed/refractory indolent non-Hodgkin lymphoma based on the high response rates observed in the ZUMA-5 trial and the potential for the therapy to generate prolonged remissions. • However, adverse events associated with the treatment limits axicabtagene ciloleucel’s potential to improve patient health outcomes. High rates of neurologic events and cytokine release syndrome and the potential for patients to develop long-lasting neuropathies are of concern. • The CAR T-cell therapy procedure’s complex nature places substantial demands on patients and caregivers. Patients must travel to a major medical center and treatment involves an inpatient stay, which has the potential to more negatively impact quality of life compared with outpatient treatment alternatives.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 26

• Axicabtagene ciloleucel would likely substantially increase cost of care for patients because of the high cost of the therapy, as well as procedural costs associated with the treatment. • The therapy’s high cost and the likelihood that it would be administered at only specialized facilities were seen as factors that could exacerbate disparities based on socioeconomic status and/or access to these facilities.

Capmatinib (Tabrecta) to Treat Metastatic, MET-Altered Non– Small Cell Lung Cancer Highlights • Capmatinib is an oral, highly selective, small-molecule inhibitor of the MET proto- oncogene, a receptor tyrosine kinase expressed by the MET proto-oncogene receptor tyrosine kinase gene, MET. The MET proto-oncogene is involved in a pathway that promotes cell survival, cell proliferation, and tissue regeneration. FDA approved the therapy in May 2020; eligibility requires a positive genetic test result using the FoundationOne CDx test. • MET alterations, including the MET exon 14–skipping mutation, occur in about 3% to 4% of non–small cell lung cancer (NSCLC) cases, and because of limited treatment options, patients usually have a poor prognosis. • Stakeholders commenting on this topic thought that, compared with off-label treatment with crizotinib or cabozantinib, capmatinib has the potential to improve patient-oriented outcomes, which is supported by available data; however, they thought that confirmatory data from randomized controlled trials are needed. • Stakeholders also thought that capmatinib has the potential to disrupt health care delivery because it will require incorporating MET genetic testing into the clinical workflow. Because capmatinib will likely be expensive (after FDA approval, its price was listed as $17 710 per 28-day supply), it could cause disparities for uninsured or underinsured patients. Patient Population Capmatinib is intended for adults aged 18 years or older with metastatic NSCLC harboring a MET exon 14–skipping mutation as detected by an FDA-approved test. Intervention NSCLC is the most common type of lung cancer, accounting for about 80% to 85% of all lung cancers. Treatment of NSCLC has been transformed the past 10 years by an increased understanding of the molecular events underlying the disease. In particular, FDA has approved multiple agents targeting specific NSCLC molecular drivers to treat NSCLC in patients with treatment-amenable mutations. Examples are mutations in the epidermal growth factor receptor gene, EGFR, and translocations in the anaplastic lymphoma kinase gene, ALK. Investigators are looking for additional molecular drivers that could lead to targeted therapy combinations, with the goal of improving health outcomes for patients with other NSCLC molecular subtypes. One such potential target is the MET gene. The American Cancer Society website offers more information on NSCLC. MET encodes a receptor tyrosine kinase involved in a pathway that promotes cell survival, cell proliferation, and tissue regeneration in the presence of hepatocyte growth factor.47 MET exon 14– skipping mutation is a type of MET gene alteration that dysregulates the pathway and may lead to

HIGH POTENTIAL DISRUPTION REPORT • November 2020 27

cancer by causing uncontrolled cell proliferation, spread, and survival.47,48 MET alterations occur in about 3% to 4% of NSCLC cases and are associated with poor prognosis.47 Therefore, patients with MET-altered NSCLC need new treatment options that can improve health outcomes. Capmatinib (Tabrecta; INC280) is a novel, highly selective, small-molecule inhibitor of the MET protein intended to treat patients with MET-altered NSCLC.47,48 Capmatinib’s antikinase activity prevents downstream MET signaling, purportedly blocking NSCLC proliferation and promoting tumor shrinkage.47 Capmatinib is an oral therapy with a recommended dosage of 400 mg taken twice daily until disease progression or intolerable toxicity.49

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 12 registered trials for this topic. We present the 3 latest-phase, comparative trials with the earliest primary completion dates in Table 2.5. Table 2.5. Ongoing Clinical Trials Study name and Patient population and Study design and outcomes Estimated National Clinical planned enrollment date of Trials identifier completion Study of Efficacy and Patients (n = 64) with locally Phase 2, multicenter, parallel- Primary and Safety of Nivolumab advanced, recurrent and/or assignment, open-label trial to study in Combination With metastatic NSCLC as follows: determine that safety and efficacy of completion EGF816 and of Cohort 1: Patients with EGFR capmatinib in combination with December 2021 Nivolumab in T790M NSCLC nivolumab in patients with MET-altered Combination With (adenocarcinoma) with disease NSCLC INC280 in Patients progression after primary Primary end point: Progression-free With Previously standard of care (eg, erlotinib, survival Treated Non-Small gefitinib) Secondary end points: Adverse events, Cell Lung Cancer Cohort 2 Patients with EGFR objective response rate, disease control (EGF816) wild-type NSCLC with disease rate, and overall survival NCT02323126 progression after standard of care (eg, platinum doublet)

HIGH POTENTIAL DISRUPTION REPORT • November 2020 28

Study name and Patient population and Study design and outcomes Estimated National Clinical planned enrollment date of Trials identifier completion Clinical Study of Oral Patients (n = 368) with locally Phase 2, multicohort, parallel- Primary cMET Inhibitor advanced or metastatic NSCLC assignment, open-label trial to evaluate completion INC280 in Adult harboring EGFR wild-type and the safety and efficacy of capmatinib in February 2022 Patients With EGFR ALK rearrangement–negative, patients with MET-altered NSCLC Study Wild-Type Advanced as follows: Patients will receive oral capmatinib at completion Non-Small Cell Lung Cohorts 1, 2, and 3: Pretreated a dosage of 400 mg twice daily. March 2023 Cancer (GEOMETRY patients stratified by MET GCN Primary end point: Objective response mono-1) Cohort 4: Pretreated patients rate NCT02414139 with MET exon 14 mutation Secondary end points: Overall survival, See preliminary regardless of MET GCN progression-free survival, disease results by Wolf et al Cohort 5: Treatment-naïve control rate, duration of response, time 2020 under Recently patients with either MET GCN to response, and adverse events Completed and without MET exon 14 mutation Ongoing Trials With or MET exon 14 mutation Available Results. regardless of MET GCN Cohort 6: Pretreated patients with either MET GCN without MET exon 14 mutation or MET exon 14 mutation regardless of MET GCN Cohort 7: Treatment-naïve patients with MET exon 14 mutation regardless of MET GCN Study of Capmatinib Patients (n = 90) with advanced Phase 3, multicenter, randomized Primary Efficacy in or metastatic lung cancer and controlled, open-label trial comparing completion Comparison With MET exon 14 alterations but capmatinib with standard care September Docetaxel in without changes in EGFR or ALK docetaxel 2022 Previously Treated Patients were previously treated with Study Participants With systemic therapy and have wild-type completion Non-Small Cell Lung EGFR, ALK-negative, locally advanced or March 2024 Cancer Harboring metastatic (stage IIIB/IIIC or IV) NSCLC MET Exon 14 Skipping harboring a MET exon 14–skipping Mutation mutation. NCT04427072 Patients will receive oral capmatinib at a dosage of 400 mg twice daily. Primary end point: Progression-free survival Secondary end points: Adverse events, overall response, time to response, duration of response, disease control rate, and overall survival

Abbreviations: ALK, anaplastic lymphoma kinase gene; EGFR, epidermal growth factor receptor gene; GCN, gene copy number; MET, MET proto-oncogene receptor tyrosine kinase gene; NSCLC, non–small cell lung cancer.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 29

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial with published results.50 We summarize results as written in an abstract of a published study. The following abbreviations are used in this section: AEs, adverse events; ALK, anaplastic lymphoma kinase gene; CI, confidence interval; EGFR, epidermal growth factor receptor gene; GCN, gene copy number; MET, MET proto-oncogene receptor tyrosine kinase gene; NSCLC, non– small cell lung cancer.

Clinical Study of Oral cMET Inhibitor INC280 in Adult Patients With EGFR Wild-Type Advanced Non-Small Cell Lung Cancer (GEOMETRY mono-1). NCT02414139. Wolf et al 2020.50 • Patient population/planned enrollment: Patients (n = 373) with locally advanced or metastatic NSCLC harboring EGFR wild-type and ALK rearrangement–negative, as follows: o Cohorts 1, 2, and 3: Pretreated patients stratified by MET GCN o Cohort 4: Pretreated patients with MET exon 14–skipping mutation regardless of MET GCN o Cohort 5: Treatment-naïve patients with either MET GCN without MET exon 14–skipping mutation or MET exon 14–skipping mutation regardless of MET GCN o Cohort 6: Pretreated patients with either MET GCN without MET exon 14–skipping mutation or MET exon 14–skipping mutation regardless of MET GCN o Cohort 7: Treatment-naïve patients with MET exon 14–skipping mutation regardless of MET GCN • Study design: Phase 2, multicohort, parallel-assignment, open-label trial to evaluate the safety and efficacy of capmatinib in patients with MET-altered NSCLC. Patients received oral capmatinib at a dosage of 400 mg twice daily. • Primary outcome: Overall response rate • Secondary outcomes: Overall survival, progression-free survival, disease control rate, duration of response, time to response, and AEs • Results presented by study authors: “A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.” Manufacturers and Regulatory Status Novartis AG (Basel, Switzerland) manufactures capmatinib. In May 2020, FDA granted capmatinib accelerated approval for treating adults with metastatic NSCLC whose tumors have a mutation that leads to MET exon 14 skipping. The approval was based on data from the phase 2 GEOMETRY mono-1 trial. Patients’ genetic eligibility for this treatment must be detected by a test that FDA also approved in May 2020, FoundationOne CDx (Foundation Medicine Inc, Cambridge, Massachusetts), which detects genetic mutations that lead to MET exon 14 skipping in tumor tissue.51 FDA earlier had granted Orphan Drug and Breakthrough Therapy designations to capmatinib for previously treated or treatment-naïve advanced NSCLC in patients with a MET exon 14– skipping mutation.52-54

HIGH POTENTIAL DISRUPTION REPORT • November 2020 30

Cost Information According to a US-based online aggregator of prescription drug prices, GoodRx, capmatinib’s retail price (as of October 8, 2020) was about $17 710 for one hundred twelve 200-mg tablets, which represents a 28-day supply of the drug.55 Thus, a 1-year supply of capmatinib would cost about $230 860.55 Key Stakeholder Perspectives Between February 11, 2020, and February 26, 2020, eight stakeholders, reflecting health systems, nursing, patient advocate, physician, and research perspectives, provided comments and ratings on this topic. These comments were received before FDA approval of the therapy in May 2020. The list below provides a summary of key stakeholder perspectives. • Patients with NSCLC who have a MET exon 14–skipping mutation have a poor prognosis, and off-label treatment with crizotinib or cabozantinib has yielded low response rates. Available data suggest that capmatinib has the potential to improve health outcomes. Because these results are from a nonrandomized trial, however, additional confirmatory data from randomized controlled trials are needed. • As an oral drug, capmatinib is unlikely to affect health center infrastructure. But if trials demonstrate safety and efficacy, it has the potential to disrupt the health care delivery system by incorporating MET genetic testing into the patient’s clinical pathway and physician workflow. The therapy could also disrupt the current care paradigm as a viable therapy for patients who have few and ineffective treatment options. • Capmatinib is expected to be expensive and could cause disparities for uninsured patients and underinsured patients. It could also cause disparities for patients living in rural areas or places that have only community health centers with limited offerings and do not have health centers affiliated with large regional centers that have access to MET genetic testing to determine eligibility. • Capmatinib has the potential to increase costs associated with genetic testing, monitoring, and mitigating adverse events. But if trials demonstrate that it slows disease progression and improves quality of life, patients could have fewer health care visits and hospitalizations, thus decreasing costs.

Idecabtagene Vicleucel (ide-cel) to Treat Relapsed and Refractory Multiple Myeloma Highlights • Idecabtagene vicleucel (ide-cel) is an engineered chimeric antigen receptor (CAR) T-cell therapy that uses the patient’s own T cells to target multiple myeloma cells overexpressing the B-cell maturation antigen (BCMA). Given intravenously as a single infusion, the therapy is under FDA priority review for approval, and a decision is anticipated in March 2021. • Most patients with multiple myeloma develop relapsed and refractory multiple myeloma (RRMM), which no longer responds to ongoing treatment and is unlikely to respond to subsequent standard treatments. • Stakeholders commenting on this topic thought that ide-cel represents a novel type of treatment with potential to improve outcomes and quality of life in patients whose disease no longer responds to standard treatments.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 31

• Stakeholders also thought that, if ide-cel is priced similarly to other CAR T-cell therapies (ie, range of $373 000 to $475 000 plus administration, monitoring, and complication costs), its high cost and limited availability might increase disparities. Patient Population Ide-cel is intended for adults who have RRMM that has been treated with 3 or more lines of therapy, including a protease inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. Intervention Multiple myeloma is the second most common hematologic malignancy, with about 32 000 new cases per year in the United States. It occurs when blood plasma cells (differentiated B cells) become malignant and grow out of control. The American Cancer Society offers more information on multiple myeloma. In the past 15 years, several new therapeutic agents for multiple myeloma have become available and, when used sequentially, have improved patient survival. However, most patients eventually have disease that no longer responds to standard therapies.56 Patients with heavily treated RRMM need new interventions to address this problem. BCMA is a receptor expressed preferentially by plasma cells, with little or no expression in other blood cells or tissues. BCMA is highly overexpressed in malignant plasma cells from patients with multiple myeloma compared with plasma cells from healthy individuals, and its high levels are associated with cell proliferation and survival and progressive disease.56,57 Therefore, BCMA is a promising target for multiple myeloma therapies. Ide-cel is a CAR T-cell therapy that has been engineered to target BCMA using the patient’s own T cells.57,58 T cells collected from a blood sample are sent to a laboratory to be genetically modified using a lentiviral vector encoding an anti-BCMA CAR. The genetically modified T cells that compose ide-cel are grown in number and then reintroduced into the patient.58 The treatment purportedly targets malignant BCMA-expressing plasma cells to promote a robust immune response against these cells to treat the disease.56-58 An oncologist prescribes ide-cel to be given at a hospital that is capable of providing the specialized care required for CAR T-cell administration. An oncology nurse gives the patient a single intravenous infusion at a dose ranging from 150 × 106 to 450 × 106 CAR T cells. After treatment, the patient remains hospitalized and is monitored for cytokine release syndrome for 14 to 21 days.58

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present these trials in Table 2.6.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 32

Table 2.6. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier An Efficacy and Safety Patients (n = 181) who Phase 2, single-group assignment, Primary Study of bb2121 in have RRMM that has been open-label, multicohort trial to evaluate completion Subjects With Relapsed treated with at least 3 the safety and efficacy of ide-cel in October 2021 and Refractory Multiple lines of therapy, including patients with RRMM Study Myeloma and in Subjects prior treatment with a Patients will receive a single ide-cel completion May With High-Risk Multiple protease inhibitor, an infusion at a dose of 150 × 106 to 2026 Myeloma (KarMMa-2) immunomodulatory 450 × 106 CAR T cells. NCT03601078 agent, and an anti-CD38 Primary end points: Overall response antibody (cohort 1) or rate and complete response rate high-risk multiple Secondary end points: Overall survival, myeloma that has been progression-free survival, duration of treated with only one response, time to response, time to previous line of therapy progression, adverse events, and (cohort 2) quality of life Efficacy and Safety Study Patients (n = 381) who Phase 3, randomized controlled Primary of bb2121 Versus have RRMM that has been parallel-assignment, open-label trial to completion May Standard Regimens in treated with 2 to 4 lines of evaluate the safety and efficacy of ide- 2022 Subjects With Relapsed therapy, including cel in patients with RRMM Study and Refractory Multiple treatment with a protease Patients will be randomly assigned to completion Myeloma (KarMMa-3) inhibitor, an receive either a single ide-cel infusion at November 2025 NCT03651128 immunomodulatory a dose of 150 × 106 to 450 × 106 CAR T agent, and an anti-CD38 cells or investigator’s choice of anti- antibody myeloma therapy. Primary end point: Progression-free survival Secondary end points: Overall survival, event-free survival, overall response rate, complete response rate, duration of response, time to response, time to progression, adverse events, and quality of life

HIGH POTENTIAL DISRUPTION REPORT • November 2020 33

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Efficacy and Safety Study Patients (n = 149) who Phase 2, single-group assignment, Primary and of bb2121 in Subjects have RRMM that has been open-label trial to evaluate the safety study With Relapsed and treated with at least 3 and efficacy of ide-cel in patients with completion Refractory Multiple lines of therapy, including RRMM November 2024 Myeloma (KarMMa) prior treatment with a Patients will receive a single ide-cel NCT03361748 protease inhibitor, an infusion at a dose of 150 × 106 to immunomodulatory 450 × 106 CAR T cells. agent, and an anti-CD38 Primary end point: Overall response antibody rate Secondary end points: Overall survival, progression-free survival, complete response rate, duration of response, time to response, time to progression, adverse events, and quality of life Abbreviations: CAR, chimeric antigen receptor; RRMM, relapsed and refractory multiple myeloma.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial with published results.59 We summarize results as written in a conference abstract. The following abbreviations are used in this section: AUC0-28d, area under the curve describing the variation of ide-cel’s concentration in blood after 28 days; CAR, chimeric antigen receptor; Cmax, maximum concentration; CRS, cytokine release syndrome; d, days; Gr, grade; mo, months; ORR, overall response rate; PFS, progression-free survival; pts, patients; RRMM, relapsed and refractory multiple myeloma, y, years.

Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma (KarMMa). NCT03361748. Munshi et al 2020.59

• Patient population/planned enrollment: Patients (n = 140) with RRMM that had been treated with at least 3 lines of therapy consisting of a protease inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, either sequentially or in the same line • Study design: Phase 2, single-group assignment, open-label trial to evaluate the safety and efficacy of ide- cel in patients with RRMM. Patients will receive a single ide-cel infusion at a dose of 150 × 106 to 450 × 106 CAR T cells. • Primary outcome: ORR • Secondary outcomes: PFS, complete response, duration of response, and adverse events • Results presented by study authors: “Of 140 pts enrolled, 128 received ide-cel. Median age was 61 y; median no. of prior regimens was 6; 84% were triple- and 26% were penta-refractory. Most pts (88%) had bridging therapy. At data cutoff (16 Oct 2019), median follow up was 11.3 mo. ORR was 73% and median PFS was 8.6 mo; both increased with higher dose (Table). All subgroups had an ORR ≥50%, including older and high-risk pts. Most common any-grade (Gr) toxicities were cytopenias (97%) and cytokine release syndrome (CRS; 84%). CRS was mainly Gr 1/2; 5 pts (5%) had Gr 3, 1 had Gr 4, and 1 had Gr 5 (at 300 × 106). Neurotoxicity developed in 23 pts (18%); 4 (3%) Gr 3 and 0 Gr ≥4. Median peak CAR+ T cell expansion

occurred at 11 d. Expansion was higher in responders and parameters (AUC0−28d, Cmax) increased with higher dose, with exposure overlap across doses. Persistence was durable, with CAR+ T cells detected in 29/49 (59%) and 4/11 pts (36%) at 6 and 12 mo.”

HIGH POTENTIAL DISRUPTION REPORT • November 2020 34

Manufacturers and Regulatory Status Investigators at bluebird bio, Inc (Cambridge, Massachusetts), in collaboration with Bristol Myers Squibb Co (New York, New York), are studying ide-cel for treating RRMM in two phase 2 clinical trials (KarMMa and KarMMa-2) and one phase 3 clinical trial (KarMMa-3). Based on results from the KarMMa trial, the companies submitted a Biologics License Application (BLA) to FDA in March 2020.60 In May 2020, FDA issued a Refusal to File letter to the companies, in which FDA determined that it needed more detail on the BLA’s chemistry, manufacturing, and control module to complete review.61 In July 2020, the companies resubmitted the BLA to address this request.62 FDA accepted the BLA on September 22, 2020, granted priority review, and issued a Prescription Drug User Fee Act (PDUFA)-prescribed action date of March 27, 2021.63 FDA has granted ide-cel Orphan Drug and Breakthrough Therapy designations to treat RRMM.64,65 Cost Information Cost information is unavailable for this topic. Costs of other CAR T-cell therapies already approved by FDA range from $373 000 to $475 000 plus costs for administration, monitoring, and treatment for complications, which can bring the total close to $1 000 000. Key Stakeholder Perspectives Between September 4, 2020, and September 22, 2020, eight stakeholders, reflecting clinical, health systems, nursing, patient, patient representative, and research perspectives, provided comments and ratings on ide-cel. The list below provides a summary of key stakeholder perspectives. • Because patients with RRMM have very few treatment options, ide-cell has potential to improve outcomes and quality of life. Ide-cel represents a novel treatment type that requires a single infusion to benefit patients. • As a cell-based therapy, ide-cel is expected to create disparities, due to high costs and additional costs for hospitalization and supportive care. Even with help from insurance, patients of low and middle economic status will likely have difficulty affording ide-cel. • Patients living in rural and remote areas might also have difficulty reaching large health centers with the necessary specialists and infrastructure to offer ide-cel treatment. • Ide-cel has potential to shift care from an outpatient setting to a hospital setting, which is required to offer treatment and monitor patients up to 3 weeks for cytokine release syndrome. • Ide-cel represents a novel treatment for patients who have exhausted their options. Its complexity involving development, treatment, monitoring, outcomes, and adverse events requires patients and clinicians to learn about the process to know what to expect.

Lifileucel (LN-144) as Second-Line Treatment for Locally Advanced or Metastatic Melanoma Highlights • Lifileucel is a cell-based therapy that uses a patient’s own tumor-infiltrating lymphocytes (TILs) to enhance antitumor immune responses against melanoma. The developer expected to submit a Biologics License Application to FDA by the end of 2020.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 35

• TIL therapy offers a new therapeutic paradigm for treating melanoma because it may address key challenges encountered with standard treatment options. • Patients with metastatic melanoma need more effective options after standard therapies have failed. • Stakeholders commenting on this topic thought lifileucel has the potential to improve patient health outcomes as a treatment option for progressive disease or after standard-of-care treatment has been exhausted. • As a second-line, personalized, cell-based therapy, lifileucel is expected to be very expensive due to complex manufacturing requirements and required adjunctive treatment, thus creating disparities that would restrict access for some patients. Patient Population Lifileucel is intended for adults aged 18 years or older who have unresectable or metastatic melanoma that has progressed after one or more lines of systemic therapy, including an immune checkpoint inhibitor. Patients with disease containing a BRAF (B homolog of the rapidly accelerated fibrosarcoma) gene V600 variation are given a BRAF inhibitor alone or in combination with a MEK (MAPKK [mitogen-activated protein kinase kinase]/ERK [extracellular signal– regulated kinase] kinase) inhibitor. Intervention Melanoma is a type of skin cancer that originates from melanocytes, which make the pigment melanin. Among skin cancers, melanoma is less common, but it is most likely to spread to other parts of the body. The American Cancer Society offers more information about melanoma. Lifileucel (LN-144) is an autologous T-cell therapy that uses TILs, which are naturally occurring T cells that are embedded in and directed against the patient’s melanoma tumor. To produce lifileucel, a patient’s tumor sample is shipped to a centralized manufacturing facility where TILs are isolated from the sample and multiplied in the laboratory until a certain number are generated.66 The manufacturing process takes about 22 days from biopsy receipt to shipping lifileucel back to the treating institution.67 The patient is then given a pretreatment chemotherapy (fludarabine and cyclophosphamide), which neither destroys bone marrow nor reduces lymphocytes, to reduce the immunosuppressive tumor environment before receiving the TIL infusion.66-68 Lifileucel purportedly offers a new therapeutic paradigm for treating solid tumors because it addresses some of the key challenges encountered in treatment: (1) tumor cells that vary in makeup, with multiple gene variants driving the cancer; (2) critical gene variants that drive the cancer and are potential treatment targets but that are unclear to physicians; (3) tumors that resist treatments targeting a single variant; (4) tumor mechanisms that reduce the body’s immune response (ie, immunosuppression); and (5) immunosuppression that arises from standard-of-care treatment options.67 After lifileucel has been manufactured, an infusion nurse gives a single intravenous infusion containing between 1 × 109 and 1 × 1011 TILs in an outpatient setting. Patients also receive up to 6 doses of interleukin 2 (IL-2) immediately after infusing lifileucel to support TIL growth, activation, and efficacy.66

HIGH POTENTIAL DISRUPTION REPORT • November 2020 36

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 4 ongoing trials for this topic. We present one phase 2 trial in Table 2.7. We excluded an unphased trial (NCT01701674), a phase 1 trial (NCT02652455), and a phase 2 trial (NCT03645928) because they focus on a different patient population (ie, patients who have not received an immune checkpoint inhibitor). Table 2.7. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier innovaTIL-01, Study of Patients (n = 178) aged 18 Phase 2, multicohort, open-label, Primary Lifileucel (LN-144), years or older with locally parallel-assignment study evaluating completion Autologous Tumor advanced or metastatic the safety and efficacy of lifileucel July 2020 Infiltrating Lymphocytes, melanoma whose disease Patients will be assigned to Study in the Treatment of has progressed after one lymphocyte-depleting treatment with completion Patients With Metastatic or more lines of systemic fludarabine and cyclophosphamide December 2024 Melanoma (C-144-01) therapy, including an followed by lifileucel infusion and up NCT02360579 immune checkpoint to 6 doses of IL-2 (600 000 IU/kg) to inhibitor and a BRAF support TIL replication and inhibitor alone or in engraftment. combination with a MEK Primary outcome: Objective response inhibitor for patients with rate BRAF V600 mutation– Secondary outcomes: Overall survival, positive melanoma, as progression-free survival, duration of follows: response, disease control rate, and Cohort 1: First-generation adverse events TILs, not cryopreserved Cohort 2: Second- generation TILs, cryopreserved (closed) Cohort 3: Patients from cohorts 1, 2, and 4 who will receive a second dose of TILs Cohort 4: Second-generation TILs, cryopreserved

Abbreviations: BRAF, B homolog of the rapidly accelerated fibrosarcoma gene; IL-2, interleukin 2; MEK, MAPKK (mitogen-activated protein kinase kinase)/ERK (extracellular signal–regulated kinase) kinase; TIL, tumor-infiltrating lymphocyte.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial with published results.69 We summarize results as written in a conference abstract and manufacturer news release. The following abbreviations are used in this section: BRAF, B homolog of the rapidly accelerated fibrosarcoma gene; CR, complete response; CTLA-4, cytotoxic T-lymphocyte- associated protein 4; DCR, disease control rate; IL-2, interleukin 2; LDH, lactate dehydrogenase; mDOR, median duration of response; MEK, MAPKK (mitogen-activated protein kinase

HIGH POTENTIAL DISRUPTION REPORT • November 2020 37

kinase)/ERK (extracellular signal–regulated kinase) kinase; ORR, objective response rate; PD1, programmed death 1; PR, partial response; TIL, tumor-infiltrating lymphocyte; ULN, upper limit of normal. innovaTIL-01, Study of Lifileucel (LN-144), Autologous Tumor Infiltrating Lymphocytes, in the Treatment of Patients With Metastatic Melanoma (C-144-01). NCT02360579. Sarnaik et al 2020,69 Iovance 2020.70

• Patient population/planned enrollment: Patients (n = 178) aged 18 years or older with locally advanced or metastatic melanoma whose disease has progressed after one or more lines of systemic therapy, including an immune checkpoint inhibitor and a BRAF inhibitor alone or in combination with a MEK inhibitor for patients with BRAF V600 mutation–positive melanoma, as follows: o Cohort 1: First-generation TILs, not cryopreserved o Cohort 2: Second-generation TILs, cryopreserved (closed) o Cohort 3: Patients from cohorts 1, 2, and 4 who will receive a second dose of TILs o Cohort 4: Second-generation TILs, cryopreserved • Study design: Phase 2, multicohort, open-label, parallel-assignment study evaluating the safety and efficacy of lifileucel. Patients were assigned to lymphocyte-depleting treatment with fludarabine and cyclophosphamide followed by lifileucel infusion and up to 6 doses of IL-2 (600 000 IU/kg) to support TIL replication and engraftment. • Primary outcome: ORR • Secondary outcomes: Duration of response, disease control rate, and adverse events • Results presented for cohort 2 by study authors: “[In 66 patients with unresectable melanoma, baseline statistics were as follows:] 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), high baseline tumor burden (106 mm mean target lesion sum of diameters), 44% liver/brain lesions, 40.9% LDH > ULN. ORR by investigator was 36.4% (2 CR, 22 PR) and DCR was 80.3%. Mean time to response was 1.9 months (range: 1.3-5.6). After a median study follow-up of 17.0 months, median DOR (mDOR) was still not reached. Six responders have progressed, 2 have died and 2 started other anti-cancer therapy without progression. The adverse event profile was consistent with the underlying advanced disease and the lymphodepletion and IL-2 regimens.” • Results presented for cohort 4 in a manufacturer news release: “[In 68 patients with 2 radiological assessments] Lifileucel shows a 32.4% overall response rate (1 complete response and 21 partial responses, 2 of which are yet to be confirmed with follow up visits) and a disease control rate of 72.1% as of the data cut off of 16 Mar 2020. This data is consistent with what was noted in Cohort 2 at 6 months of median study follow up. The ORR was 33%.” Manufacturers and Regulatory Status Iovance Biotherapeutics, Inc (San Carlos, California), in collaboration with the National Institutes of Health’s National Cancer Institute (Bethesda, Maryland), is studying lifileucel in a phase 2 clinical trial. The company reported receiving Fast Track and Regenerative Medicine Advanced Therapy designations from FDA for treating advanced melanoma.71,72 In an end-of-phase-2 meeting, FDA indicated that the available data were insufficient for regulatory approval and recommended amending the ongoing C-144-01 trial to add a new cohort. This cohort, known as cohort 4, will enroll between 80 and 100 patients and its data will be the basis of a Biologics License Application, which Iovance planned to submit to FDA in the second half of 2020.72 Cost Information Cost information is unavailable for this topic, but in general, costs of cell-based personalized therapies are very high because of complex manufacturing requirements and adjunctive treatment required (eg, IL-2).

HIGH POTENTIAL DISRUPTION REPORT • November 2020 38

Key Stakeholder Perspectives Between June 1, 2020, and August 31, 2020, six stakeholders, reflecting nursing, patient advocate, physician, and research perspectives, provided comments and ratings on lifileucel. The list below provides a summary of key stakeholder perspectives. • Lifileucel could improve health outcomes in heavily treated patients whose disease has failed to respond to previous lines of therapy and who lack effective treatment options. • Unanticipated issues with shipping the biopsies and returning the expanded TILs might create delays in treatment. • Lifileucel might create disparities for patients who cannot pay its anticipated high cost and who do not have access to large medical centers experienced in providing immunotherapies. • Lifileucel is expected to be expensive and likely to be a cost burden to patients and payers. • Results from future randomized controlled trials are needed to provide better information on treatment benefits and to substantiate current findings.

MDNA55 to Treat First Recurrence of Recurrent Glioblastoma Multiforme Highlights • MDNA55 is a genetically engineered therapy composed of a protein that binds the interleukin 4 receptor (IL-4R) and a bacteria-derived endotoxin to kill cancer cells and immunosuppressive cells overexpressing IL-4R. It is in phase 2 development. • Patients with recurrent glioblastoma multiforme (GBM) have poor outcomes and short survival and lack effective treatment options for recurrent disease. • A neurosurgeon delivers the therapy through a thin tube (ie, cannula) inserted directly into the patient’s tumor during a minimally invasive procedure using stereotactic guidance. • Stakeholders commenting on MDNA55 agreed that it offers a novel approach to treat GBM, with potential to improve patient health outcomes. Although available data seem promising, additional data from larger studies are needed to assess MDNA55’s potential for disruption. • Stakeholders also thought that, because health centers offering MDNA55 would require changes in infrastructure, care setting, and personnel, the drug also could disrupt delivery and paradigms of care and be very costly. Patient Population MDNA55 is intended for adults aged 18 years or older with recurrent or progressive GBM. Intervention GBM is a malignant brain cancer associated with poor outcomes and high death rates. GBM begins as stage IV disease with no evidence of a lower-grade precursor. The American Brain Tumor Association website offers more information about GBM. Patients who have undergone primary treatment of surgery, radiation, and temozolomide chemotherapy typically experience disease recurrence in about 7 months. Even with treatment, patients with recurrent GBM have a median overall survival of 15 months and a 2-year survival rate of 27%,73 emphasizing the need for new therapies capable of treating recurrent disease and extending survival. MDNA55 is a novel, genetically engineered fusion protein composed of a circularly permuted interleukin 4 (cpIL-4) molecule fused to Pseudomonas aeruginosa exotoxin A (PE), a protein-

HIGH POTENTIAL DISRUPTION REPORT • November 2020 39

synthesis inhibitor. MDNA55 is designed to target IL-4R, a cell-surface receptor overexpressed in various types of cancer stem cells and immunosuppressive cells composing the tumor microenvironment. MDNA55 functions like a “molecular Trojan horse” because cpIL-4 binding to IL-4R triggers receptor-mediated cell take-up to deliver the cytotoxic PE payload into the target cells’ cytoplasm. Via IL-4R targeting, MDNA55 purportedly kills GBM stem cells and immunosuppressive cells in the tumor microenvironment with high specificity.74 A neuro-oncologist prescribes MDNA55, which is administered in a hospital by a neurosurgeon during a minimally invasive surgical procedure using a technique (ie, convection-enhanced delivery) that allows delivery of the drug through a thin tube (ie, cannula) inserted directly into the tumor under stereotactic guidance. The starting dose is 63 μg. Depending on response to the initial dose, patients may be eligible for a second MDNA55 treatment.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database did not identify any ongoing trials for this topic. Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial published as a conference abstract.75 We summarize results as written in the abstract. The following abbreviations are used in this section: AEs, adverse events; CED, convection- enhanced delivery; CI, confidence interval; GBM, glioblastoma multiforme; IL4R, interleukin 4 receptor; KPS, Karnofsky performance scale; MGMT, O6-methylguanine-DNA methyltransferase; mOS, median overall survival; OS, overall survival; OS12, overall survival at 12 months; SCA, synthetic control arm, p, probability; vs, versus.

Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Recurrent or Progressive Glioblastoma (MDNA55-05). NCT02858895. Sampson et al 2020.75

• Patient population/planned enrollment: Patients (n = 46) with GBM that has recurred or progressed after primary treatment • Study design: Phase 2, single-group assignment, open-label trial to evaluate the safety and efficacy of MDNA55 in patients with GBM. Patients received a single MDNA55 infusion via CED. Based on response, patients might have received a second MDNA55 infusion. • Primary outcome: OS • Secondary outcomes: Objective response rate, progression-free survival, and AEs • Results presented by study authors: “44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide.”

HIGH POTENTIAL DISRUPTION REPORT • November 2020 40

Manufacturers and Regulatory Status Medicenna Therapeutics Corp (Toronto, Ontario, Canada) is developing MDNA55 in an ongoing phase 2 trial. FDA has granted MDNA55 Orphan Drug and Fast Track designations for treating patients with recurrent GBM.74,76 Cost Information Cost information is unavailable for this topic, but stakeholders expect the therapy to be very costly. Key Stakeholder Perspectives Between May 28, 2020, and August 12, 2020, six stakeholders, reflecting health systems, nursing, physician, and research perspectives, provided comments and ratings on MDNA55. The list below provides a summary of key stakeholder perspectives. • MDNA55 represents a new treatment approach with potential to improve health outcomes and quality of life for patients with recurrent GBM, a disease with a high death rate and short life expectancy. But larger trials are needed to fully support these claims. • MDNA55’s convection-enhanced delivery would disrupt the health care delivery system and paradigm of care because, unlike drugs taken orally or in outpatient settings, MDNA55’s delivery requires changes in care setting, infrastructure, and personnel. • Similar to many new specialty drugs and biologics, MDNA55 could be very expensive and have potential to create health disparities. • Stakeholders thought that, if subsequent data from larger studies demonstrate its safety and efficacy, MDNA55 will have high overall potential to disrupt how GBM is treated, pointing out that patients with GBM need new therapy options because the current standard of care offers limited health benefits.

Nanoparticle Albumin-Bound Sirolimus (ABI-009) to Treat Locally Advanced or Metastatic Perivascular Epithelioid Cell Sarcoma Highlights • Nanoparticle albumin-bound sirolimus (nab-sirolimus) is a novel formulation, given intravenously, of an inhibitor that targets a molecular pathway known as the mammalian target of rapamycin (mTOR) pathway. This pathway is involved in cell proliferation and is upregulated in perivascular epithelioid cell sarcoma (PEComa). • PEComa is a rare soft tissue sarcoma with no FDA-approved therapy. Nab-sirolimus is in phase 2 development, and the company has initiated a rolling New Drug Application to FDA. • Stakeholders commenting on this topic agreed that nab-sirolimus could improve health outcomes for patients with PEComa, but because it is expected to be more costly than other mTOR inhibitors, nab-sirolimus might create disparities for uninsured patients or those who cannot afford deductibles and copayments. • Stakeholders also thought that nab-sirolimus is unlikely to disrupt the health care delivery system because it will use infrastructure that is already in place for intravenous treatments, but because of a lack of treatment options, it might disrupt current care paradigms.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 41

Patient Population Nab-sirolimus is intended for adults aged 18 years or older with locally advanced or metastatic PEComa. Intervention PEComa is a rare sarcoma that originates in the soft tissues of the stomach, intestines, lungs, and genitourinary organs. Although most PEComas are noncancerous benign tumors that grow slowly and are unlikely to spread to other organs, some are malignant, with potential to spread to other parts of the body. The National Cancer Institute’s Physician Data Query offers more information about PEComa. No targeted therapies are approved by FDA for use in treating malignant PEComas, and PEComas usually do not respond well to cytotoxic chemotherapy. Therefore, patients with PEComa need new treatment options that can improve health outcomes.77 A molecular pathway called the mTOR pathway is involved in PEComa cell proliferation. Off- label use of commercially available mTOR-inhibitor drugs has shown some benefit for these patients. However, these mTOR inhibitors distribute widely in the body and affect normal cells as well as tumor cells, leading to adverse events.77,78 Nab-sirolimus is a novel mTOR inhibitor in a form that purportedly accumulates preferentially in cancer cells. The drug is a nanoparticle suspension, and each nanoparticle consists of several molecules of sirolimus (an mTOR inhibitor) bound to human albumin.78,79 Cancer cells take up blood albumin to support protein synthesis; thus, albumin may act as a carrier that helps sirolimus accumulate preferentially in tumor tissues.79 Once the nanoparticles enter cells and inhibit the mTOR pathway, nab-sirolimus purportedly prevents tumor cell growth, proliferation, nutrient metabolization, and blood vessel formation.77,78 An oncologist prescribes nab-sirolimus to be given at an infusion center. An infusion nurse administers intravenous nab-sirolimus weekly at a dosage of 100 mg/m2 in a 2-weeks-on, 1-week- off schedule until disease progression or intolerable toxicity.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 2.8.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 42

Table 2.8. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier A Phase 2 Study of ABI- Patients (n = 34) aged 18 Phase 2, single-group assignment, Primary 009 in Patients With years or older with locally open-label trial to evaluate the safety completion Advanced Malignant advanced or metastatic and efficacy of nab-sirolimus in September 2020 PEComa (AMPECT) PEComa patients with PEComa Study NCT02494570 Patients receive weekly nab-sirolimus completion intravenously in a 2-weeks-on, 1- September 2021 week-off schedule Primary end point: Objective response rate Secondary end points: Overall survival, progression-free survival, duration of response, and adverse events Nivolumab (Opdivo) Plus Patients (n = 40) aged 12 Phase 1/2 single-group assignment, Primary ABI-009 (Nab-rapamycin) years or older with a open-label trial to evaluate the safety, completion for Advanced Sarcoma histologically confirmed toxicity, and potential antitumor February 2021 and Certain Cancers diagnosis of Ewing’s activity of sequential administration of Study NCT03190174 sarcoma, PEComa, nivolumab and escalating doses of the completion April epithelioid sarcoma, mTOR inhibitor ABI-009 in patients 2021 desmoid tumor, chordoma, with diseases listed in the previous non–small cell lung cancer, column small cell lung cancer, Patients will receive escalating doses urothelial carcinoma, of intravenous ABI-009 over 30 melanoma, renal cell minutes for 2 of every 3 weeks carcinoma, squamous cell beginning in week 2. Only nivolumab carcinoma of the head and will be given in week 1. neck, hepatocellular Following a cohort-of-3 design, 3 to 6 carcinoma, classic Hodgkin patients will receive dose level 1 of 56 lymphoma, or MSI- mg/m2; 3 to 6 patients will receive H/dMMR metastatic dose level 2 of 75 mg/m2; and 3 to 6 colorectal cancer, and patients will receive dose level 3 of tumors with genetic 100 mg/m2. mutations sensitive to Primary end point: Maximum mTOR inhibitors, that is tolerable dose either metastatic or locally Secondary end points: Disease control advanced and for which rate and progression-free survival surgery is not a recommended option Abbreviations: MSI-H/dMMR, microsatellite instability–high, deficient mismatch repair; mTOR, mammalian target of rapamycin; PEComa, perivascular epithelioid cell tumor.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial with published results.80 We summarize results as written in a conference abstract.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 43

The following abbreviations are used in this section: AEs, adverse events; CI, confidence interval; CR, complete response; DOR, duration of response; IRR, independent radiology review; ORR, objective response rate; OS, overall survival; PD, progressive disease; PEComa, perivascular epithelioid cell sarcoma; PFS, progression-free survival; PFS6, 6-month progression-free survival; PR, partial response; pts, patients; SD, stable disease; TRAEs, treatment-related adverse events.

A Phase 2 Study of ABI-009 in Patients With Advanced Malignant PEComa (AMPECT). NCT02494570. Dickson et al 2019.80

• Patient population/planned enrollment: Patients (n = 34) aged 18 years or older with locally advanced or metastatic PEComa • Study design: Phase 2, single-group assignment, open-label trial to evaluate the safety and efficacy of nab-sirolimus in patients with PEComa. Patients received intravenous nab-sirolimus at a weekly dose of 100 mg/m2 in a 2-weeks-on, 1-week-off schedule. • Primary outcome: ORR • Secondary outcomes: OS, PFS, DOR, and AEs • Results presented by study authors: “A total of 34 patients were treated. At the time of primary analysis (May 29, 2019), treatment was ongoing for 29% (10/34) patients. The most common primary site of tumors was the uterus (24%), pelvis (18%), retroperitoneum (18%), lung (12%), kidney (12%). 94% of patients had prior surgery and 21% had prior systemic therapy. Of the 34 enrolled pts, 29 (85%) had metastatic disease and 5 (15%) had locally advanced inoperable disease. 31 patients were evaluable for efficacy (ie, with centrally confirmed PEComa). The median time on treatment was 6.1 months (95% CI: 0.3, 28). The confirmed ORR by IRR was 39%, all partial responses (PR, 12/31, 95% CI: 21.8, 57.8), 52% stable disease (16/31, with 10/16 SD ≥12 weeks), and 10% progressive disease (PD 3/31); the disease control rate (CR + PR + SD ≥12 weeks) was 71%. One patient had an unconfirmed PR without subsequent scans and was assessed as SD ≥12 weeks. The majority of PRs (67%) were reached at the first post-baseline scan at week 6, with a median time to response of 1.4 months (95% CI: 1.3 to 2.8). The median DOR by independent review was not yet reached (range 4.2 to 27.7+ months), 75% (9/12) of PRs are ongoing, with 4 responders >1 year and 3 responders >2 year on therapy. Median PFS by IRR was 8.9 months (95% CI: 5.5; --) and PFS6 was 70%. Median OS was not reached, with 29 patients alive at the time of the primary analysis. One patient with locally advanced inoperable disease at study entry was able to undergo surgery after treatment for 6.9 months. Investigator-assessed confirmed responses were similar, with 42% ORR, 48% SD (10/15 SD ≥12 weeks), and 10% PD. The most common (>30%) nonhematologic treatment-related AEs (TRAEs) of any grade were mucositis (79%), fatigue (59%), rash (56%), nausea (47%), diarrhea/weight loss (38% each), hyperglycemia (35%), and hypertriglyceridemia/hypercholesterolemia/decreased appetite (32% each). The most common (>30%) hematologic TRAEs were anemia (47%) and thrombocytopenia (32%). Pneumonitis (18%) was grade 1 or 2. The most common (>10%) grade 3 TRAEs were mucositis (18%), anemia (12%); No grade ≥4 TRAEs were observed. Mutational analysis was available for 25 patients and is reported separately.” Manufacturers and Regulatory Status Investigators at Aadi Bioscience, Inc (Pacific Palisades, California), are studying nab-sirolimus in a phase 2 clinical trial. FDA has granted nab-sirolimus Orphan Drug, Fast Track, and Breakthrough Therapy designations to treat PEComa.81,82 Aadi Bioscience has initiated a rolling submission for a New Drug Application to FDA based on the results of the AMPECT study.83 Cost Information Cost information is unavailable for this topic, but nab-sirolimus is expected to be more costly than generic mTOR inhibitors.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 44

Key Stakeholder Perspectives Between May 28, 2020, and July 29, 2020, five stakeholders, reflecting clinical, nursing, and research perspectives, provided comments and ratings on nab-sirolimus. The list below provides a summary of key stakeholder perspectives. • Data on nab-sirolimus show potential to improve health outcomes of patients with PEComa, who are in need of effective treatments, but additional, comparative data are needed to support these claims. • Nab-sirolimus is expected to be more expensive than generic mTOR inhibitors and might cause disparities for uninsured patients who cannot afford to pay for treatment and insured patients who cannot afford the associated deductibles and copayments. • As an intravenous drug, nab-sirolimus has little potential to disrupt the health care delivery system, but it may disrupt the paradigm of care because patients have limited treatment options available. • Nab-sirolimus’s overall potential for disruption is based on the lack of treatment options for PEComa, but data show that this treatment caused adverse events in participants, and so risk-benefit analysis may be necessary before treatment is considered.

Omidubicel to Treat Hematologic Malignancies Eligible for Hematopoietic Stem Cell Transplantation Highlights • About 8500 patients undergo an allogeneic hematopoietic stem cell transplant (allo-HSCT) each year in the United States. The preferred source of graft material for HSCT is bone marrow or peripheral blood stem cells obtained from a matched, biologically related donor. However, not all patients in need of allo-HSCT have such an available donor, and alternative grafts are used in these patients. • Omidubicel, an alternative source of hematopoietic cells, is derived from umbilical cord blood (UCB). Compared with unprocessed UCB, omidubicel purportedly decreases time to neutrophil engraftment, which could reduce treatment-related adverse events. • The therapy is in phase 3 development, and the developer expected to submit a Biologics License Application (BLA) to FDA by the end of 2020. • Stakeholders commenting on this topic thought that the observed improvement in time to neutrophil engraftment observed in the phase 3 trial of omidubicel compared with UCB suggested that omidubicel has substantial potential to improve patient health outcomes. • Stakeholders also thought that omidubicel’s impact would be greatest for patients who would currently be treated with UCB and that omidubicel has the potential to disrupt the standard of care for these patients. They also thought the therapy would be expensive. Patient Population Omidubicel is intended for patients aged 12 years or older who have a blood, bone marrow, or lymph malignancy (ie, hematologic malignancy) and are eligible for treatment with allo-HSCT. Intervention Patients eligible for HSCT who lack matched donors require alternative graft sources. One such alternative is UCB, which is used in about 5% of allo-HSCTs.84 UCB transplants demonstrate efficacy in terms of relapse-related death; however, investigators have observed increased rates of

HIGH POTENTIAL DISRUPTION REPORT • November 2020 45

treatment-related deaths.85 In particular, the lower cell counts present in a single-unit UCB transplant are thought to increase the time it takes for the transplant to engraft and restore blood cell levels in the recipient, which can lead to potentially life-threatening infections.86,87 Therefore, novel methods of increasing UCB cell counts to promote more rapid engraftment are sought.87 Omidubicel (previously known as NiCord) is made up of UCB cells that have been grown to larger numbers in culture at a laboratory and is under study for use in allo-HSCT to treat hematologic malignancies.88 To produce omidubicel, a sufficiently matched cord blood unit is selected from a cord blood bank and shipped to a centralized cell-processing facility. The cord blood unit is separated into fractions according to CD133 expression. The CD133-positive cell population, which contains immature immune cells such as CD34-positive stem cells, is cultured in the presence of growth factors and nicotinamide. Nicotinamide is an SIRT1 inhibitor that purportedly inhibits stem cell differentiation and enhances the functionality of stem cells expanded in culture. The CD133- negative cell population, which contains mature immune cells such as T cells, is not cultured. Both fractions are cryopreserved and shipped to the transplantation center for infusion into the patient.89 Omidubicel processing takes about 24 days from identification of the UCB unit to receipt of the cryopreserved expanded graft.86

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified one ongoing trial for this topic. We present this trial in Table 2.9. Our searches also identified, but we excluded, an expanded access study for omidubicel (NCT04260698). Table 2.9. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Stem Cell Transplantation Patients (n = 124) Phase 3, open-label, randomized Primary With NiCord (Omidubicel) undergoing allogeneic controlled trial of the safety and completion vs Standard Umbilical HSCT to treat hematologic efficacy of omidubicel December 2019 Cord Blood in Patients malignancies and who lack Patients will be randomly assigned to Study With Leukemia, an HLA-matched donor treatment with either omidubicel or completion Lymphoma, and and have access to 1 or 2 unmanipulated cord blood units. December 2020 Myelodysplastic partially HLA-matched cord Primary end point: Time to neutrophil Syndrome (MDS) blood units engraftment after transplantation NCT02730299 See preliminary results from Gamida Cell 2020 under Recently Completed and Ongoing Trials With Available Results

Abbreviations: HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 46

Recently Completed and Ongoing Trials With Available Results Our searches identified 2 recently completed trials with published results.86,90 We summarize their results as written in news releases and an abstract of a published study. The following abbreviations are used in this section: CI, confidence interval; GVHD, graft- versus-host disease; HLA, human leukocyte antigen; HM, hematological malignancies; HSCT, hematopoietic stem cell transplant; P or p, probability; UCB, umbilical cord blood.

Stem Cell Transplantation With NiCord (Omidubicel) vs Standard Umbilical Cord Blood in Patients With Leukemia, Lymphoma, and Myelodysplastic Syndrome (MDS). NCT02730299. Gamida Cell 2020.90,91

• Patient population/planned enrollment: Patients (n = 124) undergoing allogeneic HSCT to treat hematologic malignancies who lack an HLA-matched donor and have access to 1 or 2 partially HLA- matched cord blood units • Study design: Phase 3, open-label, randomized controlled trial of the safety and efficacy of omidubicel. Patients will be randomly assigned to treatment with either omidubicel or unmanipulated cord blood units. • Primary outcome: Time to neutrophil engraftment after transplantation • Secondary outcomes: Proportion of patients who achieved platelet engraftment by day 42, proportion of patients with grade 2 or grade 3 bacterial or invasive fungal infections in the first 100 days after transplantation, and number of days alive and out of the hospital in the first 100 days after transplantation • Results presented by study authors: “The study achieved its primary endpoint (p<0.001). In the intent- to-treat analysis, the median time to neutrophil engraftment was significantly shorter for patients who received omidubicel (12 days; 95% CI: 10-15 days) compared to the comparator group (22 days; 95% CI: 19- 25 days). Omidubicel was generally well tolerated. Among patients who were transplanted per protocol, 96 percent of patients who received omidubicel achieved successful neutrophil engraftment, compared to 88 percent of patients in the comparator group.”

“The prespecified secondary endpoints of the study, analyzed in all randomized patients (intent-to-treat), were the proportion of patients who achieved platelet engraftment by day 42, the proportion of patients with Grade 2 or Grade 3 bacterial or invasive fungal infections in the first 100 days following transplant, and the number of days alive and out of the hospital in the first 100 days following transplant. All three secondary endpoints demonstrated a statistically significant improvement among patients who received omidubicel compared to the comparator group. The company anticipates reporting the full data set at a medical meeting in the fourth quarter of 2020.”

Transplantation of NiCord, Umbilical Cord Blood-Derived Ex Vivo Expanded Cells, in Patients With HM. NCT01816230. Horwitz et al 2019.86

• Patient population/planned enrollment: Patients (n = 36) undergoing myeloablative HSCT to treat a hematologic malignancy who lack an HLA-matched donor and have access to 2 partially HLA-matched cord blood units • Study design: Phase 1/2, single-group assignment trial of the safety and efficacy of omidubicel. All patients received omidubicel as HSCT. • Primary outcome: Rate of neutrophil engraftment at 42 days after transplantation • Results presented by study authors: “The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator (P < .001). The median time to platelet recovery was 34

HIGH POTENTIAL DISRUPTION REPORT • November 2020 47

days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively (P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively.” Manufacturers and Regulatory Status Gamida-Cell (Jerusalem, Israel) is developing omidubicel, which is under study in a phase 3 trial. The developer indicated that it intended to initiate a BLA submission to FDA in the fourth quarter of 2020.90,91 In 2016, FDA granted omidubicel Breakthrough Therapy designation as a novel graft modality for bone marrow transplantation in patients with high-risk hematologic malignancies.92 Cost Information Cost information is currently unavailable for this topic, but omidubicel’s cost is expected to be high because of its complex manufacturing requirements. Key Stakeholder Perspectives Between August 6, 2020, and August 24, 2020, six stakeholders, reflecting clinical, health systems, and research perspectives, provided comments and ratings on omidubicel for treating hematologic malignancies eligible for HSCT. The list below provides a summary of key stakeholder perspectives. • Omidubicel has moderate to high potential to improve patient health outcomes, based on its reduction in the time to neutrophil engraftment compared with UCB. However, stakeholders noted that full study details on the magnitude of omidubicel’s effects on survival, infection rate, and adverse events would be needed to fully assess the therapy’s potential impact. • Omidubicel adoption should not require substantial changes to health care facilities or personnel. However, transplant teams would need to adjust procedures to accommodate the 24-day lead time associated with graft processing. • Omidubicel would likely cause a disruption in patient management. In particular, patients who would currently receive UCB transplants would instead receive omidubicel. Most stakeholders did not envision shifts to the care of patients receiving other forms of stem cell transplant. • Omidubicel’s likely high cost and the fact that its use could be more predominant in specialized centers could exacerbate existing disparities based on insurance coverage and access to these facilities. Conversely, omidubicel could reduce disparities in patient populations that are less well represented in bone marrow transplant registries.

