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

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

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

Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that 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 the Patient-Centered Outcomes Research Institute (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 Suite 900, 1828 L Street, NW, Washington, DC 20036. ©2019 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org.

Suggested citation: Hulshizer R, Carlson D, Cuevas C, Hudson K, Lynch M, Motter A, Wilkinson B, DeHaan E, De Lurio J, Erinoff E, Robertson D, Stone A, Tipton K, Schoelles K. PCORI Health Care Horizon Scanning System: Horizon Scanning Status Report. (Prepared by ECRI Institute under Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12) Washington, DC: Patient-Centered Outcomes Research Institute; June 2019.

HORIZON SCANNING STATUS REPORT ● JUNE 2019 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 will also be a tool for the public to identify information on selected new health care technologies and interventions. Any investigator or funder of research will be able to 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. It is not the goal of the PCORI HCHSS to predict future utilization and costs of any health care intervention. Rather, the reports are intended to help inform and guide planning and prioritization of research resources. This edition of the Status Report is the second of 4 editions planned for 2019 and lists topics (ie, interventions intended for a specific use within a specific patient population) that have been identified and are being monitored. We welcome comments on this report. Send comments by mail to William Lawrence, MD, MS, Patient-Centered Outcomes Research Institute, 1828 L St., NW, Suite 900, Washington, DC 20036, or by email to [email protected].

HORIZON SCANNING STATUS REPORT ● JUNE 2019 ii

Table of Contents

Statement of Funding and Purpose ...... i

Financial Disclosure Statement ...... i

Public Domain Notice ...... i

Preface ...... ii Introduction ...... 1 Section 1. Currently Monitored Topics: 66 Topics ...... 4 Table 1. Alzheimer’s Disease and Other Dementias: 2 Topics ...... 4 Table 2. : 35 Topics ...... 5 Table 3. Cardiovascular Diseases: 8 Topics ...... 33 Table 4. Mental and Behavioral Health: 8 Topics ...... 39 Table 5. Rare Diseases: 13 Topics ...... 45 Section 2. Topics Added Since Last Status Report: 94 Topics...... 56 Table 6. Alzheimer’s Disease and Other Dementias: 4 Topics ...... 56 Table 7. Cancer: 39 Topics ...... 59 Table 8. Cardiovascular: 8 Topics ...... 95 Table 9. Mental and Behavioral Health: 5 Topics ...... 101 Table 10. Rare Diseases: 36 Topics ...... 104 Section 3. Topics Archived Since Last Status Report: 6 Topics ...... 136 Table 11. Alzheimer’s Disease and Other Dementias: 2 Topics ...... 136 Table 12. Cancer: 2 Topics ...... 137 Table 13. Cardiovascular: 1 Topic ...... 138 Table 14. Mental and Behavioral Health: 0 Topics ...... 138 Table 15. Rare Diseases: 1 Topic ...... 139

HORIZON SCANNING STATUS REPORT ● JUNE 2019 iii

Introduction

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

Status Reports The PCORI HCHSS produces quarterly Status Reports, which summarize key data elements for all topics currently monitored in the system and, if applicable, topics archived since the last Status Report. The report is organized into 3 sections, titled as follows: (1) Currently Monitored Topics, (2) Topics Added Since Last Status Report, and (3) Topics Archived Since Last Status Report. Each section contains a table for each of the 5 initial PCORI-defined priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health, and rare diseases. PCORI may choose, upon future consideration, to modify or expand its list of priority areas. The tables in Sections 1 and 2 summarize information in each row, as shown in the following columns: potential patient population; intervention description, including names and locations of developers/manufacturers; potential comparators; patient-oriented outcome measures (limited to those reported in clinical trials); and regulatory information. Information in the first 4 columns is collectively referred to as PICO (patient population, intervention, comparators, and outcomes) information. In Section 3 (archived topics), the regulatory information column is replaced by the reason for archiving the topic. Within each table, topics are sorted alphabetically by intervention name (ie, the second column, intervention description). In addition to the topics included in the sections detailed above, the PCORI HCHSS identifies and monitors disruptive trends (ie, large, high-level disruptions) occurring across clinical areas or within a clinical area from a combination of factors that, taken together, create a paradigm shift in health care. Identification of these trends is not limited to PCORI’s initially defined priority areas. If or when the HCHSS identifies any such trends, an additional section summarizing the trends will be added to this report.

HORIZON SCANNING STATUS REPORT ● JUNE 2019 1

Horizon Scanning Process Overview The PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual (hereafter referred to as the Protocol) details the criteria we use to select topics. Briefly, we scan information sources broadly within each priority area to detect leads for topics likely to be available for clinical use within 3 years and likely to cause a significant disruption (ie, change, 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 setting and delivery processes, disparities, and costs of care. Analysts review leads to discover potential topics, and if they meet inclusion criteria, create topic records encompassing the PICO information and key regulatory information. Analysts present potential topics at topic nomination meetings. After a brief presentation and discussion of each topic, the HCHSS team votes to include or exclude the topic based on criteria as described in the Protocol. All included topics are reported in the Status Report. 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 5 to 9 stakeholders for comment. Stakeholders provide varied perspectives and/or areas of knowledge in health care, including at least one patient or patient representative. The commenter reads the topic profile and completes a 6-question survey, which asks the commenter to rate—on a scale of 1 (low disruption potential) to 4 (high disruption potential)—the intervention’s potential to disrupt a number of key areas of health care along with a written rationale for each rating. Twice a year, analysts review all topics for which stakeholder comments have been received in the previous 15 months. Based on stakeholder rationales and ratings, analysts nominate topics deemed to have the highest potential for disruption to be included in a High Potential Disruption Report, as described in the Protocol. At any point, 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 health care in the United States, (2) development of the intervention has ceased, or (3) the intervention has been clinically available outside of the clinical research environment for longer than 1 year.

Reporting Period Summary The PCORI HCHSS began operating in December 2018. Since then, review of about 550 leads has led to identification of about 285 potential topics across the 5 PCORI priority areas. After subjecting these potential topics to our inclusion criteria and nomination process, 164 topics have been selected and are being actively monitored in the system, or were being monitored but have been archived within the past 3 months. This Status Report lists these 164 topics, of which 66 new topics were added, 94 topics were reported previously, and 6 topics were archived. Topics are presented in alphabetic order according to intervention name (ie, the second column, intervention description) within each priority area’s table. As topics advance in development, their names often change from a research name to a generic name to the brand name .

HORIZON SCANNING STATUS REPORT ● JUNE 2019 2

The topics included in this report represent 93 diseases/conditions and span the PCORI-defined priority areas as follows: • Alzheimer’s disease and other dementias: 8 topics (5%) • Cancer: 76 topics (46%) • Cardiovascular diseases: 17 topics (10%) • Mental and behavioral health: 13 topics (8%) • Rare diseases: 50 topics (31%)

Across all priority areas, topics in this report represent the following therapeutic classes: • Biotechnology: 54 topics (33%) • Device (nonimplantable): 8 topics (5%) • Implant: 4 topics (2%) • Pharmaceutical: 98 topics (60%)

HORIZON SCANNING STATUS REPORT ● JUNE 2019 3

Section 1. Currently Monitored Topics: 66 Topics

Table 1. Alzheimer’s Disease and Other Dementias: 2 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 55 to 91 years Brexpiprazole (Rexulti), an atypical , is a Caregiver intervention Agitation, as measured (s): Phase III with Alzheimer's disease serotonin- activity modulator that purportedly and environmental by accepted clinical primary completion (AD)–associated agitation reduces agitation in patients with AD. Although modification (removed or ratings and scales November 2020; phase III are sometimes used off-label to treat this alleviated stressors) open-label extension condition, they carry an increased risk of death in patients Quality of life primary completion May with dementia. Brexpiprazole might have a better safety Antianxiety drugs 2021; phase III extension profile than other antipsychotics. According to the primary completion August manufacturer, brexpiprazole is a partial of 2021; phase II/III primary serotonin 5-HT1A and dopamine D2 receptors and an Antipsychotics (eg, completion November 2021 antagonist of serotonin 5-HT2A receptors. Brexpiprazole ) might also bind to noradrenaline α1B/2C receptors. In Atypical antipsychotics clinical trials, brexpiprazole is administered orally, once (eg, aripiprazole) daily, for 10 to 14 weeks, at a dose of 1 to 3 mg. Beta-adrenergics Developer(s): Synthetic Otsuka Holdings Co., Ltd (Tokyo, Japan), in collaboration tetrahydrocannabinol with H. Lundbeck A/S (Valby, Denmark)

Adults aged up to 90 years Leuco-methylthioninium dihydromethanesulfonate (LMTX) Cholinesterase inhibitors Brain atrophy rate Clinical trial(s): Phase II/III with early Alzheimer's is a tau aggregation inhibitor intended as a disease- (eg, , LUCIDITY primary disease (AD) modifying treatment for AD. According to the galantamine, Cognition and memory, completion December 2020 manufacturer, LMTX reduces levels of aggregated or rivastigmine) as measured by misfolded tau , which are believed to contribute to accepted clinical ratings AD disease pathology. In clinical trials, LMTX is Supportive care and scales administered orally twice daily at a dose of 8 to 16 mg per Quality of life day.

Developer(s): TauRx Pharmaceuticals, Ltd (Singapore, Republic of Singapore)

Section 1. Currently Monitored Topics 4

Table 2. Cancer: 35 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 70 years ATIR101 is an allogeneic T- immunotherapy Photopheresis alone or Overall survival FDA designation(s): Orphan with acute myeloid that isolates mature immune cells from a haploidentical combined with 8- Drug, Regenerative , acute (half match) donor's peripheral blood. Patients receiving methoxypsoralen Progression-free survival Medicine Advanced Therapy lymphoblastic leukemia, or ATIR101 purportedly do not require a perfect donor Quality of life myelodysplastic syndrome match, which could eliminate the need for prophylactic Therapy with one or Clinical trial(s): Phase III for whom allogeneic immune suppression. A haploidentical donor is typically a more HATCY primary completion hematopoietic parent or child, or, in some cases, a sibling. The immune immunosuppressants: February 2021 transplantation (HSCT) is cells from the donor also undergo a proprietary Alkylating agent (eg, being considered photodepletion procedure that eliminates T cells ) responsible for causing graft-versus-host disease (GVHD). ATIR101 is intended as an immunotherapy (eg, adjunct to allogeneic hematopoietic stem cell , transplantation (HSCT) to provide immediate immunity antithymocyte globulin) against infectious agents and residual cancer during the inhibitors 6 to 12 months after HSCT, when the patient's immune (eg, cyclosporine, system is repopulating, while minimizing patient risk for ) GVHD. In clinical trials, ATIR101 is delivered as an intravenous infusion at a single dose of 2 × 106 cells/kg Corticosteroids (eg, administered between 28 and 32 days after allogeneic , HSCT. mycophenolate mofetil, prednisone) Developer(s): mTOR inhibitor (eg, Kiadis Pharma N.V. (Amsterdam, the Netherlands) )

Section 1. Currently Monitored Topics 5

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (Bavencio) is an immune checkpoint inhibitor Maintenance Overall survival FDA designation(s): Orphan older with unresectable, consisting of a fully , monoclonal specific with one Drug locally advanced, or for programmed death-ligand 1 (PD-L1) proposed for use or more of the following: Progression-free survival Clinical trial(s): Phase III metastatic adenocarcinoma as maintenance therapy to delay disease progression Quality of life of the stomach or after primary chemotherapy. Immune tolerance is a (eg, JAVELIN Gastric 100 gastroesophageal junction cancer hallmark that may be mediated by binding PD-L1 5-, primary completion to its receptor, programmed cell death 1 (PD-1), which ) November 2019 inhibits T cells and anticancer immune responses. (eg, Preventing PD-L1/PD-1 interaction by binding of ) avelumab purportedly inhibits this immune checkpoint, potentially leading to an anticancer immune response. HER2 antibodies (eg, Patients receive avelumab in the maintenance setting ) after completing one line of induction-phase cytotoxic Platinum-based agents chemotherapy. In clinical trials, avelumab is administered (eg, , intravenously at a dose of 10 mg/kg infusion once every , ) 2 weeks until disease progression or unacceptable toxicity. (eg, , ) Developer(s): , Inc (New York, New York) in collaboration with Merck KGaA (Darmstadt, Germany)

Section 1. Currently Monitored Topics 6

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Females aged 18 years or Axalimogene filolisbac (AXAL) is an immunotherapy External beam radiation Overall survival FDA designation(s): Orphan older with locally advanced comprising live, attenuated Listeria monocytogenes (Lm) therapy alone or with Drug, Fast Track cervical cancer at high risk bacteria engineered to express the E7 of human one or more of the Disease-free survival Clinical trial(s): Phase III of recurrence who have papilloma virus (HPV) type 16, which has a crucial role in following: Quality of life completed adjuvant cervical oncogenesis. The E7 gene is cloned in a plasmid AIM2CERV primary treatment with cisplatin and containing a truncated fragment of listeriolysin O gene, Antimetabolites (eg, completion June 2023, radiation tLLO, that is introduced into Lm, which will express and 5-fluorouracil) designed under Special Protocol Assessment secrete the tLLO-E7 . Although E7 Platinum agents (eg, presented on the surface of -presenting cells carboplatin, cisplatin) Note(s): FDA placed the stimulate CD4+ and CD8+ T cells, tLLO modulates cells AIM2CERV study on clinical involved in immune suppression. According to the hold in January 2019 company, no immunotherapy is available that has shown activity for treating cervical cancer. AXAL is intended to reduce the risk for disease recurrence by promoting a cellular immune response against residual HPV 16–infected cervical cancer cells. In clinical trials, AXAL is administered as an intravenous infusion at a dose of 1 × 109, 3.3 × 109, or 1 × 1010 colony forming units every 3 weeks for 3 doses for the first 3 months and then every 8 weeks for a total of 5 doses or until disease recurrence. Developer(s): Advaxis, Inc (Princeton, New Jersey)

Section 1. Currently Monitored Topics 7

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 70 years DCVax-L is an autologous immunotherapy comprising Fractionated external Overall survival Clinical trial(s): Phase III with surgically resected activated dendritic cells loaded with patient-derived tumor beam radiation therapy GBM primary completed glioblastoma multiforme . Options for GBM treatment are very limited with Progression-free survival November 2016, interim Chemotherapy with one (GBM) who have completed poor outcomes, and DCVax-L is intended to improve Quality of life data published May 2018, 3- adjuvant radiation therapy outcomes by promoting an immune response against or more of the following: year survival data reported and chemotherapy residual glioblastoma cells after surgical resection. Alkylating agents (eg, November 2018 DCVax-L is manufactured using monocytes obtained from , the patient through a leukapheresis process. The cyclophosphamide, monocytes are differentiated into dendritic cells in vitro , , and then activated and loaded with patient-derived ) antigens from the patient's tumor tissue after surgical resection. The purified DCVax-L is then administered to inhibitors elicit adaptive immunity from T cells and B cells. (eg, ) Treatment involves total or near total tumor resection mTOR inhibitors (eg, followed by conventional external beam radiation therapy ) and concurrent temozolomide chemotherapy at least 2 weeks before treatment with the first course of Platinum agents (eg, DCVax-L. In clinical trials, DCVax-L containing carboplatin, cisplatin) 6 2.5 × 10 tumor lysate-pulsed dendritic cells is Vinca alkaloids (eg, administered as an intradermal injection in the upper arm ) at days 0, 10, and 20 and at weeks 8, 16, 32, 48, 72, 96, and 120. Developer(s): Northwest Biotherapeutics, Inc (Bethesda, Maryland)