Onureg to Treat Acute Myeloid Leukemia (Maintenance Setting) Highlights • Onureg is an oral form of azacitidine, a small-molecule drug that acts as an antimetabolite and demethylating agent. In September 2020, FDA approved Onureg use as maintenance therapy for patients with acute myeloid leukemia (AML) who have responded to prior treatment. • The cost for a typical Onureg treatment course is about $264 000.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 48

• In a phase 3, randomized controlled trial, median overall survival was about 10 months longer in patients who received Onureg than in those who received placebo. Although patients receiving Onureg experienced increased rates of gastrointestinal events, neutropenia, and serious infections, overall health-related quality of life was reportedly not adversely affected. • Stakeholders commenting on this topic agreed that Onureg is the first therapy to demonstrate a survival benefit when used in the maintenance setting after a first remission. Therefore, Onureg use in this setting would substantially disrupt the current AML treatment paradigm. • Stakeholders also thought that, as an oral alternative to injected azacitidine in other treatment settings, Onureg could reduce treatment burden by shifting treatment from an injected drug to a more convenient orally administered drug. Patient Population Onureg is intended for adults aged 18 years or older with AML who achieved first complete remission or complete remission with incomplete blood count recovery after intensive induction chemotherapy and are unable to complete intensive curative therapy.93 Intervention AML is a blood cancer characterized by the expansion of immature cells of the myeloid lineage. AML is an aggressive leukemia that is uniformly fatal unless treated. The American Cancer Society website offers more information on AML. Treatment typically consists of a 2-phased approach, consisting of induction therapy intended to achieve remission and consolidation therapy intended to achieve long-term remission or cure. However, patients often experience disease relapse after a complete response to these treatments.94 In particular, older patients have high relapse rates because their disease is typically more aggressive and they might be ineligible for more intensive induction and consolidation therapies.95 Therefore, interest exists in novel methods of extending relapse-free and overall survival in patients with AML. One such approach being explored is maintenance therapy, which consists of ongoing treatment with a low-intensity regimen to maintain the response to therapy. Although several agents have been studied in the maintenance setting, results to date have not demonstrated large enough effects on survival to become the standard of care.94 Onureg is a demethylating agent under study as maintenance treatment for AML. The drug is a novel, orally bioavailable version of the intravenously administered hypomethylating agent azacitidine (Vidaza).95 FDA approved Vidaza in 2004 for treating myelodysplastic syndrome and it is widely used off-label in treating a range of hematologic malignancies, including AML.96 Onureg, like Vidaza, is a chemical analogue of the nucleoside cytosine and purportedly exerts its effects by inhibiting DNA methyltransferase after being incorporated into cellular DNA and by direct cytotoxic effect.97 Onureg (300 mg) is taken by mouth once daily on days 1 through 14 of a 28-day treatment cycle until relapse or discontinuation for another reason.93,98

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 2.10.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 49

Table 2.10. Ongoing Clinical Trials

Study name and Patient Study design and outcomes Estimated National Clinical population and date of Trials identifier planned completion enrollment Efficacy of Oral Patients (n = 472) Phase 3, quadruple-blind (participant, care Primary Azacitidine Plus Best with newly provider, investigator, outcomes assessor), completion July Supportive Care as diagnosed AML randomized controlled trial of the safety and 2019 Maintenance Therapy who have achieved efficacy of CC-486 as maintenance therapy after Study in Subjects With Acute complete remission standard induction and consolidation therapy completion Myeloid Leukemia in or complete Patients will be randomly assigned to treatment December 2021 Complete Remission remission with with either CC-486 (300-mg oral tablet on days 1 (QUAZAR AML-001) incomplete blood through 14 of each 28-day cycle) or matching NCT01757535 recovery with placebo See preliminary results induction and Primary end point: Overall survival consolidation by Wei et al 2019 Secondary end points: Relapse-free survival, therapy under Recently safety and tolerability, health care resource use, Completed and and patient-reported outcomes (FACT-Fatigue Ongoing Trials With scale, EQ-5D) Available Results Randomised Study of Patients (n = 324) Phase 3, double-blind, randomized controlled trial Primary and Oral Azacitidine vs with AML or high- of the safety and efficacy of CC-486 versus study Placebo Maintenance risk MDS placebo as maintenance therapy in patients who completion in AML or MDS undergoing have undergone allogeneic stem cell June 2024 Patients After Allo-SCT allogeneic stem cell transplantation (AMADEUS) transplantation Patients will be randomly assigned to treatment NCT04173533 with CC-486 (oral tablet on days 1 through 14 of each 28-day cycle) or matching placebo Primary end point: Relapse-free survival Select secondary end points: Overall survival, safety, and quality of life Abbreviations: Allo-SCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; EQ-5D, EuroQol-5D measure of health outcomes; FACT-Fatigue, Functional Assessment of Cancer Therapy—Fatigue; MDS, myelodysplastic syndrome.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 3 trial with published results.98 We summarize results as written in a conference abstract. The following abbreviations are used in this section: AEs, adverse events; AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete blood recovery; EQ-5D, EuroQol-5D measure of health outcomes; FACT-Fatigue, Functional Assessment of Cancer Therapy—Fatigue; GI, gastrointestinal; HR, hazard ratio; HRQoL, health-related quality of life; OS, overall survival; P, probability; PBO, placebo; pts, patients; RFS, relapse-free survival; Tx, treatment; vs, versus.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 50

Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia in Complete Remission (QUAZAR AML-001). NCT01757535. Wei et al 2019.98

• Patient population/planned enrollment: Patients (n = 472) with newly diagnosed AML who achieved CR or Cri with induction and consolidation therapy. Median age was 68 years (range 55-86), 91% of patients had de novo AML, and 86% and 14% of patients, respectively, had intermediate-risk or poor-risk cytogenetics. After induction, 81% of patients achieved a CR and 19% achieved CRi; 80% of patients had received consolidation chemotherapy (45% received 1 consolidation cycle and 31% received 2 consolidation cycles). • Study design: Phase 3, quadruple-blind (participant, care provider, investigator, outcomes assessor), randomized controlled trial of the safety and efficacy of CC-486 as a maintenance therapy after standard induction and consolidation therapy. Patients were randomly assigned to treatment with either CC-486 (300-mg oral tablet on days 1 through 14 of each 28-day cycle) or matching placebo. • Primary outcome: OS • Secondary outcomes: Relapse-free survival, safety and tolerability, health care resource utilization, and patient-reported outcomes (FACT-Fatigue scale, EQ-5D) • Results presented by study authors: “At a median follow-up of 41.2 months, OS was significantly improved with CC-486 vs. PBO: median OS was 24.7 months vs. 14.8 months from time of randomization, respectively (P=0.0009; HR 0.69 [95%CI 0.55, 0.86]) (Figure A). RFS was also significantly prolonged: median RFS was 10.2 months in the CC-486 arm, compared with 4.8 months in the PBO arm (P=0.0001; HR 0.65 [95%CI 0.52, 0.81]) (Figure B). OS and RFS benefits of CC-486 were demonstrated regardless of baseline cytogenetic risk, the number of prior consolidation cycles received, and CR/CRi status. CC-486 did not adversely impact overall HRQoL vs. PBO, as assessed by mean changes from baseline in HRQoL measures during Tx.

“CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. Median exposure to CC-486 was 12 cycles (range 1-80) and to PBO was 6 cycles (1-73). The most frequently reported adverse events (AEs) with CC-486 and PBO were grade 1 or 2 gastrointestinal (GI) events, including nausea (64% and 23%, respectively), vomiting (59% and 10%), and diarrhea (49% and 21%). The most common grade 3-4 AEs were neutropenia (CC-486, 41%; PBO, 24%), thrombocytopenia (23% and 22%), and anemia (14% and 13%). Serious AEs were infrequent, mainly infections, which occurred in 17% of pts in the CC-486 arm and 8% of pts in the PBO arm. Few AEs led to Tx discontinuation, most often GI events (CC-486, 5%; PBO, 0.4%).” Manufacturers and Regulatory Status Celgene, a Bristol Myers Squibb company (New York, New York), is developing Onureg. On September 1, 2020, FDA approved Onureg for continued treatment of patients with AML who achieved first complete remission or complete remission with incomplete blood count recovery after intensive induction chemotherapy and are unable to complete intensive curative therapy.99 The drug’s application was reviewed under the agency’s priority review program. Onureg had previously been granted Orphan Drug designation for treating AML. Cost Information According to Drugs.com, an online aggregator of US prescription drug prices, a 14-day cycle of Onureg (300 mg) costs about $22 000.100 In the phase 3 QUAZAR AML-001 trial,98 patients received a median of 12 cycles of Onureg (range 1-80 cycles), and, therefore, a typical Onureg treatment course would cost about $264 000.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 51

Key Stakeholder Perspectives Between July 18, 2020, and September 4, 2020, seven stakeholders, reflecting clinical, health systems, and research perspectives, provided comments and ratings on Onureg for treating AML. The list below provides a summary of key stakeholder perspectives. • Onureg has moderate to high potential to improve patient health outcomes, based on the significant improvement in overall survival and relapse-free survival observed with Onureg treatment relative to placebo in the QUAZAR AML-001 trial. • Although treatment toxicity is a concern for a drug being used in a setting in which patients do not typically receive therapy, Onureg appears generally well tolerated. Additionally, the burden associated with treatment administration is low because the drug is taken by mouth. • As the first maintenance therapy to demonstrate a survival advantage in the maintenance setting, Onureg use would cause a shift in the AML treatment paradigm. Additionally, extending remission for patients with AML could decrease costs and resource requirements for downstream care to treat disease recurrence. • If Onureg were to be used as a replacement for injected azacitidine, it could facilitate improved treatment adherence, improve access to treatment, and reduce injection-related adverse events. However, questions remain regarding the relative safety and efficacy of Onureg compared with injected azacitidine because of a lack of head-to-head trials.

Oraxol to Treat Locally Advanced or Metastatic Breast Cancer Highlights • Oraxol is a novel combination of a solubilized paclitaxel capsule and encequidar tablet that can be taken by mouth with similar efficacy to that of intravenous paclitaxel and with fewer adverse events. A New Drug Application for Oraxol is under FDA priority review with a decision date scheduled for February 28, 2021. • Intravenous paclitaxel contains additives that increase the risk of neuropathy and hypersensitivity, which leads about 10% to 30% of patients to stop treatment. • Compared with intravenous paclitaxel outcomes, clinical data demonstrate that treatment with oraxol led to improved health outcomes. Patients treated with oraxol also had fewer adverse events, but some, such as neutropenia, were more common with oraxol than with paclitaxel. • Stakeholders commenting on this topic thought that Oraxol has potential to decrease disparities because it is an oral drug and patients might have broad access to it through retail pharmacies. • Stakeholders also thought that Oraxol has potential to shift care from an infusion center to a home setting. If patients do not have to travel to receive treatment, this might decrease the burden on infusion centers. Patient Population Oraxol is intended for adults who have locally advanced or metastatic breast cancer for whom treatment with intravenous paclitaxel has been recommended.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 52

Intervention Breast cancer is the most common type of cancer diagnosed in women, and it can arise from different parts of the breast (ie, ductal cancer, lobular cancer). The American Cancer Society website offers more information on breast cancer. Intravenous paclitaxel, a taxane that inhibits cell division, is the most widely used chemotherapy agent for treating breast cancer. Historically, paclitaxel has been given intravenously because the drug is a substrate of P-glycoprotein (P-gp), an active transport protein on the gastrointestinal (GI) tract’s surface that pumps paclitaxel back into the GI tract. This limits systemic exposure to paclitaxel taken by mouth.101 Because paclitaxel is not soluble in water, it is diluted in an oily solvent (ie, Cremophor EL) and alcohol, which allows it to be given intravenously. However, these additives increase the risk of neuropathy, hypersensitivity, and other adverse events.102 These adverse effects can require stopping the regimen, thereby interrupting the planned treatment cycle. Some studies have reported a paclitaxel discontinuation rate between 10% and 30% because of treatment-related adverse events.103-105 Patients and clinicians are interested in forms of taxanes with the potential to improve safety and health outcomes. Oraxol is a novel combination taxane therapy composed of a solubilized paclitaxel capsule and an encequidar tablet, both taken by mouth.101,106 Adding the P-gp inhibitor encequidar to paclitaxel purportedly prevents P-gp-mediated GI retention of paclitaxel.106 Oraxol could increase paclitaxel’s accumulation in the body. Its use could also decrease the burden of infusion clinic visits, premedication, and potentially dangerous infusion-related reactions.101,106 Additionally, oraxol might improve the rates at which paclitaxel is taken up in the body, distributed, and eliminated, avoiding the high peak concentrations and low trough concentrations associated with periodic intravenous doses. An oncologist prescribes oraxol, and patients take it for 3 consecutive days per week at a dose of 205 mg/m2 solubilized paclitaxel plus 15 mg encequidar until disease progression or intolerable toxicity.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified a single ongoing trial for this topic. We present this trial in Table 2.11.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 53

Table 2.11. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Ph3 Study to Determine Patients (n = 402) who have Phase 3, randomized, parallel- Primary Safety, Tolerability & locally advanced or assignment, open-label trial to completion July Tumor Response of metastatic breast cancer evaluate the safety and efficacy of 2019 Oraxol Compared to for whom paclitaxel oraxol in patients with breast cancer Study Taxol In Metastatic Breast monotherapy has been Patients will be randomly assigned to completion July Cancer (KX-ORAX-001) recommended treatment with either oral oraxol (205 2020 NCT02594371 mg/m2 paclitaxel plus 15 mg encequidar) for 3 consecutive days per week or intravenous paclitaxel (175 mg/m2) once every 3 weeks. Primary end points: Tumor response and adverse events Secondary end points: Overall survival and progression-free survival Abbreviation: Ph3, phase 3.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 3 trial with published results.107 We summarize results as written in a conference abstract. The following abbreviations are used in this section: AEs, adverse events; E, encequidar; ITT, intention to treat; IV, intravenous; mBC, metastatic breast cancer; mITT, modified intention to treat; OS, overall survival; p, probability; Pac, paclitaxel; Pac+E, oraxol; PFS, progression-free survival; Ph3, phase 3; vs, versus.

Ph3 Study to Determine Safety, Tolerability & Tumor Response of Oraxol Compared to Taxol in Metastatic Breast Cancer (KX-ORAX-001). NCT02594371. Umanzor et al 2019.107

• Patient population/planned enrollment: Patients (n = 402) with locally advanced or metastatic breast cancer for whom paclitaxel monotherapy has been recommended • Study design: Phase 3, randomized, parallel-assignment, open-label trial to evaluate the safety and efficacy of oraxol in patients with breast cancer. Patients were randomly assigned in a 2:1 ratio to receive either oral oraxol (205 mg/m2 paclitaxel plus 15 mg encequidar for 3 days per week) or intravenous paclitaxel (175 mg/m2 every 3 weeks). • Primary outcomes: Tumor response and AEs • Secondary outcomes: OS and PFS • Results presented by study authors: “A total of 402 mBC patients were enrolled (Pac+E 265 vs IV Pac 137); demographics were balanced. A similar percentage of subjects in each treatment group received prior taxane therapy (Pac+E, 28%; IV Pac, 31%). For the ITT population, final analysis of the primary endpoint of confirmed tumor response demonstrated a statistically significant difference between treatments; Pac+E 35.8% vs IV Pac 23.4%, a difference of 12.4%, p=0.011, favoring Pac+E. For the protocol defined mITT population (baseline evaluable scans and received at least 75% of the first cycle of dosing) the confirmed response rates were 40.4% for Pac+E vs 25.6% for IV Pac (p=0.005). For the population with evaluable post-baseline scan, the confirmed response rates were 50.3% for Pac+E vs 29.6% for IV Pac (p=0.0005). Tumor response in all clinically important subgroups was consistent with the overall confirmed response profiles. Responses were durable. Ongoing analysis of duration of confirmed response showed

HIGH POTENTIAL DISRUPTION REPORT • November 2020 54

the median durations were 39.0 weeks for Pac+E vs 30.1 weeks for IV Pac. Ongoing analysis of OS in the prespecified mITT population favors Pac+E (p=0.035) with a median of 27.9 months vs 16.9 months for Pac+E and IV Pac, respectively. Ongoing analysis of PFS in the prespecified mITT population shows a strong trend favoring Pac+E (p=0.077) with a median of 9.3 months vs 8.3 months. The Pac+E group had a lower incidence of alopecia and a lower incidence and severity of neuropathic AEs compared to IV Pac (17% versus 57% respectively to Week 23), with Grade 3 neuropathic symptoms observed in 1% for Pac+E vs 8% for IV Pac. The toxicity profile of Pac+E was generally similar to IV Pac. However higher rates of neutropenia, infection and gastrointestinal AEs were observed in Pac+E group. The risk of serious AEs on both treatments was highest among subjects with pre-treatment evidence of hepatic impairment and the protocol was amended to address this issue.” Manufacturers and Regulatory Status Investigators at Athenex Pharmaceuticals, Inc (Buffalo, New York), are studying oraxol in the phase 3 KX-ORAX-001 trial to treat locally advanced or metastatic breast cancer. Based on results from this trial, Athenex submitted a New Drug Application (NDA) to FDA.108 FDA accepted the NDA on September 1, 2020, granted priority review, and issued a Prescription Drug User Fee Act (PDUFA)-prescribed action date of February 28, 2021.109 Cost Information Cost information is unavailable for this topic. Key Stakeholder Perspectives Between June 1, 2020, and June 22, 2020, eight stakeholders, reflecting clinical, health systems, nursing, patient, patient representative, and research perspectives, provided comments and ratings on oraxol. The list below provides a summary of key stakeholder perspectives. • Oraxol has potential to improve health outcomes and quality of life because patients treated with oraxol had overall improved health versus patients treated with intravenous paclitaxel. • If patients manifest fewer adverse events with oraxol than with intravenous paclitaxel, it also could reduce hospital admissions to manage neuropathy and hypersensitivity. However, oraxol raises concerns about specific adverse events such as neutropenia. • Unlike intravenous drugs that are available through infusion centers, oraxol could improve health disparities by being broadly accessible to patients, including those living in rural areas, through retail pharmacies. • If oraxol becomes available and is more expensive than intravenous drugs, it might increase disparities for uninsured and underinsured patients. But it might decrease costs associated with treatment at infusion centers, such as supplies, labor, and personnel. • The transition of patient care from an intravenous drug to an oral medication decreases the burden on infusion centers and reduces the patient’s burden of traveling to an infusion center once every 3 weeks.

Pemigatinib (Pemazyre) to Treat Locally Advanced or Metastatic Cholangiocarcinoma Harboring Fibroblast Growth Factor Receptor-2 Fusions or Rearrangements Highlights • Pemigatinib is an oral small-molecule inhibitor of fibroblast growth factor receptor (FGFR) under study for treating advanced or metastatic cholangiocarcinoma in patients who have

HIGH POTENTIAL DISRUPTION REPORT • November 2020 55

gene fusions or rearrangements involving the FGFR2 locus. In April 2020, FDA granted accelerated approval to pemigatinib for this indication; eligibility for the therapy requires genetic testing using the FoundationOne CDx test. • About 10% to 16% of patients with intrahepatic cholangiocarcinomas, or liver bile duct cancer, have fusions or rearrangements in the fibroblast growth factor receptor 2 gene, FGFR2; these alterations are thought to drive multiple cancer-promoting processes. Pemigatinib purportedly inhibits these FGFR-dependent processes. • The drug’s cost for the median duration of therapy in trials (7.2 months) is about $173 000. • Stakeholders commenting on this topic thought that pemigatinib has substantial potential to improve patient health outcomes, based on the lack of effective therapies for cholangiocarcinoma in the second-line setting and the initial results observed in a phase 2 trial. • Stakeholders also envisioned small disruptions in health care delivery, treatment paradigm, and costs, mainly focusing on the incorporation of genetic testing into the cholangiocarcinoma treatment paradigm and a potential shift from use of drugs that are given intravenously to one taken orally. Patient Population Pemigatinib therapy is intended for adults aged 18 years or older with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 or other rearrangement as detected by the FoundationOne CDx test.110 Intervention Bile duct cancer is a rare malignancy. About 8000 cases are diagnosed each year in the United States. These cancers represent a diverse group of tumors that can be broadly classified as intrahepatic (ie, originating in bile ducts within the liver) or extrahepatic (ie, originating in bile ducts exiting the liver [perihilar] or near the gall bladder, intestine, and pancreas [distal bile ducts]). The American Cancer Society website offers more information on bile duct cancer. Bile duct cancers are typically diagnosed at late stages, and the standard of care is systemic therapy. However, systemic therapies have shown limited efficacy; median survival of patients receiving systemic therapy for bile duct cancer is about 12 months.111,112 Therefore, novel therapies are needed that could improve health outcomes for these patients. Genomic sequencing of bile duct cancers has identified multiple, potentially actionable, genetic variants, including alterations in genes encoding FGFRs. About 10% to 16% of patients with intrahepatic bile duct cancers have gene fusions or rearrangements involving the FGFR2 locus.113 These genetic alterations purportedly lead to aberrant FGFR signaling, which drives multiple cancer-promoting processes (eg, cell proliferation, cell migration, cell survival, blood vessel formation).111 Therefore, inhibiting FGFR signaling in bile duct cancers that have activating fusions or rearrangements in FGFR2 may therapeutically benefit the patient.114 Pemigatinib (Pemazyre) is a small-molecule competitive inhibitor of the kinase activity of FGFR1, FGFR2, and FGFR3.113 The drug is being tested in clinical trials as a first- and second-line systemic therapy for bile duct cancer. Pemigatinib is taken by mouth at a daily dose of 13.5 mg in a 2-weeks-on, 1-week-off schedule until disease progression or development of intolerable toxicity.110 To determine eligibility for pemigatinib treatment, clinicians must use the FDA-approved genetic test FoundationOne CDx to assess a patient’s FGFR2 mutation status.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 56

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present 2 of these trials in Table 2.12 and exclude a small (54-patient) single-arm trial conducted in China (NCT04256980). Table 2.12. Ongoing Clinical Trials

Study name and Patient population Study design and outcomes Estimated National Clinical and planned date of Trials identifier enrollment completion

Efficacy and Safety of Patients (n = 147) who have Phase 2, multicohort, parallel- Primary and study Pemigatinib in Subjects locally advanced or assignment, open-label trial to evaluate completion June With Advanced/Metastatic metastatic the safety and efficacy of pemigatinib in 2020 or Surgically Unresectable cholangiocarcinoma patients who have advanced Trial record last Cholangiocarcinoma Who harboring FGFR2 cholangiocarcinoma updated June Failed Previous Therapy rearrangements or fusions Patients receive oral pemigatinib at a 2020 (FIGHT-202) (cohort A), other FGF/FGFR daily dose of 13.5 mg in a 2-weeks-on, 1- NCT02924376 alterations (cohort B), or no week-off schedule See preliminary results by FGF/FGFR alterations (cohort Primary end point: Objective response Abou-Alfa et al 2020 under C), who have had at least rate one previous line of systemic Recently Completed and Secondary end points: Progression-free therapy in the locally Ongoing Trials With survival and adverse events Available Results advanced/metastatic setting A Study to Evaluate the Patients (n = 432) who have Phase 3, randomized, parallel- Primary Efficacy and Safety of locally advanced or assignment, open-label trial to evaluate completion Pemigatinib Versus metastatic the safety and efficacy of pemigatinib in October 2023 Chemotherapy in cholangiocarcinoma patients who have advanced Study completion Unresectable or Metastatic harboring FGFR2 cholangiocarcinoma October 2024 Cholangiocarcinoma rearrangements or fusions Patients are randomly assigned to (FIGHT-302) and who have not been receive either oral pemigatinib at a daily NCT03656536 previously treated (prior dose of 13.5 mg in a 2-weeks-on, 1- adjuvant/neoadjuvant week-off schedule or intravenous treatment completed at least gemcitabine (1000 mg/m2) plus cisplatin 6 months before enrollment (25 mg/m2) given on days 1 and 8 of and treatment for locally each 3-week cycle advanced disease with Primary end point: Progression-free transarterial survival chemoembolization; Secondary end points: Overall survival, selective internal radiation quality of life, overall response rate, therapy is permitted if clear duration of response, disease control evidence of radiologic rate, and adverse events progression is observed before enrollment)

Abbreviations: FGF, fibroblast growth factor gene; FGFR, fibroblast growth factor receptor gene; FGFR2, fibroblast growth factor receptor 2 gene.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 57

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial with published results.113 We summarize results as written in an abstract of a published report. The following abbreviations are used in this section: CI, confidence interval; FGF, fibroblast growth factor gene; FGFR, fibroblast growth factor receptor gene; FGFR2, fibroblast growth factor receptor 2 gene; IQR, interquartile range; ORR, objective response rate.

Efficacy and Safety of Pemigatinib in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Who Failed Previous Therapy (FIGHT-202). NCT02924376. Abou-Alfa et al 2020.113

• Patient population/planned enrollment: Patients (n = 146) with locally advanced or metastatic bile duct cancer harboring FGFR2 rearrangements or fusions (cohort A), other FGF/FGFR gene alterations (cohort B), or no FGF/FGFR gene alterations (cohort C), who had at least one previous line of systemic therapy in the locally advanced/metastatic setting • Study design: Phase 2, multicohort, parallel-assignment, open-label trial to evaluate the safety and efficacy of pemigatinib in patients who had advanced bile duct cancer. Patients received oral pemigatinib at a daily dose of 13.5 mg in a 2-weeks-on, 1-week-off schedule. • Primary outcome: ORR in patients with FGFR2 translocations • Secondary outcomes: Progression-free survival and ORR in patients with FGF/FGFR alterations other than FGFR2 translocations or no FGF/FGFR alterations • Results presented by study authors: “Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/ FGFR alterations, 18 with no FGF/ FGFR alterations, and one with an undetermined FGF/ FGFR alteration. The median follow-up was 17.8 months (IQR 11.6–21.3). 38 (35.5% [95% CI 26.5–45.4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related.” Manufacturers and Regulatory Status Pemigatinib is being developed by Incyte Corp (Wilmington, Delaware). On April 17, 2020, FDA granted accelerated approval to pemigatinib for treating adults with previously treated, unresectable locally advanced or metastatic bile duct cancer with an FGFR2 fusion or other rearrangement.115 At the same time, FDA approved the companion genetic test needed to confirm the presence of an FGFR2 fusion or rearrangement (FoundationOne CDx, Foundation Medicine, Inc, Cambridge, Massachusetts).115 FDA had previously granted Breakthrough Therapy designation to pemigatinib for previously treated, locally advanced or metastatic bile duct cancer harboring FGFR2 rearrangements or fusions.116 Cost Information According to a US-based online aggregator of prescription drug prices, GoodRx, pemigatinib’s retail price (as October 8, 2020) is about $16 780 for fourteen 13.5-mg tablets.117 At the FDA- approved dosing regimen of 13.5 mg once daily for 14 consecutive days followed by 7 days off

HIGH POTENTIAL DISRUPTION REPORT • November 2020 58

therapy,110 this represents a 3-week treatment cycle of the drug. In the FIGHT-202 trial, the median duration of therapy was 7.2 months (about 216 days),113 which would cost about $172 830. Key Stakeholder Perspectives Between March 3, 2020, and March 30, 2020, six stakeholders, reflecting health systems, nursing, physician, and research perspectives, provided comments and ratings on this topic. These perspectives were provided before the April 2020 FDA approval. The list below provides a summary of key stakeholder perspectives. • Based on pemigatinib’s solid scientific rationale, the lack of available treatments for bile duct cancer after initial therapy has stopped working, and the observed efficacy in the FIGHT-202 trial, pemigatinib has substantial potential to improve health outcomes in patients with FGFR2-mutated bile duct cancer. • Pemigatinib would cause minimal disruption to the health care delivery system because the drug is taken by mouth. Although pemigatinib would cause a shift from intravenously administered chemotherapy to an oral medication, this shift would be more disruptive if pemigatinib were to be used as a first-line treatment. • High rates of hyperphosphatemia observed in the FIGHT-202 trial were concerning and would require dietary and drug interventions. • The likely high cost of the drug as well as costs associated with genetic testing to determine treatment eligibility would increase costs of care. (Stakeholders reviewed the topic before cost information was available.) Conversely, the transition from intravenous chemotherapy to an orally administered drug could reduce health care facility costs for treating these patients by eliminating infusion-associated costs. • The need to incorporate genetic testing to determine pemigatinib treatment eligibility could reduce the numbers of patients treated because of the precision oncology approach represented by pemigatinib.

Selumetinib (Koselugo) to Treat Symptomatic, Inoperable Plexiform Neurofibromatosis Type 1 Highlights • Selumetinib is a novel drug that inhibits MEK1/2 (mitogen-activated protein kinase kinases 1 and 2) to prevent the uncontrolled cell proliferation of plexiform neurofibromas (PNs). In April 2020, FDA approved selumetinib, based on phase 1/2 data. • Neurofibromatosis type 1 (NF1) is a genetic disorder that is characterized by the development of PNs, noncancerous tumors in the skin and peripheral nervous system. • Stakeholders commenting on this topic thought that, because patients who have developed PNs lack effective treatment options, selumetinib could improve health outcomes and quality of life for these patients. • Stakeholders also thought that, even if PNs partially respond to selumetinib, the drug has potential to disrupt care paradigms and become standard of care. However, its cost ($11 000 for a 30-day supply; $132 000 per year) could create disparities for uninsured and underinsured patients.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 59

Patient Population Selumetinib is intended for children aged 2 years or older who have NF1 with symptomatic, inoperable PNs. Intervention NF1 is an autosomal dominant genetic disorder caused by mutations in the neurofibromin 1 gene, NF1, and characterized by development of noncancerous tumors in the skin and peripheral nervous system. Patients who have NF1 may also experience seizures, learning disabilities, speech difficulties, and skeletal malformations. About 30% to 50% of individuals with NF1 develop PNs at birth or during early childhood, and the PNs may continue to grow during adolescence and early adulthood.118 PNs are benign Schwann cell tumors that arise in multiple nerve fascicles (ie, axon bundles) and can grow along the length of a peripheral nerve and extend into surrounding tissues, causing substantial pain and bone damage. The National Organization for Rare Disorders website offers more information on NF1. Because patients with inoperable PNs have no approved treatment options, novel, effective systemic therapies are sought. Loss-of-function mutations in NF1 cause increased activity of a pathway (the renin-angiotensin system, RAS) involved in regulating cell growth and proliferation, and investigators are studying inhibition of the RAS pathway as a treatment for PNs in patients with NF1.119,120 Selumetinib (Koselugo) is an oral, selective, small-molecule inhibitor of MEK1/2. These proteins are integral members of the RAS pathway that promote cell growth and proliferation. Selumetinib-mediated MEK1/2 inhibition purportedly prevents uncontrolled proliferation of PNs and may contribute to their shrinkage.119,120 The drug is approved by FDA. A pediatrician who specializes in oncology or neurologic diseases prescribes selumetinib. According to the FDA-approved label, this drug is intended to be taken twice daily (about every 12 hours) on an empty stomach at a dose of 25 mg/m2 until disease progression or intolerable toxicity. The medication is available in 10-mg and 25-mg capsules. Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified a single ongoing trial for this topic. We present this trial in Table 2.13.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 60

Table 2.13. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier AZD6244 Hydrogen Pediatric patients (n = 99) Phase 1/2, single-group assignment, Primary Sulfate for Children With who have NF1 with open-label trial to evaluate the safety completion Nervous System Tumors symptomatic, inoperable and efficacy of selumetinib in patients January 2025 (SPRINT) PNs who have NF1 with PNs Study NCT01362803 Patients will receive oral selumetinib completion twice daily at a dose of 25 mg/m2. January 2030 Primary end point: Objective response rate Secondary end points: Quality of life, pain, duration of response, safety and tolerability, and bone mineral density Abbreviations: NF1, neurofibromatosis type 1; PNs, plexiform neurofibromas.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 1/2 trial with published results.120 We summarize results as written in an abstract of a published study. The following abbreviations are used in this section: NF1, neurofibromatosis type 1; PNs, plexiform neurofibromas.

AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors (SPRINT). NCT01362803. Gross et al 2020.120

• Patient population/planned enrollment: Pediatric patients (n = 50) who have NF1 with symptomatic, inoperable PNs • Study design: Phase 1/2, single-group assignment, open-label trial to evaluate the safety and efficacy of selumetinib in patients who have NF1 with PNs. Patients received oral selumetinib twice daily at a dose of 25 mg/m2. • Primary outcome: Objective response rate • Secondary outcomes: Quality of life, pain, duration of response, safety and tolerability, and bone mineral density • Results presented by study authors: “A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain- intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.”

HIGH POTENTIAL DISRUPTION REPORT • November 2020 61

Manufacturers and Regulatory Status Investigators at AstraZeneca plc (Cambridge, United Kingdom), in collaboration with Merck & Co, Inc (Kenilworth, New Jersey), and the National Cancer Institute (Bethesda, Maryland), are studying selumetinib. On April 13, 2020, FDA approved selumetinib, based on data from the phase 1/2 SPRINT trial, for treating pediatric patients aged 2 years or older who have NF1 with symptomatic, inoperable PNs.121 FDA had previously granted selumetinib Orphan Drug, Breakthrough Therapy, and Rare Pediatric Disease designations.122,123 Cost Information An online aggregator of US prescription drug prices, GoodRx, reported a retail price of $11 000 for a 30-day supply of selumetinib (as of October 8, 2020). If patients take the drug for a year, it would cost about $132 000.124 AstraZeneca has a Patient Savings Program for patients with commercial health insurance that could provide up to $26 000 per year in out-of-pocket copayment assistance. Key Stakeholder Perspectives Between July 20, 2020, and September 18, 2020, six stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on selumetinib. The list below provides a summary of key stakeholder perspectives. • Other than supportive care, effective therapies for PNs are nonexistent. Even with a partial response, selumetinib has potential to improve health outcomes and quality of life. • Because selumetinib is an expensive drug and must be prescribed by specialists, such as pediatric oncologists and neurologists, it could increase disparities for patients living in remote areas and those who are uninsured or underinsured. • As an oral drug, selumetinib might shift care to a home setting and potentially decrease the number of disease-related hospitalizations. However, it might not translate into reduced frequency of medical visits, which are required to monitor adverse events. • In the absence of effective treatments, selumetinib has potential to disrupt patient care paradigms by becoming the standard of care for children and possibly also being used to treat adults.

Tazemetostat (Tazverik) to Treat Locally Advanced or Metastatic Epithelioid Sarcoma Highlights • Tazemetostat (Tazverik), an oral drug, inhibits methyltransferase EZH2 (enhancer of zeste homolog 2). FDA approved the drug in January 2020 to treat locally advanced or metastatic epithelioid sarcoma (ES) that is not suitable for surgical resection. • ES is a rare, soft tissue sarcoma characterized by aberrant histone methylation and cancer- causing transformation driven by EZH2. Use of EZH2 inhibitors represents a novel mechanism of action in treating cancer and the first treatment option specifically approved by FDA to treat ES. • FDA approval was based on a single-arm trial in which treatment with tazemetostat generated an overall response rate of 15%. Among patients achieving a response, most had a response that lasted at least 6 months.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 62

• Stakeholders commenting on tazemetostat thought that it would likely disrupt the current treatment of ES patients, based on the lack of effective systemic therapies for this cancer, the preliminary data on the drug’s ability to improve patient health outcomes, and the likely high cost of the drug (ie, about $15 300 for a 30-day supply). However, they also noted that the small number of patients diagnosed with ES would limit the magnitude of its disruption to the health care system as a whole. Patient Population Tazemetostat is intended for children aged 16 years or older and adults with metastatic or locally advanced ES ineligible for complete surgical removal. Intervention Tazemetostat (Tazverik) inhibits the histone methyltransferase EZH2 and is intended to treat ES, a rare sarcoma that typically originates in the soft tissues of the upper extremities. The Liddy Shriver Sarcoma Initiative website offers more information about ES. Historically, treatment of advanced ES ineligible for surgical removal has been limited to systemic therapies consisting of cytotoxic chemotherapy, which has limited efficacy.125 Therefore, novel therapies with the potential to improve health outcomes in patients with advanced ES are needed. EZH2 is the enzymatic subunit of polycomb repressive complex 2 (PRC2), a global regulator of gene expression that silences gene transcription through histone modification.125 Gain-of-function EZH2 has been implicated in the disease process of a wide range of cancers, including ES.126,127 Most patients with ES show a loss of expression of the integrase interactor 1 protein, a core component of a second global regulator of gene expression (SWI/SNF) that has an antagonistic relationship to PRC2.125 Therefore, loss of SWI/SNF activity leads to increased PRC2 activity, which drives cancer growth. Tazemetostat purportedly inhibits the enzymatic activity of EZH2, potentially reducing PRC2 activity and reversing its cancerous effects.126,128 Tazemetostat is taken by mouth at a dosage of 800 mg twice daily until disease progression or intolerable toxicity.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present these trials in Table 2.14.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 63

Table 2.14. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical planned enrollment of completion Trials identifier A Phase 2, Multicenter Patients (n = 250) with INI1- Phase 2, multicohort, single-group Primary Study of the EZH2 negative tumors assignment, open-label trial to evaluate completion Inhibitor Tazemetostat Cohort 1: Tumors with the safety and efficacy of tazemetostat in January 2022 in Adult Subjects With rhabdoid features patients with advanced soft tissue Study INI1-Negative Tumors Cohort 2: Relapsed or sarcomas, including epithelioid sarcoma completion or Relapsed/Refractory refractory synovial Patients will receive oral tazemetostat at February 2022 Synovial Sarcoma sarcoma a dosage of 800 mg twice daily. (EZH-202) Cohort 3: Any solid tumor Primary end points: Progression-free NCT02601950 with EZH2 gain of function survival and overall response rate See preliminary results Cohort 4: Renal medullary Secondary end points: Overall survival, by Gounder et al 2020 carcinoma progression-free survival, disease control under Recently Cohorts 5 and 6: Epithelioid rate, duration of response, and adverse Completed and sarcoma events Ongoing Trials With Cohort 7: Poorly Available Results differentiated chordoma A Phase 1 Study of the Pediatric patients (n = 82) Phase 1, open-label, dose escalation, and Primary EZH2 Inhibitor aged 6 months to 17 years dose expansion study to evaluate completion Tazemetostat in with relapsed or refractory response of BID (suspension) and TID September 2022 Pediatric Subjects With INI1-negative tumors or (tablet) oral dose of tazemetostat in Study Relapsed or Refractory synovial sarcoma with prior pediatric patients with relapsed and completion INI1-Negative Tumors treatment completion and refractory malignancies including November 2022 or Synovial Sarcoma no standard treatment epithelioid sarcoma NCT02601937 options Patients will receive oral tazemetostat at a starting dose of 240 mg twice daily, which will escalate up to 1200 mg twice daily. Primary end points: Adverse events and objective response Secondary end points: Progression-free survival and overall survival

HIGH POTENTIAL DISRUPTION REPORT • November 2020 64

Study name and Patient population and Study design and outcomes Estimated date National Clinical planned enrollment of completion Trials identifier Tazemetostat in Patients (n = 164) with Phase 3, double-blind, randomized Primary Combination With previously untreated controlled trial of the safety and efficacy completion Doxorubicin as epithelioid sarcoma with of tazemetostat in combination with (phase 1b Frontline Therapy for loss of INI1 or SMARCA4 doxorubicin portion) Advanced Epithelioid confirmed by After a phase 1b portion of the trial to September 2020 Sarcoma immunohistochemistry or establish tazemetostat and doxorubicin Study NCT04204941 biallelic loss of INI1 or dosing, patients will be randomly completion May SMARCA4 in the case of assigned to treatment with either 2029 equivocal or unavailable tazemetostat plus doxorubicin or to immunohistochemistry placebo plus doxorubicin. result Primary end points: Progression-free survival and adverse events Secondary end points: Overall survival, overall response rate, duration of response, and disease control rate

Abbreviations: BID, twice daily; EZH2, enhancer of zeste homolog 2; INI1, integrase interactor 1; SMARCA4, SWI/SNF-related, matrix- associated, actin-dependent regulator of chromatin, subfamily a, member 4; TID, three times daily.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 trial with published results.129,130 We summarize results as written in an abstract of a published study and a conference abstract. The following abbreviations are used in this section: AEs, adverse events; BID, twice a day; CI, confidence interval; ES, epithelioid sarcoma; EZH2, enhancer of zeste homolog 2; INI1, integrase interactor 1; IQR, interquartile range; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; pts, patients; SD, stable disease; TAZ, tazemetostat.

A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1- Negative Tumors or Relapsed/Refractory Synovial Sarcoma (EZH-202). NCT02601950. Gounder et al 2020.129,130

• Patient population/planned enrollment: Patients (n = 106) with locally advanced or metastatic ES (n = 62) from cohort 5 and (n = 44) from cohort 6 of the multicohort trial. Patients in cohort 5 were required to have INI1 loss confirmed by immunohistochemistry. Patients in cohort 6 were required to have tumor morphology and immunophenotype consistent with ES. • Study design: Phase 2, multicohort, single-group assignment, open-label trial to evaluate the safety and efficacy of tazemetostat in patients with ES. Patients received oral tazemetostat at a dosage of 800 mg twice daily. • Primary outcomes: Overall response rate and effects of tazemetostat on tumor immune priming • Select secondary outcomes: PFS, duration of response, disease control rate, OS, and incidence of treatment-emergent AEs • Results presented by study authors through published paper: “Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7–26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8–19·0), median duration of response was not reached (95% CI 9·2–not estimable). 16 (26% [95% CI 16–39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9–7·4). Median progression-free survival was 5·5 months (95% CI 3·4–5·9), and median overall survival

HIGH POTENTIAL DISRUPTION REPORT • November 2020 65

was 19·0 months (11·0–not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths.” • Results presented by study authors through conference abstract “As of July 31 2019, 44 pts were enrolled into Cohort 6 and treated with TAZ 800 mg BID. The objective response rate (ORR) was 11.4%; 4 pts (9.1%) had a partial response and 1 pt (2.3%) had a complete response. Another 17 pts (38.6%) had stable disease (SD). 18 pts had progressive disease; 13 of these pts remained on study beyond progression. Progression-free survival (PFS) and overall survival (OS) at 56 weeks were 19.4% and 59.4%, respectively. In a pooled posthoc analysis of 106 ES pts from Cohorts 5 (n = 62), and 6, ORR was 13.2%. Grade 3–4 adverse events (AEs) were reported in 16 pts (36.4%), most commonly anemia (6.8%; n = 3) and tumor pain (6.8%; n = 3). 3 pts (6.8%) experienced grade 3–4 treatment-related AEs. One pt discontinued study drug and there were no treatment-emergent dose reductions or treatment-related deaths.” Manufacturers and Regulatory Status Tazemetostat is being developed by Epizyme, Inc (Cambridge, Massachusetts). In January 2020, FDA granted accelerated approval to tazemetostat to treat locally advanced or metastatic ES not eligible for complete resection in adults and children aged 16 years and older.131 The indication is based on overall response rate and duration of response observed in the phase 2 EZH-202 trial (NCT02601950). Continued approval for this indication may be contingent on verification and description of clinical benefit in a confirmatory trial or trials.132 FDA had previously granted Orphan Drug designation to tazemetostat for treating soft tissue sarcomas.133 In June 2020, FDA granted tazemetostat accelerated approval to treat another indication, follicular lymphoma in adults.134 Cost Information According to a US-based online aggregator of prescription drug prices, GoodRx, tazemetostat’s retail price (as of October 5, 2020) was about $15 300 for a 30-day supply of the drug.135 Thus, a 1- year supply of tazemetostat would cost about $183 600. Key Stakeholder Perspectives Between December 19, 2019, and January 30, 2020,* seven stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on tazemetostat for treating ES. The list below provides a summary of key stakeholder perspectives. • Because of the lack of effective systemic therapies for ES, tazemetostat has the potential to improve patient health outcomes. In particular, patients responding to tazemetostat in a phase 2 trial exhibited a substantial duration of response, and tazemetostat had a positive impact on ES symptoms. • The evidence base consists of a small single-arm trial in which only a minority of patients exhibited a response to tazemetostat. Additionally, the duration of response seen with tazemetostat treatment in the phase 2 trial will need to be confirmed in additional studies. • Tazemetostat will likely be adopted for treating patients with ES. Therefore, it could disrupt the current treatment paradigm by providing a novel method of treating patients who have ES and causing a switch from use of intravenous chemotherapy to an orally administered targeted therapy. • The likely high cost of tazemetostat would increase the cost of treating ES and could exacerbate existing disparities based on socioeconomic status. (Stakeholders reviewed the topic before cost information was available.) • Magnitude of impact on the health care system and health care costs will be limited by the small number of patients affected by ES.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 66

*Two additional stakeholders representing research perspectives commented on an updated profile of this topic between October 6, 2020, and October 8, 2020. Because these comments were received after the comment submission deadline of September 18, 2020, they were not fully analyzed for inclusion in this report. However, a preliminary review of their ratings and comments confirmed they agreed with those reported above.

Tazemetostat (Tazverik) to Treat Relapsed or Refractory Follicular Lymphoma Highlights • Tazemetostat, an oral drug, inhibits methyltransferase EZH2 (enhancer of zeste homolog 2), which is involved in the development of about 20% of follicular lymphomas. • FDA approved the drug in June 2020 to treat relapsed or refractory follicular lymphoma, an incurable type of non-Hodgkin lymphoma that can transform into a more aggressive form, diffuse large B-cell lymphoma. • Stakeholders commenting on this topic thought that, based on results from a single-group phase 1/2 trial, tazemetostat showed promise for improving health outcomes and could be adopted by patients whose disease has progressed within 24 months. • Stakeholders also thought that tazemetostat might decrease disparities for patients who lack effective oral treatments. Because tazemetostat represents the first molecularly directed treatment for follicular lymphoma, it also has potential to disrupt the current paradigm of care. • The drug cost is listed as $15 300 for a 30-day supply of tazemetostat; the annual cost would be about $183 600. Patient Population Tazemetostat is intended to treat relapsed or refractory follicular lymphoma in adults whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 previous lines of systemic therapy. Intervention Follicular lymphoma is an indolent B-cell non-Hodgkin lymphoma that is considered incurable. It has the potential to transform into more aggressive diffuse large B-cell lymphoma. Although many patients with follicular lymphoma respond well to available therapies, certain patients, such as those whose disease progresses within 24 months of diagnosis or after treatment with multiple agents, have limited effective treatment options and poor prognosis.136 The American Cancer Society website offers more information on follicular lymphoma. Tazemetostat (Tazverik) is a first-in-class, small-molecule inhibitor of EZH2 under study for treating relapsed or refractory follicular lymphoma. EZH2 regulates gene expression by modifying the methylation status of DNA-associated proteins called histones.126 Histone methylation patterns promoted by EZH2 activity purportedly promote cell proliferation and the growth and development of lymphoma.137 Specifically, EZH2 is thought to maintain a highly proliferative cell fate (ie, what type of cell the cell could become at maturity) that closely resembles that of germinal center B cells, which take part in an immune response in the body.138 Tazemetostat inhibition of EZH2 may reverse this cell fate specification, leading to exit of lymphoma cells from the germinal center and reducing their proliferation.137

HIGH POTENTIAL DISRUPTION REPORT • November 2020 67

About 20% of follicular lymphomas harbor gain-of-function mutations in the EZH2 gene, which may provide a biomarker that indicates which patients are likely to respond to tazemetostat.126,139 However, EZH2 activity may also play a role in the growth and development of follicular lymphomas lacking EZH2 mutations,140 and tazemetostat studies have tested the drug’s activity in patients with either EZH2 mutations or wild-type EZH2. An oncologist who specializes in hematology prescribes tazemetostat. According to the FDA- approved label, this drug is intended to be taken by mouth at a dosage of 800 mg twice daily until disease progression or intolerable toxicity.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 4 ongoing trials for this topic. We present 3 of these trials in Table 2.15. We excluded a phase 2 clinical trial that is being conducted in Japan (NCT03456726). Table 2.15. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Open-Label, Multicenter, Patients (n = 420) with Phase 1/2, single-group trial of the Primary Phase 1/2 Study of relapsed or refractory safety and efficacy of tazemetostat in completion Tazemetostat (EZH2 Histone advanced solid tumors treating relapsed or refractory November 2019 Methyl Transferase [HMT] or B-cell lymphomas, malignancies Study Inhibitor) as a Single Agent including patients Patients with relapsed/refractory completion July in Subjects With Adv. Solid (n = 99) with relapsed or follicular lymphoma received oral 2021 Tumors or With B-Cell refractory follicular tazemetostat at a dosage of 800 mg Lymphomas and lymphoma who have twice daily. Tazemetostat in received at least 2 prior Primary outcomes: Maximum Combination With systemic therapies tolerated dose of tazemetostat and Prednisolone in Subjects objective response rate With DLBCL (EZH-101) NCT01897571

HIGH POTENTIAL DISRUPTION REPORT • November 2020 68

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Study in Subjects With Patients (n = 518) with Phase 3, randomized controlled trial Primary Relapsed/Refractory relapsed or refractory of the safety and efficacy of completion June Follicular Lymphoma (EZH- follicular lymphoma who tazemetostat plus lenalidomide and 2022 302) have received at least rituximab Study NCT04224493 one prior systemic The trial consists of 3 stages: (1) a completion therapy safety run-in stage to determine the December 2024 recommended phase 3 dose, (2) a safety and efficacy stage with 2 futility analyses assessing overall response rate and progression-free survival, and (3) a safety and efficacy stage that may enroll patients irrespective of EZH2 mutation status or patients with only EZH2 gain-of-function mutation, depending on the results of stage 2. Primary outcomes: Recommended phase 3 dose and progression-free survival Tazemetostat Rollover Study Patients (n = 300) who Phase 2, single-group trial of the Primary (TRuST): An Open-Label have demonstrated safety and efficacy of extended completion Rollover Study (TRuST) clinical benefit from tazemetostat dosing December 2023 NCT02875548 tazemetostat in an Patients will receive tazemetostat at Study antecedent clinical trial the dose specified in the antecedent completion April of the drug trial. 2024 Primary outcome: Long-term safety profile of tazemetostat Secondary outcome: Overall survival

Abbreviations: Adv, advanced; DLBCL, diffuse large B cell lymphoma; EZH2, enhancer of zeste homolog 2 gene.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 1/2 trial with published results.141 We summarize results as written in an abstract of the published study. The following abbreviations are used in this section: CI, confidence interval; DLBCL, diffuse large B-cell lymphoma; EZH2, enhancer of zeste homolog 2; EZH2mut, EZH2 activating mutation– positive; EZH2WT, EZH2 activating mutation–negative; IQR, interquartile range; NE, not estimable.

Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Adv. Solid Tumors or With B-Cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With DLBCL (EZH-101). NCT01897571. Morschhauser et al 2020.141

• Patient population/planned enrollment: Patients (n = 420) with relapsed or refractory advanced solid tumors or B-cell lymphomas, including patients (n = 99) with relapsed or refractory follicular lymphoma who had received at least 2 prior systemic therapies

HIGH POTENTIAL DISRUPTION REPORT • November 2020 69

• Study design: Phase 1/2, single-group trial of the safety and efficacy of tazemetostat in treating relapsed or refractory malignancies. Patients with relapsed/refractory follicular lymphoma received oral tazemetostat at a dosage of 800 mg twice daily. • Primary outcomes: Objective response rate and maximum tolerated dose • Secondary outcomes: Progression-free survival, duration of response, and adverse events • Results presented by study authors: “Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22.0 months (IQR 12.0-26.7) for the EZH2mut cohort and 35.9 months (24.9-40.5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53-82; 31 of 45 patients) in the EZH2mut cohort and 35% (23-49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10.9 months (95% CI 7.2-not estimable [NE]) in the EZH2mut cohort and 13.0 months (5.6- NE) in the EZH2WT cohort; median progression-free survival was 13.8 months (10.7-22.0) and 11.1 months (3.7-14.6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anemia (two [2%]). Serious treatment- related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths.” Manufacturers and Regulatory Status Epizyme, Inc (Cambridge, Massachusetts), manufactures tazemetostat. On June 18, 2020, FDA granted accelerated approval to tazemetostat to treat patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as determined by an FDA-approved test and who have received at least 2 prior systemic therapies.142 The submission was based on data from the phase 2 EZH-101 trial. At the same time, FDA also approved the cobas EZH2 Mutation Test (Roche Molecular Systems, Basel, Switzerland) to determine EZH2 mutation status. Tazemetostat was previously granted accelerated approval in January 2020 to treat a different indication, metastatic or locally advanced epithelioid sarcoma that is ineligible for complete resection.132 For a list of FDA-approved indications, see the FDA prescribing information for tazemetostat. Cost Information An online aggregator of US-based prescription drug prices, GoodRx, reported a retail price of $15 300 for a 30-day supply of tazemetostat (as of October 5, 2020). If patients take the drug for a year, it would cost about $183 600.135 Key Stakeholder Perspectives Between July 22, 2020, and September 1, 2020, seven stakeholders, reflecting clinical, health systems, nursing, patient, and research perspectives, provided comments and ratings on tazemetostat. The list below provides a summary of key stakeholder perspectives. • Data from a small number of patients showed that tazemetostat improved response rates and was well tolerated. These outcomes have potential to increase tazemetostat’s adoption rate in patients whose disease progresses within 24 months compared with other salvage therapies, such as kinase inhibitors and T-cell-based therapies. • In the absence of effective oral drugs, tazemetostat could decrease disparities by allowing patients to be treated outside large medical centers. However, its high cost and need for genetic profiling might increase disparities. • Implementing tazemetostat for clinical use is not expected to disrupt health care delivery because it is an oral drug used in the third-line setting to treat only about 20% of patients with relapsed or refractory follicular lymphoma.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 70

• As the first molecularly directed therapy to treat follicular lymphoma, tazemetostat could disrupt the current paradigm of care. Patient care might be further disrupted if follow-up studies of tazemetostat show safety and efficacy in earlier lines of treatment.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 71

Chapter 3. Cardiovascular Diseases

Chapter Summary For the cardiovascular diseases priority area, we considered for inclusion 4 topics for which (1) preliminary phase 3 data for drugs, phase 2 (or equivalent) data for devices and procedures, or some human data for off-label uses or programs were available; (2) information was compiled and sent for stakeholder comment before September 8, 2020; and (3) we received at least 5 sets of comments and ratings from stakeholders between September 19, 2019, and September 18, 2020. As of September 8, 2020, we were monitoring 21 topics in this priority area, including the 4 topics considered for inclusion in this report. These 21 topics will be listed in the December 2020 PCORI Health Care Horizon Scanning System: Horizon Scanning Status Report. We also archived 5 topics between April 2020 and May 2020. A description of these 5 topics and the reasons they were archived can be found in the June 2020 Status Report. We archived 2 additional topics in early October 2020. A description of those topics and the reasons they were archived will be included in the December 2020 Status Report. The 21 monitored topics encompass pharmaceuticals, gene and cellular therapies, devices, and implants intended to treat 10 cardiovascular diseases and/or related symptoms. Of these, 17 are too early in development to meet criteria (as outlined above) for eligibility for this report. Topics Considered for Inclusion in This Report Table 3.1 lists the topic selected for inclusion in this report based on stakeholder ratings and comments and available data. Table 3.1. Included Topic for Priority Area: Cardiovascular Diseases

Topic title Organ Care System Heart to treat end-stage heart failure requiring transplantation

Table 3.2 lists 3 topics considered but not selected for inclusion in this report, based on stakeholder ratings and comments and available data. Each record notes the reasons for exclusion. Table 3.2. Topics Considered but Not Included for Priority Area: Cardiovascular Diseases

Topic title Exclusion reason(s) and notes based on stakeholder comments Inclisiran to treat heterozygous familial Inclisiran represents yet another option for treating familial hypercholesterolemia hypercholesterolemia that might be less costly and easier for patients to take than competing injectable drugs that are added to statins and other lipid-lowering drugs. Therefore, its overall disruptive potential is limited. Inclisiran to treat refractory Inclisiran could reduce the frequency of injections from every 2 to 4 atherosclerotic cardiovascular disease weeks to every 6 months, potentially improving treatment adherence. However, it is intended to be given in addition to existing lipid-lowering drugs, making it an incremental rather than disruptive change to current practice.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 72

Topic title Exclusion reason(s) and notes based on stakeholder comments Nerinetide (NA-1) to treat acute Available data suggest nerinetide offers minimal additional benefit ischemic stroke compared with placebo, likely limiting clinical acceptance. Further, nerinetide delivery is similar to existing stroke treatments and would be added to them, limiting the intervention’s disruptive potential.

Topic Summaries We present below a summary of the topic deemed to have high potential for disruption.

Organ Care System Heart to Treat End-Stage Heart Failure Requiring Transplantation Highlights • Only about 35% of donor hearts can be used because of their poor condition after donation and transport, which leads to a substantial number of patients remaining on the transplant waiting list for long periods and an annual death rate of nearly 20% in these patients. • The Organ Care System (OCS) Heart is a portable unit designed to maintain donor hearts for a longer period in a more functional state outside the body than the standard, static cold storage, during storage and transport. • By keeping donor hearts beating and perfused with a blood-based solution in a protected environment, OCS Heart offers the potential for longer transport times that might reduce geographic limitations inherent with static cold storage. • The technology might expand the pool of hearts available for transplantation by allowing expanded donor criteria, which could enable more patients on waiting lists to receive a heart transplant. • Stakeholders commenting on this technology thought OCS Heart could improve outcomes by enabling more patients on waiting lists to undergo heart transplantation sooner and saving overall care costs by reducing posttransplant complications and rehospitalizations for end- stage heart failure. Patient Population The OCS Heart is intended to preserve and allow outside-the-body assessment of donor hearts intended for transplantation into adults aged 18 years or older who are candidates for heart transplantation. Intervention Recent studies indicate that only about 35% of donor hearts are used, because of their poor condition after donation and transport.143,144 At the current levels of donor heart availability, a substantial number of patients remain on the transplant waiting list for extended periods, and the annual death rate among waiting patients is approaching 20%.145 Substantial interest exists in increasing the number of donor hearts that are suitable for use. OCS is a portable system intended to maintain a donor organ—heart, lung, or liver graft146,147— in a warm, functioning state outside the body for an extended period. This purportedly optimizes organ health and allows for continuous clinical evaluation of the donor organ and its suitability for transplantation.147

HIGH POTENTIAL DISRUPTION REPORT • November 2020 73

OCS Heart is optimized for preserving donor hearts.148 It is intended to increase the number of viable donor hearts for transplantation by making longer-distance transport possible. It also purportedly gives clinicians more clinical data to better assess donor organ suitability from a larger pool of donor hearts than are considered suitable for use with conventional cold storage.148 Like the other OCS systems, the OCS Heart comprises 2 principal components: a portable battery-powered console and an organ-specific perfusion kit that function together as a system.147,148 The system perfuses donor organs with a proprietary blood-based solution to replenish oxygen and essential nutrients. After physicians harvest the donor heart, they place it in the perfusion module and revive it to a beating state. The self-contained perfusion module maintains the proper temperature and humidity, protects the organ from external contaminants, and allows sterile ultrasound assessment of heart function and sterile blood sampling for laboratory analysis. A wireless monitor allows clinicians to assess the organ’s status and to control system functions.147,148

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present these trials in Table 3.3. Although the EXPAND Heart trial [NCT02323321] is listed as active, not recruiting [as of last update on August 14, 2019], we excluded it because final results were reported in April 2019 and published in the Journal of Heart and Lung Transplantation. See Schroder et al 2019 below. Table 3.3. Ongoing Clinical Trials

Study name and Patient population Study design and outcomes Estimated date National Clinical and planned of completion Trials identifier enrollment Heart EXPAND Adults aged 18 years Unphased, single-arm, open-label protocol to Primary Continued Access or older (n = 52) provide transplant candidates expanded completion Protocol registered as access to OCS Heart system (pending FDA November 2020 NCT03835754 candidates for regulatory review) to preserve and assess Study primary heart donor hearts that fail to meet current graft completion transplantation organ acceptance criteria December 2020 Primary outcomes: Patient survival after transplantation and absence of severe, primary right or left ventricular dysfunction of the donor heart within the first 24 hours

HIGH POTENTIAL DISRUPTION REPORT • November 2020 74

Study name and Patient population Study design and outcomes Estimated date National Clinical and planned of completion Trials identifier enrollment Donors After Adults aged 18 years Unphased, randomized, single-group Primary Circulatory Death or older (n = 180) assignment, open-label trial comparing safety completion Heart Trial registered as and efficacy of OCS Heart with that of static August 2021 NCT03831048 candidates for cold storage standard of care for preserving Study primary heart and assessing hearts from donors after completion transplantation circulatory death December 2021 Primary outcome: Patient survival at 6 months after implantation Selected secondary outcomes: Patient and graft survival at 30 days and initial hospital discharge, if longer than 30 days Observational Study Children and adults, Unphased, single-arm, 2-center, prospective Primary of the Clinical Use of ages not specified observational trial to observe clinical use of completion the OCS Heart (n = 60), who require OCS Heart for patients who require heart December 2021 NCT03687723 heart transplantation Study transplantation Primary outcome: Patient survival at 12 completion months after transplantation October 2022 Secondary outcome: Patient and graft organ survival at 30 days after transplantation

Abbreviation: OCS, Organ Care System.

Recently Completed and Ongoing Trials With Available Results Our searches identified 3 recently completed, late-phase trials with published results.149-151 We summarize these studies with results as written in an abstract of a published study and conference abstracts. The following abbreviations are used in this section: CS, cold storage; d, days; DBD, donation after brain death; DCD, donation after circulatory death; DPP, direct procurement and perfusion; ECD, expanded criteria donor; ECMO, extracorporeal membrane oxygenation; EF, ejection fraction; ESHP, ex situ heart perfusion; ICU, intensive care unit; LV, left ventricular; LVH, left ventricular hypertrophy; NRP, normothermic regional perfusion; OCS, Organ Care System; p, probability; PGD, primary graft dysfunction; RV, right ventricular; UNOS, United Network for Organ Sharing; vs, versus; y, years.

International EXPAND Heart Pivotal Trial (EXPANDHeart). NCT02323321. Schroder et al 2019.149

• Patient population/planned enrollment: Adults aged 18 years or older (n = 75) registered as candidates for heart transplantation • Study design: Single-arm, open-label trial to assess safety and efficacy of the OCS Heart system for preserving and assessing donor hearts (n = 93) that fail to meet current standard heart graft acceptance criteria for transplantation (total ischemic time of 4 hours or more or total ischemic time of 2 to 4 hours plus one of the following risk factors: LVH, EF 40% to 50%, down time of 20 minutes or more, and donor age older than 55 years) • Primary outcome: Composite of patient survival at 30 days after transplantation and absence of severe primary heart graft dysfunction in the first 24 hours after transplantation • Secondary outcomes: Rate of ECD heart utilization after preservation and assessment on the OCS Heart system

HIGH POTENTIAL DISRUPTION REPORT • November 2020 75

• Results presented by study authors: “Ninety-three eligible donor hearts with a mean UNOS match run of 66 declines were assessed on OCS Heart. Donor categories were as follows: x-clamp time ≥ 4 hours 37%, LVH 23%, EF 40-50% were 23%, downtime ≥ 20 minutes 28%, older age 13% and 33% met multiple inclusion criteria. 75 of the 93 donor hearts were successfully transplanted resulting in a utilization rate of 81%. Mean OCS perfusion time was 6.35 hours. Incidence of severe LV or RV PGD at 24 hours was 10.7%. 30-day and 6-month survival were 94.7% and 88% respectively.”

First to 50: Early Outcomes Following Heart Transplantation at Royal Papworth Hospital From Donation After Circulatory Determined Death (DCD) Donors. The Journal of Heart and Lung Transplantation. Messer et al 2019.151

• Patient population/planned enrollment: First 50 patients, ages not specified, to undergo DCD heart transplantation at a single center (Royal Papworth Hospital, Cambridge, United Kingdom) and a retrospective, matched cohort of patients who underwent standard DBD heart transplantation • Study design: Early outcomes analysis of DCD heart transplants compared with a retrospective cohort of DBD heart transplants. DCD hearts were retrieved by 1 of 3 methods: NRP followed by ESHP (NRP-ESHP), NRP followed by CS (NRP-CS), or DPP using only ESHP (DPP-ESHP). NRP indicates mechanical restoration of perfusion to the abdominal organs before donor heart removal. ESHP indicates external perfusion with the OCS Heart system. DPP indicates direct heart removal (ie, without abdominal perfusion) followed by OCS Heart perfusion outside the body. • Primary outcome: Survival at 30 days after transplantation • Secondary outcomes: Posttransplantation inotrope dependence, mechanical support, initial cardiac performance, ventilator duration, intensive care duration, and length of hospital stay • Results presented by study authors: “Sixteen DCD hearts were transplanted following (NRP-ESHP), 32 hearts following (DPP-ESHP) and 2 hearts following (NRP-CS). The 30-day survival post transplant was 100% in both DCD and DBD groups. All other outcome variables were comparable between groups with the exception of Dopamine reliance post transplant.”

Cardiac Transplantation in Higher Risk Patients: Is Ex Vivo Heart Perfusion a Safe Preservation Technique? A Two Center Experience. The Journal of Heart and Lung Transplantation. Rojas et al 2019.150

• Patient population/planned enrollment: Adults (n = 126) who underwent heart transplantation using conventional donor graft preservation (n = 82; mean age 32.1 ± 22.9 years) or OCS Heart preservation (n = 44; mean age 46.4 ± 16.2 years) • Study design: Two-center retrospective review of heart transplantation outcomes using OCS Heart donor heart preservation (group A) or standard cold storage (group B) • Primary outcomes: Thirty-day survival and 1-year survival • Secondary outcomes: Donor heart preservation time, donor heart graft rejection, and ICU stays • Results presented by study authors: “Baseline characteristics in both groups: age (y) (A:46,4±16,2 vs. B:32,1±22,9; p<0,001), male gender (%) (A:75,0 vs. B:67,1, p=0,41), time on waiting list (d) (A:639±1100 vs. B:510±789, p=0,491), [high-urgency] status (%) (A:84,1 vs. B:91,5, p=0,241), previous [ventricular assist device] (%) (A:72,7 vs. B:62,2, p=0,324). Operative results: ex situ time (min) (Total preservation time Group A, ischemia for Group B) (A: 402±67 vs. B: 225±49, p<0.001), operation time (min) (A: 488±96.3 vs. B: 451±133, p=0.073), ventilation time (d) (A: 7.1±15.4 vs. B: 17.6±36.9, p=0.123), ICU stay (d) (A: 14.2±21 vs. B: 24,7±36.9, p=0.315), postoperative ECMO (%) (A: 18.2 vs. B: 28.4, p=0.279), bleeding requiring redo surgery (%) (A: 20.5 vs. B: 20.7, p=0.199), early graft rejection (%) (A: 9.3 vs. B: 20.0, p=0.199). 30-d-survival (%) (A: 99.6 vs. B: 91.2, p=0.263), 1-y-survival (%) (A: 88.6 vs. B: 78.2, p=0.222).” Manufacturers and Regulatory Status TransMedics, Inc (Andover, Massachusetts), manufactures the OCS Heart system. TransMedics submitted a Premarket Approval (PMA) application to FDA for the system in April 2014 based on

HIGH POTENTIAL DISRUPTION REPORT • November 2020 76

results of the PROCEED II trial, designed to demonstrate noninferiority of the OCS Heart system to standard-of-care storage of donor hearts.152,153 In June 2019, TransMedics reported that FDA granted the company an investigational device exemption to begin a clinical trial, for the first time in the United States. The trial is evaluating the OCS Heart for preserving hearts obtained from donors after circulatory death.154,155 On September 28, 2020, TransMedics announced that FDA had postponed an advisory committee expert panel meeting to review the OCS Heart PMA, scheduled for October 7, 2020, to review additional, already collected, short- and long-term data from the OCS Heart EXPAND trial and the EXPAND Continued Access Protocol.156 The expert panel meeting had originally been scheduled for April 16, 2020, but was previously postponed because of impacts related to the COVID-19 pandemic.157 FDA previously approved TransMedics’s PMA for similar technology in April 2018 to preserve donor lungs (OCS Lung system) selected using standard lung graft acceptance criteria.158 Approval was further expanded in June 2019 for OCS Lung use in preserving donor lungs selected under expanded acceptance criteria.159 Cost Information According to ECRI’s SELECTPlus database, member hospitals reported an average price of about $308 200 for the OCS Heart console unit (as of October 5, 2020); US cost information for the single-use perfusion kit is unavailable.160 Key Stakeholder Perspectives Between July 9, 2020, and September 28, 2020, eight stakeholders, reflecting clinical, nursing, research, health systems, patient, and caregiver perspectives, provided comments and ratings on this topic. The list below summarizes key stakeholder perspectives. • Use of the OCS Heart system could become a new standard of care in preserving and transporting donor hearts for transplantation, if the encouraging data trends continue. • The OCS Heart system could dramatically improve outcomes by potentially expanding the pool of donor hearts and reducing deaths of patients on waiting lists. • The technology represents a large shift from existing donor organ transport procedures that rely on static cold storage. Implementing the OCS Heart system would require additional staff, equipment, supplies, and training. • The higher initial equipment costs could lower downstream care costs if posttransplant complications are reduced. • Smaller waiting lists with shorter wait times might reduce overall care costs for this population. Growing donor heart scarcity, relative to demand, has increased the acuity of patients on the waiting list, resulting in recurrent rehospitalizations and increasingly costly and complex outpatient care, including use of ventricular assist devices and intravenous inotropes.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 77

Chapter 4. Mental and Behavioral Health Conditions

Chapter Summary For the mental and behavioral health conditions priority area, we considered for inclusion 4 topics for which (1) preliminary phase 3 data for drugs, phase 2 (or equivalent) data for devices and procedures, or some human data for off-label uses or programs were available; (2) information was compiled and sent for stakeholder comment before September 8, 2020; and (3) we received at least 5 sets of comments and ratings from stakeholders between September 19, 2019, and September 18, 2020. As of September 8, 2020, we were monitoring 17 topics in this priority area, including the 4 considered for inclusion in this report. These 17 topics will be listed in the December 2020 PCORI Health Care Horizon Scanning System: Horizon Scanning Status Report. We also archived 2 topics in May 2020 and 1 in August 2020. A description of these topics and the reasons they were archived can be found in the June 2020 and September 2020 Status Reports, respectively. We archived an additional topic in early October 2020. A description of that topic and the reason it was archived will be included in the December 2020 Status Report. The 17 monitored topics encompass pharmaceuticals and devices intended to treat 9 mental and behavioral health conditions. Three topics were developed as topic profiles to be sent for stakeholder comment; however, fewer than 5 sets of stakeholder comments were received for these topics before September 18, 2020, so they were not considered for inclusion in this report. The remaining 10 topics are still too early in development to meet criteria (as outlined above) for eligibility for this report. Topics Considered for Inclusion in This Report Table 4.1 lists 2 topics selected for inclusion in this report based on stakeholder ratings and comments and available data. Topics are listed and discussed alphabetically by title. Table 4.1. Included Topics for Priority Area: Mental and Behavioral Health Conditions

Topic title 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy to treat severe posttraumatic stress disorder SEP-363856 to treat schizophrenia

Table 4.2 lists 2 topics considered but not selected for inclusion in this report, based on stakeholder ratings and comments and available data. Each record notes the reasons for exclusion.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 78

Table 4.2. Topics Considered but Not Included for Priority Area: Mental and Behavioral Health Conditions

Topic title Exclusion reason(s) and notes based on stakeholder comments EndeavorRx to treat attention- Data from clinical trials of this intervention did not demonstrate deficit/hyperactivity disorder [ADHD] meaningful, patient-centered effects (ie, improvement of ADHD symptoms). Stimulant medication is likely to remain the standard of care. Additional and long-term efficacy data are needed. Ketamine (NRX-100)/cyclurad (NRX- More efficacy data are needed to determine the intervention’s potential 101) to treat severe bipolar depression to improve meaningful, patient-centered outcomes (eg, lowering with acute suicidal ideation suicidal behavior) and safety (ie, incidence of serious side effects such as hallucinations). Future clinical trials should investigate a larger patient sample size, a longer treatment period, and additional outcomes including suicidal ideation.

Topic Summaries We present below 2 summaries of topics deemed to have high potential for disruption.

3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy to Treat Severe Posttraumatic Stress Disorder Highlights • MDMA (3,4-methylenedioxymethamphetamine) is an oral psychoactive drug given before an extended psychotherapy session that involves an overnight stay in the clinic. • The session is conducted by a specially trained therapist so the therapist and patient can efficiently establish a therapeutic relationship and increase 2-way communication during the session. • Stakeholders commenting on this topic thought that MDMA has the potential to be a quicker and more effective treatment for severe posttraumatic stress disorder (PTSD) than standard psychotherapy and selective serotonin reuptake inhibitor drugs, and because fewer sessions could be needed overall, it might treat more patients earlier. • Stakeholders also thought that several barriers would affect the widespread implementation of MDMA for treating severe PTSD. Barriers include the long duration of each therapy session, required clinical training for the therapist, infrastructure changes, cost, and concerns about appropriate patient selection. Patient Population This treatment is intended for adults aged 18 years or older who meet diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, for severe PTSD and who have had at least one unsuccessful attempt at either talk therapy or drug treatment. Intervention MDMA is a psychoactive drug under study for use during psychotherapy sessions led by specially trained therapists to improve symptoms of severe PTSD.161 MDMA works by activating the trace amine–associated receptor 1 and inhibiting vesicular monoamine transporter 2, thereby

HIGH POTENTIAL DISRUPTION REPORT • November 2020 79

increasing concentrations of neurotransmitters (eg, dopamine, norepinephrine, serotonin) involved in the regulation of emotion, arousal, and memory.162 MDMA is thought to produce a sense of euphoria, well-being,163 and “openness” that purportedly improves negative behaviors and feelings associated with PTSD, such as hostility, mistrust, and emptiness.164 When taken by the patient, MDMA purportedly enables the therapist to more efficiently establish a therapeutic relationship and increase 2-way communication during a prolonged psychotherapy session.165 Patients given MDMA have reported gaining greater access to their memories and helpful insights when revisiting traumatic events during therapy sessions.166 MDMA produces its psychological and physical effects by increasing levels of neurotransmitters in the brain, including dopamine, norepinephrine, serotonin, oxytocin, prolactin, and cortisol.161,167-170 In clinical trials, MDMA has been given to patients before an 8-hour psychotherapy session. The initial dose is 80 or 120 mg taken by mouth followed by a supplemental half-dose of 40 or 60 mg given 1.5 to 2 hours later, if necessary, totaling 80 to 180 mg per session. The treatment period consists of one session per month for 3 months. The psychotherapy session alternates between periods of patient introspection and engagement with the therapist. Patients are monitored overnight at the site and meet with their therapists for a 90-minute follow-up therapy session the next day for further emotional reprocessing.171 The National Institutes of Health’s National Institute of Mental Health website offers more information on PTSD.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified one ongoing trial for this topic. We present this trial in Table 4.3. Table 4.3. Ongoing Clinical Trial

Study name and Patient population Study design and outcomes Estimated National Clinical Trials and planned date of identifier enrollment completion A Multi-site Phase 3 Adults aged 18 years or Phase 3, randomized, double-blind, parallel- Primary Study of MDMA- older (n = 100) with assignment trial assessing the efficacy and completion Assisted Psychotherapy severe PTSD safety of MDMA-assisted manualized November for PTSD (MAPP2) psychotherapy versus manualized 2021 NCT04077437 psychotherapy with placebo for 3 monthly psychotherapy sessions Primary end point: Clinician-administered PTSD scale Secondary end point: Clinician-rated functional impairment disability scale Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; PTSD, posttraumatic stress disorder.

Recently Completed and Ongoing Trials With Available Results Our searches identified 7 recently completed late-phase trials. Data from 6 of these trials (NCT01793610, NCT01689740, NCT01211405, NCT01958593, NCT00353938, NCT00090064) were published in 2 pooled analyses, one initial and one longer term.171,172 Data from 3 of those

HIGH POTENTIAL DISRUPTION REPORT • November 2020 80

trials (NCT01793610, NCT01211405, NCT01958593) were published in another pooled analysis.173 We summarize the 3 most recent studies’ results as written in the published studies. We excluded a completed phase 2, open-label trial (NCT03282123) for brevity and a phase 3, placebo-controlled trial (NCT03537014) because no data are available yet. The following abbreviations are used in this section: BDI-II, Beck Depression Inventory-II (revised); CAPS-IV, Clinician-Administered PTSD Scale-IV; CI, confidence interval; LS, least- squares; LTFU, long-term follow-up; MDMA, 3,4-methylenedioxymethamphetamine; MMRM, mixed model for repeated measures; P or p, probability; PTG, posttraumatic growth; PTSD, posttraumatic stress disorder; SE, standard error.

MDMA-Assisted Psychotherapy for Treatment of PTSD. NCT01793610, NCT01689740, NCT01211405, NCT01958593, NCT00353938, NCT00090064. Mithoefer et al 2019.171

• Patient population/planned enrollment: Adults (n = 103) aged 18 years or older with chronic, moderate to severe PTSD with at least one unsuccessful treatment attempt at or inability to tolerate treatment for PTSD with either talk therapy or drugs • Study design: Six randomized, double-blind, controlled, phase 2 clinical trials at 5 study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75-125 mg; n = 72) or placebo or controlled doses (0-40 mg; n = 31) were given to individuals with PTSD during manualized psychotherapy sessions consisting of two to three 8-hour sessions spaced 1 month apart. Three nondrug 90-minute therapy sessions preceded the first MDMA exposure, and 3 to 4 followed each experimental session. • Primary outcome: PTSD symptoms • Secondary outcomes: Depression symptoms and severity, psychological distress, and quality of life • Results presented by study authors: “After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups − 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following.”

Long-Term Follow-up Outcomes of MDMA-Assisted Psychotherapy for Treatment of PTSD: A Longitudinal Pooled Analysis of Six Phase 2 Trials. NCT01793610, NCT01689740, NCT01211405, NCT01958593, NCT00353938, NCT00090064. Jerome et al 2020.172

• Patient population/planned enrollment: Adults (n = 105) aged 18 years or older with chronic, moderate to severe PTSD with at least one unsuccessful treatment attempt at or inability to tolerate treatment for PTSD with either talk therapy or drugs • Study design: Six randomized, double-blind, controlled, phase 2 clinical trials investigated long-term change in PTSD symptoms and additional benefits and harms after MDMA-assisted psychotherapy to treat PTSD. Participants were randomly assigned to either active group doses of 75, 100, or 125 mg or control group doses of 25, 30, or 40 mg or placebo at the beginning of 8-hour therapy sessions. An optional supplemental dose of MDMA was given 1.5 to 2.5 hours after the initial dose. Three nondrug therapy sessions followed the experimental sessions. Control participants received MDMA during an open-label crossover phase. • Primary outcome: PTSD symptoms • Secondary outcomes: Suicidal ideation and behavior, relapse of PTSD symptoms, current treatment, substance use

HIGH POTENTIAL DISRUPTION REPORT • November 2020 81

• Results presented by study authors: “There was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE) = − 44.8 (2.82), p < .0001), with a Cohen’s d effect size of 1.58 (95% CI = 1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE) = − 5.2 (2.29), p < .05), with a Cohen’s d effect size of 0.23 (95% CI = 0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation.”

Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder. NCT01793610, NCT01211405, NCT01958593. Gorman et al 2020.173

• Patient population/planned enrollment: Adults (n = 60) aged 18 years or older with chronic, moderate to severe PTSD with at least one unsuccessful treatment attempt at or inability to tolerate treatments for PTSD with either talk therapy or drugs • Study design: Three randomized, triple-blind, crossover phase 2 clinical trials investigated 3 different active doses of MDMA to treat PTSD: 75, 100, and 125 mg compared with active control doses of 30 or 40 mg or placebo. Participants were randomly assigned to receive 8 hours of manualized psychotherapy in 2 experiment sessions spaced 3 to 5 weeks apart. An optional supplemental dose of MDMA was given 1.5 to 2.5 hours after the initial dose. Three nondrug therapy sessions followed the experimental sessions. • Primary outcomes: Posttraumatic growth and PTSD symptoms • Results presented by study authors: “At primary endpoint, the MDMA group demonstrated more PTG, Hedges’ g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges’ g = 0.88, 95% CI [−0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12‐ month follow‐up, within‐subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two‐thirds of participants (67.2%) no longer met criteria for PTSD. MDMA‐assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large‐magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study.” Manufacturers and Regulatory Status MDMA-assisted psychotherapy is being investigated by Multidisciplinary Association for Psychedelic Studies (MAPS; Santa Cruz, California) in phase 3 trials for treating severe PTSD in adults. MAPS anticipates completing the phase 3 trial program and filing for FDA regulatory approval in 2021.174 FDA granted Breakthrough Therapy designation to MDMA-assisted psychotherapy for severe PTSD in August 2017.175 After MDMA was designated a Schedule 1 controlled substance in 1985, the developer, MAPS, filed a Drug Master File application in 1986, followed by an Investigational New Drug application in 2001 for the use of MDMA in combination with psychotherapy.171 Cost Information Cost information is unavailable for this topic. Key Stakeholder Perspectives Between July 2, 2020, and August 2, 2020, nine stakeholders, reflecting allied health, clinical, health systems, nursing, and research perspectives, provided comments and ratings on MDMA- assisted psychotherapy. The list below provides a summary of key stakeholder perspectives. • MDMA-assisted psychotherapy might reduce the number of therapy sessions needed to treat PTSD compared with traditional psychotherapy. This reduction in therapy sessions might result in more patients being treated more quickly. • This intervention might lead to health care disparities for patients with PTSD that does not respond to standard treatments because all patients might not have access to this treatment, which requires certain infrastructure and specially trained staff.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 82

• Infrastructure changes would be needed to accommodate the 8-hour therapy sessions, overnight stays, and posttreatment follow-up that are recommended for MDMA administration. • MDMA-assisted psychotherapy would moderately disrupt costs. Although short-term costs would likely increase (ie, due to longer sessions, overnight monitoring, and cost of the drug), long-term costs could decrease if this intervention results in quicker resolution of symptoms leading to less long-term health care utilization. • As a Schedule I drug, MDMA carries the potential for misuse and abuse, a particular risk for this patient population because of the rate of comorbid substance use disorders.

SEP-363856 to Treat Schizophrenia Highlights • SEP-363856 is a novel oral antipsychotic drug intended to treat schizophrenia without blocking dopamine receptors in the brain. • Standard-of-care antipsychotic drug treatment for schizophrenia affects patients’ quality of life and overall health because it can have substantial side effects that can lead to poor medication adherence and outcomes. • Stakeholders commenting on this topic thought that fewer side effects with SEP-363856 might significantly improve patient health outcomes and quality of life. • Stakeholders thought SEP-363856 might lower long-term costs of patient care, considering that its more favorable side effect profile might improve medication adherence and reduce use of costly health care resources to treat uncontrolled symptoms. Patient Population SEP-363856 treatment is intended for adolescents and adults aged 13 to 65 years with schizophrenia. Intervention Patients with schizophrenia report that undesirable effects from available antipsychotic medications—such as tremor, restlessness, difficulty sleeping, dizziness, sexual side effects, and weight gain—negatively affect their daily activities and quality of life.176 These negative side effects are one of the main reasons patients stop taking their medication, and nonadherence with recommended antipsychotic medication dosing reportedly occurs in 50% to 75% of patients.177,178 SEP-363856 is an oral medication that purportedly treats both positive and negative schizophrenia symptoms, as well as depression symptoms, with fewer side effects than dopamine- blocking medications. It works differently from available antipsychotics because it does not block the D2 dopamine or serotonin 2A receptors. The exact way SEP-363856 produces its antipsychotic effect is unknown, but it is believed to activate trace amine–associated receptor 1 and serotonin 1A receptors.179 SEP-363856 has not been found to cause tremors, involuntary muscle contractions, restlessness, or weight gain.180 In clinical trials, SEP-363856 (25, 50, or 75 mg) has been taken by mouth once daily for up to 26 weeks.181,182 The National Institutes of Health’s National Institute of Mental Health website offers more information about schizophrenia.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 83

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 4 ongoing trials for this topic. We present 3 of these trials in Table 4.4. One trial (DIAMOND 3, NCT04109950) was excluded because its primary completion date of November 2022 is the furthest away. Table 4.4. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated National Clinical Trials planned enrollment date of identifier completion A Clinical Trial to Study Adolescents and adults Phase 3, double-blind, randomized, 3- Primary the Efficacy and Safety of (n = 525) aged 13 to 65 arm, placebo-controlled study to assess completion an Investigational Drug in years who meet DSM-5 the efficacy and safety of 2 doses of SEP- September Acutely Psychotic People criteria for schizophrenia 363856, either 50 or 75 mg, taken orally 2021 With Schizophrenia once daily, versus placebo over a period (DIAMOND 1) of 6 weeks NCT04072354 Primary outcome: Change in schizophrenia symptoms (positive and negative) from baseline Secondary outcome: Change in CGI-S score from baseline A Clinical Trial That Will Adults (n = 462) aged up to Phase 3, multiregional, double-blind, Primary Study the Efficacy and 65 years who meet DSM-5 parallel-group, long-term trial to assess completion Safety of an criteria for schizophrenia safety and tolerability of once-daily SEP- October 2021 Investigational Drug in 363856 (75 or 100 mg) compared with Acutely Psychotic People placebo for 6 weeks With Schizophrenia Primary outcomes: Change in (DIAMOND 2) schizophrenia symptoms (positive and NCT04092686 negative) and severity, and adverse events Secondary outcome: Time to relapse A Study of the Long-Term Adults aged 18 to 65 years Phase 3, multiregional, randomized, Primary Safety and Tolerability of (n = 300) who meet DSM-5 double-blind, parallel-group, long-term completion an Investigational Drug in criteria for schizophrenia trial to assess safety and tolerability of March 2022 People With once-daily SEP-363856 Schizophrenia Patients will be randomly assigned in a (DIAMOND 4) 2:1 ratio to receive SEP-363856 (50, 75, NCT04115319 or 100 mg) or quetiapine XR (400, 600, or 800 mg/day) for 52 weeks. Primary outcome: Adverse events Secondary outcome: Time to relapse Abbreviations: CGI-S, Clinical Global Impressions–severity; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; XR, extended release.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 84

Recently Completed and Ongoing Trials With Available Results Our searches identified 2 recently completed late-phase trials with published results.179,183 We summarize these 2 most recent studies with results as written in an abstract of a published study and a poster presentation. The following abbreviations are used in this section: AE, adverse event; BNSS, Brief Negative Symptom Scale; CGI-Severity or CGI-S, Clinical Global Impressions–severity scale; C-SSRS, Columbia–Suicide Severity Rating Scale; DB, double-blind; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; EPS, extrapyramidal; LDL, low-density lipoprotein; LOCF, last observation carried forward; msec, millisecond; OL, open-label; P, probability; PANSS, Positive and Negative Syndrome Scale; PSQI, Pittsburgh Sleep Quality Index; QTcF, Fridericia’s corrected QT interval; SAE, serious adverse event.

An Extension Study of Safety and Tolerability of SEP-363856 in Adult Subjects With Schizophrenia (SEP361-202). NCT02970929. Correll et al 2019.184

• Patient population/planned enrollment: Adults aged 18 to 40 years (n = 157) meeting DSM-5 criteria for schizophrenia who completed the 4-week double-blind treatment phase of study SEP361-201 • Study design: Phase 2, multiregional, open-label extension study to assess safety and tolerability of once- daily SEP-363856 (25, 50, or 75 mg) for 26 weeks • Primary outcome: AEs • Secondary outcomes: Change in schizophrenia symptoms (positive and negative) and severity, change in depression symptoms and severity, and time to relapse • Results presented by study authors: “A total of 193 patients completed the 4-week DB study, and 156 (80.8%) entered the OL extension study and received at least one dose of SEP-363856 (safety population); 52 patients (33.3%) discontinued, and 18 (11.5%) discontinued due to an AE. A total of 15 patients (9.6%) experienced an SAE; schizophrenia was the only SAE to occur in more than one patient (n = 7, in the group switched from DB placebo to SEP-363856; n = 4, in the group continuing SEP-363856). There were no deaths in the study. Suicidal ideation (assessed using the C-SSRS) was reported by 3 patients, and 1 patient made an attempt. A total of 88 patients (56.4%) experienced at least one AE; individual AEs with an incidence ≥2% were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decreased (3.2%), and prolactin increased (2.6%). Extrapyramidal (EPS)-related symptoms were reported by 5 patients. Mean month 6 change from DB/OL baseline in PSQI global score was -4.2/-2.0. Mean month 6 change from DB/OL baseline in weight was -0.26/-0.32 kg. No clinically meaningful median changes were observed at week 26 in metabolic laboratory parameters (total and LDL cholesterol, triglycerides, hemoglobin A1c) or in prolactin levels. During 6 months of OL treatment, no patient had an increase in QTcF ≥60 msec and a prolonged QTcF interval (≥450 msec in men; ≥475 msec in women). Treatment with SEP-363856 was associated with significant improvement from OL baseline to week 26 (observed/LOCF-endpoint) in the PANSS total score (-22.6/-13.8), positive subscale score (-7.3/-4.5), negative subscale score (-5.2/-3.5), and general psychopathology score (-10.2/-5.8); and in the CGI-Severity score (-1.0/-0.6) and BNSS total score (- 11.3/-8.0).”

A Study to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic Adults With Schizophrenia (SEP361-201). NCT02969382. Koblan et al 2020.185

• Patient population/planned enrollment: Hospitalized adults aged 18 to 40 years (n = 245) meeting DSM- 5 criteria for schizophrenia and experiencing acute exacerbation of psychotic symptoms • Study design: Randomized, double-blind, parallel-group, multicenter phase 2 trial comparing the efficacy and safety of flexibly-dosed SEP-363856 (50 or 75 mg/day) with placebo • Primary outcome: Change in schizophrenia symptom (positive and negative) severity using PANSS • Secondary outcomes: Change in depression symptom severity and incidence of AEs

HIGH POTENTIAL DISRUPTION REPORT • November 2020 85

• Results presented by study authors: “A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was −17.2 points and −9.7 points, respectively (least-squares mean difference, −7.5 points; 95% confidence interval, −11.9 to −3.0; P=0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups.” Manufacturers and Regulatory Status SEP-363856 is manufactured by Sunovion (Marlborough, Massachusetts), a subsidiary of Sumitomo Dainippon Pharma (Osaka, Japan). It is in phase 3 clinical development. In May 2019, FDA granted Breakthrough Therapy designation for SEP-363856 to treat patients with schizophrenia.186 Cost Information Cost information is unavailable for this topic. Key Stakeholder Perspectives Between September 9, 2020, and September 21, 2020, seven stakeholders, reflecting allied health, clinical, nursing, and research perspectives, provided comments and ratings on SEP-363856. The list below provides a summary of key stakeholder perspectives. • SEP-363856 appears effective at improving schizophrenia symptoms, although the magnitude of these effects might be similar to that of current standard-of-care therapies. • SEP-363856 might improve patient health and quality of life by causing fewer side effects (eg, weight gain, movement disorders) than standard-of-care therapies. • A more favorable side effect profile with SEP-363856 might result in more patients able to take medication to treat schizophrenia, better medication adherence once treatment is initiated, and less use of costly health care resources for uncontrolled symptoms (eg, emergency department visits or hospitalization for acute exacerbations). • Results from longer-term studies would validate the developer’s preliminary findings and determine SEP-363856’s duration of effects and cost-effectiveness.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 86

Chapter 5. Rare Diseases

Chapter Summary For the rare diseases priority area, we considered for inclusion 24 topics for which (1) preliminary phase 3 data for drugs, phase 2 (or equivalent) data for devices and procedures, or some human data for off-label uses or programs were available; (2) information was compiled and sent for stakeholder comment before September 8, 2020; and (3) we received at least 5 sets of comments and ratings from stakeholders between September 19, 2019, and September 18, 2020. As of September 8, 2020, we were monitoring 125 topics in this priority area, including the 24 considered for inclusion in this report. These 125 topics will be listed in the December 2020 PCORI Health Care Horizon Scanning System: Horizon Scanning Status Report. We also archived 5 topics between June and August of 2020. A description of those topics and the reason they were archived can be found in the September 2020 Status Report. We archived an additional 3 topics in September 2020. A description of those topics and the reasons they were archived will be included in the December 2020 Status Report. These 125 monitored topics encompass pharmaceuticals, gene and cellular therapies, monoclonal antibodies, viral vector therapies, RNA interference therapies, surgical procedures, and implantable devices intended to treat or prevent 85 rare diseases and/or related conditions. Twelve topics were developed as topic profiles to be sent for stakeholder comment; however, fewer than 5 sets of stakeholder comments were received for these topics before September 18, 2020, so they were not considered for inclusion in this report. The remaining 89 topics are too early in development to meet criteria (as outlined above) for eligibility for this report. Topics Considered for Inclusion in This Report Table 5.1 lists 17 topics selected for inclusion in this report based on stakeholder ratings and comments and available data. Topics are listed and discussed alphabetically by title. Table 5.1. Included Topics for Priority Area: Rare Diseases

Topic title ABO-102 to treat Sanfilippo syndrome type A Arimoclomol (BRX-345) to treat Niemann-Pick disease type C Betibeglogene autotemcel to treat transfusion-dependent β-thalassemia CAP-1002 to treat Duchenne muscular dystrophy Casimersen (Amondys 45) to treat Duchenne muscular dystrophy Fenfluramine hydrochloride low-dose (Fintepla) to treat Dravet syndrome Fosdenopterin (BBP-870, ORGN001) to treat molybdenum cofactor deficiency type Aa Golodirsen (Vyondys 53) to treat Duchenne muscular dystrophy Mepolizumab (Nucala) to treat hypereosinophilic syndromea MT1621 to treat thymidine kinase 2 deficiencya Olipudase alfa (GZ402665) to treat acid sphingomyelinase deficiencya Palovarotene to treat fibrodysplasia ossificans progressiva PTC-AADC to treat aromatic l-amino acid decarboxylase deficiency RVT-802 to treat pediatric congenital athymia (DiGeorge syndrome immunodeficiency, CHARGE syndrome, FOXN1 deficiency) Setmelanotide (RM-493) to treat proopiomelanocortin deficiency obesitya

HIGH POTENTIAL DISRUPTION REPORT • November 2020 87

Topic title Teprotumumab-trbw (Tepezza) to treat thyroid eye diseasea Voxelotor (Oxbryta, GBT440) to treat sickle cell disease a Topic appears for the first time in this edition of the High Potential Disruption Report.

Table 5.2 lists 7 topics considered but not selected for inclusion in this report, based on stakeholder ratings and comments and available data. Each record notes the reasons for exclusion. Table 5.2. Topics Considered but Not Included for Priority Area: Rare Diseases

Topic title Exclusion reason(s) and notes based on stakeholder comments Ataluren (Translarna) to treat More data are needed to evaluate efficacy in a larger-sized trial and over the Duchenne muscular dystrophy long term. However, this intervention has moderate disruption potential, particularly in the areas of patient outcomes, quality of life, overall health, and health care costs. Berotralstat (BCX7353) to prevent Phase 3 trial results for berotralstat demonstrated clinical efficacy in reducing hereditary angioedema rates of hereditary angioedema (HAE) attacks relative to placebo. However, its potential adoption was not considered highly disruptive, based on the availability of several existing treatment options for HAE and the lack of comparative data among them. NT-501 (Renexus) to treat The phase 2 clinical trial results for NT-501 showed some clinical effect for macular telangiectasia type 2 improved patient health outcomes. However, more data from longer trials are needed to assess the potential for disruption. OTL-101 to treat adenosine The developer, Orchard Therapeutics, has deprioritized OTL-101, reducing deaminase–severe combined future investment in its development and prioritizing other gene therapy immunodeficiency (ADA-SCID) programs. Sutimlimab (BIVV009) to treat The preliminary trial showed some clinical effect, but it was a very small and cold agglutinin disease unpublished trial. Larger trials and more data are needed to determine the safety and efficacy of this treatment. Trofinetide (NNZ-2566) to treat The available data are limited, particularly regarding symptom severity and Rett syndrome disease progression, and the intervention might be cost prohibitive. Valoctocogene roxaparvovec In August 2020, FDA issued a Complete Response Letter to the Biological (BMN 270) to treat hemophilia A License Application for valoctocogene roxaparvovec and requested additional longer-term phase 3 results. This timeline suggests trials would not be completed until late in 2023 at the earliest, likely putting this intervention outside the 3-year scope before clinical availability of the horizon scanning system.

Topic Summaries We present below 17 summaries on topics deemed to have high potential for disruption.

ABO-102 to Treat Sanfilippo Syndrome Type A Highlights • ABO-102 is an intravenous, recombinant, adeno-associated viral vector carrying a naturally produced (ie, wild-type) copy of the N-sulfoglucosamine sulfohydrolase gene, SGSH. This gene is responsible for encoding sulfamidase enzyme function that is important for breaking down the polysaccharide heparan sulfate.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 88

• As a single-dose, one-time gene therapy, ABO-102 might correct the underlying genetic defect that causes Sanfilippo syndrome type A and delay or halt disease progression, whereas current treatment is largely supportive care. The therapy is in phase 1/2 development and received FDA’s Regenerative Medicine Advanced Therapy designation in April 2018. • Stakeholders commenting on ABO-102 thought that, based on interim clinical trial results, it has moderate potential to improve patient health outcomes, quality of life, and overall health; however, more data are needed to better assess its efficacy. • Stakeholders also thought that ABO-102 is likely to be expensive and might be cost prohibitive; however, as a one-time treatment it could be less expensive than therapies that need to be given on an ongoing basis. Patient Population ABO-102 is intended for infants and children aged 6 months or older with a developmental quotient of 60 or higher and adults with biochemically and genetically confirmed Sanfilippo syndrome type A (mucopolysaccharidosis type III A). Intervention ABO-102 is a recombinant adeno-associated viral vector carrying a naturally produced (ie, wild- type) copy of the SGSH gene. It is intended to treat Sanfilippo syndrome type A, a childhood-onset, progressive, inherited metabolic disorder caused by a loss-of-function variant in SGSH. Patients with the disorder cannot break down the polysaccharide heparan sulfate, a process normally mediated by the SGSH-encoded enzyme heparan-N-sulfamidase. Buildup of heparan sulfate in cells of the central nervous system causes neural degeneration that manifests as behavioral problems, sleeplessness, loss of speech and cognitive skills, intellectual disability, heart problems, seizures, and loss of mobility. No cure exists for Sanfilippo syndrome type A (about 60% of all Sanfilippo syndrome cases), and with supportive care only, patients typically do not survive past their 20s. In these patients, ABO-102 purportedly restores sulfamidase enzyme function, which reduces levels of heparan sulfate and other glycosaminoglycans, thereby blocking central nervous system degeneration and reducing disease-related symptoms.187 In clinical trials, ABO-102 is given as a single intravenous infusion via a peripheral-limb vein at a low dose (0.5 × 1013 viral genomes [vg]/kg), middle dose (1 × 1013 vg/kg), or high dose (3 × 1013 vg/kg). Patients also receive a tapering course of prednisone or prednisolone to prevent an immune response to the viral vector. The National MPS Society website provides more information on Sanfilippo syndrome type A.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 5.3.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 89

Table 5.3. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Phase 1/2 Gene Children (n = 22) aged 6 Phase 1/2, nonrandomized, open-label Primary and Transfer Clinical Trial of months or older with study to evaluate the safety and efficacy study scAAV9.U1a.hSGSH for biochemically and of ABO-102 at 1 of 3 doses: low (0.5 × 1013 completion Mucopolysaccharidosis genetically confirmed vg/kg), middle (1 × 1013 vg/kg), or high December 2022 (MPS) IIIA (Transpher A) Sanfilippo syndrome (3 × 1013 vg/kg) NCT02716246 type A Primary outcomes: See interim results by Children aged 2 years or • Incidence of 2 or more grade III or Flanigan et al 2020 older must have a “DQ of higher AEs or treatment-related AEs under Recently ≥60 (as measured Bayley through 24 months Completed and Scales of Infant and • Change in age-equivalent Ongoing Trials With Toddler Development - developmental score from baseline to Available Results Third Edition) and months 6, 12, 18, and 24 accepting values within Secondary outcomes: the 95% CI of the • Change in CSF heparan sulfate levels, Cognitive Developmental CSF, or plasma heparan-N-sulfamidase Age Equivalents.” enzyme activity levels • Change in liver, spleen, and brain volume • Biologic outcomes measured from baseline to months 1, 6, 12, and 24 • Change in plasma or urine heparan sulfate or other GAG levels, measured from baseline to months 1, 6, 12, 18, and 24 • Change in cognitive age equivalent • Change in adaptive age equivalent • Change in developmental quotient • Change in the Sanfilippo Behavior Rating Scale • Change in Leiter International Performance Scale-Revised • Change in PedsQL total score • Cognitive outcomes measured from baseline to months 6, 12, 18, and 24 A Phase 1/2 Open Label, Children and adults of Phase 1/2, nonrandomized, single-group, Primary and Single-Dose, Gene unspecified age (n = 12) open-label study to evaluate the safety study Transfer Study of with biochemically and and efficacy of high-dose ABO-102 completion scAAV9.U1a.hSGSH genetically confirmed (3 × 1013 vg/kg) December 2023 (ABO-102) in Patients Sanfilippo syndrome Primary outcomes: With Middle and type A and a DQ < 60 • AE and SAE incidence through 24 Advanced Phases of months MPS IIIA Disease • Change in CSF heparan sulfate levels NCT04088734 and liver or spleen volume, all measured from baseline to months 1, 6, 12, and 24

HIGH POTENTIAL DISRUPTION REPORT • November 2020 90

Abbreviations: AE, adverse event; CI, confidence interval; CSF, cerebrospinal fluid; DQ, developmental quotient; GAG, glycosaminoglycan; MPS, mucopolysaccharidosis; PedsQL, Pediatric Quality of Life Inventory; SAE, serious adverse event; vg, viral genomes. Recently Completed and Ongoing Trials With Available Results Our searches identified one ongoing clinical trial with interim results.188 We summarize this study with results as written in a conference abstract. The following abbreviations are used in this section: AEs, adverse events; CI, confidence interval; CSF, cerebrospinal fluid; CFS HS, cerebrospinal fluid—heparan sulfate; DQ, developmental quotient; GAG, glycosaminoglycan; HS, heparin sulfate; PedsQL, Pediatric Quality of Life Inventory; vg, viral genomes.

Transpher A, a Multicenter, Single-Dose, Phase 1/2 Clinical Trial of ABO-102, an Intravenous AAV9-based Gene Therapy for Sanfilippo Syndrome Type A (Mucopolysaccharidosis IIIA). NCT02716246. Flanigan et al 2020.188

• Patient population/planned enrollment: Children (n = 22) aged 6 months or older with biochemically and genetically confirmed Sanfilippo syndrome type A. Children aged 2 years or older must have a “DQ of ≥60 (as measured Bayley Scales of Infant and Toddler Development - Third Edition) and accepting values within the 95% CI of the Cognitive Developmental Age Equivalents.” • Study design: Phase 1/2, nonrandomized, open-label study to evaluate the safety and efficacy of ABO-102 at 1 of 3 doses: low (0.5 × 1013 vg/kg), middle (1 × 1013 vg/kg), or high (3 × 1013 vg/kg) • Primary outcomes: Incidence of 2 or more grade III or higher AEs or treatment-related AEs through 24 months and change in age-equivalent developmental score from baseline to months 6, 12, 18, and 24 • Secondary outcomes: Change in CSF HS levels; CSF or plasma heparan-N-sulfamidase enzyme activity levels; change in liver, spleen, and brain volume; biologic outcomes measured from baseline to months 1, 6, 12, and 24; change in plasma or urine HS or other GAG levels, measured from baseline to months 1, 6, 12, 18, and 24; change in cognitive age equivalent; change in adaptive age equivalent; change in developmental quotient; change in the Sanfilippo Behavior Rating Scale; change in Leiter International Performance Scale-Revised; change in PedsQL total score; and cognitive outcomes measured from baseline to months 6, 12, 18, and 24 • Results presented by study authors: “Fourteen patients have been enrolled across three dose cohorts (Cohort 1, 5x1012 vg/kg, n=3; Cohort 2, 1x1013 vg/kg, n=3; Cohort 3, 3x1013 vg/kg, n=8). Cohorts 1 and 2 have completed 24 months follow-up, and Cohort 3 patients were followed for a median of 19.6 months (range 11.3–26.5 months). Intravenous administration of ABO-102 was well tolerated, with no serious drug-related adverse events. ABO-102 treatment was associated with rapid, dose-dependent reduction in CSF heparan sulfate (HS), sustained for the duration of the observation period in all patients. CSF HS levels have reached the lower level of quantitation of the assay by Day 180 post-dosing in Cohort 3 patients. A rapid (day 30 post-treatment) and sustained reduction in liver volume was also measured post ABO-102 treatment and was approximately normal size for height and weight in several patients. Neurocognitive function measured by the Mullen scale (primary endpoint) tracked along the normal range in patients treated with the highest dose at younger age (≤30 months), with a follow up of 12–18 months. Several other patients showed signs of cognitive stabilization.” Manufacturers and Regulatory Status ABO-102 is being developed by Abeona Therapeutics, Inc (Dallas, Texas), and is in phase 1/2 clinical development. For the indication under study, FDA granted Orphan Drug designation in April 2014,189 Fast Track designation in October 2016,190 Regenerative Medicine Advanced Therapy (RMAT) designation in April 2018,191 and Rare Pediatric Disease designation (date not specified).191 In July 2019, the manufacturer announced plans to schedule an expedited meeting with FDA (per the drug’s RMAT designation) in the second half of 2019 to discuss the next steps toward potential agency approval.192 As of early October 2020, the developer had not provided any updates.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 91

Cost Information Cost information is unavailable for this topic, but stakeholders anticipate the therapy would be costly if approved by FDA. Other single-administration gene therapies for rare diseases have been priced (eg, Zolgensma) or have had proposed pricing (eg, Valrox) of more than $2.1 million dollars per treatment. Key Stakeholder Perspectives Between January 2, 2020, and March 11, 2020, eight stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on ABO-102. The list below summarizes key stakeholder perspectives. • The theory behind ABO-102 to treat Sanfilippo syndrome type A is sound, and ABO-102 has significant potential to improve patient health outcomes, quality of life, and overall health for patients with an otherwise devastating disease; however, more data are needed from larger trials focused on patient-centered outcomes to better assess its efficacy. • This intervention might have the most impact on patient health and outcomes if given before 3 years of age. • As a gene therapy, ABO-102 is likely to be very expensive and could be cost prohibitive to many patients, potentially increasing health disparities in this population; however, as a one- time treatment, it could be less expensive than therapies that are given on an ongoing basis. • As novel treatment option, ABO-102 might shift the paradigm of patient care from supportive to curative and partially shift the setting from inpatient to include more outpatient care, but patients might still need supportive treatments.

Arimoclomol (BRX-345) to Treat Niemann-Pick Disease Type C Highlights • Arimoclomol is an oral small-molecule drug intended to treat Niemann-Pick disease type C (NPC), a rare, progressive disease associated with mental and physical disability in infants and adults. The therapy is meant to amplify the production of heat shock proteins (HSPs) that purportedly rescue misfolded proteins and clear abnormal protein collections, which would improve liposome function and slow disease progression. • FDA accepted the company’s marketing application submission for the therapy in September 2020 and set a decision date of March 17, 2021. • Stakeholders commenting on this topic thought that, as a disease-modifying drug, arimoclomol might improve patient health outcomes and improve quality of life for patients with NPC. • Stakeholders thought that arimoclomol might become the standard of care if it becomes the first FDA-approved treatment for NPC. • Stakeholders also thought that arimoclomol is likely to be expensive—although it is not clear how its price might compare to that of off-label miglustat—and that the cost of the drug might be offset by less use of health care resources because of slowed disease progression (eg, fewer hospitalizations or follow-up visits). Patient Population Arimoclomol is intended for children aged 2 to 17 years with NPC subtypes NPC1 or NPC2.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 92

Intervention NPC is a rare, genetic, progressive disease characterized by abnormal accumulations of fats (cholesterol and other lipids) in the liver, spleen, lungs, or brain, which can eventually cause cell death in these tissues. NPC is caused by variations in the Niemann-Pick disease genes, either NPC1 or NPC2. These variant genes produce proteins that impair normal trafficking of fats related to lysosomes and endosomes in cells.193 Signs and symptoms of NPC include difficulty with walking, motor coordination, swallowing, and eating; excessive muscle contractions or eye movements; recurrent pneumonia; and sleep disturbances.194 Age of onset spans infancy to adulthood. Symptoms vary widely and can be fatal. Because no known cure is available or approved for NPC, therapies are needed.193 The Mayo Clinic website offers more information about NPC. Arimoclomol (BRX-345) is a small-molecule amine intended to treat NPC. It purportedly acts by amplifying and stabilizing heat shock factor 1, a transcription factor that regulates the production of HSPs in physiologically stressed cells. HSPs purportedly correct and promote recycling of misfolded or inappropriately aggregated proteins in cells. In NPC, abnormally folded and aggregated proteins contribute to abnormal lipid accumulation in affected cells. Arimoclomol purportedly decreases the presence of abnormal proteins in NPC, ultimately decreasing cellular stress and cell death contributing to NPC disease progression.195 In the latest clinical trial, arimoclomol was given orally 3 times daily at a weight-based dose of 150 to 600 mg/day.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified a single ongoing trial for this topic. We present this trial in Table 5.4.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 93

Table 5.4. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical planned enrollment of completion Trials identifier Arimoclomol Children and adults aged Phase 2/3, randomized, parallel-assignment, Primary Prospective Study in 2 to 18 years (n = 50) with placebo-controlled study to assess the completion June Patients Diagnosed diagnosed NPC due to efficacy and safety of arimoclomol as an 2018 With NPC variants in the NPC1 or add-on therapy to standard care Study NCT02612129 NPC2 genes with at least Patients are randomly assigned to receive completion one active neurological arimoclomol capsules orally 3 times daily at October 2020 symptom a dose of 150 to 600 mg/day (weight based) Note: The or matching placebo capsules. National Clinical Primary outcome: Change in NPC disease Trials database severity score at 12 months lists this trial as Secondary outcomes: ongoing. • Motor coordination/function change from baseline at 6, 12, 18, and 24 months • CGI change from baseline at 6, 12, 18, and 24 months • QOL change from baseline at 6, 12, 18, and 24 months

Abbreviations: CGI, Clinical Global Impression; NPC, Niemann-Pick disease type C; NPC1, NPC1 like intracellular cholesterol transporter 1 gene; NPC2, NPC intracellular cholesterol transporter 2 gene; QOL, quality of life.

Recently Completed and Ongoing Trials With Available Results Our searches identified a single recently completed phase 2/3 trial with reported results.196,197 We summarize this study with results as written in 2 news releases. Although the National Clinical Trials database lists this trial as ongoing, the company indicated in a news release that this is the full data set. The following abbreviations are used in this section: NPC, Niemann-Pick disease type C; NPC1, NPC1 like intracellular cholesterol transporter 1 gene; NPC2, NPC intracellular cholesterol transporter 2 gene; NPC-CSS or NPCCSS, Niemann-Pick Disease Type C Clinical Severity Scale.

Arimoclomol Prospective Doubleblind, Randomised, Placebo-Controlled Study in Patients Diagnosed With Niemann-Pick Disease Type C. NCT02612129. Orphazyme 2019196 and Orphazyme 2020.197

• Patient population/planned enrollment: Children and adults aged 2 to 18 years (n = 50) with diagnosed NPC due to variants in the NPC1 or NPC2 genes with at least one active neurological symptom • Study design: Phase 2/3, randomized, parallel-assignment, placebo-controlled study to assess the efficacy and safety of arimoclomol as an add-on therapy to standard care. Patients were randomly assigned to receive arimoclomol capsules orally 3 times daily at a dosage of 150 to 600 mg/day (weight based) or matching placebo capsules for a double-blinded treatment period of 12 months. Participants had the option of continuing into a 12-month open-label extension study. Primary outcome: Disease severity from baseline to 12 months as measured by the NPC-CSS • Secondary outcomes: Motor coordination/function change from baseline at 6, 12, 18, and 24 months; clinical global impression change from baseline at 6, 12, 18, and 24 months; and quality-of-life change from baseline at 6, 12, 18, and 24 months

HIGH POTENTIAL DISRUPTION REPORT • November 2020 94

• Results presented by study authors: “Treatment with arimoclomol adjunct to routine clinical care resulted in a 74% reduction in disease progression (p-value =0.0506) as measured by the primary endpoint, 5-domain Niemann-Pick disease type C Clinical Severity Scale (NPC-CSS). In the predefined subgroup of patients of 4 years and older (44 out of 50 randomized patients in the trial), the treatment difference was statistically significant with a minimal disease progression at month 12 in the arimoclomol- treated group (p-value =0.0219). A highly statistically significant treatment difference was observed in another predefined subgroup analysis, requested by the European Medicines Agency (EMA), that compared arimoclomol to placebo control in patients receiving miglustat as a part of routine clinical care (p-value =0.0071).”196 “Results from the 12-month open-label extension of the phase 2/3 randomized placebo-controlled trial (CT-ORZY-NPC-002) demonstrate sustained benefit of arimoclomol over a two-year period and further evidence of its efficacy and safety profile. Forty-one patients completed the 12-month double-blinded part of the CT-ORZY-NPC-002 trial and continued into the open-label extension, where all patients received arimoclomol treatment. Patients who switched from placebo to arimoclomol treatment experienced similar reduction of disease progression as observed earlier in those patients randomized to arimoclomol treatment in the placebo-controlled trial as measured by the 5-domain NPCCSS (0.23 progression in the open-label extension vs 2.0 progression in the placebo-controlled trial). Patients who received arimoclomol for a total of two years showed greater progression in the open-label extension compared to the placebo-controlled part. This was mainly due to patients under 4 years with continued aggressive disease course. In the predefined subgroups of patients 4 years and older and patients receiving miglustat as part of their routine clinical care, early treatment initiation with arimoclomol resulted in greater benefit than delayed start of treatment, indicating that the disease course was modified by the treatment. Arimoclomol was safe and well-tolerated over 24 months.”197 Manufacturers and Regulatory Status Orphazyme A/S (Copenhagen, Denmark), which licensed rights from developer CytRx Corp (Los Angeles, California), is evaluating arimoclomol for NPC. The drug is in phase 2/3 development. In January 2020, arimoclomol became available to patients who have NPC, through an Early Access Program in the United States.198 Orphazyme announced in July 2020 that it had completed a rolling New Drug Application (NDA) submission to FDA for arimoclomol to treat NPC.199 The developer announced in September 2020 that FDA had accepted the NDA, granted priority review, and issued a Prescription Drug User Fee Act (PDUFA)-prescribed decision date of March 17, 2021.200 Arimoclomol for treating NPC received FDA Breakthrough Therapy designation in December 2019,201 Rare Pediatric Disease designation in January 2018,202 Fast Track designation in June 2016,203 and Orphan Drug designation in January 2015.204 Cost Information Cost information is unavailable for this topic, but stakeholders thought arimoclomol would likely be expensive, if approved as the first therapy to treat NPC. Key Stakeholder Perspectives Between September 8, 2020, and September 18, 2020, eight stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on arimoclomol for treating NPC. The list below summarizes key stakeholder perspectives. • Arimoclomol has potential to meet a large unmet need in patients with NPC and, if FDA approves it, to become the standard of care as the first approved treatment. • The 74% reduction in disease progression reported from clinical trials with arimoclomol suggests it might significantly improve patient health outcomes and quality of life. The largest effect is likely to be in patients who begin this treatment early in their disease progression.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 95

• More data are needed to assess whether arimoclomol will increase life expectancy in patients with NPC and how it might compare to off-label treatment with miglustat. • The health care delivery system is unlikely to change dramatically because of arimoclomol, which would conveniently be taken by mouth at home. However, some health care utilization, such as hospitalizations, routine follow-up visits, and supportive treatment, might decrease in this patient population. • Arimoclomol is likely to be expensive, although it might not differ much from off-label comparator miglustat; thus, it is unclear whether treatment cost will be significantly disrupted. Overall health care cost might be offset by less use of health care resources (see previous bullet point).