Section 1. Currently Monitored Topics 8

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 75 years Devimistat (CPI-613) is a first-in-class, lipoate analogue, Chemotherapy with one Overall survival FDA designation(s): Orphan with distant metastatic small molecule drug that inhibits the activity of the or more of the following: Drug pancreatic adenocarcinoma mitochondrial α-ketoglutarate dehydrogenase Progression-free survival Antimetabolites (eg, Clinical trial(s): Phase III who have received no (KGDH) and pyruvate dehydrogenase (PDH) by Quality of life therapy mimicking catalytic intermediates for these enzymes. Only 5-fluorouracil, AVENGER 500 primary about 5% of patients with pancreatic cancer respond to capecitabine, completion October 2021 the standard of care ( chemotherapy), and gemcitabine) the prognosis for these patients is poor. This drug is Chemoprotectant (eg, intended as first-line therapy to improve outcomes. KGDH leucovorin) converts glutamate to α-ketoglutarate and PDH converts pyruvate to acetyl coenzyme A (acetyl-CoA). These are EGFR inhibitor (eg, essential processes for generating energy through the ) tricarboxylic acid (TCA) cycle. Pancreatic DNA synthesis inhibitor adenocarcinoma cells overexpress several enzymes (eg, ) involved in the mitochondrial TCA cycle. As a result, the metabolic activity of cancer cells is greatly increased Platinum-based agents compared with that of noncancerous cells. Devimistat (eg, cisplatin, oxaliplatin) purportedly downregulates metabolic pathways in cancer Taxanes (eg, albumin- cells that depend on α-ketoglutarate and acetyl-CoA. In bound paclitaxel, clinical trials, devimistat is administered intravenously at a docetaxel) dose of 500 mg/m2, on days 1 and 3 of a 14-day cycle, followed immediately by intravenous modified FOLFIRINOX (5-fluorouracil at 400 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and oxaliplatin at 65 mg/m2). Developer(s): Rafael Pharmaceuticals, Inc (Cranbury, New Jersey)

Section 1. Currently Monitored Topics 9

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Dianhydrogalactitol (VAL-083) is a small molecule drug Chemotherapy with one Overall survival FDA designation(s): Orphan older with recurrent that causes N7 DNA alkylation and is intended to treat or more of the following: Drug, Fast Track malignant gliomas, including recurrent malignant gliomas, which often become Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase III glioblastoma multiforme resistant to the standard-of-care temozolomide therapy Quality of life (GBM) because of the high expression of the O6- carmustine, STAR-3 primary completion methylguanine-DNA-methyltransferase (MGMT), which cyclophosphamide, June 2019 possesses DNA repair activity. VAL-083's novel N7 DNA lomustine, , alkylation activity might improve patient health outcomes procarbazine, by overcoming MGMT-mediated resistance. In clinical temozolomide) trials, VAL-083 is administered as an intravenous infusion Angiogenesis inhibitors at a dose of 40 mg/m2 on days 1, 2, and 3 of a 21-day (eg, bevacizumab) treatment cycle, for up to twelve 21-day treatment cycles. mTOR inhibitors (eg, Developer(s): everolimus) DelMar Pharmaceuticals, Inc (Vancouver, British Platinum-based drugs Columbia, Canada) (eg, carboplatin, cisplatin) Vinca alkaloids (eg, vincristine)

Adults aged 18 years or (Imfinzi) is a novel immunotherapy agent Chemotherapy with one Overall survival Clinical trial(s): Phase III intended to prevent the immune tolerance of cancer cells. or more of the following: KESTREL primary older with treatment-naïve, Progression-free survival recurrent, or metastatic Advanced head and neck have a poor prognosis completion September 2019 and high recurrence rate, suggesting the need for new Antimetabolites (eg, head and neck squamous 5-fluorouracil, Quality of life Note(s): FDA approved cell carcinoma (HNSCC) treatments. Durvalumab, intended as a first-line therapy to improve outcomes in these patients, is a monoclonal capecitabine, durvalumab for treating antibody against programmed death-1 receptor ligand gemcitabine, bladder cancer in May 2017 (PD-L1), which is frequently expressed in tumor methotrexate) and for non–small cell lung cancer in February 2018 microenvironments, and downregulates T cells via EGFR inhibitors (eg, activation of the programmed death-1 (PD-1) immune ) checkpoint. Durvalumab purportedly limits activation of the immune checkpoint by preventing the interaction Platinum agents (eg, between PD-L1 and its receptor, PD-1. Durvalumab is carboplatin, cisplatin) being studied as a monotherapy or in combination with Taxanes (eg, docetaxel, tremelimumab. In clinical trials, durvalumab is paclitaxel) administered intravenously every 2 weeks from day 1 for a maximum of 12 months or intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, UK)

Section 1. Currently Monitored Topics 10

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Dusquetide (SGX942) is a novel synthetic, water-soluble, Treatment with one or Duration of severe FDA designation(s): Fast older who develop oral 5-amino-acid with anti-inflammatory and anti- more of the following: mucositis Track mucositis (OM) while infective properties. OM is a side effect of anticancer receiving chemoradiation therapies (eg, chemotherapy and radiation) and affects Localized therapy (eg, Incidence of severe Clinical trial(s): Phase III therapy with cisplatin and about 80% of patients with oropharyngeal cancer. No low-level laser therapy, mucositis DOM-INNATE primary oral cryotherapy) completion March 2020 image-modulated radiation effective OM treatment is available. Dusquetide is a therapy for locally member of a novel drug class called innate defense Analgesics (eg, Note(s): NIH selected advanced, nonmetastatic regulators that targets the innate immune system and lidocaine, narcotics) Cancer-treatment SGX942 for its Small squamous cell carcinoma of binds to an intracellular adaptor protein, sequestosome-1, adherence Business Innovation the oral cavity or oropharynx or p62, which has a pivotal function in signal transduction Supportive care (eg, oral Research/Small Business hygiene protocols) Incidence of bacterial during activation and control of the innate immune infection Technology Transfer system. In clinical trials, it is administered intravenously at Commercialization a dose of 1.5 mg/mL as a 4-minute intravenous infusion, Quality of life Accelerator Program twice weekly starting within 3 days after initiating radiation September 2018 therapy and continuing through 2 weeks after completing radiation therapy. Developer(s): Soligenix, Inc (Princeton, New Jersey)

Adults aged 18 years or (Onzeald) is a novel formulation of the Chemotherapy with one Overall survival FDA designation(s): Fast older with advanced breast topoisomerase I inhibitor irinotecan intended to improve or more of the following: Track cancer and a history of health outcomes while reducing treatment-related Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase III stable brain metastases who adverse events in patients with breast cancer and brain Quality of life have been treated with one metastases. Etirinotecan pegol is a modified version of cyclophosphamide) BEACON completed April or two cytotoxic regimens irinotecan in which the drug is linked to a macromolecule 2016, pivotal data published Anthracyclines (eg, November 2015, quality-of- core. The linkage purportedly renders the drug inert in the ) bloodstream and allows its slow release as the linkages life data published May are metabolized in the patient. Slow release extends the Antimetabolites (eg, 2017; phase III ATTAIN time the patient’s disease is exposed to therapeutic levels fluorouracil, gemcitabine, primary completion July of the drug and limits exposure to high drug levels during ) 2020 infusion. Additionally, the large drug-polymer conjugate PARP inhibitors (eg, might preferentially accumulate in tumor tissues because , , of the increased permeability of tumor vasculature. In ) clinical trials, etirinotecan pegol is administered as an intravenous infusion at a dose of 145 mg/m2, once every Taxanes (eg, docetaxel, 21 days until disease progression or intolerable toxicity. nab-paclitaxel, paclitaxel) Developer(s): Vinca alkaloid (eg, Nektar Therapeutics, Inc (San Francisco, California) )

Section 1. Currently Monitored Topics 11

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Lefitolimod (MGN1703) is a DNA molecule developed to Chemotherapy with one Overall survival FDA designation(s): Orphan older with metastatic act as an agonist of Toll-like receptor 9 (TLR9), a or more of the following: Drug colorectal cancer whose component of the innate immune system. Lefitolimod Progression-free survival Angiogenesis inhibitors Clinical trial(s): Phase III disease has responded to offers a novel mechanism intended to induce immune Quality of life first-line chemotherapy responses against cancer cells and improve patient (eg, bevacizumab, IMPALA primary completion health outcomes. Activating TLR9 signaling promotes ) March 2019 immune system activation, possibly through dendritic cell Antimetabolites (eg, maturation or differentiation of B cells into antibody- 5-fluorouracil, secreting plasma cells or both. Immune-response capecitabine) activation by lefitolimod is intended to overcome immune tolerance to tumor-associated antigens, potentially EGFR antibodies (eg, leading to an anticancer immune response. Lefitolimod cetuximab, purportedly prevents or delays disease recurrence by ) stimulating cancer-specific immune responses in the FOLFIRI (leucovorin, maintenance setting. In clinical trials, lefitolimod solution 5-fluorouracil, irinotecan) has been administered as a subcutaneous injection 60 mg twice weekly until disease progression or FOLFOX (leucovorin, intolerable toxicity. 5-fluorouracil, oxaliplatin) Developer(s): Multikinase inhibitors (eg, ) MOLOGEN AG (Berlin, Germany) Platinum agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)

Section 1. Currently Monitored Topics 12

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Lurbinectedin (Zepsyre) is a synthetic, marine-derived Chemoradiation therapy Overall survival FDA designation(s): Orphan older with extensive-stage compound that selectively inhibits transactivated RNA Drug small-cell lung cancer polymerase II transcription. Lurbinectedin has a novel Platinum-based agents Progression-free survival (eg, carboplatin, Clinical trial(s): Phase III (SCLC) refractory to a single mechanism of action intended to improve health Quality of life platinum-containing regimen outcomes in patients whose cancer does not respond to cisplatin) ATLANTIS primary completion February 2020 platinum-based chemotherapy. Lurbinectedin selectively Topoisomerase inhibitors inhibits RNA polymerase (Pol) II activity during the (eg, , elongation phase of mRNA synthesis. Although ) lurbinectedin interacts with RNA Pol II, it does not affect the activity of RNA Pol I, mitochondrial RNA Pol, or basal transcription machinery. Lurbinectedin's binding to RNA Pol II and inhibition of mRNA synthesis purportedly induces cancer cell death by reducing the expression of cellular factors involved in tumor progression. In clinical trials, lurbinectedin is administered intravenously at a dose of 4 mg once every 3 weeks in combination with doxorubicin until disease progression or intolerable toxicity. Developer(s): Pharma Mar SA (Madrid, Spain)

Section 1. Currently Monitored Topics 13

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (MGAH22) is a that Chemotherapy with one Overall survival Submission date: Biologics older with metastatic or binds to human epidermal receptor 2 or more of the following: License Application planned locally advanced, relapsed, (HER2) to inhibit tumor cell growth. Margetuximab is Progression-free survival for fourth quarter 2019 Alkylating agents (eg, or refractory HER2-positive intended to improve health outcomes in patients whose Quality of life breast cancer, who have disease no longer responds to HER2-targeted therapies. cyclophosphamide) FDA designation(s): Fast Track received at least two lines of In contrast to other HER2-specific antibodies (eg, Anthracyclines (eg, anti-HER2 , trastuzumab), margetuximab has an doxorubicin) Clinical trial(s): Phase III optimized Fc region with higher affinity for the Fc-gamma SOPHIA primary completion receptor on macrophages. This increases their Antimetabolites (eg, March 2020, pivotal data recruitment and enhances the tumor's antibody- fluorouracil, gemcitabine, reported February 2019 dependent cellular cytotoxicity. Additionally, macrophages pemetrexed) that have phagocytosed and processed a tumor cell HER2-targeted present tumor antigens to prime T cells, which then elicit antibodies (eg, ado- antigen-specific immune responses against the tumor. In , clinical trials, margetuximab is administered intravenously pertuzumab, once every 3 weeks, at a dose of 15 mg/kg, in trastuzumab) combination with capecitabine (1000 mg/m2), (1.4 mg/m2), gemcitabine (1000 mg/m2), and vinorelbine Taxanes (eg, docetaxel, (25-30 mg/m2). Treatment continues until disease nab-paclitaxel, progression or intolerable toxicity. paclitaxel) Developer(s): Tyrosine inhibitors (eg, , MacroGenics, Inc (Rockville, Maryland), in collaboration ) with Green Cross Corp (Yongin, South Korea) Vinca alkaloids (eg, vinorelbine)

Section 1. Currently Monitored Topics 14

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 74 years Metformin is a biguanide drug (a class of drugs that Active surveillance Disease-free survival Clinical trial(s): Phase III without diabetes mellitus prevents glucose production in the ) often used in the MA32 primary completion who have localized breast treatment of type II diabetes mellitus. Some researchers Overall survival February 2022 cancer and have undergone think the drug might benefit patients with breast cancer Quality of life surgical resection and because retrospective studies of patients with diabetes completed any neoadjuvant taking metformin and window-of-opportunity studies in the or adjuvant chemotherapy neoadjuvant breast cancer setting have indicated that metformin might have anticancer effects. Metformin purportedly exerts its anticancer effects by activating AMP-activated protein kinase, which limits downstream components of the mTOR pathway. Additionally, metformin's actions in reducing circulating levels and improving in patients without diabetes might be antineoplastic because of insulin's potential growth-stimulating activity. In clinical trials, metformin (850 mg) is being administered orally, twice daily, for up to 5 years in the absence of disease progression. Developer(s): Canadian Cancer Trials Group (Kingston, Ontario, Canada)

Section 1. Currently Monitored Topics 15

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

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

Section 1. Currently Monitored Topics 16

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Nivolumab (Opdivo) is an immune checkpoint inhibitor Fractionated external Overall survival FDA designation(s): Orphan older with newly diagnosed, consisting of a fully human, monoclonal antibody specific beam radiation therapy Drug surgically resected to the cell surface receptor programmed death 1 (PD-1). with or without Progression-free survival Clinical trial(s): Phase III glioblastoma Nivolumab uses a novel immune approach and is alternating electrical Quality of life intended as adjuvant therapy for glioblastoma after fields plus chemotherapy CheckMate-498 primary surgical resection. Immune tolerance is a hallmark of with one or more of the completion March 2019; cancer and might be mediated by binding of PD-1 by its following: topline data reported May ligands (programmed cell death ligand 1 and programmed 2019; phase III CheckMate- cell death ligand 2), which inhibits T cells and anticancer Alkylating agents (eg, 548 primary completion immune responses. Using nivolumab to prevent PD-1 carmustine, February 2022 interaction with its ligands purportedly inhibits this cyclophosphamide, immune checkpoint, potentially leading to an anticancer lomustine, procarbazine, immune response. In clinical trials, nivolumab is temozolomide) administered intravenously at a dose of 240 mg every Angiogenesis inhibitors 2 weeks for 16 weeks and then 480 mg every 4 weeks (eg, bevacizumab) until disease progresses or unacceptable toxicity develops. It is being studied in combination with radiation mTOR inhibitors (eg, therapy with or without temozolomide. everolimus) Developer(s): Platinum agents (eg, carboplatin, cisplatin) Bristol-Myers Squibb (New York, New York), in collaboration with Ono Pharmaceutical Co, Ltd (Osaka, Vinca alkaloids (eg, Japan) vincristine)

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

Section 1. Currently Monitored Topics 17

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Patients aged 18 to 99 Olaparib (Lynparza) is a small molecule drug intended to Chemotherapy with one Overall survival FDA designation(s): Orphan years with germline BRCA1 inhibit poly -ribose polymerase or more of the following: Drug and/or BRCA2 mutation- (PARP), which functions in a DNA-repair pathway. Progression-free survival Antimetabolites (eg, Clinical trial(s): Phase III positive metastatic Cancers are often deficient in a DNA repair pathway, and Quality of life pancreatic cancer whose when PARP is also inhibited, the loss of two types of DNA 5-fluorouracil, POLO primary completion disease has not progressed repair results in cancer cell death in response to DNA capecitabine, January 2019, initial data during first-line, platinum- damage. Only about 5% of patients with pancreatic gemcitabine) reported February 2019 based chemotherapy cancer respond to the standard of care (gemcitabine Folic acid derivatives Note(s): FDA approved chemotherapy), and the prognosis for these patients is (eg, leucovorin) olaparib for treating ovarian poor. Olaparib purportedly induces cell death in cancer in December 2014 pancreatic tumors that harbor germline mutations in the Multikinase inhibitors and for breast cancer in breast cancer genes, BRCA1 and/or BRCA2. In clinical (eg, erlotinib) January 2018; Myriad trials, olaparib is administered orally, 300 mg, twice daily Platinum-based agents Genetics (Salt Lake City, until disease progression or intolerable toxicity. (eg, cisplatin, oxaliplatin) Utah) will file for a Developer(s): supplemental application for Taxanes (eg, docetaxel, a companion diagnostic test AstraZeneca plc (Cambridge, UK), in collaboration with nab-paclitaxel, for germline BRCA Merck & Co, Inc (Kenilworth, New Jersey) paclitaxel) mutations in patients with metastatic pancreatic cancer