Betibeglogene Autotemcel to Treat Transfusion-Dependent β-Thalassemia Highlights • Betibeglogene autotemcel (beti-cel, formerly LentiGlobin) is a gene therapy in phase 3 trials and is delivered in a single infusion. The drug is intended to permanently enhance a patient’s ability to produce functional hemoglobin B (HBB) and enhance red blood cell (RBC) production, as well as relieve transfusion-dependent β-thalassemia (TDT) symptoms. It is intended for use in children and adults aged up to 50 years with little to no β-globin expression. • The company, which plans to submit a licensing application to FDA in mid-2021, stated that it would price the therapy, administered as a one-time infusion, at less than $2.1 million and will offer special financing options and a value-based payment plan tied to how well the therapy works in a patient. • TDT substantially affects a patient’s quality of life because the standard of care consists of lifelong, regular blood transfusions or allogeneic hematopoietic stem cell transplantation (HSCT), which are burdensome and can lead to complications. • Stakeholders commenting on this topic thought that beti-cel might reduce transfusion dependence, improve quality of life, and reduce demands on the health care system, but that data from more patients would be needed before beti-cel’s potential could be fully assessed. • Stakeholders also thought that beti-cel would carry a high upfront cost but reduce transfusion dependence, which might lead to cost savings over time. Patient Population Beti-cel is intended for children and adults aged up to 50 years with TDT, also known as β- thalassemia major or Cooley anemia, who have a β0/β0 genotype (no β-globin expression) or a β+/β0 genotype (little β-globin expression). Intervention TDT is caused by variants in the hemoglobin B gene, HBB, leading to reduced or absent hemoglobin (Hb). Reduced Hb negatively affects RBC development, causing severe anemia and related complications.205 Standard supportive care for TDT consists of lifelong, regular blood transfusions. Iron overload from the transfusions can cause serious complications and organ damage, and iron chelation therapy is used to manage the overload. The National Institutes of Health’s Genetics Home Reference website offers more information on β-thalassemia.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 96

Donor-derived (ie, allogeneic) HSCT can address the underlying cause of TDT, but it carries the risk of HSCT-related death, graft failure, graft-versus-host disease, and opportunistic infections, particularly in recipients of HSCT that is not from a matched sibling donor.205 Thus, a therapy derived from the patient’s own cells (ie, autologous) could avoid these complications. As a gene therapy, beti-cel purportedly enhances the patient’s ability to produce functional HBB genes that subsequently improve RBC production. The therapy consists of bone marrow–derived CD34+ hematopoietic stem cells from the patient that are transduced in the laboratory with a lentiviral vector that inserts a functional, modified copy of the HBB gene, βA-T87Q-globin. This purportedly improves effectiveness and allows its expression in patients to be measured. Transduced cells are then grown in number in the laboratory to facilitate uptake.206 Hb consists of 4 protein subunits: 2 subunits of α-globin (encoded by the HBA1 or HBA2 genes) and 2 subunits of β-globin (encoded by the HBB gene). Patients with β0 thalassemia carry variants in HBB that prevent the production of any β-globin. Patients with β+ thalassemia carry HBB variants that allow reduced β-globin production.205 Beti-cel is under study in patients with both β0 and β+ TDT. In clinical trials, patients are first treated with busulfan to destroy the β-thalassemia-causing blood cells and then beti-cel is given as a single intravenous treatment, at an unspecified dose.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present these trials in Table 5.5.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 97

Table 5.5. Ongoing Clinical Trials

Study name and Patient population Study design and outcomes Estimated date National Clinical and planned of completion Trials identifier enrollment A Study Evaluating the Patients (n = 23) aged Phase 3, open-label, single-arm, multisite, Primary and Efficacy and Safety of 50 years or younger single-dose study to evaluate the efficacy and study the LentiGlobin BB305 with TDT who do not safety of beti-cel completion Drug Product in have a β0 mutation at Primary outcome: Proportion of patients February 2022 Subjects With both alleles of the achieving TI at 12 to 24 months after infusion Transfusion- HBB gene Secondary outcomes: Dependent β- • Engraftment, defined as an absolute Thalassemia, Who Do neutrophil count ≥ 500 cells/µL for 3 Not Have a β0/β0 consecutive days at 24 months after Genotype (Northstar-2 transplantation [HGB-207]) • Detection of vector-derived replication- NCT02906202 competent lentivirus at 24 months after See preliminary results infusion by Porter et al 2020 • Frequency of insertional mutagenesis under Recently events leading to clonal dominance or Completed and leukemia at 24 months after infusion Ongoing Trials With • Percentage of patients with a reduction of Available Results at least 50% from the 2-year pretrial average baseline annual mL/kg RBC transfused, at 12 to 24 months after infusion

HIGH POTENTIAL DISRUPTION REPORT • November 2020 98

Study name and Patient population Study design and outcomes Estimated date National Clinical and planned of completion Trials identifier enrollment A Study Evaluating the Patients (n = 18) aged Phase 3, multicenter, open-label, single-arm Primary and Efficacy and Safety of 50 years or younger study to evaluate the efficacy and safety of study the LentiGlobin BB305 with TDT who have a beti-cel completion June Drug Product in β0/β0 genotype Primary end point: Proportion of patients 2022 Subjects With meeting criteria for TR at 12 to 24 months Transfusion- after transplantation Dependent β- Secondary end points: Thalassemia, Who • Proportion of patients meeting the criteria Have a β0/β0 for TI at 12 to 24 months after infusion Genotype (Northstar-3 • Percentage of patients with a reduction of [HGB-212]) at least 50% from the 2-year pretrial NCT03207009 average baseline annual mL/kg RBC See preliminary results transfused at 12 to 24 months after by Yannaki et al 2020 infusion under Recently • Engraftment, defined as an absolute Completed and neutrophil count ≥ 500 cells/µL for 3 Ongoing Trials With consecutive days at 24 months after Available Results infusion • Detection of vector-derived replication- competent lentivirus at 24 months after transplantation • Frequency of insertional mutagenesis leading to clonal dominance or leukemia at 24 months after transplantation • Frequency of clinical AEs at 24 months after infusion Longterm Follow-up of Patients (n = 94) aged Phase 1/2, multicenter, open-label, Primary and Subjects With up to 50 years with β- randomized, parallel-assignment, follow-up study Hemoglobinopathies thalassemia or severe study to assess the long-term safety and completion Treated With Ex Vivo sickle cell disease efficacy of beti-cel through 15 years March 2031 Gene Therapy (LTF- who were treated Primary end points: 303) with beti-cel in • Overall survival 15 years after infusion manufacturer- NCT02633943 • AEs and serious AEs at 15 years after sponsored clinical infusion trials • Vector persistence at 15 years after infusion • Monitoring of βA-T87Q-globin at 15 years after infusion • Transfusions required at 15 years after infusion • Iron content in the liver and heart, measured by cardiac MRI and blood draws at 15 years after infusion

HIGH POTENTIAL DISRUPTION REPORT • November 2020 99

Abbreviations: AEs, adverse events; HBB, hemoglobin B gene; MRI, magnetic resonance imaging; RBC, red blood cell; TDT, transfusion- dependent β-thalassemia; TI, transfusion independence (defined as a weighted average hemoglobin ≥9 g/dL without any packed red blood cell transfusions for a continuous period of ≥12 months at any time during the study after study drug infusion); TR, transfusion reduction (defined as demonstration of at least a 50% reduction in volume of red blood cell transfusion requirements, in mL/kg, in the posttreatment time period of months 12 to 24 compared with the average annual transfusion requirement in the 24 months before enrollment).

Recently Completed and Ongoing Trials With Available Results Our searches identified 2 phase 3 trials with interim results.207,208 We summarize these studies with results as written in conference abstracts and news releases. The following abbreviations are used in this section: AEs, adverse events; beti-cel, betibeglogene autotemcel; Hb, hemoglobin; HbAT87Q, drug-delivered β globin gene; HBB, hemoglobin B gene; β+IVS-I-110, β-globin mutation producing minimal adult hemoglobin; RBCs, red blood cells; TDT, transfusion-dependent β-thalassemia; TI, transfusion independence (defined as a weighted average hemoglobin ≥ 9 g/dL without any packed red blood cell transfusions for a continuous period of ≥12 months at any time during the study after study drug infusion); TR, transfusion reduction (defined as demonstration of at least a 50% reduction in volume of red blood cell transfusion requirements, in mL/kg, in the posttreatment time period of months 12 to 24 compared with the average annual transfusion requirement in the 24 months before enrollment); vs, versus.

A Study Evaluating the Efficacy and Safety of the LentiGlobin BB305 Drug Product in Subjects With Transfusion-Dependent β-Thalassemia, Who Do Not Have a β0/β0 Genotype (Northstar-2 [HGB-207]). NCT02906202. Porter et al 2020.207

• Patient population/planned enrollment: Patients (n = 23) aged 50 years or younger with TDT who do not have a β0 mutation at both alleles of the HBB gene • Study design: Phase 3, open-label, single-arm, multisite, single-dose study to evaluate the efficacy and safety of beti-cel • Primary outcomes: The proportion of treated patients who become TI at 12 to 24 months after transplantation • Secondary outcomes: Percentage of patients with a reduction of at least 50% in RBCs transfused, from baseline from months 12 through 24 after treatment; and engraftment, detection of vector-derived replication-competent lentivirus, frequency of insertional mutagenesis events leading to clonal dominance or leukemia, or frequency of clinical AEs at 24 months after transplantation • Results presented by study authors: “As of 12 June 2019, 21 patients were treated and followed for 11.6 (0.9-26.3) months. The median age at enrollment was 15 (8-34) years; 6 patients were <12 years old. All patients engrafted. Ten patients with sufficient follow-up were evaluable for TI and 9 of these patients achieved transfusion independence for an ongoing duration of 15.2 (12.1-21.3) months. The weighted average Hb during TI was 12.2 (11.4-12.8) g/dL. “At Month 12, the 9 patients who achieved transfusion independence had improved bone marrow cellularity compared to baseline (44% vs 11% normocellular) and improved myeloid:erythroid ratios (baseline: 1:7.3-1:1.4; Month 12: 1:1.6-1.9:1). Seven of 9 patients had reticulocyte counts within normal range vs 44% (4/9) at baseline. Soluble transferrin receptor levels decreased from 171.8 (66-235) nmol/L at baseline to 49.4 (34-68) nmol/L with 78% (7/9) of patients within normal range at last follow-up (vs 44% [4/9] at baseline). Erythropoietin levels in patients achieving TI decreased 61.4% from 33.2 (10.8-73.4) U/L at baseline (n=9) to 12.8 (4.9-21.8) U/L at Month 12 (n=7). Finally, the hepcidin:ferritin ratio improved from 0.01 (0.00-0.06) at baseline (n=9) to 0.03 (0.01-0.4) at Month 12 (n=9). “Post-infusion non-hematologic grade ≥3 treatment-emergent adverse events (AEs) reported in ≥3 patients included stomatitis (n=12), febrile neutropenia (n=7), epistaxis (n=3), pyrexia (n=3), and veno-occlusive liver disease (n=3). Adverse events considered related to beti-cel by the investigator included

HIGH POTENTIAL DISRUPTION REPORT • November 2020 100

thrombocytopenia (n=2, one event was serious), abdominal pain (n=1), and pain in extremity (n=1). There were no deaths and no evidence of insertional oncogenesis or clonal dominance.” Updated results were presented at the conference and in a June 12, 2020, bluebird bio news release, as follows209: “As of March 3, 2020, all 23 patients in HGB-207 were treated and have been followed for a median of 19.4 months. These patients ranged in age from four to 34 years, including eight pediatric (<12 years of age) and 15 adolescent/adult (>12 years of age) patients. Only 19 patients were evaluable for transfusion independence; four additional patients do not yet have sufficient follow-up to be assessed for transfusion independence. “Eighty-nine percent of evaluable patients (17/19) achieved transfusion independence, with median weighted average total Hb levels of 11.9 g/dL (min-max: 9.4 – 12.9 g/dL) over a median of 19.4 months of follow-up to date (min-max: 12.3 – 31.4 months). These 17 patients previously required a median of 17.5 transfusions per year (min-max: 11.5 – 37 transfusions per year). “Improved iron levels, as measured by serum ferritin and hepcidin levels (proteins involved in iron storage and homeostasis), were observed and trends toward improved iron management were seen. Over half of patients stopped chelation therapy, which is needed to reduce excess iron caused by chronic blood transfusions. Seven out of 23 patients began using phlebotomy for iron reduction.”

A Study Evaluating the Efficacy and Safety of the LentiGlobin BB305 Drug Product in Subjects With Transfusion-Dependent β-Thalassemia, Who Have a β0/β0 Genotype. NCT03207009. Yannaki et al 2020.208

• Patient population/planned enrollment: Patients (n = 18) aged 50 years or younger with TDT who have a β0/β0 genotype • Study design: Phase 3, multicenter, open-label, single-arm study to evaluate the efficacy and safety of beti-cel • Primary outcome: Proportion of treated patients achieving TR from 12 to 24 months after transplantation • Secondary outcomes: Proportion of patients achieving TI from 12 to 24 months after transplantation; percentage of patients with at least a reduction of at least 50% in RBCs transfused from baseline through 12 or 24 months after treatment; and engraftment, detection of vector-derived replication-competent lentivirus, and frequency of insertional mutagenesis events leading to clonal dominance or leukemia • Results presented by study authors: “As of 30 September 2019, 13 patients were treated (8 β0/β0, 3 β+IVS- I-110/β+IVS-I-110, 2 β0/β+IVS-I-110 genotypes) and were followed for 8.8 (2.5-20.0) months. Median age at enrollment was 17 (7-33) years; 4 patients were younger than 12 years of age. Median cell dose infused was 9.6 (5.9-15.8) x106 CD34+ cells/kg. Nine of 11 patients followed for ≥6 months have discontinued transfusions for ≥3 months. Total unsupported Hb in these patients ranged from 8.3 to 14.2 g/dL at last visit, including 3 patients with total Hb >12.5 g/dL. Beti-cel-derived HbAT87Q in these 9 patients was 3.8-12.4 g/dL at last visit, contributing 38-92% to total Hb. Soluble transferrin receptor, a marker of ineffective erythropoiesis, improved in these 9 patients at Month 6 (51.8 [35.3-177.7] nmol/L) compared to baseline (109.4 [34.1-214.1] nmol/L). Only two patients had sufficient follow-up to be evaluable for TI and both achieved transfusion independence. The two patients with ≥6 months follow-up who continue to receive RBC transfusions had HbAT87Q levels of 4.6 g/dL and 0.0 g/dL at last visit (Month 9 and 6, respectively). “Neutrophil and platelet engraftment occurred at 26 (14-38) days and 41 (21-64) days, respectively. Post- infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients included febrile neutropenia (n=7) and stomatitis (n=5). AEs considered possibly related to beti-cel included abdominal pain (n=2), thrombocytopenia (n=1), leukopenia (n=1) and neutropenia (n=1). There were no deaths, graft failure, or cases of insertional oncogenesis.” Updated results were presented at the conference and in a June 12, 2020, bluebird bio press release, as follows209: “As of March 3, 2020, 15 patients (genotypes: 9 β0/β0, 3 β0/ β+IVS1-110, 3 homozygous IVS-1-110 mutation) were treated and had a median follow-up of 14.4 months (min-max: 1.1–24.0 months). Median age at enrollment was 15 (min-max: 4 – 33 years).

HIGH POTENTIAL DISRUPTION REPORT • November 2020 101

“Six of eight evaluable patients achieved transfusion independence, with median weighted average total Hb levels of 11.5 g/dL (min-max: 9.5 – 13.5 g/dL), and continued to maintain transfusion independence for a median duration of 13.6 months (min-max: 12.2– 21.2 months) as of the data cutoff. “Eighty-five percent of patients (11/13) with at least seven months of follow-up had not received a transfusion in more than seven months at time of data cutoff. These 11 patients previously required a median of 18.5 transfusions per year (min-max: 11.0 – 39.5 transfusions per year). In these patients, gene therapy-derived HbAT87Q supported total Hb levels ranging from 8.8–14.0 g/dL at last visit.” Manufacturers and Regulatory Status Beti-cel is manufactured by bluebird bio, Inc (Cambridge, Massachusetts), and is in phase 3 development for treating TDT. The company has announced plans to complete a rolling Biologics License Application with FDA for beti-cel in mid-2021.210 FDA had granted beti-cel Breakthrough Therapy designation in February 2015 for treating TDT major.211 Cost Information The company has announced plans to price beti-cel below the $2.1 million in “intrinsic value” that it estimates the therapy delivers.212 Early estimates by a financial firm put beti-cel’s price for a one-time infusion at about $1.2 million in the United States and $900 000 in the European Union.212 However, on June 14, 2019, the company announced the EU list price would be €1.58 million ($1.78 million) after winning conditional EU approval.213 The company has announced plans to offer payers annuity-based payment agreements that would allow insurers to delay paying about 80% of beti-cel’s costs for up to 5 years after an initial upfront payment. The company also announced plans to offer a value-based payment agreement, accepting payment only if the treatment works.212 Finally, the company announced plans for price stability, linking price increases to the Consumer Price Index.212 Key Stakeholder Perspectives Between April 29, 2020, and July 12, 2020, five stakeholders, reflecting caregiver, clinical, and research perspectives, provided comments and ratings on beti-cel. The list below summarizes key stakeholder perspectives. • Beti-cel interim data are encouraging, suggesting that it might provide a clinically effective and well-tolerated option as a one-time treatment for TDT with potential long-term efficacy. • Beti-cel might improve patients’ quality of life and decrease demands on the health care system, if the treatment can substantially reduce transfusion dependence, because of the substantial burden repeat transfusions place on patients in terms of health care facility visits and side effects. • Beti-cel’s high cost might lead to health disparities in patients with insufficient insurance or in patients with insurance who cannot afford their copayments. But the treatment might save costs over time by reducing costs related to transfusion dependence. • Additional data on all patients who received beti-cel in the Northstar-2 and Northstar-3 trials as well as longer-term studies are needed to determine beti-cel’s efficacy, duration of effects, and cost-effectiveness.

CAP-1002 to Treat Duchenne Muscular Dystrophy Highlights • CAP-1002, an allogeneic cell therapy derived from donor human heart tissue given intravenously every 3 months, purportedly acts as an immunomodulator to decrease

HIGH POTENTIAL DISRUPTION REPORT • November 2020 102

inflammation and muscle degeneration and promote muscle regeneration in patients with Duchenne muscular dystrophy (DMD). It is in phase 2 development. • CAP-1002 is intended for all patients with DMD, whereas 2 disease-modifying therapies for DMD approved by FDA in recent years are available only to subsets of patients with specific genetic variants in the DMD gene. • Stakeholders commenting on this topic thought that CAP-1002 would significantly increase health care costs because it will likely be expensive (likely priced similarly to approved DMD therapies) and requires infusions every 3 months. • Stakeholders also thought that CAP-1002 could disrupt the current paradigm of patient care because of the clinician learning curve required to use it and its anticipated side effects and adverse event risks. Patient Population CAP-1002 is intended to treat males aged 10 years or older who have genetically confirmed DMD, are either ambulatory or nonambulatory, and are receiving stable doses of systemic glucocorticoids. Intervention CAP-1002 is a cell-based therapy intended for DMD, an inherited, chromosome X–linked genetic disorder caused by point mutations or deletions in the dystrophin gene, DMD. DMD encodes the dystrophin protein, which helps promote muscle function. In patients, the absence of naturally produced (ie, wild-type) dystrophin protein causes progressive muscle fiber necrosis and eventual widespread muscle weakness.214 The Muscular Dystrophy Association website offers more information about DMD. No cure for DMD exists, and first-line corticosteroid treatment addresses symptoms but does not prevent disease progression and has significant side effects. Although FDA has approved 2 gene therapies for patients who have specific mutations in DMD (ie, in exon 51 or 53), patients who have other DMD mutations do not qualify. Therefore, novel therapies for treating DMD are needed. CAP-1002 consists of cardiosphere-derived cells (CDCs) from donor heart tissue. The CDCs in CAP-1002 purportedly secrete growth factors and exosomes that promote cellular regeneration by altering immune system activity.215 Data from a completed phase 1/2 trial (ie, HOPE, NCT02485938), which enrolled patients with DMD-associated cardiomyopathy, suggest that a solution of CAP-1002 containing 75 million CDCs delivered directly into the heart improves both cardiac muscle and skeletal muscle function.216,217 Based on the systemic (ie, noncardiac) effects observed in this trial, further studies are delivering CAP-1002 by a more usual route, standard intravenous infusion. In the ongoing phase 2 HOPE-2 clinical trial (see Table 5.6), a solution of CAP-1002 containing 150 million CDCs is given intravenously once every 3 months, 4 times.

Evidence Development Summary

Ongoing Trials Our searches of the National Clinical Trials database identified a single ongoing trial for this topic. We present this trial in Table 5.6.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 103

Table 5.6. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier A Phase 2, Randomized, Male children aged 10 Phase 2, randomized, double-blind, Primary and Double-Blind, Placebo- years or older and adults parallel-assignment study to evaluate study Controlled Trial (n = 18) who have the safety and efficacy of CAP-1002 completion Evaluating the Safety and genetically confirmed Patients were randomly assigned in a March 2020 Efficacy of Intravenous DMD, are ambulatory or 1:1 ratio to receive CAP-1002 (150 Delivery of Allogeneic nonambulatory, and are million CDCs) via intravenous infusion Cardiosphere-Derived receiving stable doses of every 3 months for a total of 4 doses Cells in Subjects With systemic glucocorticoids or matching placebo. Duchenne Muscular Primary outcome: Change in the Dystrophy (HOPE-2) midlevel (elbow) dimension of the PUL NCT03406780 2.0 clinical scale, from baseline to See preliminary results by month 12 Capricor Therapeutics Secondary outcomes: 2020 under Recently • Change in the midlevel (elbow) Completed and Ongoing dimension of the PUL 2.0 clinical Trials With Available scale, from baseline to months 3, 6, Results and 9 • Change in regional systolic left ventricular wall thickening, as assessed by cardiac MRI, from baseline to months 6 and 12

Abbreviations: CDCs, cardiosphere-derived cells; DMD, Duchenne muscular dystrophy; MRI, magnetic resonance imaging; PUL, Performance of the Upper Limb.

Recently Completed and Ongoing Trials With Available Results Our searches identified a single recently completed phase 2 trial with published results.218 We summarize this study with results as written in a company news release. The following abbreviations are used in this section: CDCs, cardiosphere-derived cells; DMD, Duchenne muscular dystrophy; MRI, magnetic resonance imaging; PUL, Performance of the Upper Limb.

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of Intravenous Delivery of Allogeneic Cardiosphere-Derived Cells in Subjects With Duchenne Muscular Dystrophy (HOPE-2). NCT03406780. Capricor Therapeutics 2020.218

• Patient population/planned enrollment: Male children aged 10 years or older and adults (n = 18) who have genetically confirmed DMD, are ambulatory or nonambulatory, and are receiving stable doses of systemic glucocorticoids • Study design: Phase 2, randomized, double-blind, parallel-assignment study to evaluate the efficacy of CAP-1002 versus placebo. Patients were randomly assigned in a 1:1 ratio to receive CAP-1002 (150 million CDCs) via intravenous infusion every 3 months for a total of 4 doses or matching placebo. • Primary outcome: Change in the midlevel (elbow) dimension of the PUL 2.0 clinical scale, from baseline to month 12

HIGH POTENTIAL DISRUPTION REPORT • November 2020 104

• Secondary outcomes: Change in the midlevel (elbow) dimension of the PUL 2.0 clinical scale, from baseline to months 3, 6, and 9; and change in regional systolic left ventricular wall thickening, as assessed by cardiac MRI, from baseline to months 6 and 12 • Results presented by study authors: Top-line efficacy data reported in a table in the news release are shown in Table 5.6.1 and Table 5.6.2.

Table 5.6.1. Upper Limb Function Results (12-Month Time Point)a

Outcome measure CAP-1002b Placebob P valued (n = 8)c (n = 12)c Midlevel PUL (version 1.2) –2.1 (3.63) –4.9 (2.57) 0.08

Shoulder + mid + distal PUL –2.3 (3.86) –6.4 (3.84) 0.03 (version 1.2) Shoulder + mid + distal PUL –1.3 (2.14) –3.7 (1.50) 0.05 (version 2.0)

a Mixed model repeated measures analysis. Abbreviations: P, probability; PUL, Performance of the b Mean change from baseline to 12 months (standard deviation). Upper Limb. c Intent-to-treat population. d Nominal values unadjusted for multiple testing. Table 5.6.2. Cardiac Function Results (12-Month Time Point)a

Outcome measure CAP-1002b Placebob P valued (n = 8)c (n = 12)c LV ejection fraction % –0.33 (2.01) –1.89 (2.23) 0.004

LV end-diastolic volume, indexed –7.35 (6.10) 0.00 (7.34) 0.07 mL/m2 LV end-systolic volume, indexed –3.10 (1.68) 1.70 (5.02) 0.01 mL/m2 Creatine Kinase-MB (% of total –0.50 (0.55) 2.00 (1.00) 0.006 CK)

a Mixed model repeated measures analysis. Abbreviations: CK, creatine kinase; LV, left ventricular; MB, b Mean change from baseline to 12 months (standard deviation). myocardial; P, probability. c Intent-to-treat population. d Nominal values unadjusted for multiple testing.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 105

Manufacturers and Regulatory Status CAP-1002 is being developed by Capricor Therapeutics, Inc (Beverly Hills, California), and is in phase 2 clinical development for treating DMD. For this indication, FDA granted the drug Orphan Drug designation in April 2015,219 Rare Pediatric Disease designation in July 2017,220 and Regenerative Medicine Advanced Therapy designation in February 2018.221 In December 2018, Capricor Therapeutics placed a voluntary dosing hold on the ongoing HOPE-2 trial (NCT03406780) after a patient enrolled in the trial experienced a severe allergic reaction during drug infusion.222 The patient fully recovered from the event, and the HOPE-2 trial dosing resumed in February 2019.223 Cost Information Cost information is currently unavailable for this topic, but stakeholders expected it to be costly (eg, priced similarly to other recently approved therapies for DMD). Key Stakeholder Perspectives Between December 20, 2019, and February 7, 2020, nine stakeholders, reflecting caregiver, clinical, health systems, patient representative, and research perspectives, provided comments and ratings on CAP-1002 for treating DMD. The list below summarizes key stakeholder perspectives. • CAP-1002 has moderate to large potential to improve patient health outcomes, based on signs of efficacy observed in the HOPE and HOPE-2 trials; however, the trials were small, outcomes were limited to upper limb function, and CAP-1002 demonstrated limited additional efficacy versus placebo. • CAP-1002 would increase health care costs because it is expensive and requires infusions every 3 months. • The intravenous delivery of CAP-1002 every 3 months could create barriers to patient access to treatment, might increase health disparities, and might disrupt the health care delivery system as more patients need to travel to infusion centers rather than taking the standard-of-care comparator corticosteroids at home (assuming most patients lack access to home infusions). • CAP-1002 might disrupt the current paradigm of patient care because of the clinician learning curve required to use it and its anticipated side effects and adverse event risks.

Casimersen (Amondys 45) to Treat Duchenne Muscular Dystrophy Highlights • Casimersen is a DNA analogue given to patients with Duchenne muscular dystrophy (DMD). Casimersen purportedly binds exon 45 of dystrophin pre-messenger RNA (pre- mRNA) and promotes skipping of exon 45 during mRNA processing. These molecular actions allow synthesis of a shorter, but functional, dystrophin protein. • In phase 3 development, this intervention is intended for a subset of patients with DMD (about 9%) who have a mutation in the dystrophin gene, DMD, amenable to exon 45 skipping. • Treatment with casimersen requires weekly intravenous infusions in a health care setting.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 106

• Stakeholders generally agreed that casimersen could improve patient health outcomes and quality of life, but more data are needed to determine its clinical efficacy and potential impact on patient-centered outcomes. • Stakeholders also thought that casimersen might be cost prohibitive and controversial for use if effects are evident only after years of treatment. Patient Population Casimersen is intended for males aged 7 to 23 years who have DMD with an exon 45 rearrangement in the DMD gene and who are on a stable dose of corticosteroids. Intervention Casimersen (Amondys 45, also known as SRP-4045) is a phosphorodiamidate morpholino oligomer, or DNA analogue. It is intended to treat DMD, an inherited, chromosome X–linked genetic disorder caused by point mutations or deletions in the dystrophin gene, DMD. DMD encodes the dystrophin protein, which helps promote muscle function. The absence of naturally produced (ie, wild-type) dystrophin protein causes progressive muscle fiber necrosis and eventual widespread muscle weakness.214 No cure for DMD exists, and first-line corticosteroid treatment addresses symptoms but does not prevent disease progression and has significant side effects. The Muscular Dystrophy Association website provides more information on DMD. Although FDA has approved 2 gene therapies for patients who have specific mutations in DMD (ie, in exon 51 or 53), patients who have other DMD mutations do not qualify. Therefore, novel therapies for treating DMD are needed. Casimersen purportedly binds exon 45 of dystrophin pre-mRNA (precursor RNA composed of introns and exons) and promotes skipping of exon 45 during mRNA processing. These molecular actions allow synthesis of a shorter, but functional, dystrophin protein.224 Therefore, casimersen treatment may promote skeletal muscle function and prevent or delay disease progression in patients with DMD who have DMD exon 45 mutations (about 9% of these patients).225 In clinical trials, intravenous casimersen 30 mg/kg is given once weekly for up to 144 weeks. Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 5.7.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 107

Table 5.7. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier A Double-Blind, Placebo- Male children (n = 222) Phase 3, randomized, double-blind, Primary Controlled, Multi-center aged 7 to 13 years with parallel-assignment study to evaluate completion May Study With an Open-Label genetically confirmed DMD the efficacy and safety of casimersen 2022 Extension to Evaluate the who have a mutation in the (SRP-4045) 30 mg/kg or golodirsen Study Efficacy and Safety of DMD gene that is amenable (SRP-4053) 30 mg/kg versus placebo completion May SRP4045 and SRP-4053 in to exon 45 or 53 skipping The double-blind period will be 2023 Patients With Duchenne and who are on a stable followed by an open-label extension Muscular Dystrophy dose of corticosteroids period in which all patients will (ESSENCE) receive active treatment for 48 weeks NCT02500381 (up to week 144 of study). See preliminary results by Primary outcome: 6-minute walk test Sarepta Therapeutics distance at baseline and week 96 2019 under Recently Secondary outcomes: Completed and Ongoing • Dystrophin expression at baseline Trials With Available and weeks 48 or 96, as measured Results by IHC and WB • Ability to rise independently from the floor at week 96 • Time to loss of ambulation at week 96 • Ambulatory function at baseline and week 96, as measured by NSAA • FVC percentage predicted at baseline and week 96 Long-Term, Open-Label Male children (n = 260) Phase 3, nonrandomized, open-label, Primary and Extension Study for aged 7 to 23 years with parallel-assignment study to evaluate study Patients With Duchenne genetically confirmed the safety and tolerability of long-term completion Muscular Dystrophy DMD, who have a mutation (144-week) treatment with casimersen August 2026 Enrolled in Clinical Trials in the DMD gene that is 30 mg/kg or golodirsen 30 mg/kg Evaluating Casimersen or amenable to exon 45 or 53 Primary outcome: SAEs up to week Golodirsen skipping, who are on a 148 after treatment NCT03532542 stable dose of corticosteroids, and who completed a prior study on casimersen or golodirsen

Abbreviations: DMD, Duchenne muscular dystrophy; DMD, dystrophin gene; FVC, forced vital capacity; IHC, immunohistochemistry; NSAA, North Star Ambulatory Assessment; SAEs, serious adverse events; WB, Western blot.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 3 trial with published results.226 We summarize this study with results as written in a news release.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 108

The following abbreviations are used in this section: DMD, Duchenne muscular dystrophy; DMD, dystrophin gene; FVC, forced vital capacity; IHC, immunohistochemistry; mRNA, messenger RNA; NSAA, North Star Ambulatory Assessment; p, probability; WB, Western blot.

A Double-Blind, Placebo-Controlled, Multi-center Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy (ESSENCE). NCT02500381. Sarepta Therapeutics 2019.226

• Patient population/planned enrollment: Children (n = 222) aged 7 to 13 years with genetically confirmed DMD who have a mutation in the DMD gene that is amenable to exon 45 or 53 skipping and who are on a stable dose of corticosteroids • Study design: Phase 3, randomized, double-blind, parallel-assignment study to evaluate the efficacy and safety of casimersen (SRP-4045) 30 mg/kg or golodirsen (SRP-4053) 30 mg/kg versus placebo • Primary outcome: 6-minute walk test distance at baseline and week 96 • Secondary outcomes: Dystrophin expression at baseline and weeks 48 or 96, as measured by IHC and WB; ability to rise independently from the floor at week 96; time to loss of ambulation at week 96; ambulatory function at baseline and week 96, as measured by NSAA; and FVC percentage predicted at baseline and week 96 • Results presented by study authors: “Patients amenable to exon 45 skipping were randomized to receive a once-weekly intravenous (IV) infusion of casimersen dosed at 30mg/kg (n=27) or placebo (n=16) for 96 weeks. The interim analysis was performed on data from biopsies of the bicep muscle at baseline and on-treatment at Week 48. Key findings from the interim analysis include: o In the casimersen arm, mean dystrophin protein (% normal dystrophin as measured by Western blot) increased to 1.736% of normal compared to a mean baseline of 0.925% of normal (p<0.001). o A statistically significant difference in the mean change from baseline to week 48 in dystrophin protein was observed between the casimersen-treated arm compared to the placebo arm (p=0.009). o Of the 22 patients receiving casimersen who have been tested for increased exon-skipping mRNA using reverse transcription polymerase chain reaction (RT-PCR), all have displayed an increase in skipping exon 45 (p<0.001) over their baseline levels, representing a 100% response rate. o A statistically significant positive correlation between exon 45 skipping and dystrophin production was observed (Spearman rank correlation = 0.635, p<0.001). “The study is ongoing and remains blinded to collect additional efficacy and safety data.”

Note: Data from only the casimersen (SRP-4045) and placebo arms of the trial were included in the news release. Manufacturers and Regulatory Status Sarepta Therapeutics, Inc (Cambridge, Massachusetts), is developing casimersen to treat DMD. The drug is in phase 3 clinical development for this indication. In August 2019, Sarepta Therapeutics announced that it planned to submit in the first half of 2020 a New Drug Application (NDA) for casimersen to treat DMD.227 FDA granted casimersen drug Orphan Drug designation for this indication in June 2019.228 Sarepta Therapeutics’s NDA for casimersen was accepted by the FDA on August 25, 2020, and granted priority review. The developer stated that FDA has indicated that it does not anticipate holding an advisory committee meeting to discuss the NDA. FDA also has approved Amondys 45 as a brand name for casimersen.229 Sarepta received FDA approval for another DMD therapy, golodirsen, in December 2019.230

HIGH POTENTIAL DISRUPTION REPORT • November 2020 109

Cost Information Cost information is unavailable for this topic, but stakeholders expect the therapy to be costly (eg, priced similarly to other recently approved therapies for DMD). Key Stakeholder Perspectives Between August 25, 2020, and September 4, 2020, nine stakeholders, reflecting caregiver, health systems, patient, physician, and research perspectives, provided comments and ratings on casimersen. The list below summarizes key stakeholder perspectives. • An increase in functional dystrophin production is theoretically likely to improve patient health outcomes and quality of life by slowing disease progression, and casimersen demonstrates efficacy in increasing functional dystrophin production. However, more data are needed to determine what magnitude of increase in dystrophin production is clinically significant and whether casimersen reaches that threshold. • The weekly infusions required for treatment with casimersen might disrupt patients’ lives and the paradigm of patient care, increase health care resource use related to the infusions, and increase health disparities because it might not be feasible for some patients to undergo the weekly infusions. • The cost of casimersen will likely be high and its diffusion into clinical use might be cost prohibitive, placing strain on payers, health care facilities, and patients, especially if there are insurance coverage challenges. • More data are needed to assess long-term efficacy of casimersen and should include outcomes that are more patient-centered than dystrophin protein production.

Fenfluramine Hydrochloride Low-Dose (Fintepla) to Treat Dravet Syndrome Highlights • Low-dose fenfluramine (FFA) hydrochloride is an amphetamine derivative taken twice daily in a cherry-flavored oral solution that purportedly modulates serotonergic neurotransmission to block seizure activity. FDA approved the drug in June 2020 with a Risk Evaluation and Mitigation Strategy and classification as a Schedule IV controlled substance. • Low-dose FFA is being studied as an adjunct to patients’ current antiepileptic drug treatments. • FFA’s retail price is about $15 135 for a 360 mL supply of 2.2 mg/mL and the dose required is determined by patient weight; the manufacturer estimates an annual per-patient cost of $96 000. • Stakeholder comments were received 2 to 3 months before FDA approval. Stakeholders thought that, based on positive results in clinical trials, low-dose FFA has high potential to improve patient and caregiver quality of life and overall patient health. • Stakeholders thought that FFA could decrease health disparities, disrupt the health care delivery system and current paradigm of patient care, and decrease costs over time. Patient Population FFA is indicated to treat seizures associated with Dravet syndrome in patients aged 2 years or older.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 110

Intervention Low-dose FFA (Fintepla) is an amphetamine derivative being developed as adjunctive therapy for treating Dravet syndrome. A rare, severe, infantile-onset form of epilepsy, Dravet syndrome is usually caused by a rearrangement in the sodium voltage-gated channel alpha subunit 1 gene, SCN1A. Patients with Dravet syndrome have prolonged seizures that are difficult to control with FDA-approved antiepileptic drugs. Patients also typically experience cognitive impairment, behavioral problems, muscle weakness, and sleep disorders.231 FFA has been recognized as promoting serotonin release, but this alone is not believed to account for its purported beneficial effects on seizure activity, because other serotonin reuptake inhibitors have not shown benefits for managing epilepsy. Recent research found other activity that might account for effects observed in early studies after FFA administration for epilepsy treatment: FFA binds to sigma-1 receptors (Sig-1R) and acts as a positive allosteric modulator of Sig-1R and alters activity at the Sig-1R. This activity is thought to block seizure activity and modulate serotonergic neurotransmission.232 According to the FDA-approved label, the oral solution is taken with or without food at an initial starting and maintenance dosage of 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. If patients are not taking stiripentol at the same time, the maximum daily maintenance dosage is 0.35 mg/kg twice daily up to a maximum daily dosage of 26 mg. If patients are taking stiripentol plus clobazam, the maximum daily maintenance dosage is 0.2 mg/kg twice daily up to a maximum daily dosage of 17 mg.233 The label includes a boxed warning indicating that the drug has been associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Patients must have cardiac monitoring using echocardiograms every 6 months during treatment and once 3 to 6 months after treatment is discontinued to look for signs of VHD, PAH, or other cardiac abnormalities.233 The Dravet Syndrome Foundation website offers more information on Dravet syndrome. Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified a single ongoing trial for this topic. We present this trial in Table 5.8.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 111

Table 5.8. Ongoing Clinical Trial

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier An Open-Label Extension Children and adults Phase 3, single-group, open-label Primary and Trial to Assess the Long- (n = 340) aged 2 to 35 years extension study to assess the long- study Term Safety of ZX008 with clinically diagnosed term safety and tolerability of a completion (Fenfluramine Dravet syndrome who titrated effective dose of Fintepla December 2020 Hydrochloride HCl) Oral participated in Study 1501 (beginning with 0.2 mg/kg/day, up to a Solution as an Adjunctive or Study 1502 maximum of 30 mg/day) when used Therapy in Children and Note: The clinical trial as an adjunctive therapy to Young Adults With Dravet record states that patients antiepileptic drugs Syndrome (Study 1503) aged 18 to 35 years who Primary outcome: Incidence of NCT02823145 did not participate in Study treatment-emergent adverse events See preliminary results by 1501 or Study 1502 might Secondary outcomes: Change in Lagae et al 2018 under also be eligible for monthly convulsive seizure frequency, Recently Completed and enrollment in this study. from baseline to up to 156 weeks; and Ongoing Trials With longest seizure-free interval during Available Results the 156-week study period

Recently Completed and Ongoing Trials With Available Results Our searches identified 4 recently completed phase 3 trials with published results.234-236 We summarize the 3 most recent studies with results as written in abstracts of a poster presentation and 2 published studies. The following abbreviations are used in this section: CI, confidence interval; FFA, fenfluramine; HCl, hydrochloride; MCSF, monthly convulsive seizure frequency; OLE, open-label extension; P or p, probability; SD, standard deviation; TEAE, treatment-emergent adverse event; vs, versus.

An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCL) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome (Study 1503). NCT02823145. Lagae et al 2018.234

• Patient population/planned enrollment: Children and adults (n = 340) aged 2 to 35 years with clinically diagnosed Dravet syndrome who participated in Study 1501 or Study 1502 (Note: The clinical trial record states that patients aged 18 to 35 years who did not participate in Study 1501 or Study 1502 might also be eligible for enrollment in this study.) • Study design: Phase 3, single-group open-label extension study to assess the long-term safety and tolerability of a titrated effective dose of FFA (beginning with 0.2 mg/kg/day, up to a maximum of 30 mg/day) when used as an adjunctive therapy to antiepileptic drugs • Primary outcome: TEAE frequency, from baseline to up to 156 weeks • Secondary outcomes: Percentage of patients with a clinically meaningful (≥50%) reduction in MCSF, from baseline to up to 156 weeks; and percentage of patients with a profound (≥75%) reduction in MCSF, from baseline to up to 156 weeks • Results presented by study authors: Adverse event rates (%) reported in a table within the poster are summarized below: Decreased appetite: 15.9 Diarrhea: 10.8 Nasopharyngitis: 19.4

HIGH POTENTIAL DISRUPTION REPORT • November 2020 112

Pyrexia: 21.6 Upper respiratory tract infection: 10.3 “Over the entire OLE interim analysis period (median 256 days), the median decrease in [monthly] convulsive seizure frequency was -66.8% (range, -100% to 234.9%; P<0.001). . . . The majority of patients responded to FFA over the entire OLE interim analysis period (median 256 days): 64.4% of patients demonstrated clinically meaningful (≥50%) reduction in convulsive seizure frequency; 41.2% of patients demonstrated profound (≥75%) reduction in convulsive seizure frequency.”

A Two-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome (Study 1504). NCT02926898. Nabbout et al 2020.235

• Patient population/planned enrollment: Children and adults (n = 87) aged 2 to 18 years with clinically diagnosed Dravet syndrome who were receiving stiripentol

• Study design: Phase 3, quadruple-blinded (participant, care provider, investigator, outcomes assessor), randomized controlled trial of FFA used as an adjunct to a stiripentol-containing anticonvulsive treatment regimen. After a 3-week dose-titration phase, patients were randomly assigned in a 1:1 ratio to adjunctive treatment with FFA (0.5 mg/day) or placebo. • Primary outcome: Percentage difference from placebo in mean MCSF, from baseline to 12 weeks • Secondary outcome: Median percentage reduction from baseline in MCSF at 12 weeks • Results presented by study authors: “A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%- 67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure- free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.”

A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome (Study 1501). NCT02682927; and A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome (Study 1502). NCT02826863. Lagae et al 2019236 (pooled analysis).

• Patient population/planned enrollment: Studies 1501 and 1502 were of identical design, and each enrolled children aged 2 to 18 years and adults (n = 130) with clinically diagnosed Dravet syndrome whose seizures were incompletely controlled by antiepileptic drugs. • Study design: Two phase 3, double-blind, parallel-assessment, placebo-controlled studies to assess the safety and efficacy of FFA (0.2 or 0.8 mg/kg/day, up to a maximum of 30 mg/day) when used as an adjunctive therapy to antiepileptic drugs • Primary outcome: Percentage difference from placebo in mean MCSF, from baseline to 14 weeks • Secondary outcome: Median percentage reduction from baseline in MCSF at 14 weeks • Results presented by study authors: “Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9.0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0.2 mg/kg per day (39), fenfluramine 0.7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74.9% in the fenfluramine 0.7 mg/kg group

HIGH POTENTIAL DISRUPTION REPORT • November 2020 113

(from median 20.7 seizures per 28 days to 4.7 seizures per 28 days), 42.3% in the fenfluramine 0.2 mg/kg group (from median 17.5 seizures per 28 days to 12.6 per 28 days), and 19.2% in the placebo group (from median 27.3 per 28 days to 22.0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0.7 mg/kg per day showing a 62.3% greater reduction in mean MCSF compared with placebo (95% CI 47.7–72.8, p<0.0001); fenfluramine 0.2 mg/kg per day showed a 32.4% reduction in mean MCSF compared with placebo (95% CI 6.2–52.3, p=0.0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension.” Manufacturers and Regulatory Status FFA is being developed by Zogenix, Inc (Emeryville, California). On June 25, 2020, FDA approved FFA to treat seizures associated with Dravet syndrome.237 The approval requires both a Risk Evaluation and Mitigation Strategy and classification as a Schedule IV controlled substance until the US Drug Enforcement Agency has made a final scheduling decision.238 The developer’s February 2019 New Drug Application (NDA) for FFA was accepted by FDA on November 25, 2019, granted priority review, and issued a Prescription Drug User Fee Act (PDUFA)-prescribed target action date of March 25, 2020.239 FDA had responded to the February 2019 NDA240 in April 2019 with a Refusal to File letter, which cited missing nonclinical data and incorrect clinical data.241 Zogenix stated in June 2019 that FDA had agreed to proceed with resubmission of the NDA without additional chronic-toxicity studies.242 In September 2019, it resubmitted the NDA.243 FDA had granted FFA designations of Orphan Drug in December 2013,244 Breakthrough Therapy in February 2018,245 and Fast Track in January 2016246 for treating Dravet syndrome. FFA is also in phase 3 clinical development for treating Lennox-Gastaut syndrome, a rare, severe form of infantile- or childhood-onset epilepsy. Cost Information According to a US-based online aggregator of prescription drug prices, GoodRx, FFA’s retail price (as of October 13, 2020) was about $15 135 for a 360 mL supply of 2.2 mg/mL.247 The manufacturer estimates that the average per-patient yearly cost of FFA will be about $96 000, but the actual treatment cost per patient will vary because the medication is dosed according to patient weight.248 Key Stakeholder Perspectives Between March 17, 2020, and April 13, 2020 (ie, before FDA approval), nine stakeholders, reflecting caregiver, clinical, nursing, and research perspectives, provided comments and ratings on FFA. The list below summarizes key stakeholder perspectives. • Clinical trial data demonstrate significant reductions in seizure frequency with FFA that might improve patient health outcomes and patient and caregiver quality of life because of lower risk for status epilepticus, patients being able to participate in more activities, patients and caregivers getting more uninterrupted sleep, and caregivers spending less time monitoring for and providing care during seizures. • Seizure reduction with FFA might require fewer emergency department visits and hospital admissions, fewer rescue medications, and less intensive caregiving, thus potentially lowering health care costs and impacting the current paradigm of patient care and health care delivery system as use of supportive health care resources changes.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 114

• Although cost might be a barrier to patient access to the medication, treatment with FFA might lower long-term health care costs and decrease health disparities, considering some comparators (eg, ketogenic diet) are more difficult to adhere to than an oral medication (ie, FFA). • More data are needed regarding the cardiac safety of FFA and to assess what kind of cardiac monitoring patients might need to undergo treatment with FFA.

Fosdenopterin (BBP-879, ORGN001) to Treat Molybdenum Cofactor Deficiency Type A Highlights • Molybdenum cofactor deficiency (MoCD) type A is an ultra-rare, life-threatening genetic metabolic disorder characterized by loss of the molybdenum cofactor (MoCo). • MoCD causes catastrophic and irreversible neurologic damage within the first weeks of life, and no effective treatments exist for MoCD type A. Care is mostly supportive. • Fosdenopterin is a substrate replacement therapy that restores levels of a compound absent in patients with MoCD type A that is an essential precursor in MoCo biosynthesis. • On September 29, 2020, FDA accepted a New Drug Application under priority review for fosdenopterin to treat MoCD type A; the timeline for priority review decisions is 6 months. • Stakeholders commenting on this topic thought that, as the first disease-modifying therapy for MoCD type A, fosdenopterin has substantial potential to improve patient outcomes and disrupt the current paradigm of care. • Stakeholders also thought that clinical trial results had been reported for only a small number of patients and that results from ongoing trials would need to confirm the results observed in this small patient population. Patient Population Fosdenopterin is intended for neonates aged up to 28 days who have MoCD type A. Intervention MoCD type A is caused by loss-of-function variants in a gene called the molybdenum cofactor synthesis 1 gene, MOCS1. These genetic variants prevent the conversion of guanosine triphosphate into cPMP, an essential metabolic intermediate needed to produce sufficient levels of MoCo.249,250 MoCo is a major component of the sulfite oxidase enzyme, which normally helps clear sulfite, a potent neurotoxin, from the body. Buildup of sulfite is believed to cause the rapid, severe damage to the central nervous system seen in patients with MoCD type A.249-251 The National Library of Medicine’s Genetics Home Reference offers more information about MoCD. Fosdenopterin (ORGN001, BBP-870) is a synthetic cPMP intended for use as a substrate replacement therapy. By restoring cPMP levels, fosdenopterin purportedly increases MoCo biosynthesis, which would, in turn, restore sulfite oxidase activity to allow sulfite removal and prevent neurotoxicity.252,253 In a clinical trial, fosdenopterin is given daily, intravenously, at a dose of 80 to 320 μg/kg.253

HIGH POTENTIAL DISRUPTION REPORT • November 2020 115

Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 5.9. Table 5.9. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Safety & Efficacy Study of Children (age not specified, Phase 2, open-label, single-arm, dose- Primary and ORGN001 (Formerly n = 7) with a genetically escalation study to assess the safety study ALXN1101) in Pediatric confirmed diagnosis of and efficacy of fosdenopterin to treat completion Patients With MoCD Type MoCD type A being treated MoCD type A December 2020 A Currently Treated With with rcPMP infusions at Primary outcome: Safety, measured rcPMP time of enrollment (rcPMP by type, number, and frequency of was an investigational NCT02047461 AEs and SAEs cPMP replacement therapy available to a small number of patients on a named-patient basis)254 Study of ORGN001 Children aged up to 28 Phase 2/3 open-label, single-arm Primary and (Formerly ALXN1101) in days (n = 5) with a study evaluating the safety and study Neonates With diagnosis of MoCD type A efficacy of fosdenopterin to treat completion Molybdenum Cofactor MoCD type A December 2021 Deficiency (MOCD) Type A Primary outcome: Treatment NCT02629393 response, defined as patients alive and able to sit upright independently for at least 30 seconds at 12 months

Abbreviations: AE, adverse event; cPMP, cyclic pyranopterin monophosphate; MoCD, molybdenum cofactor deficiency; rcPMP, recombinant Escherichia coli-derived cyclic pyranopterin monophosphate; SAE, serious adverse event.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed late-phase trial with published results.254 We summarize this most recent study with results as written in an abstract of a published study. The following abbreviations are used in this section: cPMP, cyclic pyranopterin monophosphate; MoCD, molybdenum cofactor deficiency; rcPMP, recombinant Escherichia coli- derived cyclic pyranopterin monophosphate.

Efficacy and Safety of Cyclic Pyranopterin Monophosphate Substitution in Severe Molybdenum Cofactor Deficiency Type A: A Prospective Cohort Study. Schwahn et al 2015.254

• Patient population/planned enrollment: Newborn children with clinical and biochemical evidence of MoCD type A (n = 11) or type B (n = 5) • Study design: Prospective, observational, single-arm study to assess compassionate use of intravenous rcPMP (80 to 320 μg/kg per day) to treat MoCD type A or B. The rcPMP was an investigational cPMP replacement therapy available to a small number of patients on a named-patient basis. • Primary outcome: Safety and efficacy

HIGH POTENTIAL DISRUPTION REPORT • November 2020 116

• Results presented by study authors: “Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease.” Manufacturers and Regulatory Status Origin Biosciences (Palo Alto, California), an affiliate of BridgeBio Pharma (Palo Alto, California), is developing fosdenopterin. On September 29, 2020, the companies announced that FDA had accepted a New Drug Application under priority review for fosdenopterin to treat patients with MoCD type A.255 The timeline for FDA decisions on drugs under priority review is 6 months. The companies state that this submission was based on data from the ongoing phase 2 and phase 2/3 clinical trials (NCT02629393, NCT02047461); however, no data have been reported from these trials.256 Cost Information Cost information is currently unavailable for this topic. Key Stakeholder Perspectives Between May 8, 2020, and July 27, 2020, six stakeholders, reflecting health systems, nursing, research, and physician perspectives, provided comments and ratings on fosdenopterin to treat MoCD type A. The list below provides a summary of key stakeholder perspectives. • Fosdenopterin represents a promising disease-modifying treatment for a disease with no such therapy. As such, fosdenopterin has substantial potential to improve patient health outcomes. • Although promising, results are available for only a small number of cPMP-treated patients. For fosdenopterin to be adopted, the 2 ongoing studies of fosdenopterin (synthetic cPMP) would need to confirm results observed recombinant cPMP in earlier trials. • As a disease-modifying therapy, fosdenopterin might cause substantial disruption of MoCD type A treatment paradigms. In addition, the requirement for daily intravenous dosing might place a substantial treatment burden on patients and caregivers. • Fosdenopterin is likely to be very costly, which could increase existing disparities based on socioeconomic status. Effects of fosdenopterin adoption on the health care system would be minimized by the small number of patients affected by MoCD type A. Additionally, fosdenopterin, if effective, could reduce costs associated with supportive care.

Golodirsen (Vyondys 53) to Treat Duchenne Muscular Dystrophy Highlights • Golodirsen is a DNA analogue given intravenously in weekly infusions. It purportedly binds exon 53 of dystrophin pre-messenger RNA (pre-mRNA) and promotes skipping of exon 53 during mRNA processing. These molecular actions allow synthesis of a shorter, but functional, dystrophin protein.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 117

• FDA approved this intervention in December 2019 for a subset of patients with Duchenne muscular dystrophy (DMD), about 8% to 10%, who have a mutation in the dystrophin gene, DMD, amenable to exon 53 skipping. • The cost is about $300 000 annually for the average patient, according to the manufacturer. • Stakeholders commenting on this topic thought that, in clinical trials, golodirsen demonstrated significant increases in functional dystrophin production, which might improve patient health outcomes and quality of life. • Stakeholders also thought that golodirsen has moderate potential to disrupt health disparities, the health care delivery system, the current paradigm of care, and health care costs; however, more data are needed to evaluate its overall disruptive potential. Patient Population Golodirsen is indicated to treat DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Intervention Golodirsen (Vyondys 53) is a phosphorodiamidate morpholino oligomer, or DNA analogue. It is intended to treat DMD, an inherited, chromosome X–linked genetic disorder caused by point mutations or deletions in the dystrophin gene, DMD. DMD encodes the dystrophin protein, which helps promote muscle function. In patients with DMD, the absence of naturally produced (ie, wild- type) protein causes progressive muscle fiber necrosis and eventual widespread muscle weakness.214 No cure exists for DMD, and first-line corticosteroid treatment addresses symptoms but does not prevent disease progression and has significant side effects. The Muscular Dystrophy Association website provides more information on DMD. FDA previously approved a gene therapy for patients who have a specific mutation in DMD that is amenable to exon 51 skipping. Golodirsen is the second FDA-approved gene therapy for patients with a specific mutation of DMD (ie, amenable to exon 53 skipping). Golodirsen purportedly binds exon 53 of dystrophin pre-mRNA (precursor mRNA composed of introns and exons) and promotes skipping of exon 53 during mRNA processing. These molecular actions allow synthesis of a shorter, but functional, dystrophin protein.224 Therefore, golodirsen treatment might promote skeletal muscle function and prevent or delay disease progression in patients with DMD who have DMD exon 53 mutations (about 8% to 10% of patients).225,257 Golodirsen is given once weekly as an intravenous infusion over the course of 35 to 60 minutes at a dose of 30 mg/kg. Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present these trials in Table 5.10.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 118

Table 5.10. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier A 48-Week, Open Label, Males older than 6 months Phase 2, nonrandomized, open-label, Primary Study to Evaluate the (n = 6) with DMD and an parallel-assignment study to completion Efficacy and Safety of out-of-frame duplication of determine the efficacy and safety of September 2021 Casimersen, Eteplirsen either exon 45, 51, or 53, casimersen, eteplirsen, and Study and Golodirsen in and a normal copy of all golodirsen completion Subjects With Duchenne other DMD exons Patients will receive weekly infusions September 2022 Muscular Dystrophy of casimersen, eteplirsen, or Carrying Eligible DMD golodirsen for 1 year, and 2 muscle Duplications biopsies will be taken at baseline and NCT04179409 month 12. Primary outcomes: Change in dystrophin expression from baseline after treatment and adverse events A Double-Blind, Placebo- Male children (n = 222) Phase 3, randomized, double-blind, Primary Controlled, Multi-center aged 7 to 13 years with parallel-assignment study to evaluate completion May Study With an Open-Label genetically confirmed DMD the efficacy and safety of casimersen 2022 Extension to Evaluate the who have a mutation in the (SRP-4045) 30 mg/kg or golodirsen Study Efficacy and Safety of DMD gene that is amenable (SRP-4053) 30 mg/kg versus placebo completion May SRP-4045 and SRP-4053 to exon 45 or 53 skipping The double-blind period will be 2023 in Patients With and who are on a stable followed by an open-label extension Duchenne Muscular dose of corticosteroids period in which all patients will Dystrophy receive active treatment for 48 weeks (ESSENCE) (up to week 144 of study). NCT02500381 Primary outcome: 6-minute walk test distance at baseline and week 96 Secondary outcomes: • Dystrophin expression at baseline and weeks 48 or 96, as measured by IHC and WB • Ability to rise independently from the floor at week 96 • Time to loss of ambulation at week 96 • Ambulatory function at baseline and week 96, as measured by NSAA • FVC percentage predicted at baseline and week 96

HIGH POTENTIAL DISRUPTION REPORT • November 2020 119

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Long-Term, Open-Label Male children (n = 260) Phase 3, nonrandomized, open-label, Primary and Extension Study for aged 7 to 13 years with parallel-assignment study to evaluate study Patients With Duchenne genetically confirmed the safety and tolerability of long-term completion Muscular Dystrophy DMD, who have a mutation (144-week) treatment with casimersen August 2026 Enrolled in Clinical Trials in the DMD gene that is 30 mg/kg or golodirsen 30 mg/kg Evaluating Casimersen or amenable to exon 45 or 53 Primary outcome: SAEs up to week Golodirsen skipping, who are on a 148 after treatment NCT03532542 stable dose of corticosteroids, and who completed a prior study on casimersen or golodirsen

Abbreviations: DMD, Duchenne muscular dystrophy; DMD, dystrophin gene; FVC, forced vital capacity; IHC, immunohistochemistry; NSAA, North Star Ambulatory Assessment; SAEs, serious adverse events; WB, Western blot.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 1/2 trial with published results in 2 papers.258,259 We summarize this study with results as written in the abstracts of those papers. The following abbreviations are used in this section: AEs, adverse events; DMD, Duchenne muscular dystrophy; FVC, forced vital capacity; IHC, immunohistochemistry; mRNA, messenger RNA; P, probability; RT-PCR, reverse transcription polymerase chain reaction; SAEs, serious adverse events; WB, Western blot.

A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose-Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping (4053-101 study). NCT02310906. Muntoni et al 2018258 and Frank et al 2020.259

• Patient population/planned enrollment: Male children (n = 39) aged 6 to 15 years with genetically confirmed DMD who were on a stable dose of corticosteroids. Enrolled patients in one group had genetic deletions amenable to exon 53 skipping and in the other group were untreated patients whose DMD had genetic deletions not amenable to exon 53 skipping. • Study design: Phase 1/2, 2-part study. Part 1 was a randomized, double-blind, parallel-assignment study to evaluate the efficacy and safety of golodirsen (SRP-4053) at escalating dose levels as follows: weeks 1 to 2, 4 mg/kg/week; weeks 3 to 4, 10 mg/kg/week; weeks 5 to 6, 20 mg/kg/week; weeks 7 to 12, 30 mg/kg/week; versus placebo. Part 2 was an open-label evaluation of golodirsen in patients from part 1, along with newly enrolled patients whose DMD had genetic deletions amenable to exon 53 skipping and an untreated group of patients whose DMD had genetic deletions not amenable to exon 53 skipping. • Primary outcomes: Incidence of AEs and SAEs at week 12; 6-minute walk test distance at baseline and week 144; and dystrophin expression at baseline and week 48, as measured by WB assay • Secondary outcomes: Dystrophin expression at baseline and week 48, as measured by IHC; FVC percentage predicted at baseline through week 144; and exon 53 skipping at baseline and week 144, as measured by RT-PCR sequence verification of exon 53–skipped mRNA • Results presented by study authors: “Mean percent of normal dystrophin protein increased from 0.095% at baseline to 1.019% at Week 48 (range: 0.09%–4.30%), a significant mean change of +0.924% (P<0.001). Muscle biopsy samples from all 25 patients displayed a significant increase from baseline in exon 53 skipping via RT-PCR at Week 48 (P<0.001), demonstrating the intended mechanism of action. A positive correlation between exon 53 skipping and de novo dystrophin production was observed

HIGH POTENTIAL DISRUPTION REPORT • November 2020 120

(Spearman-r = 0.500; P=0.011). Analysis of mean fiber intensity demonstrated a significant increase from baseline in de novo dystrophin production (P<0.001) and confirmed dystrophin sarcolemma localization.”258

“Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.”259 Manufacturers and Regulatory Status Golodirsen, developed by Sarepta Therapeutics, Inc (Cambridge, Massachusetts), received accelerated FDA approval on December 12, 2019.260 Sarepta must conduct a confirmatory clinical trial and submit data demonstrating golodirsen’s clinical benefit to maintain the approval. The developer stated in December 2019 that it was enrolling patients into a placebo-controlled, postmarketing confirmatory trial (ESSENCE, NCT02500381), expected to conclude by 2023 (primary completion May 2022).230 The New Drug Application (NDA) was originally submitted on December 19, 2018, and accepted by FDA in February 2019 with priority review status.257 On the Prescription Drug User Fee Act (PDUFA)-prescribed decision date (August 19, 2019), FDA issued a Complete Response Letter (CRL) rejecting the NDA. The developer stated that FDA had cited 2 concerns about infection risk and renal toxicity related to drug administration.261 The developer submitted a Formal Dispute Resolution Request on September 13, 2019; an Appeal Granted letter was issued on November 22, 2019; and the developer resubmitted the NDA on November 27, 2019.262 In January 2020, a month after the drug’s approval, FDA unexpectedly released the August 19, 2019, CRL,263 revealing the details of FDA’s safety and efficacy concerns, which are more extensive than those noted briefly by the developer in August.261 FDA had granted the drug Orphan Drug designation for this indication in May 2018.264 Cost Information Sarepta noted that golodirsen would be priced at parity to an existing DMD exon-skipping therapy it also developed (eteplirsen for skipping exon 51),230 which Sarepta stated at the time of FDA approval would cost about $300 000 annually for the average patient.265 Golodirsen’s cost has been estimated to be higher. An August 2019 evidence report, Deflazacort, Eteplirsen, and Golodirsen for Duchenne Muscular Dystrophy: Effectiveness and Value, from the Institute for Clinical and Economic Review (ICER) estimated the annual cost of eteplirsen for a 40-kg (88-lb) patient to be about $1 million.266 The ICER analysis was conducted before FDA approval and before pricing for golodirsen was announced. Therefore, it did not include an economic analysis specific to golodirsen. However, the report notes that, were golodirsen to have the same costs as eteplirsen, then the performed assessment of cost-effectiveness for eteplirsen would hold true for golodirsen. In its analysis of eteplirsen, ICER noted that the data on the clinical efficacy of eteplirsen and golodirsen were insufficient because they were based on surrogate outcomes (ie, dystrophin protein levels) lacking a clear threshold for meaningful clinical improvement. Therefore, ICER’s cost- effectiveness assessment was based on the assumption of large positive impacts on both patients and caregivers. However, even in the most optimistic scenario (full return to health for both the

HIGH POTENTIAL DISRUPTION REPORT • November 2020 121

patient and 2 caregivers over a 40-year time frame), the incremental cost-effectiveness ratio remained above $450 000 per quality-adjusted life-year (QALY) gained, which is higher than what ICER considers to be an acceptable cost-effectiveness threshold.266 In April 2020, the New England Comparative Effectiveness Public Advisory Council published a report, informed by the August 2019 ICER report. Its conclusions included the position that, even with an extreme curative treatment effect, golodirsen, if priced similarly to eteplirsen, “could never be cost-effective at commonly cited cost-effectiveness thresholds.”267 Key Stakeholder Perspectives Between March 24, 2020, and April 14, 2020, ten stakeholders, reflecting caregiver, clinical, health systems, nursing, patient safety, and research perspectives, provided comments and ratings on golodirsen. The list below provides a summary of key stakeholder perspectives. • Clinical trial data demonstrate that golodirsen increases functional dystrophin, which has potential to greatly impact patient health outcomes and quality of life. Still, it remains to be seen whether the increase in dystrophin translates to clinically significant outcomes. • Golodirsen might shift the current paradigm of patient care from supportive to preventive and might decrease or delay use of certain health care resources (eg, hospitalizations, wheelchairs, home care). • The dosing regimen of weekly infusions disrupts patients’ lives and might be a barrier to access for some that could increase health disparities in this patient population. • The high cost of golodirsen might also be a barrier to patient access that could increase health disparities, even if the drug could decrease health costs overall in the long run.

Mepolizumab (Nucala) to Treat Hypereosinophilic Syndrome Highlights • Mepolizumab is a humanized monoclonal antibody approved by FDA in September 2020 to treat severe eosinophilic asthma, eosinophilic granulomatosis, and hypereosinophilic syndrome (HES). • The drug is injected under the skin once every 4 weeks, a treatment patients can give to themselves at home. • Mepolizumab has an average retail cost of $118 500 per year. • Stakeholders commented on this treatment 3 to 4 months before FDA approval and thought that mepolizumab might have a moderate to high impact on patient outcomes and overall health by reducing HES flares, improving quality of life, and sparing corticosteroid usage. • Stakeholders thought that, although the cost of treatment might increase disparities if payers do not cover treatment, long-term hospital and care costs might be lower because of slower HES disease progression. Patient Population Mepolizumab is intended for children aged 12 years or older and adults with HES. Intervention HES represents a collection of rare disorders characterized by chronically elevated levels of a class of innate immune cells known as eosinophils (ie, hypereosinophilia). HES is associated with end-organ damage caused by eosinophilic tissue infiltration and mediator release. The American Partnership for Eosinophilic Disorders website offers more information on HES.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 122

Three goals of HES treatment are decreasing eosinophil counts, reducing signs and symptoms of the disorder, and preventing disease progression.268 Standard first-line treatment of HES involves corticosteroids (except in the case of certain clonal eosinophilias, which may respond to treatment with tyrosine kinase inhibitors specific to the molecular driver in that clonal disease).268,269 Although HES in many patients responds to corticosteroids, HES in other patients stops responding to steroid treatment, and long-term steroid treatment carries substantial side effects. Alternative approaches using cytoreductive agents (eg, cyclophosphamide, hydroxyurea, vincristine) are also associated with substantial adverse events, do not address the underlying disease, and are ineffective in some patients. Therefore, effective new approaches to treating HES are needed. Mepolizumab (Nucala) is a humanized monoclonal antibody that acts as an antagonist to interleukin 5 (IL-5), a key eosinophilopoietic cytokine that promotes eosinophil expansion.270,271 Increased serum IL-5 levels have been implicated in various forms of HES and, therefore, IL-5 represents a rational target for treating HES.272 According to the FDA-approved labeling, mepolizumab is injected under the skin once every 4 weeks at 3 doses of 100 mg each. Treatment is given in a doctor’s office or by patients themselves at home.273 Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified no ongoing trials for this topic. Recently Completed and Ongoing Trials With Available Results Our searches identified 2 recently completed phase 3 trials with published results.271,274 We summarize the 2 most recent studies with results as written in a news release and an abstract of a published study. The following abbreviations are used in this section: AEs, adverse events; CI, confidence interval; HES, hypereosinophilic syndrome; p, probability; vs, versus.

Efficacy and Safety Study of Mepolizumab in Subjects With Severe Hypereosinophilic Syndrome (HES) (Study 200622). NCT02836496. GlaxoSmithKline 2019.274

• Patient population/planned enrollment: Patients (n = 108) aged 12 years or older with a diagnosis of HES for at least 6 months at random assignment and who had a history of 2 or more HES flares within the past 12 months • Study design: Phase 3, randomized, double-blind study of the safety and efficacy of mepolizumab in treating patients with HES. Patients were randomly assigned to 32 weeks of treatment with either mepolizumab (300-mg subcutaneous injection once every 4 weeks) or matching placebo. Patients continued on baseline standard-of-care therapy. • Primary outcomes: Percentage of patients who experienced an HES flare or withdrew from the study • Secondary outcomes: Time to first HES flare, annualized rate of HES flares, fatigue score per Brief Fatigue Inventory • Results presented by study authors: “The phase 3 study met its primary endpoint, demonstrating a statistically significant result with 50% fewer patients experiencing a HES flare (worsening of symptoms or eosinophil threshold requiring an escalation in therapy) when treated with mepolizumab, compared to placebo, when added to standard of care treatment over the 32-week study period (28% vs 56%; p=0.002). . . . “Secondary endpoints from the study were also statistically significant and supported the primary endpoint, showing:

HIGH POTENTIAL DISRUPTION REPORT • November 2020 123

○ Risk of first HES flare over the study period was 66% lower for patients treated with mepolizumab compared to placebo (hazard ratio 0.34; 95% CI 0.18, 0.67). ○ There was a 66% reduction in the annualised rate of HES flares versus placebo (rate ratio 0.34; 95% CI 0.19, 0.63). ○ Fatigue scores improved in mepolizumab compared to placebo (p=0.036). ○ The safety results in the study were consistent with the known profile of mepolizumab.”

An Open-Label Extension of Intravenous Mepolizumab in Patients With Hypereosinophilic Syndrome (Study 100901). NCT00097370. Roufosse et all 2013.271

• Patient population/planned enrollment: Patients (n = 78) with HES who completed a phase 2 trial of mepolizumab (Study 100185, NCT00086658, reported by Rothenberg et al 2008270) • Study design: Phase 3, single-group assignment study of the long-term safety and efficacy of mepolizumab in treating patients with HES. All patients received intravenous mepolizumab (750 mg) either monthly or on an individualized dosing schedule. • Primary outcome: Frequency of AEs • Secondary outcomes: Number of participants achieving a prednisone level of ≤10 mg, an eosinophil level of <600 cell/microliter (uL) • Results presented by study authors: “Seventy-eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for ≥ 12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons.” Manufacturers and Regulatory Status Mepolizumab was developed by GlaxoSmithKline plc (Brentford, United Kingdom). On September 25, 2020, FDA approved mepolizumab for adults and children aged 12 years or older with HS for 6 months or longer without another identifiable nonblood-related cause of the disease.275 FDA had earlier granted mepolizumab Orphan Drug and Fast Track status for this indication. Mepolizumab is commercially available in the United States, having been initially approved in 2015 for treating eosinophilic asthma and subsequently for treating eosinophilic granulomatosis with polyangiitis.273 Cost Information According to a US-based online aggregator of prescription drug prices, GoodRx, mepolizumab’s retail price (as of October 14, 2020) was about $3040 for a 100-mg vial.276 At the required dosing of 300 mg every 4 weeks, a 1-year course of treatment would cost about $118 500. Dosing of mepolizumab in treating HES is 3 times higher than that of other indications (eg, eosinophilic asthma).273

HIGH POTENTIAL DISRUPTION REPORT • November 2020 124

Key Stakeholder Perspectives Between May 3, 2020, and June 19, 2020, (ie, before FDA approval) six stakeholders, reflecting nursing, patient safety, physician, and research perspectives, provided comments and ratings on mepolizumab. The list below provides a summary of key stakeholder perspectives. • Clinical trial data of mepolizumab demonstrate significant reductions in the frequency of HES flares, as well as an improvement in fatigue scores, which might improve patient outcomes, quality of life, and overall health. • Mepolizumab might give patients the opportunity to reduce or stop standard-of-care corticosteroids, which have substantial side effects and long-term tolerability issues. A treatment reducing corticosteroid use might significantly disrupt patient outcomes. • Mepolizumab might significantly disrupt the current paradigm of patient care because it is the only IL-5 agonist that is available as an injection patients can give themselves, allowing treatment in the home setting. • Although cost might be a barrier to patient access and could result in disparities if not covered by insurance, treatment with mepolizumab might lower long-term hospital and care costs associated with HES disease progression. • The clinical trials also revealed serious adverse events that might need to be considered when selecting the drug for a patient.

MT1621 to Treat Thymidine Kinase 2 Deficiency Highlights • MT1621 is an oral combination drug of deoxycytidine and deoxythymidine, 2 precursors (nucleosides) to the building blocks of genetic material (nucleotides). • The drug is in phase 2 development and is used to correct the underlying cause of thymidine kinase 2 deficiency (TK2d), a rare, inherited, mitochondrial DNA depletion disorder. It addresses the cause of TK2d by making DNA building blocks (ie, nucleotides) available for normal DNA synthesis. • Current standard of care for TK2d is supportive, and FDA has not approved any treatments for the disorder. • Stakeholders commenting on this topic thought that MT1621 might significantly improve patient health outcomes and quality of life by increasing survival, reducing disability, and reducing need for supportive care, and that, if approved, it is likely to become the standard of care for TK2d. • Stakeholders also thought that, because MT1621 is taken by mouth, it is likely to be convenient for patients and lessen potential disparities in treatment access. Patient Population MT1621 is intended for children and adults with TK2d due to a confirmed genetic mutation in the thymidine kinase 2 gene, TK2. Intervention An ultra-rare disorder with no approved treatments, TK2d is caused by a genetic variation in the gene encoding the mitochondrial matrix protein TK2. The TK2 gene normally produces the metabolic enzyme TK2 that is necessary for maintaining a balanced pool of DNA building blocks

HIGH POTENTIAL DISRUPTION REPORT • November 2020 125

(ie, nucleotides) in the mitochondria, cellular organelles often described as the power generators inside cells.277,278 TK2d-induced nucleotide imbalance causes impaired mitochondrial DNA synthesis. This leads to progressive, severe muscle weakness that impairs movement, breathing, and eating and can be fatal, most often from respiratory failure.277-279 The National Library of Medicine’s Genetics Home Reference offers more information about TK2d. MT1621 is a drug taken by mouth and intended to address the underlying cause of TK2d. The drug consists of a combination of the nucleosides deoxycytidine and deoxythymidine, precursors of 2 nucleoside triphosphates that are incorporated into DNA.280 By providing an external source of deoxycytidine and deoxythymidine, MT1621 purportedly restores balance to the nucleotide pool, potentially restoring mitochondrial DNA synthesis and mitochondrial function in patients with TK2d.281 In clinical trials, MT1621 is taken by mouth as a dissolved solution at a dosage up to 400 mg/kg daily.282 Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 5.11. Table 5.11. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier An Open-Label Study of Children and adults, no Phase 2, open-label, single-arm study Primary and Continuation Treatment ages stated (n = 47), with a to assess the safety and efficacy of study With Combination confirmed genetic MT1621 to treat TK2 taken by mouth 3 completion Pyrimidine Nucleosides in mutation in the TK2 gene, times daily at a total dosage of up to January 2022 Patients With TK2 without other genetic or 400 mg/kg daily for up to 36 months NCT03845712 polygenic disease Annual assessments of safety and efficacy will continue annually after the 36-month treatment period. Primary outcome: Safety, measured by adverse events, laboratory measurements, and electrocardiograms Selected secondary outcome: Efficacy, measured by lung function and motor function tests

HIGH POTENTIAL DISRUPTION REPORT • November 2020 126

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Treatment of TK2 Children and adults, no Phase 1/2, open-label, single-arm Primary and Deficiency With ages stated (n = 20), with a study to assess the safety and efficacy study Thymidine and confirmed genetic of MT1621 to treat TK2 taken by completion April Deoxycytidine mutation in the TK2 gene, mouth 3 times daily at a total dosage 2024 NCT03639701 without other genetic or of up to 400 mg/kg daily for up to 60 polygenic disease months Primary outcome: Safety, measured by adverse events, laboratory measurements, electrocardiograms, and diarrhea incidence Selected secondary outcomes: • Event-free survival • Motor function • Lung function Abbreviations: TK2, thymidine kinase 2 deficiency; TK2, thymidine kinase 2 gene. Recently Completed and Ongoing Trials With Available Results Our searches identified a single recently completed late-phase trial.283,284 We summarize this study with results as written in a news release283 and a poster presentation.284 The following abbreviations are used in this section: BMI, body mass index; p, probability; TK2d, thymidine kinase 2 deficiency.

A RETROspective Study of Patients With TK2d (RETRO). NCT03701568. Zogenix 2019283 and Quan et al 2019.284

• Patient population/planned enrollment: Children and adults, no ages specified (n = 38), with TK2d and previously treated with deoxycytidine and deoxythymidine • Study design: Retrospective, observational study to review data from patients previously treated with deoxycytidine and deoxythymidine. Participants were given a fixed combination of deoxycytidine and deoxythymidine at an unknown dose for a median of 77 weeks. • Primary outcome: Safety and tolerability of deoxycytidine and deoxythymidine therapy for TK2d • Secondary outcomes: BMI, clinical course (achievement, loss, or regain of developmental motor milestones), motor function, and ambulatory assessments • Results presented by study authors: “All treated patients remain alive. A survival analysis using a time- dependent Cox regression model showed that the difference in probability of survival between treated patients and untreated natural history control patients was highly statistically significant (p<0.0006) . . . the vast majority of treated patients (94.7%) had either improved (68%) or stabilized (26%) responses in major functional domains.”283 A subset of responders regained lost most motor milestones, including the following: “Ambulation: 3 subjects who had lost ambulation prior to treatment regained ambulation; 1 subjects who had never walked gained ambulation. “Respiratory function: 1 subject receiving 24 hours/day of invasive mechanical ventilation prior to treatment discontinued all respiratory support following treatment. “Feeding Support: 3 subjects had their feeding tubes removed, out of a total of 8 subjects on feeding tubes at study start.”284

HIGH POTENTIAL DISRUPTION REPORT • November 2020 127

Manufacturers and Regulatory Status MT1621 is being developed by Modis Therapeutics (Oakland, California), a subsidiary of Zogenix (Emeryville, California). It is in phase 2 clinical trials for treating TK2d. Zogenix announced in August 2020, after meeting with FDA about a regulatory pathway forward, that it anticipated having all necessary clinical trial data by 2021 and submitting a New Drug Application in the first half of 2022.285 MT1621 had received FDA Breakthrough Therapy designation in February 2019286 and Orphan Drug designation in July 2016287 for this indication. Cost Information Cost information is currently unavailable for this topic. Key Stakeholder Perspectives Between April 24, 2020, and June 23, 2020, five stakeholders, reflecting clinical, nursing, and research perspectives, provided comments and ratings on MT1621 for treating TK2d. The list below provides a summary of key stakeholder perspectives. • Clinical trial data suggest that MT1621 has significant potential to improve patient health outcomes and quality of life by increasing survival, reducing disability, and reducing supportive care utilization, although the data were observational, retrospective, and unpublished, and more data are needed. • MT1621 is likely to become the standard-of-care treatment for TK2d if FDA approves it, considering current standard of care is supportive and a large unmet need exists for treatments. • The oral delivery route of MT1621 is likely to be convenient for many patients and unlikely to cause disparities in patient access to the treatment. • MT1621 could shift the paradigm of care from supportive to preventive and therefore impact the treatment goals and management of patients with TK2d. • A reduction in the need for supportive care (eg, ambulatory devices, respiratory support, feeding support) is likely to result in significant health care cost savings.

Olipudase Alfa (GZ402665) to Treat Acid Sphingomyelinase Deficiency Highlights • Olipudase alfa is a human recombinant form of acid sphingomyelinase (ASM), an enzyme that helps break down the lipid sphingomyelin. It is in phase 3 development as an enzyme replacement therapy. • It is intended to treat patients with acid sphingomyelinase deficiency (ASMD) by replacing insufficient levels of ASM that contribute to serious health effects, including liver and spleen enlargement, neurologic disease, and early death. • The standard of care for ASMD is supportive, and FDA has not approved any treatments for the disease. • Stakeholders commenting on this topic thought that olipudase alfa might significantly improve health and quality of life for patients with ASMD and might become the standard of care, if FDA approves it.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 128

• Stakeholders thought this intervention might increase health disparities in this patient population if it is cost prohibitive to some patients or some patients are unable to travel to health care facilities to receive the biweekly infusions. Patient Population Olipudase alfa is intended for children and adults with the ASMD form of Niemann-Pick disease type B (NPB) or Niemann-Pick disease type A/B (NPA/B). Intervention ASMD is a rare, autosomal recessive, lysosomal storage disease in which a variation in the SMPD1 gene causes a deficiency or absence of ASM. An enzyme, ASM is normally found in lysosomes and is responsible for breaking down the lipid sphingomyelin.288 ASMD leads to excessive accumulation of sphingomyelin in cells, causing cell death, organ enlargement, and malfunction of major organ systems. ASMD severity exists along a spectrum historically known, in order of decreasing severity, as Niemann-Pick disease type A (NPA), NPA/B, and NPB.289 A patient with NPA presents with health complications including liver and spleen enlargement and neurologic disease that results in death in childhood. Conversely, NPB presents without neurologic involvement and patients typically survive into adulthood with health complications, including delayed growth, enlarged liver and spleen, and breathing problems. NPA/B is an intermediate form characterized by slower progression of neurologic symptoms and longer survival than NPDA.288,289 See the National Niemann-Pick Disease Foundation website for more information on ASMD. No FDA-approved treatments are available for ASMD, and treatment consists of supportive care and symptom management. Olipudase alfa (GZ402665), a human recombinant ASM, is an enzyme replacement therapy intended to correct the underlying ASM deficiency to help break down sphingomyelin. It is intended to treat NPA/B or NPB,290 the forms of ASMD with little to no neurologic involvement. Preclinical research indicated that olipudase alfa is unlikely to prevent neurodegeneration in patients with ASMD, but might reduce sphingomyelin levels in the heart, liver, and spleen, and to a lesser degree, the lungs.291 In clinical trials, olipudase alfa is given intravenously once every 2 weeks at a dose of up to 3 mg/kg (dosing is the same for children and adults). Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 5.12.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 129

Table 5.12. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Efficacy, Safety, Adults (n = 36) aged 18 Phase 2/3, placebo-controlled, Primary Pharmacodynamic, and years or older with randomized study to evaluate the efficacy completion Pharmacokinetics Study documented ASMD and and safety of olipudase alfa administered October 2019 of Olipudase Alfa in diffuse capacity of the intravenously at a dosage of up to 3 Study Patients With Acid lung for carbon mg/kg once every 2 weeks for 52 weeks completion Sphingomyelinase monoxide of 70% or less Primary outcomes: October 2023 Deficiency (ASCEND) of the predicted normal • Percentage predicted DLco Note: The value, spleen volume of 6 National Clinical NCT02004691 • Spleen volume times or more than Trials database See data from Sanofi normal, and an SRS of at Secondary outcomes: lists this trial as 2020 (2 trials) under least 5 • Liver volume ongoing. Recently Completed • Fatigue severity and Ongoing Trials With Available Results • Pain severity • Dyspnea severity • SRS • Adverse events A Long-Term Study of Children and adults Phase 2, open-label, single-group Primary and Olipudase Alfa in (n = 20) with ASMD who assignment study to evaluate the long- study Patients With Acid completed a prerequisite term safety and efficacy of olipudase alfa completion June Sphingomyelin clinical trial of olipudase given intravenously at the dose each 2023 Deficiency alfa patient was receiving at the end of their previous study (ie, up to 3 mg/kg) once NCT02004704 every 2 weeks for up to 9 years See preliminary data Primary outcomes: from Wasserstein et al 2018 and Thurberg et al • Adverse/treatment-emergent adverse 2020 under Recently events Completed and • Physical exam Ongoing Trials With • Vital signs Available Results • Various laboratory and imaging tests

Secondary outcomes: • Spleen and liver volumes • Lung imaging and function tests • Hematology and lipid profile • Health outcome questionnaire • Growth measures (children) Abbreviations: ASMD, acid sphingomyelinase deficiency; DLco, diffusing capacity of carbon monoxide; SRS, splenomegaly related score. Recently Completed and Ongoing Trials With Available Results Our searches identified 3 recently completed phase 2 and phase 2/3 trials with published results.290,292,293 We summarize these 3 most recent studies with results as written in abstracts of published studies and a news release.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 130

The following abbreviations are used in this section: ALT, alanine aminotransferase; ASMD, acid sphingomyelinase deficiency; DLco, diffusing capacity of carbon monoxide; HDL-C, high- density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; lyso-SM, sphingosylphosphorylcholine; MN, multiples of normal; p, probability; PK, pharmacokinetics; PRO, patient-reported outcome; SM, sphingomyelin; SRS, splenomegaly related score; VLDL-C, very-low-density lipoprotein cholesterol.

Safety, Tolerability, PK, and Efficacy Evaluation of Repeat Ascending Doses of Olipudase Alfa in Pediatric Patients < 18 Years of Age With Acid Sphingomyelinase Deficiency (ASCEND-Peds). NCT02292654. Sanofi 2020.290

• Patient population/planned enrollment: Children (n = 20) aged up to 17 years with documented ASMD with spleen volume of 5 times of normal or more • Study design: Phase 2, single-arm, open-label study to primarily assess the safety and tolerability and secondarily characterize the pharmacokinetic profile and evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa given intravenously to pediatric patients at a dosage of up to 3 mg/kg every 2 weeks for 64 weeks • Primary outcomes: Adverse events, laboratory parameters, and physical examination findings • Secondary outcomes: Pharmacokinetic parameters, pharmacodynamic parameters, sphingomyelin levels, lung disease, and spleen size • Results presented by study authors: “Over the 64-week treatment period, all patients experienced at least one adverse event. These events were mostly mild and moderate, with one patient experiencing a severe and serious anaphylactic reaction that was considered related to olipudase alfa. Five treatment- related serious adverse events were observed in three patients: two cases of transient, asymptomatic alanine aminotransferase (ALT) increase in one patient, one case each of urticaria and rash in one patient, and one anaphylactic reaction in one patient. No patients had to permanently discontinue treatment due to an adverse event. The most common adverse events (as defined by percentages of events greater than or equal to 2% and number of patients greater than or equal to two in all olipudase alfa treated patients) seen in this trial were pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, upper respiratory tract infection, contusion, abdominal pain, nasal congestion, rash, urticaria, scratch, and epistaxis. “The study also explored secondary endpoints of progressive lung disease and enlarged spleen. After one year of treatment (52 weeks), the percent predicted DLco increased by a mean of 33% in nine patients who were able to perform the test at baseline (children over the age of five were assessed if they were able to perform the test). Additionally, at 52 weeks, the spleen volumes decreased by 49% as assessed by mean MN (individual patient decreases ranged from 23% to 61%).”

Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency (ASCEND). NCT02004691. Sanofi 2020.290

• Patient population/planned enrollment: Adults (n = 36) aged 18 years or older with documented ASMD with diffuse capacity of the lung for carbon monoxide of 70% or less of the predicted normal value, spleen volume of 6 times of normal or more, and an SRS of at least 5 • Study design: Phase 2/3, placebo-controlled, randomized study to evaluate the efficacy and safety of olipudase alfa given intravenously at a dosage of up to 3 mg/kg once every 2 weeks for 52 weeks • Primary outcomes: Percentage predicted DLco and spleen volume • Secondary outcomes: Liver volume, fatigue severity, pain severity, dyspnea severity, SRS, and adverse events • Results presented by study authors: “The first independent primary endpoint measuring improvement in lung function, using the percent predicted diffusing capacity of carbon monoxide (DLco), was met; therefore, ASCEND is declared positive. The relative improvement from baseline to week 52 was 22% for the olipudase alfa arm compared with 3% for the placebo arm. The difference between the two treatment arms (19%) was statistically significant (p=0.0004).

HIGH POTENTIAL DISRUPTION REPORT • November 2020 131

“The other independent primary endpoint measuring the effect of olipudase alfa on spleen size, assessed as percent change from baseline in multiples of normal (MN) of spleen volume, was met per the study protocol. In the olipudase alfa arm, spleen volume was reduced by 39.5%, compared with a 0.5% increase in the placebo arm. The difference between the two treatment arms (40%) was statistically significant (p<0.0001). “For the U.S., the spleen volume endpoint was further combined with a patient-reported outcome (PRO) measurement of symptoms associated with enlarged spleen called Splenomegaly Related Score (SRS). Compared to baseline, the SRS was reduced by 8.0 points in the olipudase alfa arm and 9.3 points in the placebo arm (p=0.70); therefore, this combination endpoint was not met. . . . “Over the 52-week period, all patients in both the placebo and olipudase alfa arms experienced at least one adverse event. The number of events was lower in the olipudase alfa arm (242 events) compared with the placebo arm (267 events). Severe adverse events were less frequent in the olipudase alfa arm (3 events) compared with the placebo arm (13 events). There were five serious adverse events in the olipudase alfa arm and 11 in the placebo arm, none of which were treatment related. There were no adverse events that led to treatment discontinuation or study withdrawal. The most common adverse events (as defined by percentages of events greater than or equal to 2% and number of patients greater than or equal to two in all olipudase alfa treated patients; occurring with higher percentages in olipudase alfa patients compared to placebo patients) seen in this trial were headache, nasopharyngitis, upper respiratory tract infection, cough, and arthralgia.”

A Long-Term Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency. NCT02004704. Wasserstein et al 2018292 and Thurberg et al 2020.293

• Patient population/planned enrollment: Children and adults (n = 20) with ASMD who completed a prerequisite clinical trial (NCT02292654 for children and NCT01722526 for adults) of olipudase alfa • Study design: Phase 2, open-label, single-group assignment study to evaluate the long-term safety and efficacy of olipudase alfa given intravenously at the dose each patient was receiving at the end of their previous study (ie, up to 3 mg/kg) once every 2 weeks for up to 9 years • Primary outcomes: Treatment-emergent adverse events, physical examination findings, vital signs, and various laboratory and imaging tests • Secondary outcomes: Spleen and liver volumes, lung imaging and function tests, hematology and lipid profiles, health outcome questionnaire items, and growth measures (children) • Results presented by study authors: Note: Data were given for adult participants only. “This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti‐drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso‐sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy.”292 “Five adult patients with chronic visceral ASMD were enrolled in a 26-week phase 1b trial of enzyme replacement therapy (ERT) with olipudase alfa (NCT01722526) followed by an ongoing long-term extension study (NCT02004704). We compare the changes in hepatic SM levels, plasma lyso-SM, and lipoprotein profiles after 42 months of treatment. Progressive clearance of histologic SM storage was observed throughout the trial, along with similar reductions in plasma lyso-SM. Improvements in liver enzymes were observed at 6 months and remained stable at 42 months. Progressive reductions from baseline in pro- atherogenic lipid profiles (total cholesterol, LDL-C, VLDL-C, triglycerides) were observed at month 6 and 42.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 132

Conversely, there were progressive increases in anti-atherogenic markers, HDL-C and apolipoprotein A-1, with HDL-C increases up to 200% over baseline levels after 42 months of treatment.”293 Manufacturers and Regulatory Status Olipudase alfa to treat ASMD is being developed by Sanofi Genzyme (Cambridge, Massachusetts) and is in phase 3 clinical development. It received FDA Orphan Drug designation in August 2000294 and Breakthrough Therapy designation in June 2015295 for this indication. Sanofi stated in a January 2020 news release that it expected to begin global regulatory submissions in the second half of 2021 with data from the phase 2/3 ASCEND and phase 2 ASCEND-Peds clinical trials.290 Cost Information Cost information is currently unavailable for this topic, although stakeholders thought that olipudase alfa is likely to be expensive. Key Stakeholder Perspectives Between April 24, 2020, and July 5, 2020, five stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on olipudase alfa for treating ASMD. The list below provides a summary of key stakeholder perspectives. • Clinical trial data suggest meaningful patient-centered outcomes and significant improvement in surrogate disease markers including spleen size and lung disease. • Long-term efficacy and safety data were positive and significant, although the trial sizes were small. • Given the positive clinical trial data and olipudase alfa’s potential to become the first FDA- approved treatment for ASMD, it is likely to have a significant impact on improving patient health outcomes including life expectancy and quality of life. Further, treatment with this drug is likely to become the standard of care. • Olipudase alfa is likely to be expensive and might be cost prohibitive to some patients. • The biweekly intravenous administration of olipudase alfa might be burdensome to patients who need to travel to receive the infusions and might increase health disparities in this population if this mode of delivery is not feasible for some patients.

Palovarotene to Treat Fibrodysplasia Ossificans Progressiva Highlights • Palovarotene is an oral, retinoic acid receptor gamma agonist intended to slow the progression of fibrodysplasia ossificans progressiva (FOP). It is in phase 3 development. • FOP is a rare connective tissue disorder that leads to heterotopic ossification (HO) flares, characterized by abnormal bone growth in muscles, tendons, and ligaments leading to disability and death. • Stakeholders commenting on this topic were generally optimistic about palovarotene’s preliminary clinical trial results, and they thought palovarotene might improve patient health outcomes and quality of life by slowing disease progression and decreasing dependence on supportive care. • Stakeholders cautioned, however, that its overall disruptive potential depends on forthcoming safety and efficacy data, particularly regarding adverse events.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 133

Patient Population Palovarotene is intended to treat FOP in children aged 14 years or older and adults. Intervention FOP is a rare connective tissue disorder caused by a mutation in a gene called activin A receptor type I, ACVR1, which encodes the ACVR1/ALK2 receptor.296 This mutation leads to HO that manifests as abnormal bone growth in muscles, tendons, and ligaments.297,298 HO flares can occur spontaneously or follow physical trauma (eg, injury, infection).297,299 Once heterotopic bone forms, it cannot be surgically removed because tissue disruption causes additional HO episodes. HO progressively interferes with normal body functions, including walking, bending, breathing, chewing, and swallowing. Patients typically require a wheelchair by about 20 years of age. Registry data suggest a median life span of about 40 years, with cardiorespiratory failure and pneumonia cited as the leading causes of death.297,299,300 The National Institutes of Health’s Genetic and Rare Diseases Information Center website offers more information on FOP. Palovarotene is an elective retinoic acid receptor gamma (RARγ) agonist (ie, activator) that is taken by mouth. It is being developed to treat FOP. In patients with FOP, mutant activin receptor– like kinase-2 (ALK2) overactivates Smad 1/5/8 transcription factors in the bone morphogenetic protein (BMP) 2 pathway. This pathway is responsible for cartilage regulation and bone growth and development.297,298 Palovarotene activation of RARγ purportedly decreases Smad 1/5/8 protein levels, reducing excess BMP signaling to prevent further HO development in patients with FOP.296,298 In an ongoing phase 3 clinical trial, palovarotene is administered in a 5-mg dose, once daily, to manage chronic FOP. For an FOP disease flare, palovarotene is administered at a dose of 20 mg, once daily for 4 weeks, followed by 10 mg, once daily for 8 weeks.301 Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present these trials in Table 5.13. Table 5.13. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier MOVE Trial: An Efficacy Children aged 4 years or Phase 3, single-arm, open-label study Primary and Safety Study of older and adults (n = 110) to assess the efficacy of palovarotene completion Palovarotene for the with a clinical diagnosis of in decreasing new HO in FOP January 2020 Treatment of FOP FOP and no flares in the Data from this trial will be compared Study NCT03312634 previous 4 weeks with historical data from a natural completion (PVO-1A-301) cohort study of patients with FOP. November 2022 See preliminary results by Primary outcome: Annualized change Ipsen Group 2020 under in new HO volume Recently Completed and Ongoing Trials With Available Results

HIGH POTENTIAL DISRUPTION REPORT • November 2020 134

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier An Open-Label Extension Children and adults aged 6 Phase 2, single-arm, open-label Primary and Study of Palovarotene to 65 years (n = 58) with a extension study assessing safety and study Treatment in FOP clinical diagnosis of FOP efficacy of multiple palovarotene completion May NCT02279095 dosing regimens to treat chronic FOP 2021 See preliminary results by and flares Clementia Primary outcome: Annualized change Pharmaceuticals 2018 in new HO volume under Recently Completed and Ongoing Trials With Available Results

An Open-Label Extension Children and adults aged 6 Phase 2, single-arm, open-label Primary and Study of Palovarotene to 65 years (n = 9) with a extension study in France assessing study Treatment in FOP in clinical diagnosis of FOP safety and efficacy of multiple completion July France palovarotene dosing regimens to treat 2021 NCT02979769 chronic FOP and flares Primary outcome: Annualized change in new HO volume

Abbreviations: FOP, fibrodysplasia ossificans progressiva; HO, heterotopic ossification.

Recently Completed and Ongoing Trials With Available Results Our searches identified recently completed phase 2 and phase 3 trials with published results.302,303 We summarize these studies below with results as written in news releases. The following abbreviations are used in this section: FOP, fibrodysplasia ossificans progressiva; HO, heterotopic ossification; p or p-value, probability; PROMIS, Patient-Reported Outcomes Measurement Information System; RARγ, retinoic acid receptor gamma; WBCT, whole body computed tomography.

An Efficacy and Safety Study of Palovarotene for the Treatment of FOP (MOVE). NCT03312634. Ipsen Group 2020.303

• Patient population/planned enrollment: Children aged 4 years or older and adults (n = 90) with a clinical diagnosis of FOP and no flares in the previous 4 weeks • Study design: Phase 3, single-arm, open-label study to assess the efficacy of palovarotene in decreasing new HO in FOP. Data from this trial will be compared with historical data from a natural cohort study of patients with FOP. • Primary outcome: Annualized change in new HO volume • Secondary outcomes: Proportion of patients with any new HO, number of body regions with HO, proportion of patients with flares, rate of flares, and adverse events • Results presented by study authors: “Dosing of palovarotene in the MOVE clinical trial was paused when futility criteria were met at a pre-specified interim analysis. However, subsequent post hoc analyses showed the RARy agonist oral investigational therapy palovarotene reduced mean annualized new heterotopic ossification (HO) volume in pediatric and adult participants with FOP. This was compared with untreated patients from a natural history study over 24 months. Results from the MOVE trial demonstrated a 62% reduction in mean annualized new HO volume in participants treated with

HIGH POTENTIAL DISRUPTION REPORT • November 2020 135

palovarotene (8,821 mm3 ) (n=97) versus untreated (23,318 mm3 ) (n=98) patients (nominal weighted linear mixed effects [wLME] model est. –11,611mm3 , p-value = 0.0292). Premature physeal closure (PPC) (n=18) or epiphyseal disorder (n=1) was observed in 27.1% (19/70) of participants who were skeletally immature at baseline. Palovarotene safety data were otherwise generally consistent with the known adverse event (AE) profile of retinoids.”

An Open-Label Extension Study of Palovarotene Treatment in FOP. NCT02279095. Clementia Pharmaceuticals 2018.302

• Patient population/planned enrollment: Children aged 6 to 17 years and adults aged up to 65 years (n = 53) with a clinical diagnosis of FOP • Study design: Phase 2, single-arm, open-label extension study assessing safety and efficacy of multiple palovarotene dosing regimens to treat chronic FOP and flares • Primary outcome: Annualized change in new HO volume • Secondary outcomes: Patients with new HO, the proportion of subjects with any new HO, range of motion, change in physical function using the FOP-Physical Function Questionnaire, change from baseline in mental and/or physical health function via age-appropriate PROMIS Global Health Scale, and incidence of adverse events from baseline up to 60 months • Results presented by study authors: “New HO volume at the site of a flare-up at 12 weeks was a pre- specified secondary endpoint in the Phase 2 study, and is an objective measure that is analyzed using standardized procedures by blinded, independent central imaging readers. In a preliminary analysis of adults and skeletally mature children, we observed a statistically significant 91 percent reduction (p=0.01) in mean volume of new HO for the 29 flare-ups treated with the chronic/flare-up dosing regimen (719mm3 ) in Part B as compared to the 60 untreated flare-ups (8,001mm3). In addition to these data, Clementia analyzed data from those evaluable patients who had both 12-week flare-up scans and 12-month WBCT scans. For the 9 patients with no new HO at 12-weeks at the flare-up location, there was no new HO at 12- months anywhere in the body, including the assessed flare-up location. We believe these data suggest that flare-up data could potentially be predictive of longer term outcomes. In addition to the 12-week flare-up scans, new HO in adults and skeletally mature children receiving the chronic/flare-up dosing regimen was assessed by WBCT scan at 12 months compared to untreated patients in the natural history study, regardless of whether or not flare-up symptoms were present. This preliminary per protocol assessment included 33 evaluable patients, and a 28 percent reduction in whole body volume of new HO in treated patients (21,567mm3) was observed as compared to the 55 untreated patients (29,731mm3). Importantly, in this evaluation, one patient included in the analysis experienced multiple flare-ups which were not treated with the 20/10mg regimen because they did not meet the requirements for flare-up treatment according to the Part B protocol. Utilizing the MOVE Trial flare-up definition and treatment criteria, which require only one flare-up symptom, this patient would have qualified for high-dose treatment in the Phase 3 MOVE Trial. When we analyze these data without this one patient, treatment with palovarotene resulted in a 65 percent mean reduction of new HO by WBCT (10,682mm3) compared to the untreated control group (29,731mm3).” Manufacturers and Regulatory Status Palovarotene is manufactured by Clementia Pharmaceuticals Inc (Montreal, Québec, Canada), an Ipsen Group company (Paris, France), and is in phase 3 development (MOVE trial, NCT03312634) for preventing FOP flares. Primary data collection for the study was completed in January 2020.301 On January 24, 2020, Ipsen announced that the company would pause dosing patients in the phase 3 MOVE study as well as the ongoing phase 2 (PVO-1A-202/204) extension studies because of results of a prespecified interim futility analysis by the Independent Data Monitoring Committee (IDMC). The futility analysis revealed that the phase 3 FOP trial was unlikely to meet its primary efficacy end point (annualized change in new HO volume compared with a separate ongoing natural history study control).304

HIGH POTENTIAL DISRUPTION REPORT • November 2020 136

However, the IDMC recommended against discontinuing the study due to disparate results, and a prespecified interim analysis revealed signals of encouraging therapeutic activity in preliminary phase 3 post hoc analyses.304 Data using a modified statistical analysis were presented in August 2020.303 In addition, on December 6, 2019, Ipsen initiated a partial clinical hold for dosing pediatric patients aged 14 years or younger with palovarotene for treating chronic FOP because of safety reports submitted to FDA of cases of early growth plate closure in pediatric patients given the drug.305 On March 26, 2020, the manufacturer announced it would reinitiate palovarotene dosing in patients aged 14 years or older who were enrolled in FOP clinical trials because FDA regulators confirmed they had no safety concerns about dosing patients in that cohort.306 FDA had granted palovarotene Rare Pediatric Disease designation to treat FOP in February 2019.298 FDA has also granted palovarotene Breakthrough Therapy, Fast Track, and Orphan Drug designations for treating FOP.296,307 Cost Information Cost information is currently unavailable for this topic, but stakeholders expected the drug to be expensive. Key Stakeholder Perspectives Between June 11, 2020, and August 28, 2020, six stakeholders, reflecting clinical, health systems, and research perspectives, provided comments and ratings on palovarotene. Stakeholder comments were received before the August 2020 release of data from the phase 3 MOVE trial. The list below summarizes key stakeholder perspectives. • Palovarotene has substantial potential to improve patient outcomes in a disease with no effective disease-modifying treatments. The mechanism of action directly influencing the disease course of FOP has demonstrated reduction in flare rate and could improve long-term bone health and joint function. However, data have not yet been published in peer reviewed journals and full reporting of the drug’s adverse event profile is needed. • The availability of a disease-modifying therapy for HO would cause a shift in the patient treatment paradigm, potentially reducing the need for some supportive care and hospitalizations related to disease flares. • As a drug taken by mouth, palovarotene should not cause substantial disruption to the health care delivery system. • Palovarotene will likely be very expensive, like other drugs for rare orphan diseases. However, costs to the health care system could be mitigated by reduced costs related to supportive care, and cost burden on the overall health care system will be limited by the small number of affected patients.

PTC-AADC to Treat Aromatic l-Amino Acid Decarboxylase Deficiency Highlights • PTC-AADC is an adeno-associated viral vector containing a functional copy of the human dopa decarboxylase gene, DDC. This therapy purportedly restores the gene’s encoded enzyme, aromatic l-amino acid decarboxylase (AADC), to correct the underlying genetic defect. It is intended to enhance neurotransmitter production, restore motor function, and

HIGH POTENTIAL DISRUPTION REPORT • November 2020 137

delay or prevent other disease symptoms of aromatic l-amino acid decarboxylase deficiency (AADCD). The therapy is in phase 2 development. • PTC-AADC is administered in a one-time-only intracerebral infusion via stereotactic surgery. • Stakeholders commenting on this topic generally agreed that PTC-AADC has large potential to improve patient health outcomes, quality of life, and overall health. • Stakeholders also thought PTC-AADC has moderate to large potential to disrupt the current paradigm of patient care and the health care delivery system because this therapy might shift care from supportive to curative and requires that the treatment be given by specialized personnel in a specialized health care setting. Patient Population PTC-AADC is intended for children aged 2 years or older and adults with genetically confirmed, symptomatic AADCD. Intervention PTC-AADC (formerly known as AGIL-AADC, AAV2-hAADC, and GT-AADC) is an adeno- associated viral vector containing a functional copy of the DDC gene.308 It is intended to promote DDC gene expression in patients with AADCD, a childhood-onset, progressive, inherited neurometabolic disorder. AADCD is caused by variations in the DDC gene, inherited in an autosomal recessive pattern, that result in the loss of the gene’s encoded enzyme, AADC. This enzyme is critical for converting neurotransmitter precursors into dopamine, epinephrine, norepinephrine, or serotonin.309 Patients with AADCD experience many signs and symptoms, including severe developmental delays, decreased muscle tone, involuntary arm and leg movements, and seizures. Treatments only manage symptoms and do not prevent disease progression. The National Institutes of Health’s Genetics Home Reference website offers more information on AADCD. Delivery of a functional copy of DDC may enhance neurotransmitter production, restore motor function, and delay or prevent other disease symptoms.308 In clinical trials, patients received a single intracerebral infusion of PTC-AADC (1.8 × 1011 viral genomes [vg] or 2.4 × 1011 vg) via stereotactic surgery. Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 5.14.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 138

Table 5.14. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier A Clinical Trial for Children (n = 10) aged 2 to Phase 2, single-arm, open-label study Primary and Treatment of Aromatic l- 6 years with genetically to determine the safety and efficacy study Amino Acid confirmed AADCD of a one-time intracerebral completion Decarboxylase (AADC) administration of 2.371 × 1011 vg PTC- December 2020 Deficiency Using AAV2- AADC (AAV2-hAADC) hAADC—An Expansion Primary outcomes: (NTUH-AADC-011; MIND) • Increase of PDMS-2 score of more NCT02926066 than 10 points, from baseline to 13 See preliminary results by months after gene therapy Lee et al 2018 and Chien • 5-HIAA and HVA (neurotransmitter et al 2019 under Recently metabolite) levels in CSF 13 Completed and Ongoing months after gene therapy Trials With Available Secondary outcomes: Results • Dyskinesia severity at 13 months after gene therapy • Other SAE incidence at 13 months after gene therapy A Phase I/II Clinical Trial Children and adults (n = 10) Phase 1/2, single-arm, open-label Primary and for Treatment of aged 24 months or older study to determine the safety and study Aromatic l-Amino Acid with genetically confirmed efficacy of a one-time intracerebral completion Decarboxylase (AADC) AADCD administration of 1.8 × 1011 vg PTC- December 2020 Deficiency Using AAV2- AADC (AAV2-hAADC) hAADC Primary outcomes: NCT01395641 • Increase of PDMS-2 score of more See preliminary results by than 10 points, from baseline to 1 Chien et al 2017 under year after gene therapy Recently Completed and • 5-HIAA and HVA (neurotransmitter Ongoing Trials With metabolite) levels in CSF 1 year Available Results after gene therapy Secondary outcomes: • Dyskinesia severity at 12 months after gene therapy • Other SAE incidence at 12 months after gene therapy

Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; AADCD, aromatic l-amino acid decarboxylase deficiency; CSF, cerebrospinal fluid; HVA, homovanillic acid; PDMS-2, Peabody Developmental Motor Scales, version 2; SAE, serious adverse event; vg, viral genomes.

Recently Completed and Ongoing Trials With Available Results Our searches identified 3 recently completed phase 1/2 trials with published results.308,310,311 We summarize these studies with results as written in an abstract of a published study and conference abstracts.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 139

The following abbreviations are used in this section: 5-HIAA, 5-hydroxyindoleacetic acid; AADCD, aromatic l-amino acid decarboxylase deficiency; AEs, adverse events; AIMS, Alberta Infant Motor Scale; Bayley-III, Bayley Scales of Infant Development, third edition; CSF, cerebrospinal fluid; HVA, homovanillic acid; IQR, interquartile range; P, probability; PDMS-2, Peabody Developmental Motor Scales, version 2; SAE, serious adverse event; vg, viral genomes.

Pooled Analysis of: A Clinical Trial for Treatment of Aromatic l-Amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC—An Expansion (NTUH-AADC-011; MIND), NCT02926066, and A Phase I/II Clinical Trial for Treatment of Aromatic l-Amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC, NCT01395641. Lee at al 2018310 and Chien et al 2019.311

• Patient population/planned enrollment: Children and adults (n = 25) aged 2 years or older with genetically confirmed AADCD Note: Some of these patients are also included in data presented in the next recently completed trial. • Study design: NCT02926066: Phase 2, single-arm, open-label study to determine the safety and efficacy of a one-time intracerebral administration of 2.371 × 1011 vg PTC-AADC (AAV2-hAADC); NCT01395641: Phase 1/2, single-arm, open-label study to determine the safety and efficacy of a one-time intracerebral administration of 1.8 × 1011 vg PTC-AADC (AAV2-hAADC) • Outcomes: Developmental milestone achievement (ie, full head control, unassisted sitting, standing with support, and unassisted or assisted walking, as measured by AIMS, Bayley-III, and PDMS-2 scales) at 2 or 5 years after gene therapy; use of assistive devices; and AEs • Results presented by study authors: “Patients received a total dose of either 1.8x1011 vg total of AGIL- AADC [PTC-AADC] (n=21) or 2.4x1011 vg total of AGIL-AADC (n=4). Of the 25 children given AGIL-AADC, 3 are now more than seven years post-gene therapy, 7 are more than six years post-gene therapy, and 16 are more than two years post-gene therapy. Clinical results of the first 18 patients given AGIL-AADC were compared to natural history cohort. At baseline, ages ranged from 21 months to 8.5 years and no child had developed full head control, sitting unassisted or standing capability, consistent with the published natural history cohort of severe AADC patients who never achieve these motor milestones over their lifetime. Compared to the natural history cohort, among the 18 patients receiving the 1.8x1011 vg total dose of AGIL-AADC, 5/15 gain full head control (P<.0001), 4/15 gain sitting unassisted (P =.0004), and one subject achieved standing with support at 2 years. At five years, 4/7 gain full head control and sit unassisted (P <.0001), and 2/7 stand with support (P=.0054). Regarding ambulatory function, two patients are using wheeled walkers, one additional patient is able to take steps holding an examiner’s hand and one patient is walking independently. Adverse events in the first year after AGIL-AADC administration, in general, were associated with overall disease state.”310 An update of this cohort reported, “all patients had 2 years of posttreatment data; 8 patients had 5 years of posttreatment data. PDMS-2 total score and single-item motor developmental milestones demonstrated clinically meaningful improvements versus natural history controls. AIMS and Bayley-III total and cognitive and language subscale scores also improved. All patients demonstrated sustained de novo dopamine production. No new safety signals were observed.”311

A Phase I/II Clinical Trial for Treatment of Aromatic l-Amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC. NCT01395641. Chien et al 2017.308

• Patient population/planned enrollment: Children and adults (n = 10) aged 24 months or older with genetically confirmed AADCD Note: Some of these patients are also included in data presented in the previous recently completed trial. • Study design: Phase 1/2, single-arm, open-label study to determine the safety and efficacy of a one-time intracerebral administration of 1.8 × 1011 vg PTC-AADC • Primary outcomes: Increase of PDMS-2 score of more than 10 points from baseline to 1 year after gene therapy and 5-HIAA and HVA (neurotransmitter metabolite) levels in CSF 1 year after gene therapy

HIGH POTENTIAL DISRUPTION REPORT • November 2020 140

• Secondary outcomes: Dyskinesia severity at 12 months after gene therapy and other SAE incidence at 12 months after gene therapy • Results presented by study authors: “Ten patients (median age 2.71 years, IQR 2.46-6.35) were enrolled from Oct 1, 2014, to Dec 2, 2015. All patients tolerated the surgeries and vector injections. One patient died from influenza B encephalitis during an endemic outbreak 10 months after treatment; therefore, 9 months of data were included in the analyses for this patient. All patients met the primary efficacy endpoint: 12 months after gene therapy, PDMS-2 scores were increased by a median of 62 points (IQR 39- 93; P=.005) and HVA concentrations by a median of 25 nmol/L (IQR 11-48; P=.012); however, there was no significant change in 5-HIAA concentrations (median difference 0, IQR 0-5; P=.20). In total, 101 adverse events were reported, with the most common being pyrexia (16 [16%] of 101 events) and orofacial dyskinesia (ten [10%]). 12 serious adverse events occurred in six patients, including one death (treatment- unrelated encephalitis due to influenza B infection), one life-threatening pyrexia, and ten events that led to hospital admission. Transient post-gene therapy dyskinesia occurred in all patients but was resolved with risperidone. Of 31 treatment-related adverse events, only one (patient 1) was severe in intensity, and none led to hospital admission or death.” Manufacturers and Regulatory Status PTC-AADC is being developed by PTC Therapeutics, Inc (South Plainfield, New Jersey). It is in phase 2 clinical development. In January 2020, PTC Therapeutics announced a short delay in its plan to submit a Biologics License Application (BLA), because FDA had requested “additional information concerning the use of the commercial delivery system for PTC-AADC in young patients” and announced anticipating submitting the BLA in the second quarter of 2020.312 In April 2020, PTC announced plans to submit a BLA in the second half of 2020; the company’s study of the delivery system was delayed because of the effects of the COVID-19 pandemic.313 FDA had granted Orphan Drug designation to PTC-AADC to treat AADCD in June 2016314 and Rare Pediatric Disease designation in November 2016.315 Cost Information Cost information is currently unavailable for this topic, but stakeholders expected that, as a gene therapy, it will be expensive. Key Stakeholder Perspectives Between January 6, 2020, and March 16, 2020, seven stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on PTC-AADC. The list below summarizes key stakeholder perspectives. • PTC-AADC has large potential to improve patient health outcomes and quality of life because of significant efficacy data in clinical trials (ie, improvement in full head control, sitting without assistance, ambulation compared with natural history data, and sustained de novo dopamine production) that support the underlying theory of PTC-AADC to treat AADCD. • Stakeholders anticipate PTC-AADC will be expensive and potentially cost prohibitive, potentially increasing health disparities. However, the anticipated cost might be offset by a decrease in other lifetime health care costs (eg, caregiving, therapy, medications). • PTC-AADC has moderate to large potential to disrupt the paradigm of patient care for reasons including that it purportedly cures the disease while current treatment is ongoing and supportive and that the new treatment is given in a highly specialized care setting as an intracerebral infusion via stereotactic surgery. • PTC-AADC has moderate potential to disrupt the health care delivery system; although treatment requires a specialized care setting (and a reviewer noted that not every health

HIGH POTENTIAL DISRUPTION REPORT • November 2020 141

facility has a Gamma Knife for this stereotactic surgery procedure), the treatment procedure is needed only once.

RVT-802 to Treat Pediatric Congenital Athymia (DiGeorge Syndrome Immunodeficiency, CHARGE Syndrome, FOXN1 Deficiency) Highlights • RVT-802 is a cell-based therapy derived from donor (ie, allogeneic) infant thymus tissue; it is intended to restore thymus function in pediatric patients born without a thymus (ie, athymia) so they can develop a functional immune system. The tissue is implanted in the patient’s quadriceps muscle. • No FDA-approved treatments are available for pediatric congenital athymia, which often leads to death by 2 years of age. This therapy is in phase 3 development and the company anticipates completing its licensing application submission to FDA by the end of 2020. • Stakeholders commenting on this topic thought that RVT-802 might be an effective one- time treatment that provides immune reconstitution for patients with congenital athymia. However, they also thought that larger, longer-term studies are needed to better understand RVT-802’s safety and effectiveness relative to other treatments such as hematopoietic stem cell transplant. • Stakeholders further thought that RVT-802’s likely high cost and the likelihood that thymus transplants would be available at only a small number of facilities might limit access to therapy. Patient Population RVT-802 is intended for infants and children with pediatric congenital athymia, a condition associated with genetic syndromes including complete DiGeorge genetic anomaly (cDGA); coloboma, heart defects, atresia choanae, retarded growth and development, genital hypoplasia, and ear abnormalities and deafness (CHARGE) syndrome; and Forkhead Box N1 (FOXN1) deficiency. Intervention Pediatric congenital athymia is a very rare disorder associated with several rare, life-threatening genetic diseases (ie, cDGA, CHARGE syndrome, and FOXN1 deficiency) that arise from gene rearrangements that cause an affected individual to be born without a thymus. About 20 infants are born with congenital athymia each year in the United States. Affected infants cannot produce T cells, which are a critical part of a functioning immune system. Lack of T cells leads to a severe inability to fight infections and eventually results in death, typically by 2 years of age due to infection. No FDA-approved therapies are available for athymic diseases.316 More information on disorders caused by athymia is available from the Immune Deficiency Foundation (DiGeorge syndrome), National Institutes of Health’s Genetics Home Reference (CHARGE syndrome), and Orphanet Journal of Rare Diseases (FOXN1 deficiency). RVT-802 is an allogeneic cell-based therapy derived from infant donor thymus tissue; it is intended to reconstitute thymus function in patients with athymia so they develop a working immune system. According to the manufacturer, these patients are still capable of producing bone marrow–derived precursor T cells that can migrate from the bone marrow to the implanted RVT- 802 tissue product, where these precursors can grow into working thymus cells (ie,

HIGH POTENTIAL DISRUPTION REPORT • November 2020 142

thymopoiesis).317 RVT-802 is intended to be a one-time therapy to permanently restore normal immune function in patients.318 Donor tissue composing RVT-802 is typically obtained from infants undergoing cardiac surgery, during which thymus tissue is frequently removed to gain access to the heart. After tissue donation, RVT-802 is processed and cultured for 14 to 21 days in a manufacturing facility before the patient receives the implant at a specialized treatment center. In clinical trials, RVT-802 is administered by placing a cultured thymus slice into a small incision in the patient’s quadriceps muscle that is then pulled over the slice using an insoluble stitch. Physicians implant between 4 and 18 g of thymus tissue per square meter of body surface area. Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database did not identify any ongoing trials for this topic. Recently Completed and Ongoing Trials With Available Results Thymus transplants have been performed at a single center in the United States since the mid-1990s and at a single European center since 2009. Multiple papers covering partially overlapping patient populations from these studies have been published (Markert et al 1999,319 Markert et al 2004,320 Markert et al 2007,321 and Markert et al 2010322). We summarize the most recent data as written in a news release. The following abbreviation is used in this section: BLA, Biologics License Application.