Section 1. Currently Monitored Topics 18

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 12 years or Omidubicel (NiCord) is an allogeneic stem cell therapy Allogeneic marrow Overall survival FDA designation(s): Orphan older and adults aged up to using umbilical cord blood that has been expanded ex transplant Drug, Breakthrough Therapy 65 years with a hematologic vivo using proprietary nicotinamide (NAM) technology. Bone marrow malignancy (acute NAM is an epigenetic approach intended to “inhibit Pooled unexpanded cord engraftment rate Clinical trial(s): Phase III lymphoblastic leukemia, differentiation and increase the migration, bone marrow blood transplantation primary completion Neutrophil recovery rate December 2019 acute myelogenous homing and engraftment efficiency” of allogeneic blood Unexpanded cord blood leukemia, chronic progenitor cells. Omidubicel is intended as a curative transplantation recovery rate myelogenous leukemia, or approach for high-risk blood cancers in patients who have myelodysplastic syndrome) no fully matched donor available. The therapy is intended to efficiently and quickly restore blood and immune cells and improve resistance to infections and related complications. NAM prevents umbilical cord blood cells from differentiating rapidly in culture, resulting in increased stem cells (CD34+CD38-Lin-). Continuous growth in the presence of NAM enhances stem cell functionality, which includes migration, homing, and engraftment in the bone marrow. In clinical trials, omidubicel is administered as a single intravenous infusion (unspecified dose). Developer(s): Gamida Cell, Ltd (Jerusalem, Israel), in collaboration with Be The Match BioTherapies, LLC (Minneapolis, Minnesota), a subsidiary of the National Marrow Donor Program/Be The Match (Minneapolis, Minnesota)

Section 1. Currently Monitored Topics 19

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (Vicinium) is an antibody-drug Cystectomy Time to cystectomy FDA Designation(s): Fast older with non–muscle conjugate comprising a humanized monoclonal antibody Track invasive bladder cancer fragment specific for the epithelial cell adhesion molecule Intravesicular Overall survival chemotherapy with one Clinical trial(s): Phase III whose disease is refractory (EpCAM) linked to a truncated form of Progression-free survival to or relapsed after Pseudomonas aeruginosa A (ETA). ETA is a or more of the following: primary completion intravesicular treatment with cytotoxic agent that acts by inhibiting protein synthesis Quality of life December 2020, preliminary Anthracyclines (eg, data published January bacillus Calmette-Guérin through inactivation of elongation factor-2. EpCAM is ) highly expressed by bladder cancer cells, and 2019 oportuzumab monatox is intended to preferentially deliver Antimetabolites (eg, the linked exotoxin to these cells and delay the time to gemcitabine) major surgery (cystectomy) and associated side effects of DNA synthesis inhibitors surgery (eg, urinary diversion). In clinical trials, (eg, mitomycin-C) oportuzumab monatox (30 mg) is administered intravesically in an office setting. Treatment includes a 12-week induction phase (12 twice-weekly instillations followed by 6 weekly instillations) and a maintenance phase of up to 2 years of instillations once every 2 weeks. Developer(s): Sesen Bio (Cambridge, Massachusetts)

Adults aged 18 years or Pegargiminase (ADI-PEG 20) is a pegylated preparation Chemotherapy with one Overall survival FDA designation(s): Orphan older with malignant pleural of the enzyme arginine deiminase, which catalyzes the or more of the following: Drug mesothelioma exhibiting low hydrolysis of arginine, depleting the supply of this Progression-free survival Antimetabolites (eg, Clinical trial(s): Phase II/III argininosuccinate essential amino acid from the bloodstream. Cells of many Quality of life synthetase 1 expression tumor types cannot autonomously synthesize arginine pemetrexed) ATOMIC primary completion October 2020 who have undergone no and, therefore, might be sensitive to arginine depletion. In Platinum agents (eg, systemic therapies for particular, tumor cells that express low levels of the cisplatin) mesothelioma arginosuccinate synthetase 1 gene, ASS1 (involved in cellular arginine synthesis), might be dependent on exogenous arginine. In treating patients with pleural malignant mesothelioma expressing low levels of ASS1, pegargiminase targets a novel biomarker that might change patient management paradigms. In clinical trials, pegargiminase is administered weekly by intramuscular injection at a dose of 36 mg/m2 in combination with standard chemotherapy with cisplatin and pemetrexed until disease progression or intolerable toxicity. Developer(s): Polaris Group (San Diego, California)

Section 1. Currently Monitored Topics 20

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pegylated human recombinant hyaluronidase (PEGPH20) Chemotherapy with one Overall survival FDA designation(s): Orphan older with previously is a formulation of the enzyme hyaluronidase, which or more of the following: Drug, Fast Track untreated stage IV functions to degrade the hyaluronan (HA) component of Progression-free survival Antimetabolites (eg, Clinical trial(s): Phase III pancreatic ductal the extracellular matrix. HA is a gel-like component of Quality of life adenocarcinoma and at normal body tissues (eg, skin, cartilage), but it also forms 5-fluorouracil, HALO-109-301 primary least one metastasis a layer on the tumor surface, which might limit tumor capecitabine, completion November 2019 exposure to therapeutic compounds. PEGPH20 is gemcitabine) intended to temporarily degrade HA to increase Folic acid derivatives chemotherapy efficacy and immune cells in metastatic (eg, leucovorin) pancreatic cancer. Only about 5% of patients with pancreatic cancer respond to the standard of care Multikinase inhibitors (gemcitabine chemotherapy), and the prognosis for these (eg, erlotinib) patients is poor. In clinical trials, PEGPH20 is Platinum-based agents administered intravenously in combination with standard (eg, cisplatin, oxaliplatin) chemotherapy drugs nab-paclitaxel and gemcitabine at a dose of 3 μg/kg twice weekly for weeks 1 to 3 of the first Taxanes (eg, docetaxel, 28-day cycle, then once weekly for weeks 1 to 3 of nab-paclitaxel, subsequent 28-day cycles. Nab-paclitaxel (125 mg/m2) paclitaxel) and gemcitabine (1000 mg/m2) are administered once weekly for weeks 1 to 3 of all 28-day cycles. Developer(s): Halozyme Therapeutics, Inc (San Diego, California)

Section 1. Currently Monitored Topics 21

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pexastimogene devacirepvec (Pexa-Vec) is a Wyeth Systemic therapy with Overall survival FDA designation(s): Orphan older with advanced strain of vaccinia virus that has had its viral thymidine one or more of the Drug hepatocellular carcinoma kinase gene, TK, disrupted to selectively infect and following: Progression-free survival Clinical trial(s): Phase III (HCC) who have received replicate in tumor cells, which commonly express high TK Quality of life no systemic therapy levels. HCC historically responded poorly to systemic Anthracyclines (eg, PHOCUS primary therapies and patients with advanced disease had very doxorubicin) completion December 2020, poor prognoses until the approvals of (2007) designed under Special Antimetabolites (eg, Protocol Assessment and (2018) showed some improvement in 5-fluorouracil, survival. Pexa-Vec is intended to have a synergistic effect gemcitabine) with sorafenib to eliminate HCC cells and further improve outcomes. Pexa-Vec has also been engineered to Multikinase inhibitors express human granulocyte-macrophage colony- (eg, , stimulating factor (GM-CSF) and β-galactosidase. lenvatinib, regorafenib, Although GM-CSF induces an antitumor immune sorafenib) response and disrupts the tumor’s vascularization, Platinum agents (eg, presentation of β-galactosidase peptides stimulates T-cell cisplatin, oxaliplatin) responses. Pexa-Vec purportedly targets and destroys cells in liver tumors and tumor-associated blood vessels, as well as activating tumor-specific immune responses. In clinical trials, Pexa-Vec is administered as 3 biweekly intratumoral injections at a dose of 1 × 109 plaque forming units on day 1 and weeks 2 and 4. At week 6 after the first dose of Pexa-Vec, sorafenib treatment begins at a dose of 400 mg twice daily. Developer(s): SillaJen, Inc (Busan, South Korea) Green Cross Corp (Yongin, South Korea), regional partner Transgene SA (Strasbourg, France), regional partner Lee's Pharmaceutical Holdings, Ltd (Sha Tin, Hong Kong), regional partner

Section 1. Currently Monitored Topics 22

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or is a small-molecule multikinase inhibitor with Radiation therapy Response rate PDUFA date: Priority older with a tenosynovial activity against several receptor tyrosine including review, August 3, 2019 giant cell tumor (TGCT) not colony stimulating factor 1 receptor (CSF1R), FMS-like Off-label Patient-reported physical eligible for surgical resection 3 (FLT3), and KIT. No FDA-approved function (PROMIS FDA designation(s): interventions are available for treating TGCT. Pexidartinib physical function scale) Breakthrough Therapy is intended to provide a new treatment option to improve Patient-reported pain Clinical trial(s): Phase III outcomes. TGCTs typically overexpress colony- and stiffness ENLIVEN primary stimulating factor 1 (CSF1), which is an activating ligand completion date December for CSF1R. TGCT-expressed CSF1 leads to recruitment 2019; topline data reported of CSF1R-expressing cells such as osteoclasts, June 2018 macrophages, and mast cells, which initiate an inflammatory reactive process that contributes to TGCT pathogenesis. Therefore, inhibiting CSF1R by pexidartinib might limit CSF1/CSF1R-driven chemotaxis of inflammatory cells and limit the proinflammatory process underlying TGCT. In clinical trials, pexidartinib is administered orally at a dose of 1000 mg/day for 2 weeks followed by 800 mg/day for 22 weeks. Developer(s): Daiichi Sankyo, Inc (Tokyo, Japan)

Males aged 18 years or ProstAtak is a gene-mediated cytotoxic immunotherapy Radiation therapy with or Disease-free survival Clinical trial(s): Phase III older with localized prostate consisting of an adenovirus vector containing a herpes without androgen- PrTK03 primary completion cancer undergoing radiation simplex virus thymidine kinase gene (aglatimagene deprivation therapy Overall survival December 2021, designed therapy who have besadenovec) that is injected intratumorally and leads to Quality of life under Special Protocol intermediate or high-risk infected cells expressing thymidine kinase. After viral Assessment; phase II/III disease with a single high- injection, a low dose of a synthetic guanosine analogue ULYSSES primary risk feature (eg, valacyclovir) activated by thymidine kinase is completion December 2019 administered, potentially killing tumor cells expressing the transgene. The intervention is intended to provide antitumor effects while preserving critical structures around the prostate. Release of tumor-associated antigens by dying tumor cells purportedly leads to an antitumor immune response. ProstAtak is administered in 3 rounds of intratumoral aglatimagene besadenovec injection/systemic valacyclovir administration in addition to standard radiation therapy with or without androgen deprivation therapy. Developer(s): Advantagene, Inc (Auburndale, Massachusetts)

Section 1. Currently Monitored Topics 23

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Infants and children aged 2 Remestemcel-L (Prochymal) is an allogeneic Photopheresis alone or Overall survival Submission date: Rolling months to 17 years with mesenchymal precursor cell therapy that uses a donor's combined with 8- Biologics License steroid-refractory acute bone marrow and selectively expands mesenchymal stem methoxypsoralen Progression-free survival Application to begin fourth graft-versus-host disease cells. It is intended to treat GVHD that is refractory to Quality of life quarter 2019 (GVHD) steroid treatment. GVHD is a life-threatening immune Therapy with one or disorder that is a frequent complication of allogeneic more FDA designation(s): Orphan hematopoietic stem cell transplantation and affects many immunosuppressants: Drug, Fast Track organ systems. It arises when donor T cells recognize Alkylating agents (eg, Clinical trial(s): Phase III host cells as foreign by virtue of their expression of cyclophosphamide) MSB0GVHD001 completed alloantigens and mount an immune response. January 2018, 180-day Remestemcel-L purportedly secretes growth factors and Antibodies (eg, survival data reported anti-inflammatory cytokines that facilitate tissue repair by alemtuzumab, anti- September 2018 downregulating immune and inflammatory responses of thymocyte globulin) immunocompetent T cells contained in the graft. In clinical Calcineurin inhibitors trials, remestemcel-L is delivered by intravenous infusion, (eg, cyclosporine, 6 at a dose of 2 × 10 cells/kg twice a week for tacrolimus) 4 consecutive weeks. Corticosteroids (eg, Developer(s): methotrexate, Mesoblast, Ltd (Melbourne, Australia, and New York, New mycophenolate mofetil, York) prednisone) mTOR inhibitors (eg, sirolimus)

Section 1. Currently Monitored Topics 24

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 81 years Rigosertib (Estybon) is a small-molecule, multikinase Immunomodulatory Overall survival FDA designation(s): Orphan with myelodysplastic inhibitor with activity against both the alpha and beta agents (eg, Drug syndrome whose cancers isoforms of phosphoinositide 3 kinase (PI3K) and polo- ) Overall response rate Clinical trial(s): Phase III have exhibited primary like kinase 1 (). No effective treatment is available Quality of life resistance to for resistant myelodysplastic syndrome and patients INSPIRE primary hypomethylating agents (ie, generally have a poor prognosis when the syndrome has completion March 2019, disease progression without not responded to treatment with a . designed under Special attaining a complete Inhibiting PI3K is intended to disrupt cell signaling that Protocol Assessment response, partial response, promotes cell growth and survival; inhibiting PLK1 might or hematologic disrupt mitosis, leading to cell-cycle arrest in transformed improvement) cells. Rigosertib is under study in patients whose condition has not responded to first-line therapy with hypomethylating agents. In clinical trials, rigosertib is administered intravenously at a dose of 1800 mg daily for 3 days every 2 weeks for 8 cycles, then every 4 weeks until disease progression or intolerable toxicity. Developer(s): Onconova Therapeutics, Inc (Newtown, Pennsylvania)

Section 1. Currently Monitored Topics 25

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Selinexor is a first-in-class, reversible, potent, selective Chemotherapy with one Overall survival PDUFA date: Priority older with refractory or inhibitor of nuclear export that specifically binds to and or more of the following: review, July 6, 2019 relapsed multiple myeloma inhibits the nuclear export protein XPO1 (also called Progression-free survival Alkylating agents (eg, FDA designation(s): Orphan (MM) after two or more CRM1). Selinexor's novel mechanism of action is Quality of life therapies comprising intended to provide another treatment option for MM in , Drug, Fast Track cyclophosphamide) alkylating agents, patients with a poor prognosis. Selinexor's binding to Clinical trial(s): Phase III angiogenesis inhibitors, anti- XPO1 purportedly restores nuclear localization, or the Anthracyclines (eg, BOSTON primary CD38 monoclonal antibody, accumulation of tumor suppressor proteins in the cell doxorubicin) completion June 2020; glucocorticoids, and/or nucleus, thereby restoring and amplifying their tumor phase II STORM primary proteasome inhibitors suppressor function. Selinexor might also activate cancer Glucocorticoids (eg, completion April 2018, cell death (selective ) while sparing normal cells. ) topline data reported April In clinical trials, selinexor is administered orally at a dose Immunomodulatory 2018 of 60 to 80 mg twice weekly or 100 mg once weekly in agents (eg, lenalidomide, combination with various MM treatments until disease , progression or intolerable toxicity. ) Developer(s): Monoclonal antibodies Karyopharm Therapeutics, Inc (Newton, Massachusetts) (eg, , ) Proteasome inhibitors (eg, , , ) Topoisomerase inhibitors (eg, etoposide)