Enzyvant Announces FDA Acceptance of Biologics License Application (BLA) and Priority Review Status for RVT-802, a Novel Investigational Tissue-Based Regenerative Therapy for Pediatric Congenital Athymia. Enzyvant 2019.317

• Patient population/planned enrollment: Patients (n = 93) with pediatric congenital athymia • Study design: Pooled patients from multiple single-arm trials of the safety and efficacy of RVT-802 • Primary outcome: Overall survival at 1 year after transplantation • Results presented by study authors: “At the time of the BLA filing, a total of 93 patients received RVT-802 across multiple clinical studies, including 85 patients who met the criteria for inclusion in the efficacy analysis. The Kaplan-Meier estimates of survival [95% confidence interval] at year one and year two post treatment were 76% [66 - 84] and 75% [66 - 83], respectively. For patients surviving 12 months post- treatment, there was a 93% probability of surviving 10 years post-treatment. During clinical development, the most commonly (≥ 5%) reported RVT-802 related adverse events included thrombocytopenia (11%), neutropenia (8%), pyrexia (5%), and proteinuria (5%).” Manufacturers and Regulatory Status RVT-802 is being developed by Enzyvant Therapeutics GmbH (Basel, Switzerland), a subsidiary of Roivant Sciences GmbH (Basel, Switzerland), in collaboration with Duke University (Durham, North Carolina). In December 2019, Roivant entered into a strategic alliance with Sumitomo Dainippon Pharma (Osaka, Japan) in which ownership of Enzyvant and several other Roivant subsidiaries was transferred to a new company fully owned by Sumitomo Dainippon.323 FDA had accepted a Biologics License Application (BLA) for RVT-802 for treating pediatric congenital athymia; however, in December 2019, the company announced that FDA declined to approve the BLA.317,324 The developer indicated that FDA’s Complete Response Letter cited questions regarding RVT-802’s manufacturing process and other issues based on the agency’s

HIGH POTENTIAL DISRUPTION REPORT • November 2020 143

inspection of the manufacturing site. Sumitomo Dainippon said it intended to refile the BLA, possibly before the end of 2020.325 FDA had granted Rare Pediatric Disease designation to RVT-802 in September 2017 to treat primary immune deficiency resulting from congenital athymia associated with cDGA.326 FDA also granted RVT-802 Breakthrough Therapy and Regenerative Medicine Advanced Therapy designations in April 2017 to treat cDGA.327 Cost Information Although cost data are not yet available from the manufacturer, a presentation at the Academy of Managed Care Pharmacy Nexus 2018 conference estimated that RVT-802 might have a budget impact of $1.5 million per treated patient.328 Key Stakeholder Perspectives Between June 22, 2020, and August 5, 2020, six stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on RVT-802. The list below summarizes key stakeholder perspectives. • RVT-802 might disrupt health outcomes by providing a treatment option for patients with athymia. In particular, athymic patients who lack a suitable donor for hematopoietic stem cell transplant could benefit substantially from another available treatment. • RVT-802’s high cost (an estimated $1.5 million per patient) might create disparities for families that are underinsured or lack sufficient financial resources. In addition, RVT-802 transplants will likely be offered only at specialty facilities like major children’s hospitals and, therefore, RVT-802 would likely increase disparities for patients who live far from these facilities. • If effective, RVT-802 could disrupt the paradigm of patient care by causing a shift from mainly palliative care and treatment of opportunistic infections to an approach that reconstitutes the patient’s immune system. In addition, health care facilities offering RVT- 802 transplantation would need to develop protocols to ensure the timely acquisition of the thymus graft and appropriate preoperative and postoperative patient management. • Long-term controlled studies are needed to assess the safety and effectiveness of RVT-802 and donor-matched thymus transplantation, hematopoietic stem cell transplantation, and supportive care to better understand the therapies’ tradeoff between benefit (immune reconstitution) and risk (death or autoimmune complications).

Setmelanotide (RM-493) to Treat Proopiomelanocortin Deficiency Obesity Highlights • Setmelanotide is an injectable drug intended to treat proopiomelanocortin (POMC) deficiency obesity, a rare form of obesity caused by mutations in certain genes regulating hunger. Setmelanotide purportedly activates MC4 receptors in the brain to help restore normal appetite and energy regulation pathways. • FDA accepted the company’s New Drug Application (NDA), and a decision on setmelanotide approval was expected by November 27, 2020. • Candidates for setmelanotide therapy might require a companion diagnostic test to identify whether they carry the genetic variants that the drug targets.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 144

• Stakeholders reviewing this topic thought that early results reported in a small patient group were impressive, with average weight loss of about 32 kg (70 lb) per patient over 1 year. • Stakeholders also thought that additional data in a larger patient sample are needed to better define the long-term safety and effectiveness of setmelanotide for treating POMC deficiency obesity. Patient Population Setmelanotide is intended to treat patients aged 6 years or older with genetically confirmed POMC deficiency obesity. Intervention POMC deficiency obesity is a rare type of obesity caused by variants in the proopiomelanocortin gene, POMC, or the proprotein convertase subtilisin/kexin type 1 gene, PCSK1.329 Variants in these 2 genes lead to deficient production of proopiomelanocortin protein, a precursor required to synthesize the peptides adrenocorticotropic hormone (ACTH), α-melanocyte- stimulating hormone (α-MSH), and β-MSH in the brain. ACTH stimulates cortisol release from the adrenal glands, which plays an important role in maintaining blood sugar levels.329,330 In the brain, α-MSH and β-MSH maintain the balance of energy from food intake and energy expenditure329 by activating melanocortin-4 (MC4) receptors. Inadequate activation of MC4 receptors is thought to result in hunger dysregulation. POMC deficiency obesity is one of a few genetic obesities that has been identified to originate upstream of MC4 receptors in the brain.330 See Rhythm Pharmaceutical’s Uncommon Obesity website for more information on POMC deficiency obesity. Setmelanotide (RM-493), a peptide, is a selective MC4 receptor agonist intended to treat POMC deficiency obesity. Setmelanotide purportedly activates MC4 receptors, restoring function to the MC4 pathway, to affect weight loss and reduce hunger.331,332 In a phase 2 clinical trial, setmelanotide was given as an injection under the skin once daily at a starting dose of 0.25 or 0.5 mg and later increased to 1.0 or 1.5 mg.333 Determining eligibility for the drug might require genetic testing using a companion diagnostic, which is an FDA-approved test to identify patients with the genetic variants that the drug targets.334 In phase 3 clinical trials in progress, setmelanotide is given as an injection under the skin once daily at an unspecified dose. Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 2 ongoing trials for this topic. We present these trials in Table 5.15.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 145

Table 5.15. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Setmelanotide (RM-493) Patients aged 6 years or Phase 2/3, single-group, open-label Primary Phase 2 Treatment Trial older (n = 150) with rare study to determine the effect on completion May in Patients With Rare genetic disorders of weight of once-daily under-the-skin 2021 Genetic Disorders of obesity, including POMC injections of setmelanotide (at an Study Obesity deficiency, leptin receptor unspecified dose) over the course of 1 completion deficiency, Bardet-Biedl year NCT03013543 August 2021 syndrome, Alström Primary outcome: Body weight syndrome, and Smith reduction Magenis syndrome Long Term Extension Trial Patients aged 6 years or Phase 2/3, single-group, open-label Primary and of Setmelanotide older (n = 100) with obesity study to assess the safety and study associated with defects in tolerability of continued once-daily completion NCT03651765 leptin-melanocortin under-the-skin injections of March 2023 pathways who completed a setmelanotide (at an unspecified previous setmelanotide dose) over the course of 2 years clinical trial Primary outcome: Safety and tolerability Selected secondary outcomes: • Weight loss • Hunger • Body fat mass • Waist circumference • Change in total body mass, nonbone lean mass, and bone density • Quality of life • Measure of health status

Abbreviation: POMC, proopiomelanocortin.

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed late-phase trial with reported results.335 We summarize this study with results as written in a manufacturer news release. The following abbreviations are used in this section: p, probability; PCSK1, proprotein convertase subtilisin/kexin type 1 gene; POMC, proopiomelanocortin; POMC, proopiomelanocortin gene.

Setmelanotide for the Treatment of Early-Onset POMC Deficiency Obesity. NCT02896192. Rhythm Pharmaceuticals 2019.335

• Patient population/planned enrollment: Patients aged 6 years or older with POMC deficiency obesity due to biallelic POMC or PCSK1 gene mutations • Study design: Phase 2/3 single-group study to evaluate the effect of once-daily under-the-skin injections of setmelanotide (dose unspecified) on weight and other factors. All patients received setmelanotide for

HIGH POTENTIAL DISRUPTION REPORT • November 2020 146

12 weeks, followed by an 8-week double-blind withdrawal period during which patients received placebo treatment for a randomly timed 4-week window. After the placebo withdrawal period, all patients received setmelanotide for another 32 weeks. • Primary outcome: Weight loss • Secondary outcomes: Treatment-related adverse events and changes in body fat mass, hunger, insulin resistance, waist circumference, and weight during withdrawal phase • Results presented by study authors: “Eight of 10 patients with POMC deficiency obesity achieved the primary endpoint of greater than 10 percent weight loss over approximately one year (p<0.0001). The mean reduction from baseline in body weight for POMC deficiency obesity patients was -25.4 percent (p<0.0001), and the mean reduction from baseline in most hunger rating for POMC deficiency obesity patients was -27.8 percent (p=0.0005). In addition, 50 percent of the POMC deficiency obesity patients in the trial met or exceeded a 25 percent improvement in self-reported hunger scores (p=0.0004). Mean weight loss for these patients was 31.9 kg, or 70.2 pounds, over one year on therapy.” Manufacturers and Regulatory Status Rhythm Pharmaceuticals, Inc (Boston, Massachusetts), manufactures setmelanotide. In May 2020, FDA accepted the company’s NDA for setmelanotide to treat POMC deficiency and to treat leptin receptor deficiency obesity.336 FDA previously granted setmelanotide Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease designations for these indications.337 FDA indicated it would not convene an expert panel advisory committee meeting to discuss the NDA and assigned a Prescription Drug User Fee Act (PDUFA)-prescribed decision date of November 27, 2020.336 Setmelanotide is also in phase 3 clinical development to treat Bardet-Biedl syndrome and Alström syndrome, and in phase 2 clinical development to treat other rare, genetically linked forms of obesity.331 Cost Information Cost information is currently unavailable for this topic. Key Stakeholder Perspectives Between March 20, 2020, and September 13, 2020, nine stakeholders, reflecting clinical, health systems, nursing, patient, and research perspectives, provided comments and ratings on this topic. The list below provides a summary of key stakeholder perspectives. • Initial results for setmelanotide, including average weight loss of about 32 kg (70 lb) per patient in 1 year, appear impressive, and no apparent safety concerns have been reported thus far. • Most patients and family caregivers would welcome a new treatment for POMC obesity that is more effective than diet modification and less invasive than bariatric surgery. • Although POMC is a rare condition, the scarcity of available data, based on company reporting for only very few patients, can limit the ability to extrapolate or make strong projections about this intervention. • Longer-term data in a larger patient group are needed to fully establish the safety and duration of effect of setmelanotide to treat POMC deficiency obesity and to identify any unexpected adverse events related to its mechanism of action. • Some ongoing trials include patients with different genetically linked obesity types, potentially complicating analysis of findings.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 147

Teprotumumab-trbw (Tepezza) to Treat Thyroid Eye Disease Highlights • Teprotumumab-trbw is a fully human monoclonal antibody targeting the insulin-like growth factor-1 receptor, purportedly blocking IGF-1R-mediated signaling in orbital fibroblasts. This mechanism of action is designed to stop the accumulation of glycosaminoglycans and relieve the autoimmune symptoms of thyroid eye disease (TED), thereby improving quality of life and health outcomes. • Teprotumumab-trbw was approved by FDA in January 2020 as the first therapy to treat active TED. • Costs for a course of teprotumumab-trbw treatment may exceed $200 000 per patient. • Stakeholders commenting on this topic thought that teprotumumab-trbw would be a disruptive, noninvasive alternative to surgery that would reduce patients’ recovery time and risk of surgical complications. • Stakeholders thought published data suggested that teprotumumab-trbw was highly effective at reducing proptosis (ie, eye bulging) due to TED. • Stakeholders also thought that this intervention will likely increase health disparities due to the high treatment cost, uncertain insurance coverage, and inconvenient dosing regimen. However, stakeholders noted that additional data demonstrating teprotumumab-trbw’s long- term safety and effectiveness could help overcome such obstacles to widespread use. Patient Population Teprotumumab-trbw is intended to treat adults who have active TED. Intervention TED (also known as Graves orbitopathy) is a rare autoimmune disease in which inflammation and increased volume of muscle and fatty tissue behind the eyes cause them to be pushed forward and bulge outward (ie, proptosis). It has no cure and limited options for symptom management.338,339 Symptoms may persist even after treatment of an overactive thyroid gland. The recommended surgical interventions present significant risk of complications to the patient, including double vision (ie, diplopia) and blindness.338,339 The American Thyroid Association offers more information about TED. Teprotumumab-trbw (Tepezza) is a fully human monoclonal antibody specific for insulin-like growth factor-1 receptor (IGF-1R) and intended to treat TED.340 FDA has approved it for marketing. IGF-1R plays a central role in TED development and progression, promoting the structural changes that drive the disease. Teprotumumab-trbw purportedly inhibits IGF-1R-mediated signaling in orbital fibroblasts, which stops the accumulation of glycosaminoglycans, such as hyaluronan, behind the eye muscles.341 Additionally, teprotumumab-trbw purportedly inhibits IGF-1R-mediated signaling in the immune system’s B cells and T cells, reducing production of cytokines that promote inflammation. By doing so, teprotumumab might provide an alternative, nonsurgical treatment option for patients with TED.342 According to FDA-approved labeling, teprotumumab-trbw is given intravenously over 60 to 90 minutes once every 3 weeks over 21 weeks at a dose of 10 mg/kg for the first dose and 20 mg/kg for the remaining treatment course, for a total of 8 infusions.343

HIGH POTENTIAL DISRUPTION REPORT • November 2020 148

Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 3 ongoing trials for this topic. We present these trials in Table 5.16. Table 5.16. Ongoing Clinical Trials

Study name and Patient Study design and outcomes Estimated date National Clinical Trials population and of completion identifier planned enrollment Treatment of Graves’ Adults aged 18 Phase 3, double-blind, placebo-controlled Primary Orbitopathy (also known as years or older study to evaluate the safety and efficacy completion TED) to Reduce Proptosis With (n = 83) with of teprotumumab-trbw infusions to treat February 2019 Teprotumumab Infusions in a moderate to TED Study Randomized, Placebo- severe active TED Primary outcome: Proptosis responder completion Controlled, Clinical Study rate at week 24 January 2021 (OPTIC) Secondary outcomes, all at week 24: NCT03298867 • CAS See preliminary results by • Diplopia responder rate Douglas et al 2020 under • QOL Recently Completed and Ongoing Trials With Available Results

Treatment of Graves’ Adults aged 18 Phase 3, single-arm, open-label extension Primary Orbitopathy to Reduce years or older study to evaluate the safety and efficacy completion Proptosis With (n = 51) with TED of teprotumumab-trbw infusions to treat June 2020 Teprotumumab Infusions in TED Study an Open-Label Clinical Primary outcome: Proptosis responder completion Extension Study (OPTIC-X) rate at week 24 March 2022 NCT03461211 Secondary outcomes, all at week 24: • CAS • Diplopia responder rate • QOL A Study Evaluating Tepezza Adults aged 18 Phase 4, double-blind, placebo-controlled Primary Treatment in Patients With years or older study to assess the safety and efficacy of completion Chronic (Inactive) Thyroid Eye (n = 39) with teprotumumab-trbw to treat chronic September 2021 Disease stable, chronic (inactive) TED Study (inactive) TED NCT04583735 Primary outcome: Change in proptosis at completion April week 24 2022 Secondary outcomes, all at week 24: • Diplopia responder rate • Visual analog scale pain score • QOL Abbreviations: CAS, clinical activity score; QOL, quality of life; TED, thyroid eye disease.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 149

Recently Completed and Ongoing Trials With Available Results Our searches identified one recently completed phase 2 and one recent phase 3 trial with published results.340,342 We summarize these 2 most recent studies with results as written in abstracts of published studies. The following abbreviations are used in this section: AE, adverse event; CAS, clinical activity score; P, probability; QoL, quality of life; TED, thyroid eye disease.

A Phase 3 Randomized Controlled Trial of Teprotumumab in Active TED (OPTIC). NCT03298867. Douglas et al 2020.342

• Patient population/planned enrollment: Patients aged 18 years or older (n = 83) with moderate to severe active TED • Study design: A double-blind, placebo-controlled study to evaluate the safety and efficacy of teprotumumab-trbw infusions to treat TED • Primary outcome: Proptosis responder rate at week 24 • Results presented by study authors: “A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), CAS of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis ( 2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in Graves’ ophthalmopathy-specific QoL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most AEs were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.”

A Phase 2 Randomized Controlled Trial of Teprotumumab in active TED. NCT01868997. Smith et al 2017.340

• Patient population/planned enrollment: Adults aged 18 years or older (n = 88) with active TED • Study design: A double-blind, placebo-controlled study to evaluate the safety and efficacy of teprotumumab-trbw infusions to treat TED • Primary outcome: Proptosis responder rate at week 24 • Results presented by study authors: “In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related AE was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes.” Manufacturers and Regulatory Status Horizon Therapeutics plc (Dublin, Ireland) manufactures teprotumumab-trbw. FDA approved teprotumumab-trbw, under the trade name Tepezza, for treating active TED on January 21, 2020, under the agency’s priority review program.344,345 Teprotumumab-trbw is the first medication with FDA approval for treating TED. The agency previously granted teprotumumab-trbw Orphan Drug, Breakthrough Therapy, and Fast Track designations for treating active TED.345,346 Cost Information With an initial list price of $14 900 per 500-mg vial, the cost of a full course of teprotumumab treatment over 6 months is expected to exceed $200 000.347 According to ECRI’s PriceGuide

HIGH POTENTIAL DISRUPTION REPORT • November 2020 150

database, member hospitals reported a median price paid of about $11 500 for a 500-mg vial of teprotumumab (as of October 14, 2020).348 Key Stakeholder Perspectives From July 22, 2020, to August 20, 2020, nine stakeholders, reflecting clinical, health systems, nursing, and research perspectives, provided comments and ratings on teprotumumab-trbw to treat TED. The list below provides a summary of key stakeholder perspectives. • Teprotumumab-trbw could disrupt the health care delivery system while improving patient outcomes by reducing the need for eye surgery and recovery time for patients with this condition. • With an estimated price for a 6-month treatment regimen that could top $200 000, teprotumumab-trbw has high potential to disrupt treatment costs, which are likely to shift away from surgical centers to infusion centers. • Teprotumumab-trbw might increase disparities for poor, uninsured, and underinsured patients because of its high upfront costs. Prior-authorization requirements could also create some barriers for well-insured patients. • Patients eligible for this treatment might face access issues due to the logistics of receiving intravenous infusions every 3 weeks for a period of 21 weeks. • Longer-term studies are needed to evaluate whether the improvement lasts longer than the temporary relief seen with other available medical treatments for TED.

Voxelotor (Oxbryta) to Treat Sickle Cell Disease Highlights • Voxelotor is an oral drug intended to treat the underlying sickle cell disease (SCD) process by reducing or preventing the clumping of misshapen red blood cells (RBCs). • FDA approved voxelotor, under the trade name Oxbryta, in November 2019 for use in treating SCD in children aged 12 years or older and adults. In June 2020, the developer announced plans to seek expanded FDA approval to treat children aged 4 to 11 years. • The drug has an estimated annual retail price between $123 000 and $131 000. • Stakeholders commenting on this topic thought that voxelotor could change how physicians treat SCD, by altering the disease process rather than managing symptoms. • Stakeholders also thought that disparities could increase if insurance coverage is unavailable and access to voxelotor is limited to specialized SCD referral centers. Patient Population Voxelotor is indicated to treat children aged 12 years or older and adults who have SCD. Intervention SCD is an inherited blood disorder caused by mutations in the hemoglobin subunit beta gene, HBB. This gene encodes a subunit (beta globin) of the oxygen-carrying protein hemoglobin present in RBCs. Mutated beta globin forms abnormal hemoglobin (sickle hemoglobin, or HbS) that polymerizes into rigid protein strands in low-oxygen conditions, leading to changes in the shape (ie, sickling) of RBCs. Sickled RBCs are prone to destruction (ie, hemolysis) and can block blood vessels, leading to hemolytic anemia and extremely painful veno-occlusive crises.349 The National Institutes of Health’s National Heart, Lung, and Blood Institute website offers more information on SCD.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 151

Although some recently developed drugs target the root cause of SCD pathology—the HbS—by delaying its deoxygenation, they do not work in all patients and have side effects that many patients cannot tolerate. Voxelotor (Oxbryta) has potential as a disease-modifying, small-molecule drug. It inhibits sickle hemoglobin polymerization and is intended to prevent or reverse the sickling and destruction of RBCs that characterizes SCD and causes vaso-occlusive crises.350 Voxelotor purportedly binds to variant hemoglobin (ie, HbS) and increases its affinity for oxygen.351 This process prevents polymerization of mutated hemoglobin and the sickling and clumping of RBCs that follow hemoglobin polymerization.351-354 Additionally, voxelotor purportedly reverses sickling of RBCs under conditions of low oxygen (ie, hypoxia).354 Voxelotor tablets are taken by mouth at a recommended dosage of 1500 mg (three 500-mg tablets) once daily.350 Evidence Development Summary Ongoing Trials Our searches of the National Clinical Trials database identified 7 ongoing trials for this topic. We present 3 of these trials in Table 5.17. We excluded a phase 2 safety, pharmacokinetics-pharmacodynamics, and dose-escalation trial (NCT04247594) in adults aged 18 to 60 years; a phase 2 safety and pharmacokinetics study (NCT02850406) in children aged 9 months to 17 years; and two phase 3 long-term safety extension studies assessing treatment-related adverse events and disease complications in children aged 4 to 18 years (NCT04188509) and patients aged 12 years or older (NCT03573882). Table 5.17. Ongoing Clinical Trials

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Voxelotor Sickle Cell Patients aged 12 years or Phase 4, single-arm, open-label study Primary Exercise Study older (n = 10) with severe assessing voxelotor’s effect on completion NCT04581356 sickle cell disease and cardiopulmonary exercise capacity August 2021 anemia Primary outcome: Change in peak Study

oxygen consumption (VO2) completion September 2021

HIGH POTENTIAL DISRUPTION REPORT • November 2020 152

Study name and Patient population and Study design and outcomes Estimated date National Clinical Trials planned enrollment of completion identifier Actigraphy Improvement Patients aged 12 to 55 Phase 4, single-arm, open-label study Primary With Voxelotor (ActIVe) years (n = 50) with sickle assessing voxelotor’s effect on completion Study cell disease and chronic physical activity and sleep quality September 2021 moderate anemia measured by wrist-worn activity NCT04400487 Study monitor completion Primary outcomes (all through 24 November 2021 weeks): • Changes in daily physical activity • Total sleep time • Wake time after sleep onset • Sleep efficiency • Mean nocturnal hemoglobin oxygen saturation percentage • Median number of overnight dips in oxygen saturation >3% per

hour on pulse oximetry (SpO2) • Proportion of patients with >1 g/dL hemoglobin increase Study to Evaluate the Children aged 2 to 14 years Phase 3, randomized, double-blind Primary and Effect of GBT440 on TCD (n = 224) with sickle cell study comparing safety and efficacy of study in Pediatrics With Sickle disease voxelotor with placebo for treating completion Cell Disease (HOPE Kids sickle cell disease March 2026 2) Primary outcome: Change in time- NCT04218084 averaged maximum of the mean velocity arterial cerebral blood flow, as measured by TCD Selected secondary outcomes: Change in TCD flow velocity and proportion of patients with TCD flow velocity reduction

Abbreviation: TCD, transcranial Doppler ultrasound.

Recently Completed and Ongoing Trials With Available Results Our searches identified a single recently completed phase 3 trial with published results.355 We summarize this study with results as written in the abstract of the published study. We excluded subsequent post hoc analyses of this study reporting primarily non–patient oriented outcomes (eg, hemolysis markers) presented at scientific meetings. The following abbreviations are used in this section: CI, confidence interval; HbS, hemoglobin S; SCD, sickle cell disease; VOC, vaso-occlusive crisis.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 153

Study to Evaluate the Effect of Voxelotor Administered Orally to Patients With Sickle Cell Disease (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization [HOPE]). NCT03036813. Vichinsky et al 2019.355

• Patient population/planned enrollment: Children aged 12 years or older and adults (n = 274) who had SCD with at least one VOC episode in the past 12 months • Study design: Phase 3, double-blind, parallel-assignment trial comparing the safety and efficacy of once- daily oral voxelotor (either 900 or 1500 mg) with placebo to treat SCD • Primary outcome: Percentage of patients with a hemoglobin response, defined as an increase of more than 1.0 g/dL from baseline at week 24 • Secondary outcomes: Annualized VOC incidence rate, change in hemoglobin level from baseline to week 24, and hemolysis laboratory markers (indirect bilirubin level, absolute reticulocyte count, percentage of reticulocytes, and lactate dehydrogenase level) • Results presented by study authors: “In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators.” Manufacturers and Regulatory Status Global Blood Therapeutics, Inc (South San Francisco, California), manufactures voxelotor. On November 25, 2019, FDA granted accelerated approval for voxelotor, under the trade name Oxbryta, to treat SCD in children aged 12 years or older and adults.356,357 Continued approval might be contingent on verification and description of clinical benefit in confirmatory trials.350,356 FDA previously granted Breakthrough Therapy, Fast Track, Orphan Drug, and Rare Pediatric Disease designations to voxelotor to treat SCD.358 In June 2020, Global Blood Therapeutics announced plans to apply to FDA for expanded New Drug Application (NDA) approval for voxelotor to treat SCD in children aged 4 to 11 years under an accelerated approval pathway.359 Cost Information Global Blood Therapeutics reportedly priced voxelotor at $125 000 per year per patient before unspecified discounts.360 GoodRx, an aggregator of prescription drug prices at US retail pharmacies, lists prices (as of October 13, 2020) from about $10 300 to $10 900 with a coupon for a typical 30- day supply of voxelotor (90 tablets, 500 mg each; recommended dose 1500 mg once daily). This suggests annual costs of about $123 600 to $130 800 per patient.361 Key Stakeholder Perspectives Between February 11, 2020, and March 4, 2020, nine stakeholders, reflecting caregiver, clinical, health systems, nursing, patient, and research perspectives, provided comments and ratings on voxelotor for treating SCD. The list below summarizes key stakeholder perspectives. • As an effective disease-modifying therapy for SCD rather than a means to manage symptoms, voxelotor has great potential to improve patient outcomes and quality of life.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 154

• Voxelotor could disrupt how clinicians manage SCD. The prospect of increasing hemoglobin levels could ultimately decrease painful crises and prevent long-term organ damage, although additional trials would be needed to track such outcomes. • At an annual retail price of more than $120 000 per year per patient, voxelotor could disrupt health care costs, especially in light of new competing SCD treatments with similarly high prices. • Economic disparities could arise if insurance coverage is unavailable. Further disparities might develop with access to voxelotor, if treatment is limited to SCD referral centers, at least until more clinicians become familiar with voxelotor. • By improving hemoglobin levels and preventing sickling, voxelotor might reduce emergency department visits and hospitalizations. However, available data have not assessed these patient-oriented outcomes.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 155

Chapter 6. Potentially Disruptive Trends

Chapter Summary In addition to the topics included in the previous chapters, the PCORI HCHSS identifies and monitors trends, which are large, high-level disruptions. These trends can occur across or within clinical areas and arise from a combination of factors that, taken together, create a paradigm shift in health care. Identification of these trends goes beyond the 5 priority areas PCORI initially defined as a focus. Because of the different nature and focus of trends compared with the topics summarized in the previous chapters, the trend summaries that follow use a modified format. Each trend summary begins with a brief list highlighting key takeaways for the reader, followed by a description of the nature and importance of the trend, a listing of clinical areas potentially affected, a brief discussion of opportunities and threats (ie, potential positive and negative disruptions) posed by the trend, and a summary of key stakeholder comments. As of September 8, 2020, we were monitoring 24 potentially disruptive trends. These 24 trends will be listed in the December 2020 PCORI Health Care Horizon Scanning System: Horizon Scanning Status Report. We also archived 7 trends in September 2020. A description of those trends will be included in the December 2020 Status Report. All 24 monitored trends were sent for comment to internal ECRI stakeholders and each received at least 5 sets of ratings and comments from these stakeholders between September 19, 2019, and September 18, 2020. From among these 24 trends, 8 were selected that internal ECRI stakeholders indicated have high-moderate to high disruption potential and are likely to cause disruption within the next 3 years in the United States (Table 6.1). Table 6.1. Included Trends

Trend title Artificial intelligence to predict antidepressant treatment responsea Comprehensive genomic profiling in patients who have cancer to identify personalized targeted therapy Direct-to-consumer genetic testing collaborations with pharmaceutical companies to facilitate drug development and treatment Identifying drug synergies with artificial intelligence to optimize regimensa Proteomic profiling to diagnose cancer and guide personalized targeted therapy Psychedelic drugs to treat mental health conditions Smartphone-guided medical examinations and diagnostics for use by patients and caregivers Telehealth to treat mental health conditions a Trend appears for the first time in this edition of the High Potential Disruption Report.

Trend Summaries We present below 8 summaries on trends deemed to have high potential for disruption. Trends are ordered alphabetically by trend title.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 156

Artificial Intelligence to Predict Antidepressant Treatment Response Highlights • Researchers are studying whether artificial intelligence (AI) can identify which antidepressant drugs are most likely to work for individual patients, based on AI-assisted analysis of brain examinations. • Fewer than half of patients with depression have treatment success with their first-prescribed antidepressant drug, leaving many discouraged enough to stop further treatment. • Early research suggests AI-assisted analysis of electroencephalography (EEG) results before treatments are prescribed might help predict whether patients will benefit from certain drugs or other interventions, such as transcranial magnetic stimulation (TMS). • Stakeholders commenting on this trend thought that, if AI assistance could successfully personalize antidepressant therapy, it would represent a major advance over standard care in depression treatment. • Stakeholders also thought AI assistance could increase upfront costs for treating depression because it requires EEG or other brain examinations for analysis to estimate a patient’s likely response to treatment. Description Results from the STAR*D trial suggest that fewer than half of patients who have major depressive disorder achieve remission with use of a first-line antidepressant medication.362,363 This might be because major depressive disorder is a biologically varied mental health condition that has demonstrated distinct neurophysiological subtypes.364 Researchers are investigating whether AI techniques might predict a patient’s response to an antidepressant medication, particularly when applied to EEG results. One study developed an EEG computation model to predict treatment outcomes with sertraline to lay the groundwork for machine learning approaches.365 The researchers found that participants who were unlikely to respond to sertraline treatment were more likely to respond to treatment with TMS.365 Another study, investigating the application of machine learning to EEG to predict response to escitalopram treatment, found a prediction accuracy of 79.2% using baseline EEG data.366 Clinical Area(s) Potentially Disrupted Applying AI to the selection of appropriate drugs or other interventions could disrupt patient management, the clinician learning curve, and treatment models for mental health indications and affect which providers deliver care. Patient outcomes could improve if the most effective interventions are identified sooner. AI-assisted treatment selection could increase initial costs by requiring additional tests, such as EEGs; however, it could decrease long-term treatment costs if multiple ineffective drug regimens and ineffective care leading to hospitalization are avoided and patient outcomes improve. The intervention could also impact understanding of disease and varying responses to treatment among different patients. Opportunities The use of AI assistance to identify antidepressant interventions most likely to work for individual patients could greatly improve patient outcomes. By finding the most effective drugs sooner, patients are less likely to become discouraged with their antidepressant treatment regimen

HIGH POTENTIAL DISRUPTION REPORT • November 2020 157

and less likely to stop their treatment. Adding AI assistance to treatment selection might decrease overall costs by avoiding the use of several ineffective drugs before an effective one is identified. The use of AI assistance in selecting appropriate antidepressants could change the care paradigm by making depression treatment more personalized. Better targeting therapy might also improve providers’ understanding of depression treatment and why different patients respond differently to various antidepressant interventions. Threats Economic disparities might arise if the costs to perform EEG or brain imaging examinations for AI-assisted antidepressant treatment selection prevent some patients from accessing this intervention. Additional disparities in access might develop if machine learning algorithms applied to EEG, brain imaging, or other tests are restricted to research institutions, where most psychiatrists and other behavioral health specialists experienced in this technology are likely to be concentrated. Key Stakeholder Perspectives Between June 17, 2020, and June 24, 2020, nine ECRI stakeholders, reflecting health care generalist, health systems, nursing, and research perspectives, provided comments and ratings on this topic. The list below provides a summary of key stakeholder perspectives. • Societal influences (eg, the current coronavirus pandemic, the highly charged political climate) could trigger depressive conditions, so any innovations that can improve behavioral health care will likely have impact. • Using AI to identify drugs most likely to benefit individual patients could help personalize mental health treatment and represent a major advance compared with standard care. • Applying AI to identify appropriate drug therapy could increase upfront costs because of the need to conduct EEG or other testing for drug selection. • As more studies are completed, the effectiveness of AI-assisted drug selection for mental health indications could increase and benefit more patients overall.

Comprehensive Genomic Profiling in Patients Who Have Cancer to Identify Personalized Targeted Therapy Highlights • Comprehensive genomic profiling (CGP) analyzes DNA or RNA or both isolated from a patient’s tumor or blood sample to detect actionable genomic alterations (AGAs) in a large panel of cancer-associated genes. • CGP is intended to detect AGAs that increase inherited cancer risk or promote aggressive cancer growth that could be treated with FDA-approved targeted therapies or help clinicians refer patients to appropriate clinical trials of targeted therapies. • Stakeholders commenting on this trend thought that implementing CGP into routine cancer care might improve patient health outcomes by helping identify safer, more effective, targeted therapies that could decrease use of chemotherapy and biologic therapies, which might be less safe and effective. • Stakeholders also thought that CGP’s cost might cause disparities for uninsured patients or patients whose insurance does not cover CGP. Even if criteria are met to cover CGP, insurance companies might not cover targeted therapies used to treat off-label indications.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 158

However, some laboratories offering CGP might be willing to absorb costs, to gain access to patients’ data. Description CGP involves sequencing a large panel (ie, thousands) of cancer-associated genes in DNA or RNA or both isolated from a patient’s tumor tissue or blood sample. CGP is intended to detect AGAs known to be therapeutic targets. Clinicians are using CGP (in both germline and somatic testing scenarios) to determine the aggressiveness and inheritable factors of cancers upon initial diagnosis (germline testing) and to select on-label or off-label targeted therapies along the patient’s clinical pathway (somatic testing) to benefit patients with cancers that harbor AGAs.367-369 CGP also is being used to help identify patients who are eligible for clinical trials of investigational therapies for cancers with specific AGAs.367 Clinical Area(s) Potentially Disrupted The technique of using CGP to identify AGAs has potential to disrupt oncology departments by strengthening collaborations between genetic counselors and clinicians. These collaborations would consider results of germline genetic testing as well as the expanding number of AGAs that affect the risk and aggressiveness of cancer. New gene variants that might drive the formation of cancer and resistance to existing therapies are being identified continuously through research. The data provided by CGP can contribute to understanding which gene variants play a role and how they function to drive disease processes, as well as which therapies might target the pathogenic variants identified. Opportunities Having sufficient quantity and quality of a tumor sample to conduct multiple single-gene tests over time has been a long-standing problem in oncology. Next-generation sequencing of hundreds or thousands of genes at once, using a single tissue sample, has made CGP more feasible, as has the development of “liquid biopsy” methods to examine circulating tumor DNA (ctDNA) in the blood. Thus, CGP makes more information available to clinicians for future decisions about therapeutic targets. Compared with single-gene sequencing approaches, CGP also can identify AGAs quicker without the need for additional testing. In addition to improving patient health outcomes, CGP and related management has the potential to be cost-effective.367 In clinical practice, targeted therapy for treating cancers (eg, breast, lung, kidney) is associated with better outcomes and fewer adverse events for many patients compared with systemic chemotherapy.367,370-372 In cancers such as gastric or pancreatic cancer, which lack effective targeted therapies, CGP might help identify gene variants that will be critical to developing effective treatments.368 Threats Clinically, CGP performed on tumors whose cellular makeup varies might not identify all relevant AGAs or offer information that would benefit patients.367 Also, the timing of blood sampling for liquid biopsy can affect the amount of ctDNA in the blood.373 Access to CGP and therapy options targeting identified variants could be limited. This relates to cost. Most FDA-approved targeted therapies are indicated for treating cancers that harbor specific genetic alterations, and third-party payers often reimburse for FDA-approved indications. However, third-party payers are reluctant to pay for genetic testing for variants that lack definitive evidence of being an effective target or that have not been approved by FDA as companion diagnostic tests for a labeled therapy.369 Even if CGP is covered by insurance, disparities might increase because only

HIGH POTENTIAL DISRUPTION REPORT • November 2020 159

patients with insurance might have access to testing, and when test results identify potential targeted therapies, patients without insurance might be unable to afford the out-of-pocket costs of therapy.367 Key Stakeholder Perspectives Between March 18, 2020, and June 11, 2020, eight ECRI stakeholders, reflecting health care generalist, health systems, nursing, and research perspectives, provided comments and ratings on this trend. The list below provides a summary of key stakeholder perspectives. • If incorporated into the clinical workflow, CGP could disrupt health care delivery by helping clinicians select targeted therapies, thus avoiding treatments that may be expensive or less effective. • CGP has potential to improve health outcomes because it helps tailor treatment to the tumor’s genetic makeup. It might also improve a patient’s quality of life by leading to use of targeted therapies, which usually cause fewer adverse events compared with cytotoxic chemotherapy. • CGP might also improve the clinical development of investigational drugs that target a specific AGA. Patients might benefit from investigational drugs when they are enrolled in clinical trials based on CGP results. • Even if insurance companies cover CGP, its high cost might create disparities for uninsured patients and prevent them from receiving this care. Costs might also be higher when clinicians select off-label targeted therapies that insurance companies do not cover for unapproved indications.

Direct-to-Consumer Genetic Testing Collaborations With Pharmaceutical Companies to Facilitate Drug Development and Treatment Highlights • Laboratories offering direct-to-consumer (DTC) genetic testing services are establishing collaborations with drug manufacturers to share patients’ genetic data and volunteered genetic testing questionnaire data. • Large data sets from DTC genetic testing might enhance drug development, enrollment in clinical trials, and, ultimately, patient access to targeted therapies. • The first new experimental treatments created through some of these collaborations have entered early testing. • Stakeholders commenting on this trend thought that DTC genetic testing might improve patient outcomes by speeding up drug development but cautioned that it might increase disparities due to the out-of-pocket cost of testing. That is, this approach to drug development and subsequent clinical trials might tend to favor those with high enough socioeconomic status to afford DTC genetic testing and exclude populations that cannot afford DTC genetic testing but that might benefit from newly discovered therapies. • Stakeholders also expressed concern about inadequately managed collaborations posing substantial threats to patient health data privacy, possibly leading to higher insurance premiums or exploitation of personal health information.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 160

Description Laboratories that offer DTC genetic testing services are using patients’ genetic data, and data patients volunteer on questionnaires to drive drug development and treatment.374 By partnering with pharmaceutical companies, DTC genetic testing companies can provide large data sets that might give insight into new disease targets worth pursuing. The databases from DTC testing might also make it easier for pharmaceutical companies to identify people who have a disease, are asymptomatic, or are carriers for conditions of interest and recruit them for clinical trials in a cost- effective manner.374 For example, genetic testing company 23andMe has established a collaboration with GlaxoSmithKline. Another genetic testing company, Nebula Genomics, is collaborating with EMD Serono to use consumer data to drive the drug-development process.375,376 The number of collaborations is growing. In January 2020, 23andMe reported it granted Almirall, SA (Barcelona, Spain), worldwide rights to develop a 23andMe-designed monoclonal antibody targeting the interleukin (IL)-36 cytokine subfamily for dermatologic indications.377 In July 2020, GlaxoSmithKline announced the start of a phase 1 trial of its first-in-class monoclonal antibody targeting the CD96 immune checkpoint receptor, codeveloped with 23andMe, to treat advanced solid tumor cancers.378,379 Clinical Area(s) Potentially Disrupted Collaborations between companies offering DTC genetic tests and drug developers could shift paradigms for drug development, drug target identification, and clinical trial recruitment and might expedite these processes. Among the clinical areas being affected are medical genetics, neurology, cardiology, oncology, and rare and orphan diseases. Opportunities These collaborations might increase insights into the most promising targets to pursue for drug development, decreasing the cost and time needed to develop new agents. Such collaborations might also help investigators recruit patients and asymptomatic carriers with rare diseases into clinical trials faster and more cost-effectively. This, in turn, might result in additional new targeted therapies that address unmet needs and improve patient outcomes. Threats Poorly managed collaborations between DTC genetic test companies and drug developers might pose significant threats to patient health data privacy. Well-managed collaborations might put competing firms at a competitive disadvantage. Consumers who used DTC genetic test services and signed initial consent forms allowing their data to be used might not have realized how companies would use or profit from their data: DTC companies can profit by selling the data and drug- development companies can profit from the drugs they successfully create based on those data. Key Stakeholder Perspectives Between March 25, 2020, and June 15, 2020, nine ECRI stakeholders, reflecting business and finance, health care generalist, health systems, nursing, and research perspectives, provided comments and ratings on this topic. The list below provides a summary of key stakeholder perspectives. • DTC genetic testing might help individuals identify health conditions early enough to make lifestyle changes, seek medical help, or delay disease progression.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 161

• DTC genetic testing might promote self-diagnosis by individuals who might skip reading the fine print associated with genetic testing, which might lead to misdiagnosis and mistreatment. • Effective collaboration might reduce development costs for drug developers. However, consumers could be unaware that companies are profiting from their genetic data. • DTC genetic testing might increase health care costs for individuals opting to pay for the testing; however, information gained from these tests might reduce long-term costs of treating certain health conditions. Further, this approach to drug development might prioritize testing for people who can afford DTC testing and exclude populations that cannot, creating disparities. • Poor regulatory oversight might allow insurance companies to gain access to consumers’ genetic information and raise their insurance premiums. • Companies trading consumers’ genetic data might raise more privacy risks by creating new targets for hackers.

Identifying Drug Synergies With Artificial Intelligence to Optimize Regimens Highlights • Artificial intelligence (AI) algorithms are being developed to identify potentially beneficial new drug combinations in much less time than that needed for traditional, preclinical drug research and development. • Use of AI assistance to find new drug combinations might particularly benefit rare-disease research, for which the small number of patients who have rare diseases makes it challenging for researchers conducting clinical trials of investigative therapies to recruit enough participants for meaningful results. • Relying too heavily on AI assistance upfront to find new drug combinations might not identify the potential for adverse events that could harm patients. • Stakeholders commenting on this trend thought that AI assistance to identify potential drug synergies could speed drug development and reduce research costs. • Stakeholders also thought that ensuring the safety and efficacy of new drug combinations to improve patient outcomes should take precedence over cutting drug development costs and shortening time to market. Description AI algorithms that analyze gene expression signatures from available databases might help scientists predict which drugs might be combined to better treat diseases with high unmet needs, including SARS-CoV-2,380 cancer,381 and tuberculosis.382 These AI algorithms might promote, inform, and accelerate studies putting existing drugs to new uses or creating new ones for patients who need more options. In one AI-based model, investigators found that predicted synergies for treating tuberculosis could be confirmed in a laboratory test tube or culture dish 88% of the time.382 Researchers purport that AI algorithms based on laboratory studies have successfully identified synergistic regimens confirmed in human studies.382 These findings suggest that AI might save scientists valuable research time in identifying optimized treatment regimens, expediting these options for patients.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 162

Clinical Area(s) Potentially Disrupted Reducing the total research time to identify potential new drug combinations could positively affect both individual patient and population health outcomes. Using AI to find effective drug combinations sooner might disrupt costs. New drug synergies identified with AI help could change treatment models and patient management for diseases of interest. Including AI protocols in the research process could disrupt clinician learning curves and the understanding of certain disease processes. Opportunities Adding AI assistance to find new drug synergies might shorten the time needed to discover the safest and most effective drug combinations. AI’s help might also reduce the costs of drug development by identifying the compounds most likely to succeed before proceeding with costly clinical trials. Further, using AI to find the most effective drug combinations could improve outcomes for patients with hard-to-treat conditions or rare diseases. For many rare diseases or small subgroups of common conditions, researchers have difficulty recruiting enough patients for clinical trials that can produce statistically meaningful results. Threats Overuse of AI to identify the most effective drug combinations, especially to lower research costs, could cause researchers to abandon other effective methods of drug development. Further, AI assistance to find promising new drug combinations might not detect or predict adverse events that could harm patients. Key Stakeholder Perspectives Between May 20, 2020, and May 29, 2020, seven ECRI stakeholders, reflecting clinical engineering, health care generalist, nursing, and research perspectives, provided comments and ratings on this topic. The list below provides a summary of key stakeholder perspectives. • AI assistance might substantially shorten preclinical research time to select the most promising drugs for clinical testing and eventual treatment. • Since the risk of future pandemics is likely to increase, the use of AI to speed preclinical research to identify the most promising agents for clinical testing will become more important. • The driving principle behind wider use of AI to help select and develop drugs should be improving patient outcomes and safety rather than lowering drug-development costs and time to market. • Effectiveness of AI in this setting could increase, provided that high-quality data continue to be available and that only the best-quality data are used to train algorithms for drug selection.

Proteomic Profiling to Diagnose Cancer and Guide Personalized Targeted Therapy Highlights • Proteomic profiling uses test results from tissue or blood samples to identify proteins that are associated with cancer.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 163

• Proteomic profiling is intended to identify protein biomarkers that can help confirm a diagnosis of cancer and help guide selection of targeted therapies or match patients to clinical trials. • Stakeholders thought that the cost of proteomic profiling is likely to be the most disruptive factor. It will be an expensive technology that insurance companies might not reimburse without sufficient evidence of clinical utility. • Stakeholders also thought that, if proteomic profiling is used properly to detect cancer in its early stages and guides selection of safe targeted therapies for patients, it could improve health outcomes and reduce health care costs for managing late-stage disease. Description Proteomic profiling involves the systematic separation, identification, and characterization of proteins present in a patient’s tumor or blood sample.383,384 In patients with suspected cancer, clinicians use proteomic profiling to identify a cancer-associated protein that might confirm the presence and origin of a specific cancer type.384 For these patients, proteomic profiling helps identify overexpressed proteins that are known to be therapeutic targets, such as those caused by chromosomal rearrangements. Clinicians then use this information to select an on-label or off-label targeted therapy that is most likely to benefit a patient with cancer or to help enroll patients in clinical trials of investigational therapies.383,385 Clinical Area(s) Potentially Disrupted Proteomic profiling has potential to disrupt the oncology clinical area by simultaneously confirming a diagnosis of cancer and recommending targeted therapies that are likely to benefit patients.385 In patients suspected of having cancer (eg, clinical features, family history), proteomic profiling might disrupt radiology departments by detecting cancers that have not progressed to a stage that medical imaging can detect.384 Opportunities Proteomic profiling could improve health outcomes by detecting cancer early in patients suspected of having the disease and matching patients with targeted therapies or clinical trials likely to benefit them.384,385 In tumors that are composed of more than one cell type, proteomic analysis might identify several biomarkers that are involved in cancer growth.386 Threats As a novel testing approach, proteomics might add to clinician burden by requiring them to learn about protein signatures for different cancer types and understand which could be drug targets.385,386 Implementing proteomics into the workflow has potential to increase disparities by being available only to patients who are insured or able to pay for treatment out of pocket.386 Key Stakeholder Perspectives Between March 11, 2020, and June 3, 2020, eight ECRI stakeholders, reflecting health care generalist, health systems, nursing, and research perspectives, provided comments and ratings on this trend. The list below provides a summary of key stakeholder perspectives. • If proteomic profiling can identify cancer at its early stages and direct clinicians to targeted therapies for patients, it will improve health outcomes and quality of life. • Adopting proteomic profiling into clinical use could disrupt health care delivery. Because new technologies are regularly brought into clinical practice, proteomic profiling might be moderately disruptive.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 164

• Proteomic profiling is likely to be very expensive; it is unclear whether insurance companies will cover it. Its use can also increase costs if clinicians prescribe off-label targeted therapies for unapproved indications, use proteomic profiling for all circumstances, or are unfamiliar with proper use of proteomic results to guide patient management. • Even with its high cost, if proteomic profiling can inform decisions on targeted therapies that are safe and effective for treating early-stage cancer, it might reduce overall health care costs, especially those associated with treating late-stage disease.

Psychedelic Drugs to Treat Mental Health Conditions Highlights • Psychedelic drugs (psychedelics) are being investigated as a novel drug class to treat a variety of mental health conditions, including depression and anxiety disorders. • Psychedelics purportedly work by altering mood states, changing perception, and facilitating life-altering perspectives. • Various psychedelics are being studied in clinical trials (including late-phase trials) in pursuit of FDA approval. • Stakeholders commenting on this trend thought that psychedelics could improve patient health outcomes, especially for those who have found other treatments to be ineffective, and that the controlled settings prescribed for their use might improve their safety. • Stakeholders also thought they might significantly impact health care delivery due to changes needed in staffing, training, and infrastructure for their clinical use. Description Psychedelic drugs (eg, psilocybin, lysergic acid diethylamide [LSD], N,N-dimethyltryptamine [DMT], 3,4-methylenedioxymethamphetamine [MDMA], ketamine) alter one’s state of consciousness, purportedly by altering certain neurotransmitters in the brain. Their use might provide the patient with altered perception, increased introspection, feelings of closeness with others, and positive mood states. These experiences are often reported as deeply profound and life altering. Although most psychedelics are currently designated as Schedule I drugs in the United States, researchers are investigating their potential to treat a variety of mental and behavioral health disorders that have not responded to conventional treatments. Psilocybin is in clinical trials to investigate treatment for depression, anorexia nervosa, obsessive-compulsive disorder, alcohol use disorder, nicotine dependence, cocaine use disorder, and cancer-related anxiety.387-392 LSD is being explored to treat anxiety associated with life-threatening illness, other anxiety disorders, and depression.393-395 DMT, a drug present in a psychoactive brew called ayahuasca, is being researched to treat depression.396,397 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.398,399 Ketamine, while not traditionally considered a psychedelic drug, has some psychedelic properties and is being explored off-label to treat PTSD.400 A closely related molecule, esketamine (Spravato), is FDA-approved to treat depression.401 In clinical trials, psychedelics are given and patients are monitored under medical supervision.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 165

Clinical Area(s) Potentially Disrupted The use of psychedelics for treating mental health conditions could disrupt treatment models for practitioners of psychiatry and other mental health disciplines. The use of these drugs requires a learning curve; different approaches to prescribing, administering, and monitoring their effects; and changes in the duration and setting of psychotherapy and counseling sessions. Opportunities Psychedelics, as a novel approach to treat mental health conditions, might improve patient health outcomes and quality of life by providing new and quicker mechanisms for emotional and cognitive reframing compared with traditional drug treatments and psychotherapy. Psychedelics might be an important additional treatment option as demand for mental health care grows in the wake of the COVID-19 pandemic.402,403 Psychedelics might reduce the prevalence of treatment-resistant mental health conditions and thus reduce costs associated with longer-term mental health treatment. Special considerations for implementing psychedelic treatment (eg, specialized clinician training, tight drug dispensing, patient monitoring) might significantly change the paradigm and infrastructure of mental health care. The use of psychedelics for mental health conditions might encourage continued research into additional potential therapeutic uses for psychedelics and might enhance understanding of mental health conditions. Threats Psychedelics can cause serious negative mental health effects for some patients (eg, acute psychosis) not commonly observed with current standard-of-care psychiatric medications. Greater availability of these drugs might increase the risk of diversion to people the drug is not intended for, posing population health risks and legal consequences. Disparities in access to care might increase if clinicians hesitate to prescribe psychedelics (for reasons such as stigma), making the treatment option less readily available to those who might benefit. Disparities might also increase for patients with underlying psychiatric illnesses (eg, schizophrenia, bipolar disorder), who are generally advised not to take psychedelics due to increased risk of negative adverse events (eg, acute psychosis, exacerbation of underlying illness). Psychedelic treatment could be costly in the short term to build the necessary infrastructure needed to deliver the treatments (eg, areas for patient monitoring, increased clinician training). Key Stakeholder Perspectives Between June 3, 2020, and June 30, 2020, seven ECRI stakeholders, reflecting clinical engineering, health care generalist, nursing, and research perspectives, provided comments and ratings on this trend. The list below summarizes stakeholder perspectives. • Psychedelics given in a controlled setting have potential to improve mental health conditions for some patients (eg, those who have not had success with currently available treatments), although they are unlikely to become the standard of care. • The controlled settings used for administration and monitoring might improve the safety of psychedelics. • Treating mental health conditions with psychedelics is likely to disrupt health care delivery because of changes in staffing (eg, more clinicians needed for medical supervision), clinician training (ie, therapists need special training for psychedelic-assisted sessions), and infrastructure (eg, providing adequate space for longer therapy sessions and patient monitoring).

HIGH POTENTIAL DISRUPTION REPORT • November 2020 166

• The initial cost of treatment might be high due to necessary infrastructure changes and because mental health treatments such as therapy are costly.

Smartphone-Guided Medical Examinations and Diagnostics for Use by Patients and Caregivers Highlights • Smartphone-based applications (apps; ie, mHealth) are expanding care delivery models by providing remote options for diagnosing conditions and identifying optimal treatments. • These apps are accompanied by handheld examination kits that allow patients to perform guided medical examinations and share results with their providers in real time. • Stakeholders commenting on this trend generally agreed that smartphone-guided medical examinations would improve patient outcomes by providing patients and their caregivers an option to receive medical care in a convenient and timely manner. • Stakeholders also thought that this intervention would reduce health care costs while reducing disparities by enabling health care access to underserved individuals who have internet access and live in rural areas or have difficulty getting to a medical facility. Description An accurate diagnosis, when made in a timely manner, can provide the best insight into treatment options for patients.404 For instance, in August 2019, a case study highlighted a patient for whom acute appendicitis was diagnosed via telehealth, allowing timely surgery to take place.405 Smartphone apps can deliver examinations and diagnostic services to patients in remote areas for multiple age groups. For example, in August 2020, Avram et al reported that smartphones using an optical measurement of blood flow in small blood vessels performed with a fingertip pulse oximeter and coupled with artificial intelligence could detect diabetes.406 As with the diabetes- detecting system, these apps are accompanied by handheld examination kits that allow patients to perform guided medical examinations and share results with their provider for diagnosis and treatment (eg, TytoCare, MoleScope, RetinaScope).407-409 Clinical Area(s) Potentially Disrupted The practice of using physician-guided patient self-examinations using smartphones is likely to disrupt telehealth systems and influence the delivery of care to patients in both rural and urban locations. For patients who travel outside their usual care area and wish to be evaluated and receive treatment recommendations from their home clinicians, this technology could provide that option. Opportunities Smartphone-based medical self-examinations might decrease the overall cost related to both patient care and care delivery by reducing clinician office visits. These technologies might also reduce disparities in terms of access to care for patients in rural areas. Involving patients and caregivers in the diagnostic process might increase patient autonomy and satisfaction. In addition, mHealth app use might reduce burden on the health system, such as sequelae from overlooked symptoms for which patients did not have the time or opportunity to seek in-person evaluation. Threats Because of a lack of comprehensive privacy laws for telehealth systems and the fact that patients’ smartphones might not be secure, personal health information might be at risk of being

HIGH POTENTIAL DISRUPTION REPORT • November 2020 167

hacked, collected, used, or shared for unintended purposes. Additionally, user or device errors could lead to misdiagnosis or mistreatment. The move from in-person to virtual care might also adversely affect patient-clinician relationships. Key Stakeholder Perspectives Between March 23, 2020, and July 2, 2020, eleven ECRI stakeholders, reflecting clinical engineering, health care generalist, health systems, nursing, and research perspectives, provided comments and ratings on this topic. The list below provides a summary of key stakeholder perspectives. • Smartphone-guided medical examinations might improve the decision-making process by allowing patients and caregivers to send reports to their provider in real time and receive medical care in a timely manner. • They might also improve access to medical care, particularly specialists, for patients residing in rural areas and those who are unable to leave their home often. Conversely, they might increase disparities because of costs associated with device implementation and lack of a stable broadband connection. • Due to a patient learning curve associated with the use of smartphones and the lack of quality control for the handheld examination kits, user or device errors could lead to misdiagnosis or mistreatment. Hence, many patients might still prefer an in-person visit with a health care professional. • Smartphone-guided medical examinations might require additional trained staff if several patients opt for using these apps for their ongoing medical needs; however, this could be offset by the individuals cutting back on in-person doctor visits.