Section 1. Currently Monitored Topics 26

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 80 years Seviprotimut-L (POL-103A) is a polyvalent vaccine Active surveillance Recurrence-free survival FDA designation(s): Orphan with stage IIb, IIc, or III intended to induce immune responses against residual Drug who have melanoma cells after primary surgery to improve Chemotherapy with one Overall survival undergone surgical outcomes in patients at high risk of recurrence. or more of the following: Clinical trial(s): Phase III resection of the primary skin Seviprotimut-L is generated by isolating peptides secreted MAVIS primary completion BRAF inhibitors (eg, January 2019 lesion and have a high risk by 3 human melanoma cell lines grown in culture. The ) of recurrence isolated peptides are combined with an adjuvant (aluminum hydroxide) to generate the vaccine. The Immune checkpoint polyvalent nature of the vaccine purportedly allows its use inhibitors (eg, nivolumab, in all patients irrespective of tumor and/or human pembrolizumab) leukocyte antigen genotypes. In clinical trials, MEK inhibitors (eg, seviprotimut-L is administered in 4 injections (0.2 mL ) each) into the volar surface of forearms and anterior upper thighs. Developer(s): Polynoma, LLC (San Diego, California)

Children aged 1 month to 18 Sodium thiosulfate (Pedmark) is a proprietary formulation Platinum-based Ototoxicity Submission date: Rolling years with localized, that inactivates the metabolic byproducts of systemic chemotherapy (eg, New Drug Application nonmetastatic, solid tumors platinum-based (cisplatin) chemotherapy. It is intended to cisplatin) alone without Hearing ability initiated December 2018 eligible for cisplatin reduce the risk of cisplatin-induced ototoxicity, a common adjuvant preventive Quality of life chemotherapy side effect that can damage hearing and for which no therapy FDA designation(s): Orphan effective treatment is available. Sodium thiosulfate Drug, Fast Track, purportedly acts only on cisplatin metabolites in general Breakthrough Therapy circulation and does not interfere with cisplatin Clinical trial(s): Phase III effectiveness within targeted tumor cells. In clinical trials, completed April 2015, data sodium thiosulfate is administered intravenously at a dose published January 2017; of 16 g/m2 or 533 mg/kg, 6 hours after receiving cisplatin- phase III SIOPEL6 based chemotherapy. Treatment with sodium thiosulfate completed February 2018, continues until completion of cisplatin treatment. data published June 2018 Developer(s): Fennec Pharmaceuticals, Inc (Research Triangle Park, North Carolina)

Section 1. Currently Monitored Topics 27

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Synthetic hypericin (SGX301) is a photosensitizing agent Chemotherapy Overall survival FDA designation(s): Orphan older with newly diagnosed for use with visible light. Standard care for CTCL often Drug, Fast Track patch/plaque-phase requires with ultraviolet light, which Ultraviolet A Damage to tumor- cutaneous T-cell can damage surrounding tissue and lead to skin burns, phototherapy with adjacent tissue Clinical trial(s): Phase III (CTCL) who have received increased pigmentation, or secondary skin cancer. psoralen FLASH primary completion Progression-free survival December 2019 no systemic therapy SGX301 purportedly clears CTCL lesions without Ultraviolet B increasing the patient's risk for skin burns. In clinical phototherapy Quality of life trials, SGX301 is applied topically to the CTCL lesion twice weekly (covered with an opaque bandage for 12-24 hours) followed by fluorescent light activation of the compound. Developer(s): Soligenix, Inc (Princeton, New Jersey)

Children and adults of all Tabelecleucel (Tab-cel) is a chimeric antigen receptor Chemotherapy with one Overall survival FDA designation(s): Orphan ages who developed (CAR) T-cell immunotherapy engineered to target EBV or more of the following: Drug, Breakthrough Therapy Epstein-Barr virus– antigens using allogeneic and haploidentical (half match) Progression-free survival Adrenocortical steroid Clinical trial(s): Phase III associated post-transplant cytotoxic T (CTLs). Haploidentical CTLs are Quality of life lymphoproliferative disorder typically obtained from a parent or child, or, in some (eg, prednisolone) MATCH primary completion November 2020; phase III (EBV+PTLD) after receiving cases, a sibling. The collected CTLs are transduced with Alkylating agent (eg, an allogeneic hematopoietic an adenoviral vector (AdE1-LMPpoly) encoding CARs ALLELE primary completion cyclophosphamide, November 2020 cell transplant or solid organ that target epitopes from EBV nuclear antigen 1, latent ) transplant and whose membrane protein 1, and latent membrane protein 2A. disease has not responded AdE1-LMPpoly also encodes for a PD-1-dominant Antitumor (eg, to negative receptor to shield the CAR CTLs from ) checkpoint inhibition. The EBV-specific CAR-transduced Anthracyclines (eg, CTLs are proliferated and frozen until ready to be doxorubicin) introduced into a patient. Tabelecleucel purportedly offers immunity against EBV-associated malignancies in Vinca alkaloid (eg, patients who have received a hematopoietic cell , vincristine) transplant or organ transplant. EBV+PTLD can be hard to treat with standard therapies, and treatment is associated with many comorbidities. In clinical trials, tabelecleucel is administered as an intravenous infusion, at a dose of 2 × 106 cells/kg on days 1, 8, and 15 of a 35-day cycle until maximal response or unacceptable toxicity. Developer(s): Atara Biotherapeutics, Inc (South San Francisco, California), in collaboration with Memorial Sloan Kettering Cancer Center (New York, New York)

Section 1. Currently Monitored Topics 28

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

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

Section 1. Currently Monitored Topics 29

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Patients of any age with Varlitinib (ASLAN001) is a small-molecule inhibitor of the Chemotherapy with one Overall survival FDA designation(s): Orphan advanced, unresectable epidermal (EGFR) family of or more of the following: Drug biliary tract cancer (eg, receptor tyrosine kinases, including human EGFR Progression-free survival Antimetabolites (eg, Clinical trial(s): Phase II/III cholangiocarcinoma, gall (HER1), HER2, and HER4. Because no EGFR inhibitors Quality of life bladder cancer, carcinoma have been approved for biliary tract cancer, this might 5-fluorouracil, TreeTopp primary of ampulla of Vater) who offer an option for these patients, who have few effective capecitabine, completion July 2019 have received one prior treatments, particularly in the second-line setting. EGFR gemcitabine) round of gemcitabine-based signaling promotes biliary tract cell growth and Immune checkpoint systemic therapy proliferation, and the majority of biliary tract cancers inhibitors (eg, nivolumab, overexpress EGFR; therefore, inhibiting the EGFR family pembrolizumab) for of receptor tyrosine kinases might have efficacy in these patients with defects in cancers. In clinical trials, varlitinib is administered orally at mismatch repair or a dose of 300 mg twice daily in combination with microsatellite instability capecitabine until disease progression or intolerable toxicity. Platinum agents (eg, cisplatin, oxaliplatin) Developer(s): Aslan Pharmaceuticals (Singapore, Republic of Singapore), in collaboration with Array BioPharma, Inc (Boulder, Colorado)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

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

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 75 years Vocimagene amiretrorepvec (Toca 511) is a cancer- Fractionated external Overall survival FDA designation(s): Orphan with recurrent high-grade selective comprising a retroviral replicating beam radiation therapy Drug, Breakthrough glioma (eg, glioblastoma vector that stably inserts itself into the genome of dividing Progression-free survival Therapy, Fast Track Chemotherapy with one multiforme, anaplastic cells. Toca 511 has been genetically modified to encode Quality of life astrocytoma) who have the enzyme cytosine deaminase, a prodrug activator or more of the following: Clinical trial(s): Phase II/III Toca5 primary completion undergone surgical enzyme that converts the orally administered antifungal Alkylating agents (eg, resection and completed prodrug Toca FC (5-fluorocytosine) to the anticancer December 2019, interim carmustine, data reported August 2018 adjuvant radiation and agent 5-fluorouracil (5-FU) in cells. Toca 511 is intended cyclophosphamide, temozolomide therapy to improve outcomes by purportedly generating high lomustine, procarbazine, levels of 5-FU in replicating glioma cells to cause cell temozolomide) death. In clinical trials, 4 mL of Toca 511 is injected into the wall of the resected tumor cavity on day 1 (about 40 Angiogenesis inhibitors injections of 0.1 mL). At least 6 weeks after resection, (eg, bevacizumab) Toca FC is administered orally at a dose of 220 mTOR inhibitors (eg, mg/kg/day for 7-day courses and repeated about every everolimus) 6 weeks. Platinum agents (eg, Developer(s): carboplatin, cisplatin) Tocagen, Inc (San Diego, California) Vinca alkaloids (eg, vincristine)

Section 1. Currently Monitored Topics 32

Table 3. Cardiovascular Diseases: 8 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Apabetalone is a novel epigenetic selective inhibitor of Statins MACE Clinical trial(s): Phase III older with type 2 diabetes bromodomain extra-terminal (BET) proteins intended to BETonMACE primary mellitus (T2DM) and high- reduce incidence of major adverse cardiac events Bile-acid-binding resins All-cause mortality completion June 2019 risk coronary artery disease, (MACE) in high-risk patients with T2DM. By blocking Ezetimibe Kidney function defined as having had acute BET proteins at the transcription level, apabetalone coronary syndrome purportedly slows the abnormally increased production of Fibrates (myocardial infarction or dysregulated, disease-associated proteins, moving them Niacin unstable angina) within the closer to normal levels. Apabetalone is intended to reduce past 90 days and a low level MACE by reducing various mediators that promote of high-density lipoprotein vascular inflammation, calcium deposition, coagulation cholesterol cascade, and other mechanisms, including metabolism, cholesterol transport, and the complement cascade. Developer(s): Resverlogix Corp (Calgary, Alberta, Canada)

Section 1. Currently Monitored Topics 33

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 21 to 90 years CardiAMP cell therapy is a novel regenerative medicine Aldosterone receptor NYHA HF functional Clinical trial(s): Phase III with New York Heart therapy that delivers autologous bone marrow–derived antagonists class CardiAMP primary Association (NYHA) mononuclear cells to damaged heart muscle. It is completion June 2020 functional class II or III heart intended to improve heart function and exercise capacity Angiotensin-converting Exercise tolerance enzyme (ACE) inhibitors failure (HF) who have through two mechanisms: direct and indirect –related chronic ischemic left regeneration. In direct regeneration, the transplanted cells Angiotensin II receptor hospitalizations ventricular dysfunction purportedly travel to injured myocardium and differentiate blockers (ARBs) secondary to myocardial into new functional heart cells. In indirect regeneration, Mortality Beta blockers infarction, with ventricular the transplanted cells purportedly secrete stimulatory Quality of life ejection fraction between cytokines to instruct resident stem cells to initiate tissue Digoxin 20% and 40% on stable, regeneration. Clinicians first collect about 15 cc of bone guideline-directed medical marrow aspirate and send it to a partner laboratory for Diuretics and device therapy for HF proprietary molecular analysis to estimate a candidate's Hydralazine/nitrate likelihood of successful cell therapy. If assay results are positive, patients return to the cardiac catheterization Ivabradine laboratory after 3 or more days to undergo the procedure. Clinicians collect about 60 cc of bone marrow aspirate /valsartan from the patient to concentrate a sufficient dose of autologous cells at the point of care and inject the prepared cell product into the myocardium, using a proprietary needle-injection catheter. Patients are discharged the same day or the next day. Developer(s): BioCardia, Inc (San Carlos, California)

Section 1. Currently Monitored Topics 34

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 45 years or Dalcetrapib is an inhibitor of cholesteryl ester transfer Angiotensin-converting Major cardiovascular Clinical trial(s): Phase III dal- older who were recently protein (CETP), a plasma protein responsible for lipid enzyme (ACE) inhibitors adverse events (MACE), GenE primary completion hospitalized for acute transport. Dalcetrapib was originally developed to raise including cardiovascular August 2020 coronary syndrome and in high-density lipoprotein levels by modulating CETP Angiotensin II receptor death, myocardial whom the AA polymorphism activity and presumably lower cardiovascular risk by blockers (ARBs) infarction, and at the rs1967309 location in helping to lower levels of harmful low-density lipoproteins. Antiplatelet drugs the adenylate cyclase type However, although dalcetrapib failed to reduce 9 gene, ADCY9, has been cardiovascular events in large phase III trials, patients Beta blockers diagnosed treated with dalcetrapib who carried the AA polymorphism Bile-acid sequestrants at the rs1967309 location in the ADCY9 gene showed a 39% drop in cardiovascular adverse events. DalCor Calcium channel licensed dalcetrapib and the AA allele genetic marker blockers from Roche for use in a genetically defined subpopulation Ezetimibe at increased cardiovascular risk. Roche is developing a companion diagnostic test to identify potential candidates Fibrates for dalcetrapib therapy in a phase III trial, which is also testing the drug. Dalcetrapib is administered orally, 600 Niacin mg, once daily. Proprotein convertase Developer(s): subtilisin kexin 9 (PCSK9) inhibitors DalCor Pharmaceuticals (Montreal, Québec, Canada), in collaboration with F. Hoffmann-La Roche, Ltd (Basel, Ranolazine Switzerland) Statins

Adults aged 18 to 85 years Omecamtiv mecarbil is a cardiac myosin activator Aldosterone receptor NYHA heart failure Clinical trial(s): Phase III with chronic heart failure, intended to increase the duration of cardiac muscle antagonists functional class GALACTIC-HF primary New York Heart Association contractility and improve cardiac muscle performance. completion January 2021, (NYHA) functional class II to The mechanism of action purportedly improves cardiac Angiotensin-converting Improved exercise designed under Special IV, left ventricular ejection muscle performance without increasing cellular calcium enzyme (ACE) inhibitors tolerance Protocol Assessment; phase fraction of 35% or less concentrations that can occur with other common heart Angiotensin II receptor Heart failure–related III METEORIC-HF primary despite maximally tolerated, failure drugs, thereby avoiding risk of increasing heart blockers (ARBs) hospitalizations completion February 2021 guideline-directed medical rate, blood pressure, and arrhythmias. In clinical trials, therapy, and elevated levels omecamtiv mecarbil is administered orally at 25 to 50 mg, Beta blockers Mortality of B-type twice daily. Digoxin Quality of life or N-terminal pro b-type natriuretic peptide Developer(s): Diuretics Cytokinetics, Inc (South San Francisco, California), in Hydralazine/nitrate collaboration with Amgen, Inc (Thousand Oaks, California) Ivabradine Sacubitril/valsartan

Section 1. Currently Monitored Topics 35

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Optimizer is a cardiac implant that delivers nonexcitatory Aldosterone receptor NYHA heart failure Approval date: March 21, older with New York Heart electrical pulses during the myocardial absolute refractory antagonists functional class 2019 Association (NYHA) period in an effort to improve systolic contraction. Called functional class III heart cardiac contractility modulation (CCM), this action Angiotensin-converting Exercise tolerance FDA designation(s): enzyme (ACE) inhibitors Breakthrough Device failure who remain purportedly normalizes phosphorylation of regulatory Heart failure–related symptomatic despite proteins to improve calcium handling—ultimately Angiotensin II receptor hospitalization Clinical trial(s): Unphased guideline-directed medical interrupting the remodeling cascade to reverse left blockers (ARBs) FIX-HF-5C2 primary therapy and are in normal ventricular remodeling—and to improve left ventricular Mortality completion November 2019; Beta blockers sinus rhythm with left contractile strength. Physicians implant the pulse Quality of life unphased FIX-HF-5CA ventricular ejection fraction generator subcutaneously in the right pectoral region Digoxin primary completion January between 25% and 45% similarly to standard pacemaker or defibrillator 2020 implantation. Two standard pacemaker leads are placed Diuretics transvascularly into the right ventricle on the right Hydralazine/nitrate ventricular septum to sense local electrical activity and deliver CCM. An optional atrial lead may be placed in the Ivabradine right atrium for additional electrical sensing. The device delivers pulses at regular intervals during the day, Sacubitril/valsartan purportedly unnoticed by patients. Patients recharge the pulse generator at home for 60 to 90 minutes once a week, using a noninvasive charging system placed over the implant. The Optimizer Smart model replaced all earlier Optimizer versions (II, III, IV) used in clinical trials since 2016. Developer(s): Impulse Dynamics (USA), Inc (Orangeburg, New York)

Section 1. Currently Monitored Topics 36

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 45 to 99 years Placental expanded cells for treating peripheral artery Antiplatelet therapy Wound healing in the FDA designation(s): Fast with critical limb ischemia disease (PLX-PAD) are mesenchymal-like adherent treated leg Track, Expanded Access and ischemic lesions with stromal cells derived from full-term human placentas and Bile-acid-binding resins Program (EAP), EAP Cost Ischemic pain minor tissue loss up to the cultured in a proprietary bioreactor. PLX-PAD cells Cilostazol Recovery ankle level (Rutherford purportedly release cytokines, chemokines, and growth Major amputation category 5) and deemed factors to promote angiogenesis and increase circulation Ezetimibe Clinical trial(s): Phase III PACE primary completion unsuitable for peripheral in ischemic tissue, induce muscle tissue regeneration, Fibrates artery revascularization by and modulate inflammation to reduce connective tissue May 2020 any conventional method deposition and scarring. Clinicians administer the cell Niacin product by intramuscular injection to the affected leg. Pentoxifylline Developer(s): Proprotein convertase Pluristem Therapeutics, Inc (Haifa, Israel) subtilisin kexin 9 (PCSK9) inhibitors Statins

Adults aged 18 to 80 years Revascor (MPC-150-IM) cellular therapy is a regenerative Aldosterone receptor NYHA heart failure Clinical trial(s): Phase III with chronic (diagnosed for therapy made from human bone marrow–derived, antagonists functional class DREAM HF-1 primary at least 6 months) ischemic allogeneic adult mesenchymal precursor cells (MPCs) completion December 2019 or nonischemic New York isolated from bone mononuclear cells with anti-stromal ACE inhibitors Exercise tolerance Heart Association (NYHA) precursor antigen (STRO)-3 antibodies, expanded ex Angiotensin II receptor Heart failure–related functional class II or III heart vivo, and cryopreserved until it is administered. MPCs blockers (ARBs) hospitalizations failure on stable, maximally purportedly release a range of factors when triggered by tolerated doses of a beta- specific receptor-ligand interactions within heart damaged Beta blockers Mortality blocker, an angiotensin- tissue. These factors are believed to induce functional Digoxin Quality of life converting enzyme (ACE) cardiac recovery by activating multiple pathways to inhibitor or angiotensin- induce new blood vessel growth, reduce inflammation, Diuretics receptor blocker, and/or an reduce fibrosis and scar tissue formation, and regenerate Hydralazine/nitrate aldosterone antagonist, plus heart muscle. The product is intended to be an off-the- a diuretic shelf therapy administered as a single injection of 25 Ivabradine million to 150 million cells delivered into the endocardium using standard cardiac catheterization techniques. Sacubitril/valsartan Developer(s): Mesoblast, Ltd (Melbourne, Australia)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Wireless Stimulation Endocardially for Cardiac Aldosterone receptor New York Heart Clinical trial(s): IDE pivotal older with heart failure and Resynchronization Therapy (WiSE-CCRT) purportedly antagonists Association (NYHA) (SOLVE CRT) primary a class I or IIa guideline improves on conventional CRT devices. It replaces heart failure functional completion September 2019; indication for conventional epicardial left ventricular pacing stimulation from an Angiotensin-converting class CT Guided WiSE-CRT cardiac resynchronization electrode lead placed within the coronary sinus vein along enzyme (ACE) inhibitors primary completion Exercise tolerance therapy (CRT) and whose the left ventricular wall with endocardial left ventricular Angiotensin II receptor December 2020 disease either does not pacing from a wireless electrode implanted inside the left blockers (ARBs) Heart failure–related respond to CRT or was ventricle. A conventional pacemaker implanted hospitalizations previously untreatable, subcutaneously in the chest senses and paces the right Beta blockers Mortality defined as having an ventricle with a conventional right atrial lead and a right Conventional implanted CRT system ventricular lead. A wireless electrode (2.7 × 16.3 mm) biventricular Quality of life turned off due to electrode anchored in the left ventricular wall paces the left pacing/cardiac lead failure or relative ventricle. A wireless transmitter placed subcutaneously in resynchronization contraindications to an the chest senses the right ventricular pacing and sends therapy with epicardial implanted lead ultrasound energy to the implant to generate endocardial left ventricular lead left ventricular pacing in synchrony with right-sided pacing. A battery pack placed subcutaneously along the Digoxin patient’s ribs and under the arm powers the wireless Diuretics transmitter via a thin cable tunneled under the skin. Hydralazine/nitrate Developer(s): Ivabradine EBR Systems, Inc (Sunnyvale, California) Sacubitril/valsartan

Section 1. Currently Monitored Topics 38

Table 4. Mental and Behavioral Health: 8 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 55 years Dasotraline is a dual-acting dopamine and Lisdexamfetamine Binge days per week Clinical trial(s): Phase II/III with moderate to severe reuptake inhibitor (DNRI) that purportedly reduces the (Vyvanse) completed October 2016; (BED) frequency of binge eating episodes in patients with BED. BED severity phase III completed May Dasotraline has a novel mechanism of action relative to Off-label 2018, pivotal phase III data pharmacotherapies (eg, Cessation of binge Vyvanse (Takeda Pharmaceutical Co, Ltd, Osaka, eating reported July 2018; phase Japan), the only FDA-approved for BED, and antiepileptics, III extension primary might offer a safer, more effective alternative to patients norepinephrine reuptake completion June 2019 with BED. Dasotraline was given to participants in a inhibitors [NRIs], randomized, controlled trial twice a day (4 or 6 mg/day) serotonin-norepinephrine for 12 weeks. reuptake inhibitors [SNRIs]) Developer(s): Sunovion (Marlborough, Massachusetts), a subsidiary of Sumitomo Dainippon Pharma (Osaka, Japan)

Adults aged 22 to 68 years Deep transcranial magnetic stimulation (deep TMS) is a Off-label use of repetitive PTSD symptoms and Clinical trial(s): Unphased with moderate to severe noninvasive outpatient treatment that uses directed TMS severity primary completion June posttraumatic stress electromagnetic fields to target and stimulate the 2019; phase I/II completed disorder (PTSD) prefrontal cortex to treat PTSD. The unique coil design Psychotherapy (cognitive Change in cognitive July 2011, data published allows for deeper stimulation at safe stimulation levels behavioral therapy function May 2013 [CBT], prolonged and purportedly reduces PTSD symptoms and severity. In Adverse events an ongoing trial, the treatment is given in 20-minute exposure therapy [PET], sessions, 3 times a week for 4 weeks, with a booster eye movement treatment at week 5 and another at week 9, totaling desensitization and 14 treatment sessions. At least 8 sessions are required reprocessing [EMDR] therapy) for treatment. The manufacturer purports that the H1 coil used in the device stimulates deeper regions of the Selective serotonin prefrontal cortex than the figure-8 coil used in repetitive reuptake inhibitors TMS. The treatment is intended as an adjunct to (, ) pharmacologic and/or psychological treatment. Developer(s): BrainsWay, Ltd (Hackensack, New Jersey)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 64 years HCL nasal spray (Spravato) is the (S+)- Psychotherapy Depression symptoms Approval date: March 6, with treatment-resistant enantiomer of , delivered through a single-use and severity 2019 major depressive disorder intranasal device. The drug is indicated for use in Selective serotonin (MDD) with no response to combination with an oral for treatment- reuptake inhibitors Functional impairment FDA designation(s): two or more currently resistant depression in adults. Esketamine is absorbed by (SSRIs) and associated disability Breakthrough Therapy available antidepressants of the lining of the nasal passages and into the bloodstream, Serotonin- Adverse events Clinical trial(s): Phase III adequate dose and duration purportedly leading to rapid (within hours) improvement in norepinephrine reuptake TRANSFORM-1 completed in the current moderate to depression-symptom severity in patients with MDD. inhibitors (SNRIs) Severity of February 2018; phase III severe episode of Esketamine works through noncompetitive antagonism of psychopathology TRANSFORM-2 completed Tricyclic antidepressants depression the N-methyl-D-aspartate (NMDA) receptor. Blocking November 2017; phase III (TCAs) Overall activation of the NMDA receptor facilitates sensory input, SUSTAIN-1 completed moderates emotional responses, and might increase Monoamine oxidase Health-related quality of February 2018; phase III dopamine, norepinephrine, and serotonin levels in the inhibitors (MAOIs) life and health status SUSTAIN-2 completed brain. The single-use nasal spray device contains 28 mg October 2017; phase III of esketamine HCL and delivers two 14-mg sprays per Transcranial magnetic SUSTAIN-3 primary device. Treatment is initiated in the induction phase stimulation (TMS) completion August 2021 at weeks 1 to 4 at a dose of 56 mg on day 1 and 56 or Deep brain stimulation 84 mg subsequently, twice weekly. During the maintenance phase, from weeks 5 to 8, esketamine is Vagal nerve stimulation administered once weekly at a dose of 56 or 84 mg, and Electroconvulsive from week 9 and after, it is given every 1 or 2 weeks at a therapy dose of 56 or 84 mg. Off-label intravenous Developer(s): ketamine Janssen Research & Development, LLC, unit of Johnson & Johnson (New Brunswick, New Jersey)

Section 1. Currently Monitored Topics 40

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 75 years External trigeminal nerve stimulation (eTNS) sends Psychotherapy (cognitive PTSD severity and Clinical trial(s): Phase I with posttraumatic stress electrical stimulation to the trigeminal nerve through a behavioral therapy symptoms completed January 2012, disorder (PTSD) patch placed on the forehead to treat patients with PTSD, [CBT], prolonged data published April 2016; which has limited, effective treatment options. This small exposure therapy [PET], Depression severity and unphased primary portable device is intended to improve patient symptoms eye movement symptoms completion September 2019 and symptom severity and quality of life and might desensitization and Life functional capacity provide an additional treatment option for patients with reprocessing [EMDR] PTSD. The eTNS system is a cell phone–sized electrical therapy) Autonomic function pulse generator that delivers mild electrical signals via 2 Quality of life wires connected to a small single-use electric patch that Selective serotonin adheres to the forehead. The therapy is intended to be reuptake inhibitors self-administered at home for 8 hours a day, while (sertraline, paroxetine) sleeping, as an adjunct to pharmacotherapy. The eTNS therapy purportedly changes the neuronal activity in key regions of the brainstem, thalamus, and cortex, increasing activity in underactive regions. It is used in conjunction with pharmacotherapy. Developer(s): Neurosigma (Los Angeles, California), in collaboration with University of California (Los Angeles, California)

Adults aged 18 to 65 years Ketamine, an anesthetic that is an N-methyl-D-aspartate Psychotherapy (eg, PTSD severity and Clinical trial(s): Phase II/III who fulfill DSM-5 criteria for (NMDA) and cognitive behavioral symptoms primary completion January current civilian or combat- modulator, purportedly restores synaptic connections in therapy [CBT], prolonged 2020 (repeated dose); related posttraumatic stress the brain. As such, it purportedly has potential to provide exposure therapy [PET], Depression symptoms phase II completed disorder (PTSD) rapid and sustained therapeutic effects for patients with eye movement Adverse effects September 2013 (single PTSD. In the most recent clinical trial, participants were desensitization and dose), data published June given 0.5 mg/kg doses of ketamine intravenously 3 times reprocessing [EMDR] 2014 a week for 2 weeks, for 6 total doses. The active control therapy) was midazolam, a similar acute anesthetic not shown to be effective in treating PTSD. After treatment, patients Selective serotonin must be monitored for at least 4 hours before discharge. reuptake inhibitors (SSRIs; eg, sertraline, Developer(s): paroxetine) Icahn School of Medicine at Mount Sinai (New York, New Off-label use of repetitive York) in collaboration with VA Office of Research and transcranial magnetic Development (Washington, DC) stimulation (rTMS)

Section 1. Currently Monitored Topics 41

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 65 years Oxytocin administered intranasally purportedly mitigates Antipsychotics (oral and Social cognition Clinical trial(s): Unphased with schizophrenia negative symptoms associated with schizophrenia by injectable) completed August 2012, increasing oxytocin levels. Oxytocin is a naturally Negative schizophrenia data published July 2013; occurring hormone that works as a neurotransmitter in the Antidepressants symptoms phase II completed July (selective serotonin brain. Other antipsychotic drugs have been used Quality of life 2014; phase II completed successfully to treat the positive symptoms of patients reuptake inhibitors November 2015, data with schizophrenia but have minimal effects on negative [SSRIs] and serotonin published April 2016; symptoms and cognitive deficits. Studies have shown that and norepinephrine unphased primary patients with schizophrenia have lower oxytocin levels, reuptake inhibitors completion June 2019 which has been associated with impaired trust, empathy, [SNRIs]) and ability to interpret mental states, as well as decreased Combination therapy cortisol release and anxiety. Oxytocin might help normalize social dysfunction in patients with Electroconvulsive schizophrenia. It has been studied both as a standalone therapy and an adjunct treatment. In the most recent clinical trial, Mood stabilizers oxytocin was used in combination with . In this study, oxytocin is administered intranasally at a dose of Psychotherapy (cognitive three 4-IU puffs per nostril for a total dose of 24 IU. Other behavioral therapy trials used doses of 24 to 80 IU per day, for 1 to 6 weeks, [CBT]) and a dose-range study evaluated doses of 6 to 84 IUs. Trials have studied single-dose treatments as well as daily treatment for up to 4 weeks. Developer(s): Emory University (Atlanta, Georgia) in collaboration with Atlanta VA Medical Center (Atlanta, Georgia)

Section 1. Currently Monitored Topics 42

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adolescents aged 12 years Sodium benzoate (NaBen) is a prescription-strength Antipsychotics (oral and Positive and negative FDA designation(s): Orphan or older, adults aged 18 to formulation of the sodium salt often used as a common injectable) schizophrenia symptoms Drug, Breakthrough 55 years with a confirmed food preservative. Existing pharmacotherapies for Therapy DSM-IV or DSM-5 diagnosis schizophrenia have limited efficacy in reducing both Antidepressants Efficacy of antipsychotics (selective serotonin Clinical trial(s): Phase IIb/III of schizophrenia who are positive and negative symptoms in patients with Quality of life clinically stable with residual schizophrenia, and many are associated with serious side reuptake inhibitors primary completion symptoms, and adults aged effects. A key factor in schizophrenia pathophysiology is [SSRIs] and serotonin December 2018; phase and norepinephrine IIb/III primary completion 18 to 55 years with N-methyl-D-aspartate (NMDA) receptor hypofunctioning. treatment-refractory NaBen inhibits D-amino acid oxidase (DAAO) reuptake inhibitors June 2019 schizophrenia metabolism, increasing DAAO activity, leading to [SNRIs]) production of more D-, which increases NMDA Combination therapy activity in the hypothalamus. Increasing NMDA activity affects both positive and negative schizophrenia Mood stabilizers symptoms. In ongoing phase IIb trials for patients with Psychotherapy (cognitive clinically stable schizophrenia, 500 mg NaBen oral tablets behavioral therapy are administered twice daily at a total dose of [CBT]) 1000 mg/day for 6 to 8 weeks. Participants' current antipsychotic medication regimens remained unchanged for at least 8 weeks before study screening and will remain unchanged during the study. In an ongoing phase IIb trial for patients with treatment-refractory schizophrenia, two 500-mg NaBen oral tablets are administered twice daily, at a total dose of 2000 mg/day, or one 500-mg NaBen oral is administered twice daily, at a total dose of 1000 mg/day, for 8 weeks, with participants’ current dose of clozapine. Participants' clozapine regimens remained unchanged for at least 3 months before study screening and during the study. After the 6 to 8-week treatment, phase III open-label extension studies will continue treatment for a randomized sample of these participants. Developer(s): SyneuRx International (Taiwan) Corp (Taipei, Taiwan)

Section 1. Currently Monitored Topics 43

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 21 to 70 years Zonisamide (Zonegran) is a sulfonamide anticonvulsant Pharmacotherapy (eg, consumption Clinical trial(s): Pilot with alcohol use disorder demonstrated to modulate GABAergic and glutamatergic acamprosate, disulfiram, unphased completed March (AUD) neurotransmission. Approved for treating naltrexone) Alcohol cravings 2009; pilot phase IV AUD have shown limited effectiveness; only one-third of completed May 2009; phase Psychotherapy (cognitive Alcohol withdrawal patients achieve full remission with available therapies. symptoms III primary completion Zonisamide is intended to reduce alcohol consumption in behavioral therapy October 2018; phase III patients with heavy drinking behaviors or AUD; treatment [CBT]) Relapse primary completion with zonisamide might also ameliorate the symptoms of Quality of life February 2021 alcohol withdrawal syndrome. In completed and ongoing clinical trials, zonisamide is administered orally, at doses Health outcomes up to 500 mg daily. associated with abstinence Developer(s): VA Office of Research and Development (Washington, DC)