Telehealth to Treat Mental Health Conditions Note: The use of telehealth increased significantly after COVID-19 was declared a national emergency in the United States. The commentary and associated stakeholder perspectives below do not specifically address these recent developments. Highlights • Telehealth to assess and treat mental health conditions is the use of digital communication modalities to provide patients with psychiatric and psychological assessment and treatment. • It might be especially helpful in reducing patient access-to-care issues, which are affected by the limited number of health care providers available and geographic, financial, and psychosocial factors. • Telehealth might also help bridge gaps in behavioral health care caused by unexpected obstacles, such as stay-at-home orders during the COVID-19 pandemic. • Stakeholders commenting on this trend thought that using telehealth to assess and treat mental conditions might significantly improve patient outcomes, primarily because of its potential to increase patient access to care and treatment adherence. • Stakeholders noted that, as use of smartphone apps grows across health care, it might be prudent for behavioral health specialty societies to develop guidelines that identify which diagnoses are appropriate for telehealth interactions and which are not.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 168

Description Telehealth, the use of digital communication modalities to provide health care, is being increasingly harnessed to provide patients with psychiatric and psychological assessment and treatment. A main driver for its adoption is the need to address access-to-care issues due to the limited number of health care providers and geographic, financial, and psychosocial factors. Many telehealth platforms are on the market.410,411 Concerns are growing over the increasing shortage of psychiatrists and mental health professionals available to treat mental health conditions both now and in the future. A 2017 Merritt Hawkins report found that 77% of US counties reported a severe shortage of psychiatrists.412 The 2017 America’s Health Rankings data show a wide range of available mental health providers per 100 000 population, from as few as 85 providers per 100 000 population in Alabama to 547 providers per 100 000 population in Massachusetts,413 demonstrating disparities in current accessibility of mental health care. A 2015 Association of American Medical Colleges report of active physicians found that more than 60% of psychiatrists were aged 55 or older,414 touching on a concern that the shortage of providers is growing. Further, telehealth might help overcome unexpected obstacles to behavioral health care, such as stay-at-home orders during the COVID-19 pandemic. In July 2020, Ben-Zeev et al reported that evidence-based, mobile phone texting interventions were feasible and safe, and could play an important role in supporting the continuity of behavioral health care when access to in-person patient-provider meetings was restricted.415 Clinical Area(s) Potentially Disrupted Telehealth to treat mental health conditions might disrupt the treatment of a range of mental health conditions, including anxiety disorders (eg, generalized anxiety disorder, panic disorder, posttraumatic stress disorder), depression (eg, major depression, bipolar depression, postpartum depression), attention-deficit/hyperactivity disorder, schizophrenia and other psychotic disorders, and substance abuse disorders (eg, alcohol use disorder, opioid use disorder). It might disrupt the delivery of both psychiatry and auxiliary psychological services (eg, psychological counseling) to patients. Opportunities Telehealth eliminates barriers to mental health care access, such as regional scarcity of providers and transportation difficulties, which might significantly decrease health disparities and improve patient health, outcomes, and quality of life. Patients who have been unable to afford travel to receive care or cannot seek care logistically might be more inclined to try telehealth than to not seek care at all. Certain mental health conditions make it more difficult for patients to seek mental health care in person (eg, panic disorder triggered by driving, social anxiety in waiting rooms, depression that makes it hard to get dressed to go out). Telehealth might encourage patients with such conditions to seek care sooner and more often if telehealth is more convenient and comfortable. Additionally, some patients hesitate to seek care in person due to stigma. Telehealth offers more provider options to patients; therefore, a patient who does not establish an adequate therapeutic relationship with one provider could seek another more easily through telehealth instead of discontinuing treatment. Threats Telehealth poses a risk to patient confidentiality if communications are not secure. Patients without internet access might be unable to use telehealth. It might pose risks to patient health if medical providers (eg, psychiatrists) are unable to collect crucial information such as vital signs or

HIGH POTENTIAL DISRUPTION REPORT • November 2020 169

weight for medical decision making, as they would be able to in an in-person setting. It might be difficult to treat life-threatening health issues such as active suicidal ideation or alcohol withdrawal from a distance, especially if providers are unfamiliar with local inpatient facilities and mental health resources for referral. Telehealth might impede providers from establishing patient rapport as readily compared with in-person visits, and providers might lack full understanding of a patient’s geographical, cultural, and psychosocial contexts. Key Stakeholder Perspectives Between March 20, 2020, and July 14, 2020, seventeen ECRI stakeholders, reflecting clinical engineering, health care generalist, health systems, nursing, and research perspectives, provided comments and ratings on this topic. The list below provides a summary of key stakeholder perspectives. • Telehealth has significant potential to positively disrupt patient health outcomes for reasons including increased access to care, increased treatment rates, increased patient adherence, more comprehensive evaluation and data collection, more patients feeling comfortable seeking mental health care, and decreased wait times for appointments. • The smartphone modality for telehealth is likely to be convenient for many patients but carries risks for maintaining patient confidentiality. • Telehealth might positively impact patients in rural areas the most, and it could help decrease health disparities. However, some patients in rural or underserved urban communities might lack access to high-speed internet required for video conferencing. • Without in-person visits, providers might miss subtle patient cues (eg, hygiene) difficult to detect during video encounters. • With the prevalence of smartphone-based apps proliferating in health care, behavioral health specialty organizations might want to develop guidelines defining which indications are appropriate for telehealth interactions and which are not.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 170

References 1. What is Alzheimer’s disease? Alzheimer’s 8. FDA accepts Biogen’s aducanumab Biologics Association. Accessed September 5, 2019. License Application for Alzheimer’s disease https://www.alz.org/alzheimers- with priority review. News release. Biogen dementia/what-is-alzheimers Inc; August 7, 2020. Accessed August 7, 2020. https://investors.biogen.com/news- 2. Aducanumab. FBRI LLC. Accessed July 9, releases/news-release-details/fda-accepts- 2020. biogens-aducanumab-biologics-license- https://www.alzforum.org/therapeutics/aducan application umab 9. Biogen and Eisai to discontinue phase 3 3. Arndt JW, Qian F, Smith BA, et al. Structural Engage and Emerge trials of aducanumab in and kinetic basis for the selectivity of Alzheimer’s disease. News release. Biogen aducanumab for aggregated forms of amyloid- Inc; March 21, 2019. Accessed May 13, 2019. ß. Sci Rep. 2018;8(1). doi:10.1038/s41598- http://investors.biogen.com/news- 018-24501-0 releases/news-release-details/biogen-and- 4. Sevigny J, Chiao P, Bussière T, et al. The eisai-discontinue-phase-3-engage-and- antibody aducanumab reduces Aß plaques in emerge-trials Alzheimer’s disease. Nature. 10. Biogen’s investigational Alzheimer’s disease 2016;537(7618):50-56. treatment aducanumab granted FDA Fast doi:10.1038/nature19323 Track designation. News release. Biogen Inc; 5. Biogen completes submission of Biologics September 1, 2016. Accessed July 27, 2020. License Application to FDA for aducanumab https://investors.biogen.com/news- as a treatment for Alzheimer’s disease. News releases/news-release-details/biogens- release. Biogen Inc; July 8, 2020. Accessed investigational-alzheimers-disease-treatment- July 27, 2020. aducanumab https://investors.biogen.com/news- 11. The AMBAR hypothesis. Grifols SA. releases/news-release-details/biogen- Accessed August 23, 2019. completes-submission-biologics-license- https://www.grifols.com/en/the-ambar- application-fda hypothesis 6. A study to evaluate safety and tolerability of 12. Grifols research lines in Alzheimer’s move aducanumab in participants with Alzheimer’s forward with both treatment and prevention. disease who had previously participated in the News release. Grifols SA; September 21, aducanumab studies 221AD103, 221AD301, 2017. Accessed August 23, 2019. 221AD302 and 221AD205. ClinicalTrials.gov https://www.grifols.com/en/view-news/- identifier: NCT04241068. Accessed July 27, /news/grifols-research-lines-in-alzheimer-s- 2020. move-forward-with-both-treatment-and- https://clinicaltrials.gov/ct2/show/NCT042410 prevention 68 13. A Multicenter, Randomized, Controlled Study 7. Biogen plans regulatory filing for to Evaluate the Efficacy and Safety of Short- aducanumab in Alzheimer’s disease based on Term Plasma Exchange Followed by Long- new analysis of larger dataset from phase 3 Term Plasmapheresis With Infusion of Human studies. News release. Biogen Inc; October Albumin Combined With Intravenous 22, 2019. Accessed July 27, 2020. Immunoglobulin in Patients With Mild- https://investors.biogen.com/news- Moderate Alzheimer’s Disease [Protocol releases/news-release-details/biogen-plans- IG1002, Version 5.0, Including Appendices]. regulatory-filing-aducanumab-alzheimers- Grifols SA; 2018:381. disease

HIGH POTENTIAL DISRUPTION REPORT • November 2020 171

14. Boada M, López OL, Olazarán J, et al. A 25. Simsek M, Tekin SB, Bilici M. randomized, controlled clinical trial of plasma Immunological agents used in cancer exchange with albumin replacement for treatment. Eurasian J Med. 2019;51(1):90-94. Alzheimer’s disease: primary results of the doi:10.5152/eurasianjmed.2018.18194 AMBAR study. Alzheimers Dement. 26. Lombardi A, Mondelli MU. Review article: 2020;16(10):1412-1425. immune checkpoint inhibitors and the liver, doi:10.1002/alz.12137 from therapeutic efficacy to side effects. 15. A study to evaluate albumin and Aliment Pharmacol Ther. 2019;50(8):872- immunoglobulin in Alzheimer’s disease 884. doi:10.1111/apt.15449 (AMBAR). ClinicalTrials.gov identifier: 27. Pinter M, Peck-Radosavljevic M. Review NCT01561053. Accessed September 5, 2019. article: systemic treatment of hepatocellular https://clinicaltrials.gov/ct2/show/NCT015610 carcinoma. Aliment Pharmacol Ther. 53 2018;48(6):598-609. doi:10.1111/apt.14913 16. FDA approves Grifols Biological’s albutein. 28. Finn RS, Qin S, Ikeda M, et al. Atezolizumab World History Project, McHaBu. Accessed plus bevacizumab in unresectable August 23, 2019. hepatocellular carcinoma. N Engl J Med. https://worldhistoryproject.org/1978/fda- 2020;382(20):1894-1905. approves-grifols-biologicals-albutein doi:10.1056/NEJMoa1915745 17. Flebogamma 5% DIF immune globulin 29. Galle PR, Finn RS, Qin S, et al. Patient- intravenous (human) for intravenous reported outcomes (PROs) from the phase III administration, 5% liquid preparation. IMbrave150 trial of atezolizumab (atezo) + Package insert. Grifols SA; 2017. bevacizumab (bev) vs sorafenib (sor) as first- 18. Grifols presents its latest Alzheimer’s clinical line treatment, TX for patients (pts) with trial data. News release. Grifols SA; unresectable hepatocellular carcinoma (HCC). December 6, 2019. Accessed May 6, 2020. Abstract presented at: 2020 Gastrointestinal https://www.grifols.com/en/view-news/- Cancers Symposium; January 23-25, 2020; /news/grifols-presents-its-latest-alzheimer-s- San Francisco, CA. Accessed February 21, clinical-trial-data 2020. https://meetinglibrary.asco.org/record/181914/ 19. Albutein 5% 250ML. PriceGuide database abstract online. Accessed August 29, 2019. 30. FDA approves Roche’s Tecentriq in 20. Albutein 25% 50ML. PriceGuide database combination with Avastin for people with the online. Accessed August 29, 2019. most common form of liver cancer. News 21. Flebogamma 5% 10GM. PriceGuide database release. F Hoffman La-Roche Ltd; June 2, online. Accessed August 29, 2019. 2020. Accessed October 6, 2020. https://www.roche.com/media/releases/med- 22. Faivre S, Rimassa L, Finn RS. Molecular cor-2020-06-02.htm therapies for HCC: looking outside the box. J Hepatol. 2020;72(2):342-352. 31. Search Orphan Drug designations and doi:10.1016/j.jhep.2019.09.010 approvals: atezolizumab + bevacizumab for the treatment of hepatocellular carcinoma 23. Tagliamonte M, Mauriello A, Cavalluzzo B, (HCC). US Food and Drug Administration. et al. Tackling hepatocellular carcinoma with Accessed February 24, 2020. individual or combinatorial immunotherapy https://www.accessdata.fda.gov/scripts/opdlist approaches. Cancer Lett. 2020;473:25-32. ing/oopd/detailedIndex.cfm?cfgridkey=61931 doi:10.1016/j.canlet.2019.12.029 7 24. Cheng H, Sun G, Chen H, et al. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res. 2019;9(8):1536- 1545.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 172

32. FDA grants Breakthrough Therapy 41. Kite submits supplemental Biologics License designation for Genentech’s TECENTRIQ in Application to US Food and Drug combination with Avastin as first-line Administration for Yescarta in relapsed or treatment for advanced or metastatic refractory indolent non-Hodgkins lymphomas. hepatocellular carcinoma (HCC). News News release. Kite, a Gilead Company; release. Genentech Inc; July 17, 2018. September 4, 2020. Accessed October 5, Accessed February 24, 2020. 2020. https://www.gene.com/media/press- https://www.kitepharma.com/news/press- releases/14736/2018-07-17/fda-grants- releases/2020/9/kite-submits-supplemental- breakthrough-therapy-designat biologics-license-application-to-us-food-and- drug-administration-for-yescarta-in-relapsed- 33. Tecentriq prices, coupons and patient assistant or-refractory-indolent-nonhodg programs. Drugs.com. Accessed October 5, 2020. https://www.drugs.com/price- 42. Yescarta (axicabtagene ciloleucel) suspension guide/tecentriq for intravenous infusion. Package insert. Kite, a Gilead Company; 2020. 34. Avastin prices, coupons and patient assistance programs. Drugs.com. Accessed October 5, 43. What is the Yescarta and Tecartus REMS 2020. https://www.drugs.com/price- program? Kite, a Gilead Company. Accessed guide/avastin July 30, 2020. https://www.yescartatecartusrems.com/ 35. Non-Hodgkin Lymphoma. Leukemia & Lymphoma Society; 2020:76. 44. What is the cost of Yescarta? Drugs.com. October 29, 2019. Accessed July 30, 2020. 36. Yescarta—manufacturing. Kite, a Gilead https://www.drugs.com/medical-answers/cost- Company. Accessed July 30, 2020. yescarta-3342568/ https://www.yescartahcp.com/car-t- technology 45. Chimeric Antigen Receptor T-Cell Therapy for B-Cell Cancers: Effectiveness and Value. 37. Wall DA, Krueger J. Chimeric antigen Final Evidence Report. Institute for Clinical receptor T cell therapy comes to clinical and Economic Review; 2018. practice. Curr Oncol. 2020;27(suppl 2):S115- S123. doi:10.3747/co.27.5283 46. Staggering prices slow insurers’ coverage of CAR-T cancer therapy. Kaiser Family 38. Neelapu SS. CAR-T efficacy: is conditioning Foundation. July 17, 2018. Accessed July 30, the key? Blood. 2019;133(17):1799-1800. 2020. https://khn.org/news/staggering-prices- doi:10.1182/blood-2019-03-900928 slow-insurers-coverage-of-car-t-cancer- 39. Jacobson CA, Chavez JC, Sehgal AR, et al. therapy/ Interim analysis of ZUMA-5: a phase II study 47. Vansteenkiste JF, Van De Kerkhove C, of axicabtagene ciloleucel (axi-cel) in patients Wauters E, Van Mol P. Capmatinib for the (pts) with relapsed/refractory indolent non- treatment of non-small cell lung cancer. Hodgkin lymphoma (R/R iNHL). J Clin Expert Rev Anticancer Ther. 2019;19(8):659- Oncol. 2020;38(suppl 15):8008. 671. doi:10.1080/14737140.2019.1643239 doi:10.1200/JCO.2020.38.15_suppl.8008 48. Ko B, Halmos B. Capmatinib and gefitinib 40. Yescarta (axicabtagene ciloleucel) combination therapy: will EGFR-mutated demonstrates high rates of response in MET-dysregulated NSCLC “capitulate”? relapsed or refractory indolent non-Hodgkin Transl Lung Cancer Res. 2018;7(suppl lymphoma. News release. Kite, a Gilead 4):S321-325. doi:10.21037/tlcr.2018.12.05 Company; May 29, 2020. Accessed July 30, 2020. 49. Tabrecta (capmatinib) tablets, for oral use. https://www.kitepharma.com/news/press- Package insert. Novartis AG; 2020. releases/2020/5/yescarta-axicabtagene- 50. Wolf J, Seto T, Han JY, et al. Capmatinib in ciloleucel-demonstrates-high-rates-of- MET exon 14-mutated or MET-amplified response-in-relapsed-or-refractory-indolent- non-small-dell lung cancer. N Engl J Med. nonhodgkin-lymphoma 2020;383(10):944-957. doi:10.1056/NEJMoa2002787

HIGH POTENTIAL DISRUPTION REPORT • November 2020 173

51. Novartis announces FDA approval of MET 58. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA inhibitor Tabrecta for metastatic non-small CAR T-cell therapy bb2121 in relapsed or cell lung cancer with METex14. News release. refractory multiple myeloma. N Engl J Med. Novartis AG; May 6, 2020. Accessed October 2019;380(18):1726-1737. 8, 2020. doi:10.1056/NEJMoa1817226 http://www.globenewswire.com/news- 59. Munshi NC, Anderson LD Jr, Shah N, et al. release/2020/05/06/2028748/0/en/Novartis- Idecabtagene vicleucel (ide-cel; bb2121), a announces-FDA-approval-of-MET-inhibitor- BCMA-targeted CAR T-cell therapy, in Tabrecta-for-metastatic-non-small-cell-lung- patients with relapsed and refractory multiple cancer-with-METex14.html myeloma (RRMM): initial KarMMa results. J 52. Novartis starts 2019 with strong sales and Clin Oncol. 2020;38(suppl):abstr 8503. double digit core[1] operating income growth, doi:10.1200/JCO.2020.38.15_suppl.8503 Mayzent launch and Alcon spin-off; profit 60. Bristol Myers Squibb and bluebird bio guidance upgraded. News release. Novartis announce submission of Biologics License AG; April 24, 2019. Accessed December 16, Application (BLA) for anti-BCMA CAR T 2019. https://www.novartis.com/news/media- cell therapy idecabtagene vicleucel (Ide-cel, releases/novartis-starts-2019-strong-sales-and- bb2121) to FDA. News release. bluebird bio; double-digit-core1-operating-income-growth- March 31, 2020. Accessed July 30, 2020. mayzent-launch-and-alcon-spin-profit- http://investor.bluebirdbio.com/news- guidance-upgraded releases/news-release-details/bristol-myers- 53. Novartis shows growing strength in lung squibb-and-bluebird-bio-announce-submission cancer innovation with new capmatinib 61. Bristol Myers Squibb and bluebird bio investigational data and novel canakinumab provide regulatory update on idecabtagene clinical trials. News release. Novartis AG; vicleucel (ide-cel, bb2121) for the treatment June 3, 2019. Accessed December 16, 2019. of patients with multiple myeloma. News https://www.novartis.com/news/media- release. bluebird bio; May 13, 2020. Accessed releases/novartis-shows-growing-strength- July 30, 2020. lung-cancer-innovation-new-capmatinib- http://investor.bluebirdbio.com/news- investigational-data-and-novel-canakinumab- releases/news-release-details/bristol-myers- clinical-trials squibb-and-bluebird-bio-provide-regulatory- 54. Novartis investigational lung cancer therapy update capmatinib (INC280) granted FDA 62. Bristol Myers Squibb and bluebird bio Breakthrough Therapy designation for patients announce submission of Biologics License with MET-mutated advanced non-small cell Application (BLA) to FDA for idecabtagene lung cancer. News release. Novartis AG; vicleucel (Ide-cel, bb2121) for adults with September 6, 2019. Accessed December 16, relapsed and refractory multiple myeloma. 2019. https://www.novartis.com/news/media- News release. bluebird bio; July 29, 2020. releases/novartis-investigational-lung-cancer- Accessed August 3, 2020. therapy-capmatinib-inc280-granted-fda- http://investor.bluebirdbio.com/news- breakthrough-therapy-designation-patients- releases/news-release-details/bristol-myers- met-mutated-advanced-non-small-cell-lung squibb-and-bluebird-bio-announce- 55. Tabrecta pricing info. GoodRx Inc. Accessed submission-0 October 8, 2020. https://www.goodrx.com/tabrecta 56. Szalat R, Munshi NC. Novel agents in multiple myeloma. Cancer J. 2019;25(1):45- 53. doi:10.1097/PPO.0000000000000355 57. Shah N, Chari A, Scott E, Mezzi K, Usmani SZ. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia. 2020;34(4):985-1005. doi:10.1038/s41375- 020-0734-z

HIGH POTENTIAL DISRUPTION REPORT • November 2020 174

63. US Food and Drug Administration accepts for 69. Sarnaik A, Khushalani NI, Chesney JA, et al. priority review Bristol Myers Squibb and Long-term follow up of lifileucel (LN-144) bluebird bio application for anti-BCMA CAR cryopreserved autologous tumor infiltrating T cell therapy idecabtagene vicleucel (ide-cel, lymphocyte therapy in patients with advanced bb2121). News release. Bristol Myers Squibb; melanoma progressed on multiple prior September 22, 2020. Accessed October 6, therapies. J Clin Oncol. 2020;38(suppl 2020. https://news.bms.com/news/corporate- 15):abstr 10006. financial/2020/U.S.-Food-and-Drug- doi:10.1200/JCO.2020.38.15_suppl.10006 Administration-FDA-Accepts-for-Priority- 70. Iovance reports pivotal cohort 4 data for Review-Bristol-Myers-Squibb-and-bluebird- tumor infiltrating lymphocyte (TIL) therapy bio-Application-for-Anti-BCMA-CAR-T- lifileucel from C-144-01 clinical study in Cell-Therapy-Idecabtagene-Vicleucel-Ide-cel- advanced melanoma. News release. Iovance bb2121/default.aspx Biotherapeutics Inc; May 27, 2020. Accessed 64. Celgene corporation and bluebird bio October 6, 2020. https://ir.iovance.com/news- announce bb2121 anti-BCMA CAR-T cell releases/news-release-details/iovance-reports- therapy has been granted Breakthrough pivotal-cohort-4-data-tumor-infiltrating Therapy designation from FDA and prime 71. Iovance Biotherapeutics announces FDA Fast eligibility from EMA for relapsed and Track designation for LN-144 for treatment of refractory multiple myeloma. News release. advanced melanoma. News release. Iovance bluebird bio; November 16, 2017. Accessed Biotherapeutics Inc; August 31, 2017. July 30, 2020. Accessed July 19, 2019. http://investor.bluebirdbio.com/news- http://ir.iovance.com/news-releases/news- releases/news-release-details/celgene- release-details/iovance-biotherapeutics- corporation-and-bluebird-bio-announce- announces-fda-fast-track-designation- bb2121-anti-bcma ln?ID=2297863&c=254507&p=irol- 65. Bristol-Myers Squibb reports fourth quarter newsArticle and full year financial results for 2019. News 72. Iovance Biotherapeutics reports results from release. Bristol-Myers Squibb Company; FDA end of phase 2 meeting and previous February 6, 2020. Accessed July 30, 2020. updates about the company’s clinical program. https://news.bms.com/press- News release. Iovance Biotherapeutics Inc; release/corporatefinancial-news/bristol-myers- October 11, 2018. Accessed July 19, 2019. squibb-reports-fourth-quarter-and-full-year-fi- http://ir.iovance.com/news-releases/news- 1 release-details/iovance-biotherapeutics- 66. Clinical pipeline. Iovance Biotherapeutics Inc. reports-results-fda-end-phase-2-meeting Accessed April 19, 2019. 73. Zanders ED, Svensson F, Bailey DS. Therapy https://www.iovance.com/clinical/pipeline/ for glioblastoma: is it working? Drug Discov 67. Iovance Biotherapeutics Inc. Annual Report Today. 2019;24(5):1193-1201. Pursuant to Section 13 or 15(d) of the doi:10.1016/j.drudis.2019.03.008 Securities Exchange Act of 1934 for the Fiscal 74. MDNA55 our lead program—a meaningful Year Ended December 31, 2018 [Form 10-K]. medicine supporting a broad pipeline. US Securities and Exchange Commission; Medicenna Therapeutics Corp. Accessed June 2019. 24, 2019. 68. Sarnaik A, Kluger HM, Chesney JA, et al. 75. Sampson JH, Achrol A, Aghi MK, et al. Efficacy of single administration of tumor- MDNA55 survival in recurrent glioblastoma infiltrating lymphocytes (TIL) in heavily (rGBM) patients expressing the interleukin-4 pretreated patients with metastatic melanoma receptor (IL4R) as compared to a matched following checkpoint therapy. J Clin Oncol. synthetic control. J Clin Oncol. 2020;38(suppl 2017;35(15):3045. 15):2513. doi:10.1200/JCO.2017.35.15_suppl.3045 doi:10.1200/JCO.2020.38.15_suppl.2513

HIGH POTENTIAL DISRUPTION REPORT • November 2020 175

76. Medicenna announces initiation of phase 2 83. Aadi Bioscience initiates rolling submission clinical trial of MDNA55 for the treatment of of NDA to FDA for nab-sirolimus (ABI-009, recurrent glioblastoma. News release. FYARRO) for the treatment of advanced Medicenna Therapeutics Corp; December 13, malignant PEComa. News release. Aadi 2016. Accessed November 12, 2020. Bioscience Inc; June 25, 2020. Accessed https://ir.medicenna.com/news-releases/news- October 8, 2020. https://aadibio.com/aadi- release-details/medicenna-announces- bioscience-initiates-rolling-submission-of- initiation-phase-2-clinical-trial-mdna55 nda-to-fda-for-nab-sirolimus-abi-009-fyarro- for-the-treatment-of-advanced-malignant- 77. Ben-Ami E, Hornick JL, Wagner AJ. The pecoma/ potential of emerging new therapeutics for the treatment of perivascular epithelioid cell 84. Gamida Cell: company overview. Slide tumors (PEComa). Expert Opin Orphan presentation. Gamida Cell. 2019. Accessed Drugs. 2018;6(9):537-543. June 9, 2020. https://www.gamida- doi:10.1080/21678707.2018.1493376 cell.com/wp-content/uploads/Gamida-Cell- Corporate-Presentation.pdf 78. Haeri A, Osouli M, Bayat F, Alavi S, Dadashzadeh S. Nanomedicine approaches for 85. Ballen KK, Gluckman E, Broxmeyer HE. sirolimus delivery: a review of pharmaceutical Umbilical cord blood transplantation: the first properties and preclinical studies. Artif Cells 25 years and beyond. Blood. 2013;122(4):491- Nanomed Biotechnol. 2018;46(suppl 1):1-14. 498. doi:10.1182/blood-2013-02-453175 doi:10.1080/21691401.2017.1408123 86. Horwitz ME, Wease S, Blackwell B, et al. 79. Aadi Bioscience—the technology. Aadi Phase I/II study of stem-sell transplantation Bioscience Inc. Accessed August 6, 2019. using a single cord blood unit expanded ex https://aadibio.com/our-technology/ vivo with nicotinamide. J Clin Oncol. 2019;37(5):367-374. 80. Dickson M, Ravi V, Riedel RF, et al. Weekly doi:10.1200/JCO.18.00053 nab-sirolimus in patients with advanced malignant perivascular epithelioid cell tumors 87. Cord blood transplantation: state of the (PEComa): results from AMPECT, an open- science. Cord Blood Association. March 1, label phase 2 registration trial with 2020. Accessed June 9, 2020. https://www.cb- independent radiology review. Paper #12. association.org/state-of-the-science 2019 CTOS Annual Meeting; November 13- 88. Omidubicel fact sheet. Gamida Cell. Accessed 16, 2019; Tokyo, Japan. June 9, 2020. http://www.gamida- https://www.ctos.org/Portals/0/PDF/2019%20 cell.com/wp-content/uploads/Omidubicel- CTOS%20Final%20Program.pdf Fact-Sheet.pdf 81. Search Orphan Drug designations and 89. Horwitz ME, Chao NJ, Rizzieri DA, et al. approvals—rapamycin for the treatment of Umbilical cord blood expansion with perivascular epithelioid cell tumors nicotinamide provides long-term multilineage (PEComa). US Food and Drug engraftment. J Clin Invest. 2014;124(7):3121- Administration. Accessed August 6, 2019. 3128. doi:10.1172/JCI74556 https://www.accessdata.fda.gov/scripts/opdlist ing/oopd/detailedIndex.cfm?cfgridkey=61621 90. Gamida Cell announces positive topline data 7 from phase 3 clinical study of omidubicel in patients with high-risk hematologic 82. Aadi Bioscience receives breakthrough malignancies. News release. Gamida Cell; therapy designation for ABI-009 in PEComa May 12, 2020. Accessed June 9, 2020. indication. News release. Aadi Bioscience Inc; https://investors.gamida-cell.com/news- January 3, 2019. Accessed August 6, 2019. events/press-releases/news-release- https://aadibio.com/aadi-bioscience-recieves- details/gamida-cell-announces-positive- fda-orphan-product-development-grant-for- topline-data-phase-3 treatment-of-advanced-pecoma-2/

HIGH POTENTIAL DISRUPTION REPORT • November 2020 176

91. Gamida Cell announces positive topline data 99. FDA approves Onureg (azacitidine tablets) for on secondary endpoints from phase 3 clinical acute myeloid leukemia. US Food and Drug study of omidubicel in patients with Administration. September 1, 2020. Accessed hematologic malignancies. News release. October 6, 2020. Gamida Cell; October 6, 2020. Accessed https://www.fda.gov/drugs/resources- October 9, 2020. https://investors.gamida- information-approved-drugs/fda-approves- cell.com/news-events/press-releases/news- onureg-azacitidine-tablets-acute-myeloid- release-details/gamida-cell-announces- leukemia omidubicel-secondary-endpoints 100. Onureg prices, coupons and patient assistant 92. Gamida Cell receives FDA Breakthrough programs. Drugs.com. Accessed October 6, Therapy designation for NiCord. News 2020. https://www.drugs.com/price- release. Gamida Cell; October 11, 2016. guide/onureg Accessed June 9, 2020. 101. Lee KW, Lee KH, Zang DY, et al. Phase I/II https://investors.gamida-cell.com/news- study of weekly oraxol for the second-line releases/news-release-details/gamida-cell- treatment of patients with metastatic or receives-fda-breakthrough-therapy- recurrent gastric cancer. Oncologist. designation 2015;20(8):896-897. 93. Onureg (azacitidine) tablets, for oral use. doi:10.1634/theoncologist.2015-0202 Package insert. Celgene Corporation; 2020. 102. Abu Samaan TM, Samec M, Liskova A, 94. Molica M, Breccia M, Foa R, Jabbour E, Kubatka P, Büsselberg D. Paclitaxel’s Kadia TM. Maintenance therapy in AML: the mechanistic and clinical effects on breast past, the present and the future. Am J cancer. Biomolecules. 2019;9(12):789. Hematol. 2019;94(11):1254-1265. doi:10.3390/biom9120789 doi:10.1002/ajh.25620 103. Fujiwara Y, Mukai H, Saeki T, et al. A multi- 95. Roboz GJ, Montesinos P, Selleslag D, et al. national, randomised, open-label, parallel, Design of the randomized, phase III, phase III non-inferiority study comparing QUAZAR AML Maintenance trial of CC-486 NK105 and paclitaxel in metastatic or (oral azacitidine) maintenance therapy in recurrent breast cancer patients. Br J Cancer. acute myeloid leukemia. Future Oncol. 2019;120(5):475-480. doi:10.1038/s41416- 2016;12(3):293-302. doi:10.2217/fon.15.326 019-0391-z 96. NCCN Clinical Practice Guidelines in 104. Hertz DL, Kidwell KM, Vangipuram K, et al. Oncology (NCCN Guidelines): Acute Myeloid Paclitaxel plasma concentration after the first leukemia. Version 3.2020. National infusion predicts treatment-limiting peripheral Comprehensive Cancer Network; 2019:139. neuropathy. Clin Cancer Res. 2018;24(15):3602-3610. doi:10.1158/1078- 97. NCI Drug Dictionary: azacitidine. National 0432.CCR-18-0656 Cancer Institute, National Institutes of Health. Accessed May 13, 2020. 105. Rugo HS, Barry WT, Moreno-Aspitia A, et al. https://www.cancer.gov/publications/dictionar Randomized phase III trial of paclitaxel once ies/cancer-drug/def/azacitidine per week compared with nanoparticle albumin-bound nab-paclitaxel once per week 98. Wei AH, Döhner H, Pocock C, et al. The or ixabepilone with bevacizumab as first-line QUAZAR AML-001 maintenance trial: chemotherapy for locally recurrent or results of a phase III international, metastatic breast cancer: CALGB randomized, double-blind, placebo-controlled 40502/NCCTG N063H (Alliance). J Clin study of CC-486 (oral formulation of Oncol. 2015;33(21):2361-2369. azacitidine) in patients with acute myeloid doi:10.1200/JCO.2014.59.5298 leukemia (AML) in first remission. Blood. 2019;134 (suppl 2):LBA-3. 106. Orascovery platform. Athenex Inc. Accessed doi:10.1182/blood-2019-132405 March 2, 2020. https://www.athenex.com/pipeline/orascovery -platform/

HIGH POTENTIAL DISRUPTION REPORT • November 2020 177

107. Umanzor G, Cutler DL, Barrios FJ, et al. GS6- 114. Borad MJ, Davis SL, Lowery MA, et al. Phase 01. Oral paclitaxel with encequidar: the first 2, open-label, multicenter study of the efficacy orally administered paclitaxel shown to be and safety of INCB054828 in patients (pts) superior to IV paclitaxel on confirmed with advanced, metastatic, or surgically response and survival with less neuropathy: a unresectable cholangiocarcinoma (CCA) with phase III clinical study in metastatic breast inadequate response to prior therapy. Abstract cancer. Abstract presented at: San Antonio CT063. Cancer Res. 2017;77(suppl 13). Breast Cancer Symposium (SABCS); doi:10.1158/1538-7445.AM2017-CT063 December 10-14, 2019; San Antonio, TX. 115. FDA grants accelerated approval to Accessed March 2, 2020. pemigatinib for cholangiocarcinoma with an https://www.abstractsonline.com/pp8/#!/7946/ FGFR2 rearrangement or fusion. US Food and presentation/2050 Drug Administration. April 20, 2020. 108. Athenex Inc reports second quarter ended Accessed April 28, 2020. June 30, 2020 financial results and provides https://www.fda.gov/drugs/resources- corporate update. News release. Athenex Inc; information-approved-drugs/fda-grants- August 6, 2020. Accessed October 7, 2020. accelerated-approval-pemigatinib- https://ir.athenex.com/news-releases/news- cholangiocarcinoma-fgfr2-rearrangement-or- release-details/athenex-inc-reports-second- fusion quarter-ended-june-30-2020-financial 116. Incyte reports 2018 fourth quarter and year- 109. Athenex announces FDA acceptance for filing end financial results, provides 2019 financial of US NDA for oral paclitaxel and encequidar guidance and provides updates on key clinical in metastatic breast cancer with priority programs. News release. Incyte Corporation; review. News release. Athenex Inc; February 14, 2019. Accessed November 12, September 1, 2020. Accessed October 7, 2020. https://investor.incyte.com/press- 2020. https://ir.athenex.com/news- releases/press-releases/2019/Incyte-Reports- releases/news-release-details/athenex- 2018-Fourth-Quarter-and-Year-End- announces-fda-acceptance-filing-us-nda-oral- Financial-Results-Provides-2019-Financial- paclitaxel Guidance-and-Provides-Updates-on-Key- Clinical-Programs/default.aspx 110. Pemazyre (pemigatinib) tablets, for oral use. Package insert. Incyte Corporation; 2020. 117. Pemazyre pricing info. GoodRx Inc. Accessed October 8, 2020. 111. Li F, Peiris MN, Donoghue DJ. Functions of https://www.goodrx.com/pemazyre FGFR2 corrupted by translocations in intrahepatic cholangiocarcinoma. Cytokine 118. Hirbe AC, Gutmann DH. Neurofibromatosis Growth Factor Rev. Published online type 1: a multidisciplinary approach to care. December 19, 2019. Lancet Neurol. 2014;13(8):834-843. http://dx.doi.org/10.1016/j.cytogfr.2019.12.00 doi:10.1016/S1474-4422(14)70063-8 5 119. Ahsan S, Ge Y, Tainsky MA. Combinatorial 112. Valle JW. Targeted therapy for therapeutic targeting of BMP2 and MEK-ERK cholangiocarcinoma. Lancet Gastroenterol pathways in NF1-associated malignant Hepatol. 2019;4(9):661-662. peripheral nerve sheath tumors. Oncotarget. doi:10.1016/S2468-1253(19)30200-6 2016;7(35):57171-57185. doi:10.18632/oncotarget.11036 113. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally 120. Gross AM, Wolters PL, Dombi E, et al. advanced or metastatic cholangiocarcinoma: a Selumetinib in children with inoperable multicentre, open-label, phase 2 study. Lancet plexiform neurofibromas. N Engl J Med. Oncol. 2020;21(5):671-684. 2020;382(15):1430-1442. doi:10.1016/S1470-2045(20)30109-1 doi:10.1056/NEJMoa1912735

HIGH POTENTIAL DISRUPTION REPORT • November 2020 178

121. Koselugo (selumetinib) approved in US for 130. Gounder MM, Stacchiotti S, Schöffski P, et al. paediatric patients with neurofibromatosis Efficacy, safety, and immune priming effect type 1 plexiform neurofibromas. News of tazemetostat in patients with epithelioid release. AstraZeneca; April 13, 2020. sarcoma. J Clin Oncol. 2020;38(suppl):abstr Accessed June 4, 2020. 11564. Accessed July 2, 2020. https://www.astrazeneca.com/content/astraz/m https://meetinglibrary.asco.org/record/186752/ edia-centre/press-releases/2020/koselugo- abstract selumetinib-approved-in-us-for-paediatric- 131. FDA approves first treatment option patients-with-neurofibromatosis-type-1- specifically for patients with epithelioid plexiform-neurofibromas.html sarcoma, a rare soft tissue cancer. News 122. Selumetinib granted US Breakthrough release. US Food and Drug Administration; Therapy designation in neurofibromatosis type January 23, 2020. Accessed April 1, 2020. 1. News release. AstraZeneca; April 1, 2019. https://www.fda.gov/news-events/press- Accessed June 4, 2020. announcements/fda-approves-first-treatment- https://www.astrazeneca.com/content/astraz/m option-specifically-patients-epithelioid- edia-centre/press-releases/2019/selumetinib- sarcoma-rare-soft-tissue granted-us-breakthrough-therapy-designation- 132. Tazverik (tazemetostat) tablets, for oral use. in-neurofibromatosis-type-1-01042019.html Package insert. Epizyme Inc; 2020. 123. Full-year and Q4 2019 results. AstraZeneca. 133. Epizyme announces tazemetostat granted February 14, 2020. Accessed June 4, 2020. Orphan Drug designation for the treatment of https://www.astrazeneca.com/content/dam/az/ soft tissue sarcoma. News release. Epizyme PDF/2019/full-year/Full- Inc; June 21, 2017. Accessed November 19, year_and_Q4_2019_results_announcement.pd 2019. https://epizyme.gcs-web.com/news- f releases/news-release-details/epizyme- 124. Koselugo pricing info. GoodRx Inc. Accessed announces-tazemetostat-granted-orphan-drug- October 8, 2020. designation-0 https://www.goodrx.com/koselugo 134. FDA granted accelerated approval to 125. Agaimy A. What is new in epithelioid soft tazemetostat for follicular lymphoma. US tissue tumors? Virchows Arch. Food and Drug Adminsitration. June 18, 2020. 2019;476(1):81-96. doi:10.1007/s00428-019- Accessed October 5, 2020. 02677-8 https://www.fda.gov/drugs/fda-granted- accelerated-approval-tazemetostat-follicular- 126. Kim KH, Roberts CW. Targeting EZH2 in lymphoma cancer. Nat Med. 2016;22(2):128-134. doi:10.1038/nm.4036 135. Tazemetostat (Tazverik) pricing info. GoodRx Inc. Accessed October 5, 2020. 127. Gulati N, Béguelin W, Giulino-Roth L. https://www.goodrx.com/tazemetostat?dosage Enhancer of zeste homolog 2 (EZH2) =200mg&form=tablet&label_override=Tazve inhibitors. Leuk Lymphoma. 2018;59(7):1574- rik&quantity=240 1585. doi:10.1080/10428194.2018.1430795 136. Casulo C, Barr PM. How I treat early- 128. Kurmasheva RT, Sammons M, Favours E, et relapsing follicular lymphoma. Blood. al. Initial testing (stage 1) of tazemetostat 2019;133(14):1540-1547. doi:10.1182/blood- (EPZ-6438), a novel EZH2 inhibitor, by the 2018-08-822148 Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 137. For US healthcare professionals—EZH2. 2017;64(3):10.1002/pbc.26218. Epizyme Inc. Accessed May 12, 2020. doi:10.1002/pbc.26218 https://www.levelupezh2.com/ 129. Gounder M, Schöffski P, Jones RL, et al. 138. Béguelin W, Popovic R, Teater M, et al. Tazemetostat in advanced epithelioid sarcoma EZH2 is required for germinal center with loss of INI1/SMARCB1: an formation and somatic EZH2 mutations international, open-label, phase 2 basket promote lymphoid transformation. Cancer study. Lancet Oncol. Published online Cell. 2013;23(5):677-692. October 6, 2020. doi:10.1016/S1470- doi:10.1016/j.ccr.2013.04.011 2045(20)30451-4

HIGH POTENTIAL DISRUPTION REPORT • November 2020 179

139. Morschhauser F, Tilly H, Chaidos A, et al. 149. Schroder JN, D’Alessandro D, Esmailian F, et Phase 2 multicenter study of tazemetostat, an al. Successful utilization of extended criteria EZH2 inhibitor, in patients with relapsed or donor (ECD) hearts for transplantation— refractory follicular lymphoma. Blood. results of the OCS heart EXPAND trial to 2019;134(suppl 1):123. doi:10.1182/blood- evaluate the effectiveness and safety of the 2019-128096 OCS heart system to preserve and assess ECD hearts for transplantation. J Heart Lung 140. Huet S, Xerri L, Tesson B, et al. EZH2 Transplant. 2019;38(suppl 4):S42. alterations in follicular lymphoma: biological doi:10.1016/j.healun.2019.01.088 and clinical correlations. Blood Cancer J. 2017;7(4):e555. doi:10.1038/bcj.2017.32 150. Rojas SV, Ius F, Schibilsky D, et al. Cardiac transplantation in higher risk patients: is ex 141. Morschhauser F, Tilly H, Chaidos A, et al. vivo heart perfusion a safe preservation Tazemetostat for patients with relapsed or technique? A two center experience. J Heart refractory follicular lymphoma: an open-label, Lung Transplant. 2019;38(suppl 4):S43. single-arm, multicentre, phase 2 trial. Lancet doi:10.1016/j.healun.2019.01.091 Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1 151. Messer S, Page A, Berman M, et al. First to 50: early outcomes following heart 142. Epizyme announces US FDA accelerated transplantation at Royal Papworth Hospital approval of Tazverik (tazemetostat) for from donation after circulatory determined relapsed/refractory follicular lymphoma. death (DCD) donors. J Heart Lung News release. Epizyme Inc; June 18, 2020. Transplant. 2019;38(suppl 4):S43. Accessed July 14, 2020. https://epizyme.gcs- doi:10.1016/j.healun.2019.01.090 web.com/news-releases/news-release- details/epizyme-announces-us-fda- 152. TransMedics announced final results of the accelerated-approval-tazveriktm-0 PROCEED II heart FDA pivotal trial at ISHLT. News release. TransMedics Inc; April 143. Khush KK, Zaroff JG, Nguyen J, Menza R, 14, 2014. Accessed January 28, 2015. Goldstein BA. National decline in donor heart http://www.prnewswire.com/news- utilization with regional variability: 1995- releases/transmedics-announced-final-results- 2010. Am J Transplant. 2015;15(3):642-649. of-the-proceed-ii-heart-fda-pivotal-trial-at- doi:10.1111/ajt.13055 ishlt-255166131.html 144. Trivedi JR, Cheng A, Gallo M, Schumer EM, 153. Randomized study of organ care system Massey HT, Slaughter MS. Predictors of cardiac for preservation of donated hearts for donor heart utilization for transplantation in eventual transplantation (PROCEEDII). United States. Ann Thorac Surg. ClinicalTrials.gov identifier: NCT00855712. 2017;103(6):1900-1906. Accessed July 10, 2019. doi:10.1016/j.athoracsur.2016.08.101 https://www.clinicaltrials.gov/ct2/show/NCT0 145. Blackstone EH, Rajeswaran J, Cruz VB, et al. 0855712 Continuously updated estimation of heart 154. Donors after circulatory death heart trial. transplant waitlist mortality. J Am Coll ClinicalTrials.gov identifier: NCT03831048. Cardiol. 2018;72(6):650-659. Accessed July 10, 2019. doi:10.1016/j.jacc.2018.05.045 https://www.clinicaltrials.gov/ct2/show/NCT0 146. OCS Lung. TransMedics Inc. Accessed July 3831048 11, 2019. https://www.transmedics.com/ocs- 155. TransMedics reports first quarter 2019 hcp-lung/ financial results. News release. TransMedics 147. TransMedics OCS: science that mirrors life. Inc; July 11, 2019. Accessed July 12, 2019. TransMedics Inc. Accessed July 12, 2019. https://investors.transmedics.com/news- https://www.transmedics.com/ocs-hcp/ releases/news-release-details/transmedics- reports-first-quarter-2019-financial-results 148. OCS Heart. TransMedics Inc. Accessed July 10, 2019. https://www.transmedics.com/ocs- hcp-heart/

HIGH POTENTIAL DISRUPTION REPORT • November 2020 180

156. TransMedics announces temporary 163. Vollenweider FX, Gamma A, Liechti M, postponement of OCS Heart FDA Advisory Huber T. Psychological and cardiovascular Panel Committee meeting. News release. effects and short-term sequelae of MDMA TransMedics Inc; September 28, 2020. (“ecstasy”) in MDMA-naïve healthy Accessed October 5, 2020. volunteers. Neuropsychopharmacology. https://investors.transmedics.com/news- 1998;19(4):241-251. doi:10.1016/S0893- releases/news-release-details/transmedics- 133X(98)00013-X announces-temporary-postponement-ocs- 164. Wagner MT, Mithoefer MC, Mithoefer AT, et heart-fda-0 al. Therapeutic effect of increased openness: 157. TransMedics announces temporary investigating mechanism of action in MDMA- postponement of OCS Heart FDA advisory assisted psychotherapy. J Psychopharmacol. panel committee meeting due to COVID-19 2017;31(8):967-974. emergency. News release. TransMedics Inc; doi:10.1177/0269881117711712 March 17, 2020. Accessed March 27, 2020. 165. Nichols DE. Differences between the https://investors.transmedics.com/news- mechanism of action of MDMA, MBDB, and releases/news-release-details/transmedics- the classic hallucinogens. Identification of a announces-temporary-postponement-ocs- new therapeutic class: entactogens. J heart-fda Psychoactive Drugs. 1986;18(4):305-313. 158. TransMedics Inc receives FDA pre-market doi:10.1080/02791072.1986.10472362 approval (PMA) for its OCS lung system for 166. Krieger K. MDMA opens door for PTSD near-physiologic preservation and assessment patients to work through trauma. University of of lungs for transplantation. News release. Conneticut. May 15, 2018. Accessed August TransMedics Inc; April 12, 2018. Accessed 1, 2019. July 11, 2019. https://today.uconn.edu/2018/05/mdma-opens- https://investors.transmedics.com/news- door-ptsd-patients-work-trauma/# releases/news-release-details/transmedics-inc- receives-fda-pre-market-approval-pma-its-ocs 167. Gold LH, Hubner CB, Koob GF. A role for the mesolimbic dopamine system in the 159. TransMedics announces the second FDA psychostimulant actions of MDMA. PMA approval for its OCS Lung System, Psychopharmacology (Berl). 1989;99(1):40- allowing access to a larger pool of donor lungs 47. doi:10.1007/bf00634450 that are currently seldomly utilized for transplantation due to limitations of cold 168. Dumont GJ, Sweep FC, van der Steen R, et al. storage. News release. TransMedics Inc; June Increased oxytocin concentrations and 3, 2019. Accessed March 27, 2020. prosocial feelings in humans after ecstasy https://investors.transmedics.com/news- (3,4-methylenedioxymethamphetamine) releases/news-release-details/transmedics- administration. Soc Neurosci. 2009;4(4):359- announces-second-fda-pma-approval-its-ocs- 366. doi:10.1080/17470910802649470 lung 169. Hysek CM, Domes G, Liechti ME. MDMA 160. TransMedics Inc, OCS Heart. PriceGuide enhances “mind reading” of positive emotions database online. Accessed October 5, 2020. and impairs “mind reading” of negative emotions. Psychopharmacology (Berl). 161. Hysek CM, Schmid Y, Simmler LD, et al. 2012;222(2):293-302. doi:10.1007/s00213- MDMA enhances emotional empathy and 012-2645-9 prosocial behavior. Soc Cogn Affect Neurosci. 2014;9(11):1645-1652. 170. van Wel JH, Kuypers KP, Theunissen EL, doi:10.1093/scan/nst161 Bosker WM, Bakker K, Ramaekers JG. Effects of acute MDMA intoxication on mood 162. de la Torre R, Farré M, Roset PN, et al. and impulsivity: role of the 5-HT2 and 5-HT1 Human pharmacology of MDMA: receptors. PLoS One. 2012;7(7):e40187. pharmacokinetics, metabolism, and doi:10.1371/journal.pone.0040187 disposition. Ther Drug Monit. 2004;26(2):137-144. doi:10.1097/00007691- 200404000-00009

HIGH POTENTIAL DISRUPTION REPORT • November 2020 181

171. Mithoefer MC, Feduccia AA, Jerome L, et al. 179. Koblan K, Hopkins S, Justine K, Hailong C, MDMA-assisted psychotherapy for treatment Goldman R, Loebel A. O12.5. Efficacy and of PTSD: study design and rationale for phase safety of SEP-363856, a novel psychotropic 3 trials based on pooled analysis of six phase agent with a non-D2 mechanism of action, in 2 randomized controlled trials. the treatment of schizophrenia: a 4-week, Psychopharmacology (Berl). randomized, placebo-controlled trial. 2019;236(9):2735-2745. doi:10.1007/s00213- Schizophr Bull. 2019;45(suppl 2):S199. 019-05249-5 doi:10.1093/schbul/sbz021.269 172. Jerome L, Feduccia AA, Wang JB, et al. 180. An extension study of safety and tolerability Long-term follow-up outcomes of MDMA- of SEP-363856 in adult subjects with assisted psychotherapy for treatment of PTSD: schizophrenia. ClinicalTrials.gov identifier: a longitudinal pooled analysis of six phase 2 NCT02970929. Accessed August 1, 2019. trials. Psychopharmacology (Berl). https://clinicaltrials.gov/ct2/show/NCT029709 2020;237(8):2485-2497. doi:10.1007/s00213- 29 020-05548-2 181. Sunovion and PsychoGenics announce 173. Gorman I, Belser AB, Jerome L, et al. positive results from pivotal phase 2 study of Posttraumatic growth after MDMA-assisted novel investigational agent SEP-363856 for psychotherapy for posttraumatic stress the treatment of schizophrenia. News release. disorder. J Trauma Stress. 2020;33(2):161- Sunovion Pharmaceuticals Inc; December 13, 170. doi:10.1002/jts.22479 2018. Accessed August 1, 2019. https://news.sunovion.com/press- 174. MDMA-assisted psychotherapy. releases/press-releases-details/2018/Sunovion- Multidisciplinary Association for Psychedelic and-PsychoGenics-Announce-Positive- Studies (MAPS). Accessed June 3, 2020. Results-from-Pivotal-Phase-2-Study-of- https://maps.org/research/mdma Novel-Investigational-Agent-SEP-363856-for- 175. Participant screening begins in phase 3 the-Treatment-of-Schizophrenia/default.aspx clinical trials of MDMA-assisted 182. A study to evaluate the efficacy and safety of psychotherapy for PTSD. News release. SEP-363856 in acutely psychotic adults with Multidisciplinary Association for Psychedelic schizophrenia. ClinicalTrials.gov identifier: Studies; November 29, 2018. Accessed NCT02969382. Accessed August 1, 2019. August 1, 2019. https://clinicaltrials.gov/ct2/show/NCT029693 https://maps.org/news/media/7466-press- 82 release-participant-screening-begins-in-phase- 3-clinical-trials-of-mdma-assisted- 183. Sunovion announces results from its open- psychotherapy-for-ptsd label extension study of SEP-363856 in schizophrenia. News release. Sunovion 176. Brooks M. Antipsychotic side effects tough to Pharmaceuticals Inc; December 12, 2019. take, patients say. Medscape Medical News. Accessed November 12, 2020. May 28, 2019. Accessed August 1, 2019. https://www.bloomberg.com/press- https://www.medscape.com/viewarticle/91355 releases/2019-12-12/sunovion-announces- 2 results-from-its-open-label-extension-study- 177. Dibonaventura M, Gabriel S, Dupclay L, of-sep-363856-in-schizophrenia Gupta S, Kim E. A patient perspective of the 184. Correll C, Koblan K, Hopkins S, et al. W204. impact of medication side effects on Safety and effectiveness of SEP-363856 in adherence: results of a cross-sectional schizophrenia: results of a 6-month, open- nationwide survey of patients with label extension study. Poster presented at: schizophrenia. BMC Psychiatry. 2012;12:20. ACNP 58th Annual Meeting: Poster Session doi:10.1186/1471-244X-12-20 III; December 8-11, 2019; Orlando, FL. 178. Moritz S, Favrod J, Andreou C, et al. Beyond 185. Koblan KS, Kent J, Hopkins SC, et al. A non- the usual suspects: positive attitudes towards D2-receptor-binding drug for the treatment of positive symptoms is associated with schizophrenia. N Engl J Med. medication noncompliance in psychosis. 2020;382(16):1497-1506. Schizophr Bull. 2013;39(4):917-922. doi:10.1056/NEJMoa1911772 doi:10.1093/schbul/sbs005

HIGH POTENTIAL DISRUPTION REPORT • November 2020 182

186. Sunovion and PsychoGenics announce that 192. Abeona Therapeutics announces positive SEP-363856 has received FDA Breakthrough interim data from the ABO-102 phase 1/2 Therapy designation for the treatment of gene therapy clinical trial in MPS IIIA. News people with schizophrenia. News release. release. Abeona Therapeutics Inc; July 25, Sunovion Pharmaceuticals Inc; May 10, 2019. 2019. Accessed November 15, 2019. Accessed August 1, 2019. https://investors.abeonatherapeutics.com/press https://news.sunovion.com/press- -releases/detail/159/abeona-therapeutics- releases/press-releases-details/2019/Sunovion- announces-positive-interim-data-from and-PsychoGenics-Announce-that-SEP- 193. Geberhiwot T, Moro A, Dardis A, et al. 363856-Has-Received-FDA-Breakthrough- Consensus clinical management guidelines for Therapy-Designation-for-the-Treatment-of- Niemann-Pick disease type C. Orphanet J People-with-Schizophrenia/default.aspx Rare Dis. 2018;13(1):50. doi:10.1186/s13023- 187. Pipeline. Abeona Therapeutics Inc. Accessed 018-0785-7 November 15, 2019. 194. Niemann-Pick: symptoms & causes. Mayo https://www.abeonatherapeutics.com/science# Foundation for Medical Education and pipeline Research. January 25, 2018. Accessed 188. Flanigan KM, Smith NJC, Couce ML, et al. September 12, 2019. Transpher A, a multicenter, single-dose, phase https://www.mayoclinic.org/diseases- 1/2 clinical trial of ABO-102, an intravenous conditions/niemann-pick/symptoms- AAV9-based gene therapy for Sanfilippo causes/syc-20355887 syndrome type A (Mucopolysaccharidosis 195. About arimoclomol. Orphazyme. Accessed IIIA) (4898). Neurology. 2020;94(suppl September 12, 2019. 15):4898. https://www.orphazyme.com/about- 189. Search Orphan Drug designations and arimoclomol-1 approvals: recombinant AAV9 expressing 196. Orphazyme reports positive results from full human sulfoglucosamine sulfohydrolase for data set of phase II/III arimoclomol trial in the treatment of mucopolysaccharidosis type Niemann-Pick disease type C (NPC). News III-A (Sanfilippo Syndrome Type A). US release. Orphazyme A/S; January 30, 2019. Food and Drug Administration. Accessed Accessed September 12, 2019. November 11, 2019. https://www.orphazyme.com/news- https://www.accessdata.fda.gov/scripts/opdlist feed/2019/1/30/orphazyme-reports-positive- ing/oopd/detailedIndex.cfm?cfgridkey=43371 results-from-full-data-set-of-phase-iiiii- 4 arimoclomol-trial-in-niemann-pick-disease- 190. Abeona Therapeutics announces Fast Track type-c-npc designation from FDA for ABO-102 in 197. Orphazyme reports positive arimoclomol data Sanfilippo Syndrome Type A. News release. from open-label phase 2/3 extension in Abeona Therapeutics Inc; October 25, 2016. Niemann-Pick disease type C. News release. Accessed November 15, 2019. Orphazyme A/S; January 3, 2020. Accessed https://investors.abeonatherapeutics.com/press May 13, 2020. -releases/detail/56/abeona-therapeutics- https://www.orphazyme.com/news- announces-fast-track-designation-from feed/2020/1/3/orphazyme-reports-positive- 191. Abeona announces FDA grants RMAT arimoclomol-data-from-open-label-phase-23- designation to ABO-102 gene therapy in MPS extension-in-niemann-pick-disease-type-c IIIA. News release. Abeona Therapeutics Inc; 198. Orphazyme announces US early access April 23, 2018. Accessed November 15, 2019. program for Niemann-Pick disease type C. https://investors.abeonatherapeutics.com/press News release. Orphazyme A/S; January 6, -releases/detail/123/abeona-announces-fda- 2020. Accessed May 13, 2020. grants-rmat-designationto-abo-102 https://www.orphazyme.com/news- feed/2020/1/6/orphazyme-announces-us-early- access-program-for-niemann-pick-disease- type-c