Section 1. Currently Monitored Topics 44

Table 5. Rare Diseases: 13 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Neonates aged up to 28 ALXN1101 is intended to minimize disease burden of Anticonvulsants Survival at 12 months FDA designation(s): days with molybdenum MoCD type A, an ultra-rare, life-threatening, genetic Breakthrough Therapy deficiency (MoCD) metabolic disorder that causes catastrophic and Supportive care Ability to sit upright independently for at least Clinical trial(s): Phase II/III type A irreversible neurologic damage within the first weeks of Ventilator life. MoCD Type A is caused by a mutation in the 30 seconds at 12 months primary completion September 2019 molybdenum cofactor synthesis 1 gene, MOCS1, that Bayley Scales of Infant converts guanosine triphosphate (GTP) to cyclic Development at 12 pyranopterin monophosphate (cPMP), an intermediate months in the synthesis of molybdenum cofactor (MoCo). ALXN1101 is a synthetic version of cPMP. It is intended Pediatric Evaluation of to restore MoCo levels and sulfite oxidase activity, Disability Inventory promoting the clearance of the neurotoxic metabolite (PEDI) at 12 months sulfite. In a clinical trial, ALXN1101 is given daily intravenously at a dose of 80 to 320 μg/kg. Developer(s): Origin Biosciences (Palo Alto, California), a subsidiary of BridgeBio Pharma (Palo Alto, California)

Adults aged 18 years or (Otezla) is a drug approved for other Corticosteroids Visual symptoms FDA designation(s): Orphan older with active Behçet's indications and under study for treating Behçet's disease, Drug disease which has few treatment options. The drug inhibits Immunosuppressants Pain, frequency, or phosphodiesterase type 4 and increases intracellular (eg, , duration of oral and Clinical trial(s): Phase III cyclic AMP, which decreases proinflammatory mediators cyclosporine) genital ulcers primary completion September 2017, pivotal such as tumor necrosis factor (TNF)-alpha, Nonsteroidal anti- Disease progression (IL)-17, and IL-23. Blood vessel inflammation, which is data reported February inflammatory drugs 2018, data from meeting characteristic of Behçet's disease, has been linked by (NSAIDs) Quality of life investigators to overactive Th17 cells and increased abstract reported March IL-17 production, suggesting apremilast might alleviate 2019 Behçet's disease symptoms, including oral ulcers. In Note(s): FDA-approved clinical trials, the drug is administered orally at a dose of March 2014 for treating 30 mg, twice daily. psoriatic arthritis. FDA- Developer(s): approved September 2014 for treating plaque psoriasis. Celgene Corp (Summit, New Jersey)

Section 1. Currently Monitored Topics 45

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (BRX-345) is a small-molecule amine Combined assessment Submission date: New Drug older with amyotrophic intended for treating ALS. In patients with ALS, abnormal of function and survival, Application anticipated lateral sclerosis (ALS) protein aggregates in the brain cause neuronal death and Edaravone as measured by second half of 2021 contribute to disease progression. The exact cause of Supportive care accepted clinical ratings these aggregates is unknown, but patients with inherited and scales FDA designation(s): Orphan forms of ALS harbor mutations in genes, such as copper- Drug Time to permanent superoxide dismutase 1 gene, SOD1, which might Clinical trial(s): Phase III contribute to neuronal protein aggregation. FDA-approved assisted ventilation, tracheostomy, or death ORARIALS-01 primary drugs for treating the disease (eg, riluzole, edaravone) completion December 2020; can decrease symptom severity for some patients, but do Functional capacity, as planned phase III open-label not block disease progression. Therefore, additional measured by accepted extension primary therapies are needed. Arimoclomol purportedly increases clinical ratings and completion July 2022 the activity of heat shock factor 1, a transcription factor scales that promotes expression of heat shock proteins, which in turn regulate protein folding and degradation of misfolded Breathing function and proteins. An initial proof-of-concept study of arimoclomol quality found that in animal models expressing SOD1 mutations, arimoclomol administration alleviated oxidative stress and reduced misfolded protein aggregates containing mutant SOD1. Phase II trials of arimoclomol were limited to patients with inherited, SOD1 mutation–positive ALS, but the drug's manufacturer expanded its phase III trials to include patients with sporadic, noninherited forms of the disease. If effective, arimoclomol could reduce protein aggregate formation and improve disease symptoms in patients with ALS. In clinical trials, patients self-administer arimoclomol orally; one recent trial reported giving a dosage of 200 mg 3 times daily for up to 12 months; the dosage in the ongoing phase III trial has not been specified. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)

Section 1. Currently Monitored Topics 46

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Budesonide (Nefecon) is a synthetic corticosteroid Corticosteroids Proteinuria change from FDA designation(s): Orphan older with biopsy-proven intended to treat IgA nephropathy, also known as Berger baseline Drug immunoglobulin A (IgA) disease, which occurs when IgA antibody complexes Immunosuppressants nephropathy whose accumulate in the kidneys. IgA nephropathy causes local (eg, mycophenolate, Occurrence of end-stage Clinical trial(s): Phase III estimated glomerular inflammation and reduced glomerular filtration and leads azathioprine, renal disease Nefigard primary completion cyclophosphamide) October 2020 filtration rate (eGFR) is to chronic kidney disease within 10 to 20 years in 20% to Change in eGFR from between 45 and 90 40% of affected patients. Standard of care (high-dose baseline mL/min/1.73 m2 (stage 2 to systemic corticosteroids) has been controversial because 3A chronic kidney disease) of the increased risks of adverse events and serious Change in quality of life and who have medically infections, hypertension, weight gain, diabetes mellitus, from baseline controlled blood pressure and osteoporosis. Budesonide, a targeted therapy intended to avert systemic side effects, is delivered to the Peyer patches of the small intestine, where IgA complexes are thought to originate. The manufacturer's proprietary TARGIT technology is used to deliver the therapy. Drug tolerability is purportedly optimized due to the drug's low (about 90% is inactivated in the liver before reaching the circulation) compared with corticosteroids typically used for treating IgA nephropathy. In clinical trials, budesonide is administered 16 mg orally, once daily, for 9 months. Developer(s): Calliditas Therapeutics AB (Stockholm, Sweden)

Section 1. Currently Monitored Topics 47

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or -yhdp (Cablivi) is a highly potent and Antiplatelet therapy Disease recurrence Approval date: February 6, older with acquired selective bivalent antibody fragment targeting von 2019 thrombotic Willebrand factor and designed to treat aTTP, which Corticosteroids Major thromboembolic thrombocytopenic purpura develops when the spleen produces antibodies against events FDA designation(s): Orphan Cyclosporine A Drug, Priority Review (aTTP) ADAMTS13 (ie, von Willebrand factor–cleaving protease), Mortality an enzyme involved in blood clotting. The current Daily plasmapheresis Clinical trial(s): Phase III standard treatment is plasma exchange. Caplacizumab (plasma exchange) Quality of life HERCULES completed purportedly inhibits the interaction between von Rituximab August 2017, pivotal data Willebrand factor and by targeting von published January 2019; Willebrand factor A1 domain, potentially blocking ultra- Splenectomy (to phase III Post-HERCULES large von Willebrand factor–mediated platelet interactions eliminate production of primary completion October and the formation of string-like blood clots. It is intended antibodies to 2020 to reduce aTTP recurrence and its serious or life- ADAMTS13) threatening effects. The recommended first dose is an 11- Vincristine mg bolus intravenous injection at least 15 minutes before plasma exchange, with an 11-mg subcutaneous injection after completing plasma exchange, continuing daily for 30 days after the last plasma exchange. If signs of aTTP persist after the initial treatment course (eg, suppressed ADAMTS13 activity), caplacizumab treatment may be extended another 28 days. Developer(s): Ablynx NV (Ghent, Belgium)

Section 1. Currently Monitored Topics 48

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 12 years or Crizanlizumab (SEG101) is a humanized immunoglobulin Analgesia (eg, morphine, Amount and length of Submission date: Biologics older and adults with sickle G2 (IgG2) antibody against P-selectin, which promotes nonsteroidal anti- intravenous use License Application cell disease (SCD) who the inflammation and adhesion involved in VOC. inflammatory drugs, anticipated second quarter experience a vaso-occlusive Crizanlizumab is intended to improve treatment efficacy acetaminophen) Frequency of VOCs 2019 crisis (VOC) by blocking P-selectin to prevent red blood cell occlusion Hospital length of stay in small blood vessels and maintain blood flow. Sickled Hydration FDA designation(s): Orphan Drug, Breakthrough Therapy red blood cells are more susceptible to oxidative damage, Hydroxyurea Rehospitalizations within inappropriate adhesion, and vascular obstruction, leading 3 days of discharge Clinical trial(s): Phase III to VOCs that cause severe pain, requiring hospitalization. Quality of life STAND primary completion Patients can progress to thromboembolic events, stroke, May 2022; key phase II organ failure, or early death, and available treatments are SUSTAIN data reported suboptimal. The only FDA-approved treatment for SCD, December 2018 hydroxyurea, can reduce VOC incidence but is ineffective in about one-third of adult patients. In clinical trials, crizanlizumab is administered by intravenous infusion at a dose of 5.0 or 7.5 mg/kg, once every 4 weeks. Developer(s): Novartis AG (Basel, Switzerland)

Children aged 4 years or choline controlled release (DCCR) is an Cognitive and behavioral Hyperphagia (abnormal FDA designation(s): Orphan older and adults with investigational proprietary crystalline salt formulation of therapy appetite) change from Drug, Fast Track hyperphagic Prader-Willi diazoxide, a potassium channel activator that inhibits baseline syndrome (PWS) insulin secretion, for treating PWS. DCCR purportedly Dietary intervention and Clinical trial(s): Phase III blocks the synthesis and secretion of the appetite close supervision of food Aggression and primary completion June stimulatory Y and agouti-related protein intake behavioral problems 2019; phase III open-label change from baseline extension primary (AgRP) and also blocks fatty acid synthesis. DCCR might Exercise programs also potentiate the action of GABA receptors, which are completion December 2019 Rate of comorbidities thought to be disrupted in patients with PWS who (cardiovascular disease, experience behavioral problems such as aggression. diabetes mellitus, Thus, DCCR might address hyperphagic and behavioral obesity) change from PWS symptoms and decrease body fat and circulating baseline lipid levels. Often, PWS is managed with off-label diazoxide (Proglycem), which is approved for treating Mortality ; however, patients with PWS require lower Quality of life change doses of diazoxide than the current formulation, with from baseline a common side effect. In clinical trials, DCCR is administered as an oral tablet at a dose of 75 to 450 mg (depending on body weight), once daily. Developer(s): Soleno Therapeutics, Inc (Redwood City, California)

Section 1. Currently Monitored Topics 49

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (Soliris) is a recombinant humanized Intravenous Functional impairments PDUFA date: June 28, 2019 older with a confirmed monoclonal antibody that binds to the complement protein corticosteroids (vision, mobility, and Priority Review diagnosis of neuromyelitis C5 (a soluble component of the innate immune system) bowel or bladder optica or neuromyelitis with high affinity. No FDA-approved therapies are Plasmapheresis incontinence) change FDA designation(s): Orphan Drug optica spectrum disorder available to treat neuromyelitis optica, so eculizumab Azathioprine from baseline who have experienced at could become the first approved treatment. However, Clinical trial(s): Phase III least 2 relapses in the past eculizumab labeling for other FDA-approved indications Mycophenolate mofetil Incidence of relapse from baseline PREVENT completed July 12 months or 3 relapses in carries a boxed warning about risk of serious Rituximab 2018, data published May the past 24 months despite meningococcal infections and also requires adherence to Quality of life change 2019; phase III open-label stable immunosuppressive a Risk Evaluation and Mitigation Strategy program. from baseline extension primary therapy Eculizumab is intended to mitigate the autoimmune and completion June 2020 neurodegenerative symptoms and pathology of neuromyelitis optica by binding C5 and inhibiting its cleavage to C5a and C5b, which prevents the downstream generation and activation of the cytolytic terminal complement complex C5b-9, which damages cell membranes targeted with the complexes. C5b-9 complex production is thought to directly drive the uncontrolled complement activation that propagates some autoimmune reactions. In clinical trials, patients received eculizumab intravenously, 900 mg, weekly for 4 weeks, followed by 1200 mg, every 2 weeks for a maximum up to 4 years. Developer(s): Alexion Pharmaceuticals, Inc (Boston, Massachusetts)

Section 1. Currently Monitored Topics 50

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 8 years or Idebenone is a small-molecule drug intended to treat Corticosteroids (eg, Forced vital capacity FDA designation(s): Orphan older with Duchenne DMD, an inherited, X-linked genetic disorder caused by deflazacort [Emflaza]) (FVC; total, percentage Drug, Rare Pediatric muscular dystrophy (DMD), mutations or deletions in the dystrophin gene, DMD. DMD predicted) Disease, Fast Track who are most likely male encodes dystrophin, a protein that helps keep muscle Respiratory support because of chromosome cells intact. The absence of wild-type dystrophin protein devices Percentage predicted Clinical trials(s): phase III X–linked disease causes progressive muscle fiber necrosis and eventual peak expiratory flow SIDEROS primary transmission widespread muscle weakness. No cure is available for (PEF) completion August 2021; phase III SIDEROS-E DMD, and first-line corticosteroid treatment (eg, Emflaza; Percentage predicted PTC Therapeutics, Inc, South Plainfield, New Jersey) primary completion forced expiratory volume December 2023; phase III manages symptoms but does not prevent disease in 1 second (FEV1) progression and has significant side effects. FDA DELOS study completed approved a gene therapy for patients who have a specific Muscle strength April 2014, data published April 2015, additional data mutation in DMD (eg, in exon 51), but patients who have Quality of life other DMD mutations do not qualify. Therefore, additional published December 2017 therapies are needed. Idebenone is similar to coenzyme Q10 and purportedly facilitates electron transport within mitochondria. According to the manufacturer, maintaining correct electron balance is essential for normal energy metabolism, particularly in nerve and muscle cells, which demand more energy, making them more prone to rapid cell damage or death from mitochondrial dysfunction. In patients with DMD, preserving mitochondrial function and protecting cells from oxidative stress through idebenone treatment might prevent cell damage and increase energy production within impaired respiratory nerve and muscle tissue, potentially improving symptoms. In clinical trials, patients or caregivers orally administer a total of 900 mg idebenone daily, divided into 3 equal doses of two 150-mg tablets each, taken with meals. Developer(s): Santhera Pharmaceuticals (Pratteln, Switzerland)

Section 1. Currently Monitored Topics 51

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 16 years or PXT3003 is a proprietary combination of 3 FDA-approved Analgesics Functional mobility FDA designation(s): Orphan older and adults aged up to pharmaceuticals ([RS]-baclofen, naltrexone Drug, Fast Track 67 years with genetically hydrochloride, and D-sorbitol) intended for treating Occupational and Quality of life confirmed Charcot-Marie- CMT1A. Patients with CMT1A overexpress PMP22 physical therapy Clinical trial(s): Phase II Pain completed December 2012, Tooth disease type 1A protein due to an extra copy of the peripheral myelin Orthotic devices (CMT1A) protein 22 gene, PMP22. PMP22 overexpression data available December degrades the protective myelin sheath on nerve fibers, Mobility aids 2014; phase III PLEO-CMT completed September 2018, leading to peripheral nerve dysfunction and eventual Foot surgery nerve conduction loss. No curative or disease-modifying topline data reported treatments are available for the disease, and patients October 2018, additional typically receive supportive care to address functional data reported May 2019; disability and neuropathic pain. Therefore, additional phase III PLEO-CMT-FU therapies for CMT1A are needed. The 3 drugs in follow-up extension primary PXT3003 are all involved in modulation of cellular activity completion September 2019 in the central : (RS)-baclofen is a gamma- aminobutyric acid receptor agonist that blocks excitatory neurotransmitter release, naltrexone hydrochloride is an antagonist, and D-sorbitol purportedly is a muscarinic acetylcholine receptor activator that might promote expression of genes involved in myelin production. Thus, PXT3003 might improve myelination, protect nerve and muscle cell function, and prevent disease progression in patients with CMT1A. In clinical trials, patients orally self-administer PXT3003 as a liquid solution twice daily with food, for 15 months. Developer(s): Pharnext SA (Paris, France)

Section 1. Currently Monitored Topics 52

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 6 years or Rivipansel is a synthetic glycomimetic, pan-selectin Analgesia (eg, morphine, Opioid use FDA designation(s): Orphan older and adults with sickle inhibitor that targets inflammatory and adhesion nonsteroidal anti- Drug, Fast Track cell disease (SCD) who are processes that might contribute to VOC. It is intended to inflammatory drugs, Frequency of vaso- experiencing a vaso- reduce the duration of VOC and hospital stays. In SCD, acetaminophen) occlusive crises (VOCs) Clinical trial(s): Phase III primary completion June occlusive crisis (VOC) sickled red blood cells are more susceptible to oxidative Hospital stay damage and inappropriate adhesion, which can lead to Hydration 2019, designed under Special Protocol VOCs and severe pain, requiring hospitalization. VOC Hydroxyurea Rehospitalizations within complications can include thromboembolic events, stroke, 3 days of discharge Assessment; phase III primary completion June organ failure, or early death. In clinical trials, Rivipansel is Quality of life infused intravenously every 12 hours for up to 15 doses. 2021 For patients older than 12 years and heavier than 40 kg, the first dose is 1680 mg and subsequent doses are 840 mg. For patients aged 6 to 12 years or weighing less than 40 kg, the first dose is 40 mg/kg up to 1680 mg and subsequent doses are 20 mg/kg up to 840 mg every 12 hours. Developer(s): GlycoMimetics, Inc (Rockville, Maryland) in partnership with Pfizer, Inc (New York, New York)

Section 1. Currently Monitored Topics 53

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 6 months or Triheptanoin (UX007) is a purified synthetic triglyceride High-carbohydrate, fat- Energy production FDA designation(s): Orphan older and adults with a that purportedly treats FAODs by providing supplemental, restricted diet to maintain Drug, Fast Track, Rare confirmed diagnosis of a medium-length, odd-chain fatty acids that can be constant energy supply Incidence of symptoms Pediatric Disease long-chain fatty acid metabolized into ketones to increase intermediates used Intravenous glucose Incidence of disease- Clinical trial(s): Phase II oxidation disorder (FAOD), in Krebs cycle energy generation and improve energy related hospitalization, including carnitine production. Triheptanoin purportedly can also be administration (if oral primary completion feeding not tolerated) emergency department, September 2021; unphased palmitoyltransferase (CPT) converted into glucose when patients' glucose levels are acute care visits or other deficiency (CPT1 or CPT2), low. No pharmacologic therapies are available for retrospective observational unscheduled emergency chart review primary very long chain acyl-CoA FAODs; therefore, triheptanoin could provide an option interventions dehydrogenase deficiency, beside traditional dietary supplementation for these completion September 2019 long chain 3-hydroxy-acyl- patients. Traditional dietary supplementation with Quality of life CoA dehydrogenase medium-chain triglycerides provides only even-chain fatty deficiency, trifunctional acids, potentially depleting odd-chain carbon protein deficiency, or intermediates during tricarboxylic acid (TCA) cycle energy carnitine-acylcarnitine generation and compromising optimal energy production deficiency and gluconeogenesis during hypoglycemia. In clinical trials for treating FAOD, triheptanoin is administered as an orally ingested oil with food or by gastronomy tube, at dosages equivalent to 25% to 35% of individual patients' caloric requirements. Developer(s): Ultragenyx Pharmaceutical, Inc (Novato, California); licensed rights to UX007 from Baylor Scott & White Research Institute (Dallas, Texas)

Section 1. Currently Monitored Topics 54

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children and adults aged up Zynteglo (formerly LentiGlobin) is an autologous CD34+ Allogeneic stem cell Transfusion-need status FDA designation(s): Orphan to 50 years with transfusion- hematopoietic stem cell (HSC) gene therapy intended to transplant Drug, Breakthrough Therapy dependent β-thalassemia, treat β-thalassemia, an inherited blood disorder caused Organ function Repeated blood Clinical trial(s): Phase III also known as β- by a mutation in the hemoglobin subunit beta gene, HBB Level of iron overload thalassemia major, who This mutation causes ineffective red blood cell production transfusions NORTHSTAR-2 primary have a β0/β0 genotype (no leading to severe . Zynteglo consists of cells Quality of life completion January 2020, β-globin expression) or a collected from the patient's bone marrow and transduced interim data reported β+/β0 genotype (little β- ex vivo with a lentiviral vector to insert a functional copy December 2018; phase III globin expression) of the HBB gene, expanded to facilitate uptake. This NORTHSTAR-3 primary autologous HSC therapy does not require completion April 2021, immunosuppressive therapy. In clinical trials, Zynteglo preliminary data reported is administered as a single intravenous infusion, at an December 2018 unspecified dose, after patients are treated with to destroy the β-thalassemia–causing blood cells. Developer(s): bluebird bio, Inc. (Cambridge, Massachusetts)

Section 1. Currently Monitored Topics 55

Section 2. Topics Added Since Last Status Report: 94 Topics

Table 6. Alzheimer’s Disease and Other Dementias: 4 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 55 to 80 years COR388 is an orally administered bacterial protease Cholinesterase Cognitive performance, Clinical trial(s): Phase II/III with mild to moderate inhibitor that targets the infectious pathogen inhibitors: donepezil measured by Alzheimer’s primary completion Alzheimer's disease (AD) Porphyromonas gingivalis gingipains, a bacterium rivastigmine, Disease Assessment December 2021 purportedly linked with periodontal disease and AD, galantamine Scale-Cognitive including the production of (Aβ) in preclinical Subscale 11 and clinical models. COR388 purportedly could be the (off-label) Progression of AD first disease-modifying treatment to reduce brain infection, block Aβ production, reduce neuroinflammation, and Quality of life impart neuroprotection for patients with mild to moderate AD. COR388 targets P. gingivalis gingipains found in the brain tissue and cerebral spinal fluid of people with AD. In clinical trials, COR388 is administered in 40 or 80 mg capsules, twice daily. Developer(s): Cortexyme, Inc (San Francisco, California)

Adults aged 55 to 79 years Cromolyn and ibuprofen combination therapy (ALZT-OP1) Cholinesterase inhibitors Disease progression Clinical trial(s): Phase III with evidence of early is being developed as a disease-modifying treatment for (eg, donepezil, COGNITE primary Alzheimer's disease (AD) AD that is intended to slow or reverse cognitive and galantamine, Morbidity completion November 2019, functional decline in patients with early-stage AD. rivastigmine) Mortality designed under Special Cromolyn is intended to act as an amyloid beta (Aβ) Protocol Assessment polymerization inhibitor to purportedly block the Supportive care Quality of life development and spread of Aβ plaques; the ibuprofen Aβ aggregation component of the therapy is intended to reduce neuronal inflammation caused by existing plaques. In clinical trials, Cromolyn is inhaled and ibuprofen is administered orally (dosage and treatment duration are unspecified for both components). Developer(s): AZTherapies, Inc (Boston, Massachusetts)

Section 2. Topics Added Since Last Status Report 56

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 50 to 90 years Deuterated hydrobromide and Caregiver intervention Agitation, as measured FDA designation(s): Fast with Alzheimer's disease sulfate (AVP-786) is being developed to treat and environmental by accepted clinical Track (AD)-associated agitation AD agitation. AD-associated agitation is thought to result modification (removed or ratings and scales from reduced serotonin levels and increased levels of alleviated stressors) Clinical trial(s): Phase III noradrenaline and dopamine. AVP-786 is intended to Quality of life study completed January modulate neurotransmitter levels and decrease AD- Antipsychotics: 2019, topline data reported associated agitation with fewer side-effects than other aripiprazole March 2019; phase III available treatments. Deuterated dextromethorphan brexpiprazole, primary completion hydrobromide is intended to act as an uncompetitive haloperidol, olanzapine, September 2019; phase III , risperidone, long-term extension primary N-methyl-D-aspartate (NMDA) receptor antagonist, agonist, and a serotonin and norepinephrine and completion June 2022 inhibitor. Low-dose quinidine sulfate, a class Ia Antidepressants: antiarrhythmic agent and CYP2D6 inhibitor, increases , , plasma levels of dextromethorphan hydrobromide. In , paroxetine, clinical trials, AVP-786 is administered orally, twice daily, and sertraline at 1 of 3 unspecified doses, for up to 52 weeks. Antianxiety medications: Developer(s): alprazolam, buspirone, Avanir Pharmaceuticals, Inc (Aliso Viejo, California), a lorazepam, and wholly owned subsidiary of Otsuka Holdings Co, Ltd oxazepam (Tokyo, Japan) Synthetic tetrahydrocannabinol

Section 2. Topics Added Since Last Status Report 57

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 50 to 85 years Troriluzole (BHV-4157) is a third-generation, tripeptide Cholinesterase Symptom severity, as Clinical trial(s): Phase II/III with mild to moderate prodrug conjugate of riluzole being developed as a inhibitors: donepezil, measured by accepted primary completion January Alzheimer's disease (AD) disease-modifying treatment for AD. In patients with AD, rivastigmine, clinical ratings and 2020 damaged brain cells are susceptible to cellular injury by galantamine scales overactivity of the excitatory neurotransmitter glutamate. Note(s): Troriluzole is also in Riluzole (Rilutek, -aventis US, LLC, Bridgewater, Memantine (off-label) Bioavailability, safety phase III clinical New Jersey) is a sodium channel blocker and glutamate and dosing development for treating spinocerebellar modulator approved by FDA for treating amyotrophic Disease progression lateral sclerosis (ALS). It purportedly reduces glutamate- mediated excitotoxicity and nerve cell deterioration by Quality of life promoting glutamate's reuptake into nerve cells. Troriluzole purportedly has the same mechanism of action as riluzole but with improved bioavailability and tolerability, which could reduce adverse events typically associated with riluzole, such as , weakness, dizziness, and hepatotoxicity. Troriluzole purportedly could decrease glutamate-mediated neuronal damage to reduce symptoms in patients with AD and delay AD progression by preventing the loss of synapses. In clinical trials, patients receive troriluzole 280 mg, orally at bedtime, once daily, for 48 weeks. Developer(s): Biohaven Pharmaceuticals, Inc (New Haven, Connecticut)

Section 2. Topics Added Since Last Status Report 58

Table 7. Cancer: 39 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (BYL719) is a selective small-molecule inhibitor Chemotherapy with one Overall survival Approval date: May 24, older with locally advanced of the phosphoinositide-3-kinase (PI3K) signaling or more of the following: 2019 or metastatic pathway that specifically targets PI3Kα, the catalytic Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase III receptor (ER)-positive, subunit of PI3K encoded by the phosphatidylinositol-4, Quality of life human epidermal growth 5-bisphosphate 3-kinase catalytic subunit alpha gene, cyclophosphamide) SOLAR-1 primary completion June 2018, factor receptor 2 (HER2)- PIK3CA. Alpelisib has a novel mechanism of action and is Anthracyclines (eg, negative breast cancer intended to target mutated PI3K in patients with breast topline data published May doxorubicin, epirubicin, 2019 harboring PIK3CA gene cancer who have the alteration, because they have liposomal doxorubicin) alterations, including point limited treatment options after developing resistance to mutations and PIK3CA endocrine therapy. Upon binding to PI3Kα, alpelisib Antimetabolites (eg, amplification, whose prevents the enzyme from phosphorylating 5-fluorouracil, disease has progressed phosphatidylinositol, thus preventing activation of capecitabine, during or after one line of downstream serine- kinases associated with cell gemcitabine, treatment with an growth and proliferation. Alpelisib purportedly prevents methotrexate, aromatase inhibitor the uncontrolled proliferation of breast cancer cells with pemetrexed) constitutive PI3Kα activity, which makes the disease Immune checkpoint resistant to endocrine therapy. Determining PIK3CA inhibitors (eg, mutation status requires use of a companion diagnostic atezolizumab) test. In clinical trials, alpelisib is administered orally at a once-daily dose of 300 mg in combination with Microtubule inhibitors intramuscular fulvestrant at a dose of 500 mg (eg, eribulin, ) administered on days 1 and 15 of cycle 1 and then on mTOR inhibitors (eg, day 1 of each 28-day cycle until disease progression or everolimus) intolerable toxicity. PARP inhibitors (eg, Developer(s): olaparib, talazoparib) Novartis AG (Basel, Switzerland) Platinum agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, nab-paclitaxel, paclitaxel) Vinca alkaloids (eg, vinorelbine)

Section 2. Topics Added Since Last Status Report 59

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Atezolizumab (Tecentriq) is a monoclonal antibody that Chemotherapy with one Overall survival Approval date: March 11, older with surgically targets the programmed death-ligand 1 (PD-L1), an or more of the following: 2019 resectable triple-negative inhibitory surface molecule expressed by cells to Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase III breast cancer (TNBC) or modulate immune responses. A hallmark of cancer is its Quality of life locally advanced or ability to evade an immune response. Several types of cyclophosphamide) IMpassion131 primary metastatic TNBC who have cancer cells, including TNBC, activate an immune- completion January 2020; Anthracyclines (eg, phase III IMpassion132 received no systemic checkpoint pathway in T cells by overexpressing PD-L1, doxorubicin) therapy which binds to the programmed death-1 (PD-1) co- primary completion July inhibitory receptor and limits the activation of cancer- Antimetabolites (eg, 2019; phase III specific T cells. Atezolizumab purportedly prevents the fluorouracil, gemcitabine, IMpassion130 primary interaction between PD-1 and PD-L1 to inhibit the pemetrexed) completion April 2020, immune-checkpoint pathway. Treatment with pivotal data published PARP inhibitors (eg, November 2018; phase III atezolizumab is intended to overcome the immune niraparib, olaparib) tolerance of TNBC by enhancing cancer-specific T-cell IMpassion031 primary responses. In clinical trials, atezolizumab is administered Taxanes (eg, docetaxel, completion September as an intravenous infusion at a dose of 840 mg on nab-paclitaxel, paclitaxel) 2020; phase III days 1 and 15 of a 4-week cycle for up to 24 months IMpassion030 primary Vinca alkaloid (eg, until disease progression or unacceptable toxicity, in completion January 2022 vinorelbine) combination with nab-paclitaxel (100 mg/m2), Note(s): FDA approved paclitaxel (90 mg/m2), or gemcitabine (1000 mg/m2) plus atezolizumab for treating capecitabine (1000 mg/m2) and carboplatin (AUC 2). urothelial carcinoma in May Developer(s): 2016, for non–small cell lung cancer in October Genentech, Inc (South San Francisco, California), a 2016, and for small cell lung subsidiary of F. Hoffman-La Roche AG (Basel, cancer in March 2019 Switzerland)