HIGH POTENTIAL DISRUPTION REPORT • November 2020 183

199. Orphazyme completes rolling submission of 205. bluebird bio announces first patient treated in New Drug Application to US FDA for northstar-3 (HGB-212), phase 3 study of arimoclomol for Niemann-Pick disease type LentiGlobin in patients with transfusion- C. News release. Orphazyme A/S; July 20, dependent ß-thalassemia (TDT) and ß0/ß0 2020. Accessed October 15, 2020. genotype. News release. bluebird bio; https://www.orphazyme.com/news- November 16, 2017. Accessed June 4, 2019. feed/2020/7/20/orphazyme-completes-rolling- http://investor.bluebirdbio.com/news- submission-of-new-drug-application-to-us- releases/news-release-details/bluebird-bio- fda-for-arimoclomol-for-niemann-pick- announces-first-patient-treated-northstar-3- disease-type-c hgb-212 200. Orphazyme announces US FDA acceptance 206. bluebird bio receives positive opinion from and priority review of New Drug Application CHMP for Zynteglo (autologous CD34+ cells for arimoclomol for Niemann-Pick disease encoding ßA-T87Q-globin gene) gene therapy type C. News release. Orphazyme A/S; for patients 12 years and older with September 16, 2020. Accessed October 15, transfusion-dependent ß-thalassemia (TDT) 2020. https://www.orphazyme.com/news- who do not have ß0/ß0 genotype. News feed/2020/9/16/orphazyme-announces-us-fda- release. bluebird bio; March 29, 2019. acceptance-and-priority-review-of-new-drug- Accessed June 4, 2019. application-for-arimoclomol-for-niemann- http://investor.bluebirdbio.com/news- pick-disease-type-c releases/news-release-details/bluebird-bio- receives-positive-opinion-chmp-zynteglotm 201. CytRx Corporation highlights significant positive events from its two licensed drugs 207. Porter JB, Thompson AA, Walters MC, et al. Arimoclomol and Aldoxorubicin. News Improvement in erythropoiesis in patients release. CytRx Corporation; December 19, with transfusion-dependent B-thalassemia 2019. Accessed June 29, 2020. following treatment with betibeglogene http://www.cytrx.com/wp- autotemcel (LentiGlobin for B-thalassemia) in content/uploads/2019/12/CYTR-Highlights- the phase 3 HGB-207 study. Abstract TripleNegBreastResultsDec19_FINAL.pdf presented at: EHA25; June 12, 2020; conference online. Accessed October 5, 2020. 202. Arimoclomol for NPC receives Rare Pediatric https://library.ehaweb.org/eha/2020/eha25th/2 Disease designation. News release. 95115/john.b.porter.improvement.in.erythropo Orphazyme A/S; January 19, 2018. Accessed iesis.in.patients.with.html June 29, 2020. https://www.orphazyme.com/news- 208. Yannaki E, Locatelli F, Kulozik AE, et al. feed/2018/3/19/arimoclomol-for-npc-receives- Betibeglogene autotemcel (LentiGlobin) in rare-pediatric-disease-designation patients with transfusion-dependent B- thalassemia and B0/B0, B+IVS-I-110/B+IVS- 203. FDA grants Fast Track designation for the I-110, or B0/B+IVS-I-110 genotypes: updated phase III clinical investigation of arimoclomol results from the HGB-212 study. Abstract as a treatment of Niemann-Pick disease type presented at: EHA25; June 12, 2020; C. News release. Orphazyme; June 27, 2016. conference online. Accessed October 15, Accessed September 12, 2019. 2020. https://www.orphazyme.com/news- https://library.ehaweb.org/eha/2020/eha25th/2 feed/2017/2/21/fda-grants-fast-track- 93980/evangelia.yannaki.betibeglogene.autote designation-for-the-phase-iii-clinical- mcel.28lentiglobin29.in.patients.with.html investigation-of-arimoclomol-as-a-treatment- of-niemann-pick-disease-type-c 204. Search Orphan Drug designations and approvals—arimoclomol citrate for the treatment of Neimann-Pick disease, type C. US Food and Drug Administration. January 13, 2015. Accessed September 23, 2019. https://www.accessdata.fda.gov/scripts/opdlist ing/oopd/detailedIndex.cfm?cfgridkey=45881 4

HIGH POTENTIAL DISRUPTION REPORT • November 2020 184

209. Majority of evaluable patients across 216. Victor R, Marban E, Ascheim D, et al. genotypes achieve transfusion independence [Abstract 21682] Cardiosphere-derived cells and maintain it with near-normal hemoglobin for the treatment of Duchenne levels in phase 3 studies of betibeglogene cardiomyopathy: results of the Halt autotemcel (LentiGlobin for ß-thalassemia) cardiomyopathy progression (HOPE)- gene therapy presented at EHA Congress. Duchenne trial. Circulation. News release. bluebird bio; June 12, 2020. 2017;136(24):e463. Accessed October 15, 2020. doi:10.1161/CIR.0000000000000546 http://investor.bluebirdbio.com/news- 217. Taylor M, Jefferies J, Byrne B, et al. Cardiac releases/news-release-details/majority- and skeletal muscle effects in the randomized evaluable-patients-across-genotypes-achieve- HOPE-Duchenne trial. Neurology. transfusion 2019;92(8):e866-e878. 210. bluebird bio provides assessment of impact of doi:10.1212/WNL.0000000000006950 COVID-19, update on business operations and 218. Capricor announces positive top-line final clinical program development. News release. results from HOPE-2 study in patients with bluebird bio; March 26, 2020. Accessed Duchenne muscular dystrophy treated with March 31, 2020. lead candidate CAP-1002. News release. http://investor.bluebirdbio.com/news- Capricor Therapeutics; May 13, 2020. releases/news-release-details/bluebird-bio- Accessed October 9, 2020. provides-assessment-impact-covid-19-update- https://www.irdirect.net/prviewer/release/id/4 business# 322252 211. FDA grants breakthrough therapy designation 219. Search Orphan Drug designations and to LentiGlobin for treatment of beta- approvals—allogeneic cardiosphere-derived thalassemia major. News release. bluebird bio; cells for the treatment of Duchenne muscular February 2, 2015. Accessed June 4, 2019. dystrophy. US Food and Drug Administration. http://investor.bluebirdbio.com/news- Accessed November 7, 2019. releases/news-release-details/fda-grants- https://www.accessdata.fda.gov/scripts/opdlist breakthrough-therapy-designation-lentiglobin ing/oopd/detailedIndex.cfm?cfgridkey=47461 212. Jensen K. Bluebird proposes installment plan 5 for LentiGlobin gene therapy. BioPharma 220. Capricor receives Rare Pediatric Disease Dive, Industry Dive. January 9, 2019. designation from FDA for CAP-1002 for Accessed April 24, 2019. patients with Duchenne muscular dystrophy. https://www.biopharmadive.com/news/jpm19- News release. Capricor Therapeutics; July 18, bluebird-proposes-installment-plan-for- 2017. Accessed November 7, 2019. lentiglobin-gene-therapy/545646/ http://www.irdirect.net/prviewer/release/id/25 213. Beasley D, Mathias T. Bluebird prices gene 96682 therapy at 1.58 million euros over 5 years. 221. Capricor receives FDA Regenerative Reuters. June 14, 2019. Accessed June 17, Medicine Advanced Therapy (RMAT) 2019. designation for Duchenne muscular dystrophy 214. Nowak KJ, Davies KE. Duchenne muscular therapy. News release. Capricor Therapeutics; dystrophy and dystrophin: pathogenesis and February 5, 2018. Accessed November 7, opportunities for treatment. EMBO Rep. 2019. 2004;5(9):872-876. http://www.irdirect.net/prviewer/release/id/29 doi:10.1038/sj.embor.7400221 27430 215. Duchenne muscular dystrophy. Capricor 222. Form 8-K—Current Report Pursuant to Therapeutics. Accessed November 7, 2019. Section 13 or 15(d) of the Securities Exchange http://capricor.com/news/events/duchenne- Act of 1934: Capricor Therapeutics Inc. muscular-dystrophy-data-presentation/ Capricor Therapeutics Inc; 2018:4.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 185

223. Capricor resumes dosing of enrolled patients 230. Sarepta Therapeutics announces FDA in HOPE-2 clinical trial for Duchenne approval of VYONDYS 53 (golodirsen) muscular dystrophy. News release. Capricor injection for the treatment of Duchenne Therapeutics; February 6, 2019. Accessed muscular dystrophy (DMD) in patients November 7, 2019. amenable to skipping exon 53. News release. http://www.irdirect.net/prviewer/release/id/36 Sarepta Therapeutics; December 12, 2019. 09717 Accessed February 10, 2020. https://investorrelations.sarepta.com/news- 224. Niks EH, Aartsma-Rus A. Exon skipping: a releases/news-release-details/sarepta- first in class strategy for Duchenne muscular therapeutics-announces-fda-approval- dystrophy. Expert Opin Biol Ther. vyondys-53tm 2017;17(2):225-236. doi:10.1080/14712598.2017.1271872 231. Dravet syndrome. Rare Disease Database database online. Accessed April 16, 2019. 225. Bladen CL, Salgado D, Monges S, et al. The https://rarediseases.org/rare-diseases/dravet- TREAT-NMD DMD Global Database: syndrome-spectrum/ analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat. 232. Martin P, Gammaitoni A, Farfel G, Boyd B, 2015;36(4):395-402. doi:10.1002/humu.22758 Galer B. An examination of the mechanism of action of fenfluramine in Dravet syndrome: a 226. Sarepta Therapeutics announces positive look beyond serotonin. Poster presented at: expression results from the casimersen (SRP- Society of Biological Psychiatry’s 72nd 4045) arm of the ESSENCE study. News Annual Scientific Convention and Meeting; release. Sarepta Therapeutics Inc; March 28, May 18-20, 2017; San Diego, CA. Accessed 2019. Accessed June 27, 2019. October 28, 2020. http://investorrelations.sarepta.com/news- https://www.zogenix.com/wp- releases/news-release-details/sarepta- content/uploads/2018/11/51890_SOBP_Poster therapeutics-announces-positive-expression- 2017-05-15v1.pdf results 233. Fintepla (fenfluramine) oral solution, CIV. 227. Sarepta Therapeutics announces second Package insert. Zogenix Inc; 2020. quarter 2019 financial results and recent corporate developments. News release. 234. Lagae L, Sullivan J, Nabbout R, et al. Fintepla Sarepta Therapeutics Inc; August 7, 2019. (Fenfluramine HCl oral solution) provides Accessed October 16, 2019. long-term clinically meaningful reduction in https://investorrelations.sarepta.com/news- seizure frequency: results of an open-label releases/news-release-details/sarepta- extension study. Poster presented at: therapeutics-announces-second-quarter-2019- American Epilepsy Society Annual Meeting; financial November 30-December 4, 2018; New Orleans, LA. Accessed April 22, 2019. 228. Search Orphan Drug designations and https://www.zogenix.com/wp- approvals—casimersen for the treatment of content/uploads/2018/12/3.463_AES-Study- Duchenne muscular dystrophy. US Food and 1503-Effectiveness.pdf Drug Administration. June 4, 2019. Accessed June 20, 2019. 235. Nabbout R, Mistry A, Zuberi S, et al. https://www.accessdata.fda.gov/scripts/opdlist Fenfluramine for treatment-resistant seizures ing/oopd/detailedIndex.cfm?cfgridkey=69001 in patients with Dravet syndrome receiving 9 stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77(3):300- 229. Sarepta Therapeutics announces FDA 308. doi:10.1001/jamaneurol.2019.4113 acceptance of casimersen (SRP-4045) New Drug Application for patients with Duchenne 236. Lagae L, Sullivan J, Knupp K, et al. muscular dystrophy amenable to skipping Fenfluramine hydrochloride for the treatment exon 45. News release. Sarepta Therapeutics of seizures in Dravet syndrome: a randomised, Inc; August 25, 2020. Accessed October 12, double-blind, placebo-controlled trial. Lancet. 2020. 2019;394(10216):2243-2254. https://investorrelations.sarepta.com/news- doi:10.1016/S0140-6736(19)32500-0 releases/news-release-details/sarepta- therapeutics-announces-fda-acceptance- casimersen-srp

HIGH POTENTIAL DISRUPTION REPORT • November 2020 186

237. FDA approves new therapy for Dravet 243. Zogenix resubmits New Drug Application for syndrome. News release. US Food and Drug FINTEPLA for the treatment of Dravet Administration; June 25, 2020. Accessed syndrome to US Food and Drug October 13, 2020. https://www.fda.gov/news- Administration. News release. Zogenix Inc; events/press-announcements/fda-approves- September 26, 2019. Accessed October 28, new-therapy-dravet-syndrome 2019. https://zogenixinc.gcs- web.com/node/11971/pdf 238. Kozauer N (Acting Director, Division of Neurology 2, Office of Neuroscience, Center 244. Search Orphan Drug designations and for Drug Evaluation and Research). NDA approvals: fenfluramine HCI for the treatment approval for Fintepla (fenfluramine) oral of Dravet syndrome. US Food and Drug solution 2.5 mg per mL. June 25, 2020. Administration. December 20, 2013. Accessed February 25, 2020. 239. Zogeniz announces FDA acceptance for filing https://www.accessdata.fda.gov/scripts/opdlist of New Drug Application and priority review ing/oopd/detailedIndex.cfm?cfgridkey=41461 for FINTEPLA for the treatment of Dravat 3 syndrome. News release. Zogenix Inc; November 25, 2019. Accessed February 25, 245. Zogenix announces receipt of FDA 2020. https://zogenixinc.gcs-web.com/news- breakthrough therapy designation for ZX008 releases/news-release-details/zogenix- in Dravet syndrome. News release. Zogenix announces-fda-acceptance-filing-new-drug- Inc; February 6, 2018. Accessed April 19, application-and 2019. https://zogenixinc.gcs-web.com/news- releases/news-release-details/zogenix- 240. Zogenix submits New Drug Application to US announces-receipt-fda-breakthrough-therapy- Food & Drug Administration and marketing designation authorization application to European Medicines Agency for Fintepla for the 246. Zogenix receives Fast Track designation from treatment of Dravet syndrome. News release. FDA for development of ZX008 in Dravet Zogenix Inc; February 6, 2019. Accessed syndrome. News release. Zogenix Inc; April 19, 2019. https://zogenixinc.gcs- January 19, 2016. Accessed April 19, 2019. web.com/news-releases/news-release- https://zogenixinc.gcs-web.com/news- details/zogenix-submits-new-drug- releases/news-release-details/zogenix- application-us-food-drug-administration receives-fast-track-designation-fda- development-zx008 241. Zogenix receives Refusal to File letter from US Food and Drug Administration for 247. Fintepla pricing info. GoodRx Inc. Accessed Fintepla New Drug Application. News October 13, 2020. release. Zogenix Inc; April 8, 2019. Accessed https://www.goodrx.com/fintepla April 19, 2019. 248. Fintepla approval "fills us with a lot of pride," https://www.globenewswire.com/news- Zogenix CEO says in interview. BioNews release/2019/04/08/1799322/0/en/Zogenix- Services LLC. July 14, 2020. Accessed Receives-Refusal-to-File-Letter-from-U-S- October 13, 2020. Food-and-Drug-Administration-for- https://dravetsyndromenews.com/2020/07/14/f FINTEPLA-New-Drug-Application.html intepla-approval-zogenix-ceo-interview/ 242. Zogeniz announces FDA agreement to 249. Encephalopathy due to sulfite oxidase proceed with resubmission of FINTEPLA deficiency. Orphanet database online. NDA. News release. Zogenix Inc; June 27, Accessed March 17, 2020. 2019. Accessed February 25, 2020. https://www.orpha.net/consor/cgi- https://zogenixinc.gcs-web.com/news- bin/OC_Exp.php?lng=EN&Expert=833 releases/news-release-details/zogenix- announces-fda-agreement-proceed- 250. Molybdenum cofactor deficiency. Genetics resubmission-finteplar Home Reference database online. Accessed March 17, 2020. https://ghr.nlm.nih.gov/condition/molybdenu m-cofactor-deficiency

HIGH POTENTIAL DISRUPTION REPORT • November 2020 187

251. Mechler K, Mountford WK, Hoffmann GF, 258. Muntoni F, Frank D, Sardone V, et al. Ries M. Ultra-orphan diseases: a quantitative Golodirsen induces exon skipping leading to analysis of the natural history of molybdenum sarcolemmal dystrophin expression in cofactor deficiency. Genet Med. Duchenne muscular dystrophy patients with 2015;17(12):965-970. mutations amenable to exon 53 skipping. doi:10.1038/gim.2015.12 Neurology. 2018;90(suppl 15):S22.001. 252. Science. Origin Biosciences. Accessed March 259. Frank DE, Schnell FJ, Akana C, et al. 17, 2020. https://www.origintx.com/#science Increased dystrophin production with golodirsen in patients with Duchenne 253. Veldman A, Santamaria-Araujo JA, Sollazzo muscular dystrophy. Neurology. S, et al. Successful treatment of molybdenum 2020;94(21):e2270-e2282. cofactor deficiency type A with cPMP. doi:10.1212/WNL.0000000000009233 Pediatrics. 2010;125(5):e1249-e1254. doi:10.1542/peds.2009-2192 260. FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular 254. Schwahn BC, Van Spronsen FJ, Belaidi AA, dystrophy mutation. News release. US Food et al. Efficacy and safety of cyclic and Drug Administration; December 12, 2019. pyranopterin monophosphate substitution in Accessed February 10, 2020. severe molybdenum cofactor deficiency type https://www.fda.gov/news-events/press- A: a prospective cohort study. Lancet. announcements/fda-grants-accelerated- 2015;386(10007):1955-1963. approval-first-targeted-treatment-rare- doi:10.1016/S0140-6736(15)00124-5 duchenne-muscular-dystrophy-mutation 255. BridgeBio Pharma and affiliate Origin 261. Sarepta Therapeutics receives Complete Biosciences announces FDA acceptance of its Response Letter from the US Food and Drug New Drug Application for fosdenopterin for Administration for golodirsen New Drug the treatment of MoCD Type A. News release. Application. News release. Sarepta BridgeBio Inc; September 29, 2020. Accessed Therapeutics; August 19, 2019. Accessed October 16, 2020. August 20, 2019. https://bridgebio.com/news/bridgebio-pharma- https://investorrelations.sarepta.com/news- and-affiliate-origin-biosciences-announces- releases/news-release-details/sarepta- fda-acceptance-of-its-new-drug-application- therapeutics-receives-complete-response- for-fosdenopterin-for-the-treatment-of-mocd- letter-us-food type-a 262. Summary Review for Vyondys 53. Application 256. Mast J. Eyeing their first approval, BridgeBio Number: 211970Orig1s000. US Food and sends their first drug to the FDA and lands a Drug Administration, Center for Drug speedy review. Endpoints News. September Evaluation and Research; 2019. 29, 2020. Accessed October 16, 2020. https://endpts.com/eyeing-their-first-approval- 263. Other Action Letters for Vyondys 53 bridgebio-sends-their-first-drug-to-the-fda- (Glodirsen) Injection. Application Number: and-lands-a-speedy-review/ 211970Orig1s000. US Food and Drug Administration, Center for Drug Evaluation 257. Sarepta announces FDA acceptance of and Research; 2019. golodirsen (SRP-4053) New Drug Application for patients with Duchenne muscular 264. Search Orphan Drug designations and dystrophy amenable to skipping exon 53. approvals—golodirsen for the treatment of News release. Sarepta Therapeutics; February Duchenne muscular dystrophy (DMD). US 14, 2019. Accessed July 22, 2019. Food and Drug Administration. May 22, 2018. http://investorrelations.sarepta.com/news- Accessed July 12, 2019. releases/news-release-details/sarepta- https://www.accessdata.fda.gov/scripts/opdlist announces-fda-acceptance-golodirsen-srp- ing/oopd/detailedIndex.cfm?cfgridkey=63681 4053-new-drug 8

HIGH POTENTIAL DISRUPTION REPORT • November 2020 188

265. Silverman E. Sarepta to charge $300K for 274. Nucala (mepolizumab) is the first treatment to Duchenne drug. "We tried to be reasonable," show a significant reduction in flares for CEO says. Stat. September 19, 2016. patients with hypereosinophilic syndrome Accessed April 20, 2020. (HES). News release. GlaxoSmithKline plc; https://www.statnews.com/pharmalot/2016/09 November 13, 2019. Accessed April 9, 2020. /19/sarepta-duchenne-drug-prices/ https://www.gsk.com/en-gb/media/press- releases/nucala-mepolizumab-is-the-first- 266. Deflazacort, Eteplirsen, and Golodirsen for treatment-to-show-a-significant-reduction-in- Duchenne Muscular Dystrophy: Effectiveness flares-for-patients-with-hypereosinophilic- and Value. Final Evidence Report. Institute syndrome-hes/ for Clinical and Economic Review; 2019. 275. FDA approves first drug to treat group of rare 267. Agboola F, Lin GA, Fluetsch N, Walton SM, blood disorders in nearly 14 years. News Rind DM, Pearson SD. The effectiveness and release. US Food and Drug Administration; value of deflazacort and exon-skipping September 25, 2020. Accessed October 15, therapies for the management of Duchenne 2020. https://www.fda.gov/news-events/press- muscular dystrophy. J Manag Care Spec announcements/fda-approves-first-drug-treat- Pharm. 2020;26(4):361-366. group-rare-blood-disorders-nearly-14-years doi:10.18553/jmcp.2020.26.4.361 276. Nucala (mepolizumab) pricing info. GoodRx 268. Roufosse F, Klion AD, Weller PF. Inc. Accessed October 15, 2020. Hypereosinophilic syndromes: treatment. https://www.goodrx.com/nucala UpToDate Inc. March 1, 2020. Accessed April 9, 2020. 277. Mitochondrial DNA depletion disorders. https://www.uptodate.com/contents/hypereosi Modis Therapeutics, a Zogenix company. nophilic-syndromes-treatment Accessed March 18, 2020. https://www.modistx.com/disease/ 269. Butt NM, Lambert J, Ali S, et al. Guideline for the investigation and management of 278. Garone C, Viscomi C. Towards a therapy for eosinophilia. Br J Haematol. mitochondrial disease: an update. Biochem 2017;176(4):553-572. doi:10.1111/bjh.14488 Soc Trans. 2018;46(5):1247-1261. doi:10.1042/BST20180134 270. Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the 279. TK2-related mitochondrial DNA depletion hypereosinophilic syndrome with syndrome, myopathic form. Genetics Home mepolizumab. N Engl J Med. Reference database online. Accessed March 2008;358(12):1215-1228. 18, 2020. doi:10.1056/NEJMoa070812 https://ghr.nlm.nih.gov/condition/tk2-related- mitochondrial-dna-depletion-syndrome- 271. Roufosse FE, Kahn JE, Gleich GJ, et al. Long- myopathic-form term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy 280. Development of investigational product Clin Immunol. 2013;131(2):461-467.e461. MT1621. Modis Therapeutics, a Zogenix doi:10.1016/j.jaci.2012.07.055 company. Accessed March 19, 2020. https://www.modistx.com/product/ 272. Dispenza MC, Bochner BS. Diagnosis and novel approaches to the treatment of 281. Therapeutic solutions for rare disease: hypereosinophilic syndromes. Curr Hematol corporate overview. Slide presentation. Malig Rep. 2018;13(3):191-201. Zogenix. 2019. Accessed March 18, 2020. doi:10.1007/s11899-018-0448-8 https://zogenixinc.gcs-web.com/static- files/3b96af41-816c-493e-84c2-b58fe5e53568 273. Nucala (mepolizumab) injection, for subcutaneous use. Package insert. 282. An open-label study of continuation treatment GlaxoSmithKline plc; 2019. with combination pyrimidine nucleosides in patients with TK2 (continuation). ClinicalTrials.gov identifier: NCT03845712. Updated February 5, 2020. Accessed March 19, 2020. https://www.clinicaltrials.gov/ct2/show/NCT0 3845712

HIGH POTENTIAL DISRUPTION REPORT • November 2020 189

283. Zogenix presents positive clinical study 290. Positive topline results demonstrated by results for investigational treatment for TK2 olipudase alfa, first and only investigational deficiency. News release. Zogenix; October 7, therapy in late-stage development for acid 2019. Accessed March 18, 2020. sphingomyelinase deficiency. News release. https://zogenixinc.gcs-web.com/news- Sanofi; January 30, 2020. Accessed March 5, releases/news-release-details/zogenix- 2020. http://www.news.sanofi.us/2020-01-30- presents-positive-clinical-study-results- Positive-topline-results-demonstrated-by- investigational olipudase-alfa-first-and-only-investigational- therapy-in-late-stage-development-for-acid- 284. Quan J, Dominguez-Gonzales C, Paradas C, et sphingomyelinase-deficiency al. A RETROspective study of combination pyrimidine nucleoside therapy in patients with 291. Miranda SR, He X, Simonaro CM, et al. thymidine kinase 2 (TK2) deficiency. Poster Infusion of recombinant human acid presented at: 24th International Annual sphingomyelinase into Niemann-Pick disease Congress of the World Muscle Society mice leads to visceral, but not neurological, (WMS); October 1-5, 2019; Copenhagen, correction of the pathophysiology. FASEB J. Denmark. Accessed March 18, 2020 2000;14(13):1988-1995. doi:10.1096/fj.00- https://www.zogenix.com/wp- 0014com content/uploads/2019/10/WMS-2019- 292. Wasserstein MP, Diaz GA, Lachmann RH, et poster_092519_FINAL-002-1.pdf al. Olipudase alfa for treatment of acid 285. Zogenix provides corporate update and reports sphingomyelinase deficiency (ASMD): safety second quarter 2020 financial results. News and efficacy in adults treated for 30 months. J release. Zogenix Inc; August 5, 2020. Inherit Metab Dis. 2018;41(5):829-838. Accessed October 16, 2020. doi:10.1007/s10545-017-0123-6 https://zogenixinc.gcs-web.com/news- 293. Thurberg BL, Diaz GA, Lachmann RH, et al. releases/news-release-details/zogenix- Long-term efficacy of olipudase alfa in adults provides-corporate-update-and-reports- with acid sphingomyelinase deficiency second-quarter-4 (ASMD): further clearance of hepatic 286. Modis Therapeutics announces that MT1621 sphingomyelin is associated with additional receives Breakthrough Therapy designation improvements in pro- and anti-atherogenic from FDA for the treatment of TK2 lipid profiles after 42 months of treatment. deficiency. News release. Modis Therapeutics, Mol Genet Metab. 2020;S1096- a Zogenix company; February 19, 2019. 7192(20):30149-30149. Accessed March 18, 2020. doi:10.1016/j.ymgme.2020.06.010 https://www.modistx.com/news/pr/021919/ 294. Search Orphan Drug designations and 287. Search Orphan Drug designations and approvals: olipudase alfa for the treatment of approvals: deoxythymidine monophosphate acid sphingomyelinase deficiency (Niemann- and deoxycytidine monophosphate. US Food Pick disease). US Food and Drug and Drug Administration. Accessed October Administration. Accessed March 5, 2020. 16, 2020. https://www.accessdata.fda.gov/scripts/opdlist https://www.accessdata.fda.gov/scripts/opdlist ing/oopd/detailedIndex.cfm?cfgridkey=13290 ing/oopd/detailedIndex.cfm?cfgridkey=53271 0 6 295. FDA grants Breakthrough Therapy 288. Acid sphingomyelinase deficiency. Rare designation for Genzyme’s olipudase alfa. Disease Database database online. Accessed News release. Sanofi; June 4, 2015. Accessed March 5, 2020. https://rarediseases.org/rare- March 5, 2020. diseases/acid-sphingomyelinase-deficiency/ https://www.sanofi.com/en/media-room/press- releases/2015/2015-06-04-07-00-00 289. Niemann-Pick disease overview. National Niemann-Pick Disease Foundation Inc. 296. Our pipeline: palovarotene for FOP. Accessed March 5, 2020. Clementia Pharmaceuticals Inc. Accessed https://nnpdf.org/overview/ June 10, 2019.

HIGH POTENTIAL DISRUPTION REPORT • November 2020 190

297. Tis JE. Nonmalignant bone lesions in children 304. Ipsen’s palovarotene clinical program in and adolescents. UpToDate Inc. March 13, fibrodysplasia ossificans progressiva reaches 2019. Accessed June 13, 2019. prespecified interim analysis futility criteria. https://www.uptodate.com/contents/nonmalig News release. Ipsen Group; January 24, 2020. nant-bone-lesions-in-children-and-adolescents Accessed April 13, 2020. https://www.ipsen.com/press-releases/ipsens- 298. Clementia granted Rare Pediatric Disease palovarotene-clinical-program-in- designation by FDA for palovarotene for fibrodysplasia-ossificans-progressiva-reaches- fibrodysplasia ossificans progressiva. News prespecified-interim-analysis-futility-criteria/ release. Clementia Pharmaceuticals Inc; February 11, 2019. Accessed June 10, 2019. 305. Ipsen initiates partial clinical hold for https://www.globenewswire.com/news- palovarotene IND120181 and IND135403 release/2019/02/11/1716439/0/en/Clementia- studies. News release. Ipsen Group; December Granted-Rare-Pediatric-Disease-Designation- 6, 2019. Accessed April 13, 2020. by-FDA-for-Palovarotene-for-Fibrodysplasia- https://www.ipsen.com/press-releases/ipsen- Ossificans-Progressiva.html initiates-partial-clinical-hold-for- palovarotene-ind120181-and-ind135403- 299. Keen R, Jacobs B. Fibrodysplasia ossificans studies progressiva (FOP) an unfamiliar disease that is now important to diagnose. Arch Dis Child. 306. Ipsen provides update on palovarotene clinical 2015;100(suppl 3):A87-A88. programs. News release. Ipsen Group; March doi:10.1136/archdischild-2015-308599.199 26, 2020. Accessed April 13, 2020. https://www.ipsen.com/press-releases/ipsen- 300. Wentworth KL, Masharani U, Hsiao EC. provides-update-on-palovarotene-clinical- Therapeutic advances for blocking heterotopic programs ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 307. Search Orphan Drug designations and 2019;85(6):1180-1187. approvals—palovarotene for the treatment of doi:10.1111/bcp.13823 fibrodysplasia ossificans progressiva. US Food and Drug Administration. July 21, 2014. 301. An efficacy and safety study of palovarotene Accessed June 10, 2019. for the treatment of FOP. ClinicalTrials.gov https://www.accessdata.fda.gov/scripts/opdlist identifier: NCT03312634. Updated October ing/oopd/detailedIndex.cfm?cfgridkey=43871 26, 2020. Accessed June 10, 2019. 4 https://www.clinicaltrials.gov/ct2/show/NCT0 3312634 308. Chien YH, Lee NC, Tseng SH, et al. Efficacy and safety of AAV2 gene therapy in children 302. Clementia reports positive phase 2 part B data with aromatic l-amino acid decarboxylase showing treatment with palovarotene deficiency: an open-label, phase 1/2 trial. significantly reduces new bone growth in Lancet Child Adolesc Health. 2017;1(4):265- patients with FOP. News release. Clementia 273. doi:10.1016/S2352-4642(17)30125-6 Pharmaceuticals Inc; May 23, 2018. Accessed June 12, 2019. 309. Himmelreich N, Montioli R, Bertoldi M, et al. https://www.globenewswire.com/news- Aromatic amino acid decarboxylase release/2018/05/23/1510637/0/en/clementia- deficiency: molecular and metabolic basis and reports-positive-phase-2-part-b-data-showing- therapeutic outlook. Mol Genet Metab. treatment-with-palovarotene-significantly- 2019;127(1):12-22. reduces-new-bone-growth-in-patients-with- doi:10.1016/j.ymgme.2019.03.009 fop.html 310. Lee N, Chien Y, Tseng S, Tai C, Hwu W. 303. Ipsen to present results from MOVE, the first 270—Gene therapy for AADC deficiency global phase III trial in fibrodysplasia results in de novo dopamine production and ossificans progressiva (FOP), at ASBMR supports durable improvement in major motor 2020 annual meeting. News release. Ipsen milestones. Abstract presented at: American Group; August 25, 2020. Accessed October Society of Gene & Cell Therapy 2018; May 14, 2020. 16, 2018; Chicago, IL. Accessed April 29, https://www.ipsen.com/websites/Ipsen_Online 2019. https://plan.core- /wp- apps.com/asgct2018/abstract/a5af09b6-cbcd- content/uploads/2020/08/24181841/Ipsen_Glo 4bd7-897b-daf73dd377e6 bal-media-release_MOVE_EN.pdf

HIGH POTENTIAL DISRUPTION REPORT • November 2020 191

311. Chien Y-H, Lee N-C, Tieng S-H, et al. AGIL- 318. LaMotta L. Enzyvant initiates value-based AADC gene therapy results in sustained pricing talks ahead of filing. BioPharma Dive. improvements in motor and developmental July 11, 2018. Accessed July 8, 2019. milestones through 5 years in children with https://www.biopharmadive.com/news/enzyva AADC deficiency. Ann Neurol. 2019;86(suppl nt-initiates-value-based-pricing-talks-ahead- 23):S136-S137. of-filing/527574/ 312. PTC Therapeutics provides corporate update 319. Markert ML, Boeck A, Hale LP, et al. and highlights pipeline progress at 2020 JP Transplantation of thymus tissue in complete Morgan healthcare conference. News release. DiGeorge syndrome. N Engl J Med. PTC Therapeutics Inc; January 13, 2020. 1999;341(16):1180-1189. Accessed April 3, 2020. doi:10.1056/NEJM199910143411603 http://ir.ptcbio.com/news-releases/news- 320. Markert ML, Alexieff MJ, Li J, et al. Postnatal release-details/ptc-therapeutics-provides- thymus transplantation with corporate-update-and-highlights immunosuppression as treatment for 313. PTC Therapeutics reports first quarter 2020 DiGeorge syndrome. Blood. financial results and provides a corporate 2004;104(8):2574-2581. doi:10.1182/blood- update. News release. PTC Therapeutics; 2003-08-2984 April 30, 2020. Accessed October 13, 2020. 321. Markert ML, Devlin BH, Alexieff MJ, et al. https://ir.ptcbio.com/news-releases/news- Review of 54 patients with complete release-details/ptc-therapeutics-reports-first- DiGeorge anomaly enrolled in protocols for quarter-2020-financial-results thymus transplantation: outcome of 44 314. Agilis Biotherapeutics announces FDA consecutive transplants. Blood. Orphan Drug designation for the treatment of 2007;109(10):4539-4547. doi:10.1182/blood- aromatic l-amino acid decarboxylase 2006-10-048652 deficiency. News release. Agilis 322. Markert ML, Devlin BH, McCarthy EA. Biotherapeutics LLC; June 29, 2016. Thymus transplantation. Clin Immunol. Accessed April 22, 2019. 2010;135(2):236-246. http://www.agilisbio.com/wp- doi:10.1016/j.clim.2010.02.007 content/uploads/2016/06/ODD-Press-Release- 6-29-16-FINAL.pdf 323. Sumitomo Dainippon Pharma completes the formation of the strategic alliance with 315. Agilis Biotherapeutics achieves FDA “Rare Roivant Sciences. News release. Sumitomo Pediatric Disease” designation for AADC Dainippon Pharma Co Ltd; December 28, gene therapy candidate. News release. Agilis 2019. Accessed April 1, 2020. Biotherapeutics LLC; November 17, 2016. https://www.ds- Accessed April 22, 2019. pharma.com/ir/news/2019/20191228.html http://www.agilisbio.com/wp- content/uploads/2016/11/AADC-RPD- 324. Mathias T, Chander V. FDA declines to Designation-Press-Release-Final.pdf approve Enzyvant regenerative therapy on manufacturing concerns. Reuters. December 316. Pediatric congenital athymia. Enzyvant. 5, 2019. Accessed April 1, 2020. Accessed July 1, 2019. https://www.reuters.com/article/us-enzyvant- 317. Enzyvant announces FDA acceptance of fda/fda-declines-to-approve-enzyvant- Biologics License Application (BLA) and regenerative-therapy-on-manufacturing- priority review status for RVT-802, a novel concerns-idUSKBN1Y9212 investigational tissue-based regenerative 325. Q1 FY2020 (April 1 to June 30, 2020) therapy for pediatric congenital athymia. conference call. Slide presentation. Sumitomo News release. Enzyvant; June 5, 2019. Dainippon Pharma Co Ltd. 2020. Accessed Accessed July 1, 2019. October 13, 2020. https://www.ds- https://www.businesswire.com/news/home/20 pharma.com/ir/library/presentation/pdf/eir202 190605005305/en/ 00730.pdf

HIGH POTENTIAL DISRUPTION REPORT • November 2020 192

326. Enzyvant receives FDA Rare Pediatric 334. Preliminary Prospectus Supplement and Disease designation for investigational Prospectus. Rhythm Pharmaceuticals Inc therapy RVT-802. News release. Enzyvant; [Registration No. 333-228323]. Rhythm September 5, 2017. Accessed July 1, 2019. Pharmaceuticals Inc; 2018:74. https://www.prnewswire.com/news- 335. Rhythm Pharmaceuticals announces positive releases/enzyvant-receives-fda-rare-pediatric- topline results from pivotal phase 3 clinical disease-designation-for-investigational- trials evaluating setmelanotide in POMC and therapy-rvt-802- LEPR deficiency obesities. News release. 300513591.html?tc=eml_cleartime Rhythym Pharmaceuticals Inc; August 7, 327. Enzyvant receives FDA Breakthrough 2019. Accessed January 21, 2020. Therapy designation and Regenerative https://ir.rhythmtx.com/news-releases/news- Medicine Advanced Therapy designation for release-details/rhythm-pharmaceuticals- investigational therapy RVT-802. News announces-positive-topline-results release. Enzyvant; April 17, 2017. Accessed 336. Rhythm Pharmaceuticals announces FDA July 1, 2019. acceptance of New Drug Application for https://www.prnewswire.com/news- setmelanotide for the treatment of POMC and releases/enzyvant-receives-fda-breakthrough- LEMR deficiency obesities. News release. therapy-designation-and-regenerative- Rhythm Pharmaceuticals Inc; May 13, 2020. medicine-advanced-therapy-designation-for- Accessed October 15, 2020. investigational-therapy-rvt-802- https://ir.rhythmtx.com/news-releases/news- 300440401.html?tc=eml_cleartime release-details/rhythm-pharmaceuticals- 328. Meeting highlights & insights for pharmacy announces-fda-acceptance-new-drug specialists: an eye on the pipeline: high- 337. Rhythm Pharmaceuticals receives Rare impact drugs in 2019 and 2020. AMCP Nexus Pediatric Disease designation from US Food 2018; December 1, 2018; Orlando, FL. and Drug Administration for setmelanotide for Accessed August 27, 2019. treatment of POMC and LEMR deficiency https://www.jmcp.org/pb- obesities. News release. Rhythm assets/Outserts/2018- Pharmaceuticals Inc; July 1, 2020. Accessed NEXUS_Conference_Highlights- October 15, 2020. 1542664697660.pdf https://ir.rhythmtx.com/news-releases/news- 329. Proopiomelanocortin deficiency. Genetics release-details/rhythm-pharmaceuticals- Home Reference database online. Accessed receives-rare-pediatric-disease February 21, 2020. 338. Thyroid eye disease. Rare Disease Database https://ghr.nlm.nih.gov/condition/proopiomela database online. Accessed May 26, 2020. nocortin-deficiency# https://rarediseases.org/rare-diseases/thyroid- 330. Uncommon obesity—pathology. Rhythm eye-disease/ Pharmaceuticals Inc. Accessed February 21, 339. Your Guide to Thyroid Eye Disease. British 2020. Thyroid Foundation; 2019:4. https://www.uncommonobesity.com/patholog y 340. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated 331. Our pipeline. Rhythm Pharmaceuticals Inc. ophthalmopathy. N Engl J Med. Accessed February 21, 2020. 2017;376(18):1748-1761. https://www.rhythmtx.com/our-pipeline/ doi:10.1056/NEJMoa1614949 332. Kuhnen P, Krude H, Biebermann H. 341. Douglas RS. Teprotumumab, an insulin-like Melanocortin-4 receptor signalling: growth factor-1 receptor antagonist antibody, importance for weight regulation and obesity in the treatment of active thyroid eye disease: treatment. Trends Mol Med. 2019;25(2):136- a focus on proptosis. Eye. 2019;33(2):183- 148. doi:10.1016/j.molmed.2018.12.002 190. doi:10.1038/s41433-018-0321-y 333. Kuhnen P, Clement K, Wiegand S, et al. 342. Douglas RS, Kahaly GJ, Patel A, et al. Proopiomelanocortin deficiency treated with a Teprotumumab for the treatment of active melanocortin-4 receptor agonist. N Engl J thyroid eye disease. N Engl J Med. Med. 2016;375(3):240-246. 2020;382(4):341-352. doi:10.1056/NEJMoa1512693 doi:10.1056/NEJMoa1910434

HIGH POTENTIAL DISRUPTION REPORT • November 2020 193

343. Tepezza (teprotumumab-trbw) for injection, 352. Metcalf B, Chuang C, Dufu K, et al. for intravenous use. Package insert. Horizon Discovery of GBT440, an orally bioavailable Therapeutics plc; 2020. R-state stabilizer of sickle cell hemoglobin. ACS Med Chem Lett. 2017;8(3):321-326. 344. FDA approves first treatment for thyroid eye doi:10.1021/acsmedchemlett.6b00491 disease. News release. US Food and Drug Administration; January 21, 2020. Accessed 353. Estepp JH. Voxelotor (GBT440), a first-in- May 18, 2020. https://www.fda.gov/news- class hemoglobin oxygen-affinity modulator, events/press-announcements/fda-approves- has promising and reassuring preclinical and first-treatment-thyroid-eye-disease clinical data. Am J Hematol. 2018;93(3):326- 329. doi:10.1002/ajh.25042 345. Horizon Therapeutics plc announces the FDA has granted priority review of the 354. Dufu K, Oksenberg D. GBT440 reverses teprotumumab Biologics License Application sickling of sickled red blood cells under (BLA) for the treatment of active thyroid eye hypoxic conditions in vitro. Hematol Rep. disease (TED). News release. Horizon 2018;10(2):7419. doi:10.4081/hr.2018.7419 Therapeutics plc; September 9, 2019. 355. Vichinsky E, Hoppe CC, Ataga KI, et al. A Accessed May 18, 2020. phase 3 randomized trial of voxelotor in sickle https://ir.horizontherapeutics.com/index.php/n cell disease. N Engl J Med. 2019;381(6):509- ews-releases/news-release-details/horizon- 519. doi:10.1056/NEJMoa1903212 therapeutics-plc-announces-fda-has-granted- priority 356. FDA approves novel treatment to target abnormality in sickle cell disease. News 346. Horizon Therapeutics plc submits release. US Food and Drug Administration; teprotumumab Biologics License Application November 25, 2019. Accessed November 26, (BLA) for the treatment of active thyroid eye 2019. https://www.fda.gov/news-events/press- disease (TED). News release. Horizon announcements/fda-approves-novel-treatment- Therapeutics plc; July 10, 2019. Accessed target-abnormality-sickle-cell-disease May 18, 2020. https://ir.horizontherapeutics.com/news- 357. FDA approves Oxbryta (voxelotor), the first releases/news-release-details/horizon- medicine specifically targeting the root cause therapeutics-plc-submits-teprotumumab- of sickle cell disease. News release. Global biologics-license Blood Therapeutics Inc; November 25, 2019. Accessed November 26, 2019. 347. Mukamal R. New drug treats thyroid eye https://ir.gbt.com/news-releases/news-release- disease without surgery. American Academy details/fda-approves-oxbrytatm-voxelotor- of Ophthalmology. February 5, 2020. first-medicine-specifically Accessed May 26, 2020. https://www.aao.org/eye-health/news/tepezza- 358. GBT announces US Food and Drug nonsurgical-treatment-thyroid-eye-disease Administration acceptance of New Drug Application and priority review for voxelotor 348. Teprotumumab-TRBW 500mg SDV. for the treatment of sickle cell disease. News PriceGuide database online. Accessed October release. Global Blood Therapeutics; 14, 2020. September 5, 2019. Accessed September 5, 349. Kapoor S, Little JA, Pecker LH. Advances in 2019. https://ir.gbt.com/news-releases/news- the treatment of sickle cell disease. Mayo Clin release-details/gbt-announces-us-food-and- Proc. 2018;93(12):1810-1824. drug-administration-acceptance-new doi:10.1016/j.mayocp.2018.08.001 359. GBT announces plans to seek expanded 350. Oxbryta (voxelotor) tablets, for oral use. labeling for Oxbryta (voxelotor) to treat Package insert. Global Blood Therapeutics children ages 4 to 11 years with sickle cell Inc; 2019. disease. News release. Global Blood Therapeutics; June 8, 2020. Accessed October 351. NCI Drug Dictionary: voxelotor. National 13, 2020. https://ir.gbt.com/news- Cancer Institute (NCI), National Institutes of releases/news-release-details/gbt-announces- Health. Accessed September 6, 2019. plans-seek-expanded-labeling-oxbrytar- https://www.cancer.gov/publications/dictionar voxelotor ies/cancer-drug/def/793847

HIGH POTENTIAL DISRUPTION REPORT • November 2020 194

360. Feuerstein A. Global Blood secures FDA 371. Zaman A, Bivona TG. Emerging application approval for new pill to treat sickle cell of genomics-guided therapeutics in disease. Stat. November 25, 2019. Accessed personalized lung cancer treatment. Ann November 26, 2019. Transl Med. 2018;6(9):160. https://www.statnews.com/2019/11/25/global- doi:10.21037/atm.2018.05.02 blood-secures-fda-approval-for-new-pill-to- 372. D’Avella C, Abbosh P, Pal SK, Geynisman treat-sickle-cell-disease/ DM. Mutations in renal cell carcinoma. Urol 361. Voxelotor (Oxbryta) pricing info. GoodRx Oncol. 2020;38(10):763-773. Inc. Accessed October 12, 2020. doi:10.1016/j.urolonc.2018.10.027 https://www.goodrx.com/voxelotor 373. Li G, Pavlick D, Chung JH, et al. Genomic 362. Insel TR. Beyond efficacy: the STAR*D trial. profiling of cell-free circulating tumor DNA Am J Psychiatry. 2006;163(1):5-7. in patients with colorectal cancer and its fidelity to the genomics of the tumor biopsy. J 363. Trivedi MH, Fava M, Wisniewski SR, et al. Gastronintestinal Oncol. 2019;10(5):831-840. Medication augmentation after the failure of doi:10.21037/jgo.2019.05.05 SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252. 374. Roland D. How drug companies are using your DNA to make new medicine. Wall Street 364. Drysdale AT, Grosenick L, Downar J, et al. Journal. July 22, 2019. Accessed November Resting-state connectivity biomarkers define 1, 2019. neurophysiological subtypes of depression. https://www.wsj.com/articles/23andme-glaxo- Nat Med. 2017;23(1):28-38. mine-dna-data-in-hunt-for-new-drugs- doi:10.1038/nm.4246 11563879881 365. Wu W, Zhang Y, Jiang J, et al. An 375. You, me and 23andMe: discovering new electroencephalographic signature predicts medicines through genetics. GlaxoSmithKline antidepressant response in major depression. plc. July 25, 2018. Accessed November 1, Nat Biotechnol. 2020;38(4):439-447. 2019. https://www.gsk.com/en-gb/behind-the- doi:10.1038/s41587-019-0397-3 science/innovation/you-me-and-23andme- 366. Zhdanov A, Atluri S, Wong W, et al. Use of discovering-new-medicines-through-genetics/ machine learning for predicting escitalopram 376. A new collaboration and our vision for the treatment outcome from future of genomics. Nebula Genomics. July electroencephalography recordings in adult 11, 2019. Accessed November 1, 2019. patients with depression. JAMA Netw Open. https://blog.nebula.org/emdserono- 2020;3(1):e1918377. collaboration/ doi:10.1001/jamanetworkopen.2019.18377 377. 23andMe signs a strategic agreement with 367. Gong J, Pan K, Fakih M, Pal S, Salgia R. Almirall. News release. 23andMe Inc; January Value-based genomics. Oncotarget. 13, 2020. Accessed October 7, 2020. 2018;9(21):15792-15815. https://mediacenter.23andme.com/press- doi:10.18632/oncotarget.24353 releases/23andme-signs-a-strategic- 368. Matsuoka T, Yashiro M. Biomarkers of agreement-with-almirall/ gastric cancer: current topics and future 378. GlaxoSmithKline second quarter 2020 results perspective. World J Gastroenterol. presentation to analysts. GlaxoSmithKline plc. 2018;24(26):2818-2832. July 29, 2020. Accessed October 7, 2020. doi:10.3748/wjg.v24.i26.2818 https://www.gsk.com/media/6076/q2-2020- 369. Fountzilas E, Tsimberidou AM. Overview of results-transcript.pdf precision oncology trials: challenges and 379. GSK delivers Q2 sales of £7.6 billion -2% opportunities. Expert Rev Clin Pharmacol. AER, -3% CER (pro-forma -10% CER). News 2018;11(8):797-804. release. GlaxoSmithKline plc; July 29, 2020. doi:10.1080/17512433.2018.1504677 Accessed October 7, 2020. 370. Sachdev JC, Sandoval AC, Jahanzeb M. https://www.gsk.com/media/6064/q2-2020- Update on precision medicine in breast results-announcement.pdf cancer. Cancer Treat Res. 2019;178:45-80. doi:10.1007/978-3-030-16391-4_2

HIGH POTENTIAL DISRUPTION REPORT • November 2020 195

380. Xing J, Shankar R, Drelich A, et al. Reversal 390. Effects of psilocybin in major depressive of infected host gene expression identifies disorder. ClinicalTrials.gov identifier: repurposed drug candidates for COVID-19. NCT03181529. Updated December 27, 2019. bioRxiv. Preprint posted online April 9, 2020. Accessed November 11, 2019. doi:10.1101/2020.04.07.030734 https://clinicaltrials.gov/ct2/show/NCT031815 29 381. Madhukar NS, Khade PK, Huang L, et al. A Bayesian machine learning approach for drug 391. Clinical, neurocognitive, and emotional target identification using diverse data types. effects of psilocybin in depressed patients— Nat Commun. 2019;10(1):5221. proof of concept. ClinicalTrials.gov identifier: doi:10.1038/s41467-019-12928-6 NCT03715127. Updated November 4, 2020. Accessed November 11, 2019. 382. Ma S, Jaipalli S, Larkins-Ford J, et al. https://clinicaltrials.gov/ct2/show/record/NCT Transcriptomic signatures predict regulators 03715127 of drug synergy and clinical regimen efficacy against tuberculosis. MBio. 392. The safety and efficacy of psilocybin in 2019;10(6):e02627-e02619. participants with treatment resistant doi:10.1128/mBio.02627-19 depression (P-TRD). ClinicalTrials.gov identifier: NCT03775200. Updated November 383. Zhou L, Li Q, Wang J, Huang C, Nice EC. 9, 2020. Accessed November 11, 2019. Oncoproteomics: Trials and tribulations. https://clinicaltrials.gov/ct2/show/NCT037752 Proteomics Clin Appl. 2016;10(4):516-531. 00 doi:10.1002/prca.201500081 393. Lysergic acid diethylamide (LSD)-assisted 384. Peng L, Cantor DI, Huang C, Wang K, Baker psychotherapy in people with illness-related MS, Nice EC. Tissue and plasma proteomics anxiety. ClinicalTrials.gov identifier: for early stage cancer detection. Mol Omics. NCT00920387. Updated May 7, 2014. 2018;14(6):405-423. doi:10.1039/c8mo00126j Accessed November 11, 2019. 385. He Y, Mohamedali A, Huang C, Baker MS, https://clinicaltrials.gov/ct2/show/NCT009203 Nice EC. Oncoproteomics: current status and 87 future opportunities. Clin Chim Acta. 394. LSD treatment in persons suffering from 2019;495:611-624. anxiety symptoms in severe somatic diseases doi:10.1016/j.cca.2019.06.006 or in psychiatric anxiety disorders (LSD- 386. Nice EC. The status of proteomics as we enter assist). ClinicalTrials.gov identifier: the 2020s: towards personalised/precision NCT03153579. Updated March 13, 2020. medicine. Anal Biochem. Published online Accessed November 11, 2019. July 31, 2020. doi:10.1016/j.ab.2020.113840 https://clinicaltrials.gov/ct2/show/NCT031535 79 387. A study of psilocybin for major depressive disorder (MDD). ClinicalTrials.gov identifier: 395. LSD therapy for persons suffering from major NCT03866174. Updated October 19, 2020. depression (LAD). ClinicalTrials.gov Accessed November 11, 2019. identifier: NCT03866252. Updated January https://clinicaltrials.gov/ct2/show/NCT038661 18, 2020. Accessed November 11, 2019. 74 https://clinicaltrials.gov/ct2/show/NCT038662 52 388. Psilocybin vs escitalopram for major depressive disorder: comparative mechanisms 396. Davis AK, So S, Lancelotta R, Barsuglia JP, (Psilodep-RCT). ClinicalTrials.gov identifier: Griffiths RR. 5-methoxy-N,N- NCT03429075. Updated July 31, 2020. dimethyltryptamine (5-MeO-DMT) used in a Accessed November 11, 2019. naturalistic group setting is associated with https://clinicaltrials.gov/ct2/show/NCT034290 unintended improvements in depression and 75 anxiety. Am J Drug Alcohol Abuse. 2019;45(2):161-169. 389. Psilocybin and depression (Psilo101). doi:10.1080/00952990.2018.1545024 ClinicalTrials.gov identifier: NCT03380442. Updated December 21, 2017. Accessed November 11, 2019. https://clinicaltrials.gov/ct2/show/NCT033804 42

HIGH POTENTIAL DISRUPTION REPORT • November 2020 196

397. Antidepressant effects of ayahuasca: a 406. Avram R, Olgin JE, Kuhar P, et al. A digital randomized placebo controlled trial in biomarker of diabetes from smartphone-based treatment resistant depression. vascular signals. Nat Med. 2020;26(10):1576- ClinicalTrials.gov identifier: NCT02914769. 1582. doi:10.1038/s41591-020-1010-5 Accessed November 11, 2019. 407. TytoCare homepage. TytoCare Ltd. Accessed https://clinicaltrials.gov/ct2/show/NCT029147 November 7, 2019. https://www.tytocare.com/ 69 408. MoleScope. MetaOptima Technology Inc. 398. A multi-site phase 3 study of MDMA-assisted Accessed November 7, 2019. psychotherapy for PTSD. ClinicalTrials.gov https://www.dermengine.com/molescope identifier: NCT03537014. Accessed November 11, 2019. 409. Zalewski S. Earlier detection of diabetic https://clinicaltrials.gov/ct2/show/NCT035370 retinopathy with smartphone AI. Regents of 14 the University of Michigan. April 29, 2019. Accessed November 7, 2019. 399. MDMA-assisted therapy for social anxiety in https://labblog.uofmhealth.org/health- autistic adults. ClinicalTrials.gov identifier: tech/earlier-detection-of-diabetic-retinopathy- NCT02008396. Accessed November 11, smartphone-ai 2019. https://clinicaltrials.gov/ct2/show/NCT020083 410. Telemedicine platform reviews. VSee. 96 Accessed April 22, 2020. https://vsee.com/telemedicine-platform- 400. Liriano F, Hatten C, Schwartz TL. Ketamine reviews/ as treatment for post-traumatic stress disorder: a review. Drugs Context. 2019;8:212305. 411. Siwicki B. Comparing 11 top telehealth doi:10.7573/dic.212305 platforms: company execs tout quality, safety, EHR integrations. Healthc IT News. Published 401. FDA approves new nasal spray medication for online August 2, 2017. Accessed April 22, treatment-resistant depression; available only 2020. at a certified doctor’s office or clinic. News https://www.healthcareitnews.com/news/comp release. US Food and Drug Administration; aring-11-top-telehealth-platforms-company- March 6, 2019. Accessed May 17, 2019. execs-tout-quality-safety-ehr-integrations https://www.fda.gov/news-events/press- announcements/fda-approves-new-nasal- spray-medication-treatment-resistant- depression-available-only-certified 402. Kelly JR, Crockett MT, Alexander L, et al. Psychedelic science in post-COVID-19 psychiatry. Ir J Psychol Med. Published online August 19, 2020. doi:10.1017/ipm.2020.94 403. Zhang M. How COVID-19 will affect the psychedelic renaissance. VolteFace. Accessed October 13, 2020. https://volteface.me/covid- 19-will-affect-psychedelic-renaissance/ 404. Engineering National Academies of Sciences and Medicine. Chapter 2: the diagnostic process. In: Improving Diagnosis in Health Care. The National Academies Press; 2015:31-80. 405. Nachum S, Stern ME, Greenwald PW, Sharma R. Use of physician-guided patient self-examination to diagnose appendicitis: a telemedicine case report. Telemed J E Health. 2019;25(8):769-771. doi:10.1089/tmj.2018.0115

HIGH POTENTIAL DISRUPTION REPORT • November 2020 197

412. 2017 review of physician and advanced practitioner recruiting incentives. Merritt Hawkins; 2017:48. 413. Findings: variation in the number of health care providers between and within states. America’s Health Rankings Annual Report. United Health Foundation; 2017:32-33. 414. Physician specialty data report: active physicians by age and specialty, 2015. Association of American Medical Colleges. Accessed April 22, 2020. https://www.aamc.org/data- reports/workforce/interactive-data/active- physicians-age-and-specialty-2015 415. Ben-Zeev D, Buck B, Meller S, Hudenko WJ, Hallgren KA. Augmenting evidence-based care with a texting mobile interventionist: a pilot randomized controlled trial. Psychiatr Serv. Published online July 7, 2020:appips202000239. [[what is this?]] doi:10.1176/appi.ps.202000239

HIGH POTENTIAL DISRUPTION REPORT • November 2020 198