Section 2. Topics Added Since Last Status Report 60

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Atezolizumab (Tecentriq) is a monoclonal antibody that Chemotherapy with one Overall survival Approval date: March 18 older with newly diagnosed targets the programmed death-ligand 1 (PD-L1), an or more of the following: 2019 extensive-stage small cell inhibitory surface molecule expressed by cells to Progression-free survival Platinum-based agents Clinical trial(s): Phase III lung cancer (SCLC) who modulate immune responses. Frontline therapy for SCLC Quality of life have received no previous relies on platinum-based chemotherapy, but because (eg, carboplatin, IMpower133 primary systemic therapy response rates are low, atezolizumab might improve cisplatin) completion January 2019, health outcomes, change patient management, and pivotal data published Topoisomerase inhibitors December 2018 increase treatment-related costs. A hallmark of cancer is (eg, etoposide, its ability to evade an immune response. Several types of topotecan) Note(s): FDA approved cancer cells, including SCLC, activate an immune- atezolizumab for treating checkpoint pathway in T cells by overexpressing PD-L1, urothelial carcinoma in May which binds to the programmed death-1 (PD-1) co- 2016, for non–small cell inhibitory receptor and limits the activation of cancer- lung cancer in October specific T cells. Atezolizumab purportedly prevents the 2016, and triple-negative interaction between PD-1 and PD-L1 to inhibit the breast cancer in March 2019 immune-checkpoint pathway. Treatment with atezolizumab might overcome the immune tolerance of SCLC by enhancing cancer-specific responses. In clinical trials, atezolizumab is administered as an intravenous infusion at a dose of 1200 mg, once every 3 weeks for up to 24 months, in combination with etoposide (100 mg/m2) plus carboplatin (AUC 5). Developer(s): Genentech, Inc (South San Francisco, California), a subsidiary of F. Hoffman-La Roche AG (Basel, Switzerland)

Section 2. Topics Added Since Last Status Report 61

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (BLU-285) is a potent and selective oral type 1 Chemotherapy with one Overall survival FDA designation(s): older with advanced kinase inhibitor of mutated KIT and platelet-derived or more of the following: Breakthrough Therapy systemic mastocytosis that growth factor receptor A (PDGFRA) kinases. Because Progression-free survival Tyrosine kinase Clinical trial(s): Phase II includes aggressive there are no FDA-approved treatments for this patient Quality of life systemic mastocytosis, population, avapritinib might improve health outcomes for inhibitors (eg, imatinib, PATHFINDER primary indolent systemic these patients. Avapritinib has broad inhibition against ) completion December 2020; mastocytosis, or smoldering activating mutations in KIT and PDGFRA, which drive phase II PIONEER primary systemic mastocytosis tumor proliferation. Avapritinib is designed to have potent completion December 2020; activity against activation loop mutations in KIT and phase I EXPLORER primary PDGFRA, which currently approved multikinase inhibitors completion November 2021, do not inhibit. Avapritinib is also designed to bind and topline data reported inhibit the KIT D816V mutation, the primary driver of December 2018 disease in up to 95% of patients with systemic mastocytosis. Avapritinib purportedly has marked selectivity for inhibiting KIT and PDGFRA to prevent tumor cell proliferation, spread, and survival without having off-target activity. In clinical trials, avapritinib is administered orally once daily at a dose of 300 mg until disease progression or development of intolerable toxicity. Developer(s): Blueprint Medicines Corp (Cambridge, Massachusetts)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Avapritinib (BLU-285) is a potent and selective oral type 1 Chemotherapy with one Overall survival FDA designation(s): Fast older with a locally kinase inhibitor of mutated KIT and platelet-derived or more of the following: Track, Breakthrough advanced, unresectable or growth factor receptor A (PDGFRA) kinases. Avapritinib Progression-free survival Therapy Tyrosine kinase metastatic gastrointestinal might change patient management and improve health Quality of life stromal tumor (GIST), who outcomes in patients with KIT- or PDGFRA-driven GIST, inhibitors (eg, imatinib, Clinical trial(s): Phase III have been treated who have limited treatment options and whose disease is regorafenib, ) VOYAGER primary previously with imatinib and likely to develop resistance. Avapritinib has broad completion April 2021; one or two other tyrosine inhibition against activating mutations in KIT and phase I NAVIGATOR kinase inhibitors PDGFRA, which drive GIST proliferation. Avapritinib is primary completion also designed to have potent activity against activation December 2020, topline loop mutations in KIT and PDGFRA, which currently data reported November approved multikinase inhibitors do not inhibit. Avapritinib 2018 purportedly has marked selectivity for inhibiting KIT and Note(s): FDA designations PDGFRA to prevent GIST cell proliferation, spread, are specific for treating and survival without having off-target activity. Testing for patients harboring the KIT and PDGFRA mutation status will require use of a PDGFRA D842V mutation companion diagnostic. In clinical trials, avapritinib is administered orally, once daily, at a dose of 300 mg until disease progression or development of intolerable toxicity. Developer(s): Blueprint Medicines Corp (Cambridge, Massachusetts)

Adults aged 18 years or Avisopasem manganese (GC4419) is a small-molecule Treatment with one or Incidence of severe FDA Designation(s): older who might develop superoxide dismutase mimetic intended to detoxify more of the following: mucositis Breakthrough Therapy; Fast oral mucositis (OM) after reactive species. GC4419 is a novel agent that Track undergoing chemoradiation might improve health outcomes in patients who are likely Localized therapy (eg, Cancer-treatment therapy with cisplatin and to develop OM and have no treatment options to prevent low-level laser therapy, adherence Clinical Trial(s): Phase III image-modulated radiation the condition. Reactive oxygen species are overproduced oral cryotherapy) ROMAN primary completion Quality of life October 2020 therapy for treating locally during chemoradiation therapy, overwhelming Supportive care (eg, oral advanced, nonmetastatic endogenous superoxide dismutase enzymes and hygiene protocols) head and neck cancer resulting in oxidative tissue damage that contributes to development of OM. Exogenous administration of a superoxide dismutase, such as GC441, purportedly ameliorates chemoradiation-induced toxicity. In clinical trials, GC4419 is administered intravenously at an unspecified dose before initiating intensity-modulated radiation therapy. Developer(s): Galera Therapeutics, Inc (Malvern, Pennsylvania)

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Adults aged 18 years or Canakinumab (ACZ885) is a human monoclonal antibody Chemotherapy with one Overall survival Clinical trial(s): Phase III older with locally advanced that binds and neutralizes the immune mediator activity of or more of the following: CANOPY-2 primary or metastatic non–small cell human interleukin-1β (IL-1β), a member of the interleukin Progression-free survival completion March 2021; ALK inhibitors (eg, lung cancer (NSCLC) of (IL-1) family of cytokines. As an addition to the standard Quality of life phase III CANOPY-1 squamous or nonsquamous of care, canakinumab might improve health outcomes and , , primary completion May origin who (1) have not change patient management. Canakinumab is designed , , 2021 been treated for locally to be a highly selective antibody that binds with high ) if ALK advanced or metastatic affinity to IL-1β, but does not bind to any other member of rearrangement positive Note(s): FDA approved disease or (2) have been the IL-1 family or IL-1β from another species. canakinumab for treating ALK inhibitors (eg, cryopyrin-associated previously treated with an Canakinumab purportedly elicits an anti-inflammatory ceritinib, crizotinib) if immune checkpoint inhibitor response in the that blocks periodic syndromes in June ROS1 rearrangement 2009, for active systemic in combination or after tumor proliferation and angiogenesis. Under specific positive treatment with platinum- conditions, IL-1β and other inflammatory cytokines, which juvenile idiopathic arthritis in based chemotherapy who are produced primarily by tumor-associated Angiogenesis inhibitors May 2013, for tumor were treatment-naïve or had macrophages, play a role in growth, vascularization, (eg, bevacizumab, necrosis factor receptor– been previously treated with progression, and spread of cancer cells. In clinical trials, ramucirumab) associated periodic one or two lines of canakinumab is administered subcutaneously at an syndrome, Anthracyclines (eg, hyperimmunoglobulin D chemotherapy unspecified dose in combination with intravenous doxorubicin) docetaxel at a dose of 75 mg/m2 or intravenous syndrome/mevalonate pembrolizumab at a dose of 200 mg plus platinum-based Antimetabolites (eg, kinase deficiency, and chemotherapy every 3 weeks until disease progression or pemetrexed, familial Mediterranean fever intolerable toxicity. gemcitabine) in September 2016 Developer(s): EGFR inhibitors (eg, afatinib, , Novartis AG (Basel, Switzerland) erlotinib, , ) if EGFR mutation positive Immune checkpoint inhibitors (eg, atezolizumab, nivolumab, pembrolizumab) Platinum-based agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, nab-paclitaxel, paclitaxel) kinase inhibitors (eg, ) if NTRK rearrangement positive Vinca alkaloids (eg, vinblastine, vinorelbine)

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Adults aged 18 years or (INC280) is a highly potent and selective, Chemotherapy with one Overall survival Submission date: New Drug older with locally advanced small-molecule inhibitor of mesenchymal-epithelial or more of the following: Application anticipated or metastatic non–small cell transition factor (MET), a tyrosine receptor kinase Progression-free survival December 2019 ALK inhibitors (eg, lung cancer (NSCLC) normally required for organ regeneration and tissue Quality of life harboring MET gene damage repair. Capmatinib is a novel targeted therapy alectinib, brigatinib, FDA designation(s): Orphan alterations, including MET that might improve health outcomes in patients who have ceritinib, crizotinib, Drug, Breakthrough Therapy exon 14 deletion or MET limited treatment options and poor prognosis. Capmatinib lorlatinib) if ALK rearrangement positive Clinical trial(s): Phase II amplification, who are might also change management as a frontline treatment GEOMETRY mono-1 treatment-naïve or had for patients harboring rare alterations in the MET proto- ALK inhibitors (eg, primary completion May been previously treated with oncogene gene, MET. ceritinib, crizotinib) if 2021, preliminary data one or two lines of Capmatinib is designed to interact strongly with tyrosine ROS1 rearrangement reported October 2018 chemotherapy 1230 and a hinge motif in MET's kinase domain, which positive causes MET to adopt a unique autoinhibitory conformation that prevents access to its ATP-. Angiogenesis inhibitors Because capmatinib is highly specific for MET, it has (eg, bevacizumab, fewer off-target effects. Capmatinib purportedly blocks ramucirumab) angiogenesis, proliferation, and survival pathways in Anthracyclines (eg, NSCLC cells by inhibiting constitutive ligand-independent doxorubicin) MET signaling. Among patients with NSCLC, the reported incidence of MET gene alterations, including MET exon Antimetabolites (eg, 14 deletion and MET amplification, is about 2% to 4%. pemetrexed, Testing for MET mutations status will require use of a gemcitabine) companion diagnostic. In clinical trials, capmatinib is EGFR inhibitors (eg, administered orally at a twice-daily dose of 400 mg until afatinib, dacomitinib, disease progression or intolerable toxicity. erlotinib, gefitinib, Developer(s): osimertinib) if EGFR mutation positive Novartis AG (Basel, Switzerland), licensed by Incyte Corp (Wilmington, Delaware) Immune checkpoint inhibitors (eg, atezolizumab, nivolumab, pembrolizumab) Platinum agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, nab-paclitaxel, paclitaxel) Tropomyosin kinase inhibitors (eg, larotrectinib) if NTRK rearrangement positive Vinca alkaloids (eg, vinblastine, vinorelbine)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 60 years or Devimistat (CPI-613) is a small-molecule lipoate analogue Chemotherapy with one Complete remission rate FDA designation(s): Orphan older with relapsed/ intended to target the altered energy metabolism unique or more of the following: drug refractory acute myeloid to many cancers, including AML. Devimistat provides a Overall survival Anthracyclines (eg, Clinical trial(s): Phase III leukemia (AML) novel mechanism of action for a patient population with Quality of life poor treatment outcomes. The altered energy metabolism , ) primary completion October 2022 of cancer cells frequently depends on the activity of the Antibody-drug conjugate pyruvate dehydrogenase complex and the α-ketoglutarate (eg, gemtuzumab, dehydrogenase complex. Devimistat purportedly inhibits ozogamicin) the catalytic and regulatory functions of these cancer- dependent complexes, leading to tumor cell death. In Antimetabolites (eg, clinical trials, devimistat is being tested in combination , , with a standard induction regimen of high-dose cytarabine, ) and . Devimistat is administered Cytokine (eg, 2 intravenously at a dose of 2000 mg/m on days 1 to 5 of granulocyte colony- the induction regimen. stimulating factor) Developer(s): DNA synthesis inhibitors Rafael Pharmaceuticals, Inc (Cranbury, New Jersey) (eg, etoposide, mitoxantrone) FLT3 inhibitor (eg, ) Hypomethylating agents (eg, , ) IDH inhibitors (eg, , ) Multikinase inhibitor (eg, sorafenib)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Dilanubicel (NLA101) is an allogeneic cell therapy that Therapy with one of the Overall survival FDA designation(s): Orphan older with untreated de uses the cord blood of screened and tested healthy following: Drug, Fast Track novo or secondary acute donors to isolate and pool CD34+ hematopoietic stem Progression-free survival Growth factors (eg, Clinical trial(s): Phase II myeloid leukemia (AML) and progenitor cells (HSPCs). HSPCs are cultured in the Quality of life who are eligible for 2 or presence of Delta1Ext-IgG, an engineered form of the , granulocyte- primary completion more lines of standard Notch ligand Deltat1, to promote their ex vivo expansion colony stimulating factor) September 2018; phase II chemotherapy and lineage-specific differentiation. Unlike other LAUNCH primary hematopoietic-based cell therapies, dilanubicel is completion March 2019 purportedly a universal donor, off-the-shelf therapy because it bypasses the need for a donor with a compatible human leukocyte antigen. Dilanubicel can be manufactured ahead of time and cryopreserved until needed. Dilanubicel purportedly prevents opportunistic infections by providing temporary bone marrow function until blood and immune cell populations recover. In clinical trials, dilanubicel is administered as a single intravenous infusion (dose not specified) after the first chemotherapy cycle and up to 2 additional infusions after subsequent chemotherapy cycles. Developer(s): Nohla Therapeutics, Inc (Seattle, Washington)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (Adcetris) is a monoclonal antibody Chemotherapy with one Overall survival Submission date: Biologics older with metastatic or conjugated with a chemotherapy drug (vedotin) that has or more of the following: License Application surgically unresectable been designed to bind the surface receptor nectin 4. Progression-free survival anticipated fourth quarter Alkylating agents (eg, urothelial cancer who have Enfortumab vedotin is a novel targeted therapy that might Quality of life 2019 previously received two improve outcomes in patients who usually have poor ) lines of systemic treatment outcomes after first-line treatment and an immune FDA designation(s); Antimetabolites (eg, Breakthrough Therapy that includes platinum- checkpoint inhibitor. Vedotin is a synthetic auristatin gemcitabine, based therapy followed by with cytotoxic activity that blocks the formation of methotrexate, Clinical trial(s): Phase III an immune checkpoint . Enfortumab vedotin purportedly binds to pemetrexed) EV-301 primary completion inhibitor nectin 4 and triggers internalization of the drug into the September 2021; phase II cells. This increases vedotin's likelihood of targeting and Immune checkpoint EV-201 primary completion killing malignant cells while minimizing cytotoxicity on inhibitors (eg, November 2020, topline normal cells. The adhesion protein nectin 4 is highly atezolizumab, avelumab, data reported March 2019 expressed in various types of solid tumors, including durvalumab, nivolumab, urothelial cancer. In clinical trials, enfortumab vedotin is pembrolizumab) administered intravenously at an unspecified dose on Platinum agents (eg, days 1, 8, and 15 of each 28-day cycle until disease carboplatin, cisplatin) progression or intolerable toxicity. Taxanes (eg, docetaxel, Developer(s): nab-paclitaxel, paclitaxel) Seattle Genetics, Inc (Bothell, Washington), in collaboration with Astellas Pharma, Inc (Tokyo, Japan)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (Balversa) is a novel, highly potent and Chemotherapy with one Overall survival Approval date: April 12, older with metastatic or selective, small-molecule inhibitor of 4 members of the or more of the following: 2019 surgically unresectable receptor (FGFR) family (1, 2, 3, Progression-free survival Alkylating agents (eg, FDA designation(s): urothelial cancer harboring and 4). Erdafitinib targets only FGFRs and might improve Quality of life fibroblast growth factor health outcomes in patients who usually have poor ifosfamide) Breakthrough Therapy receptor (FGFR) genomic outcomes after first-line treatment and whose condition Antimetabolites (eg, Clinical trial(s): Phase III alterations who have been has failed therapy with an immune checkpoint inhibitor. gemcitabine, BLC3001 primary previously treated with only Erdafitinib is designed specifically to target FGFRs and methotrexate, completion November 2020; one line of systemic not bind to similar signaling domains in the vascular pemetrexed) phase II BLC2001 primary chemotherapy or no more endothelial growth factor receptor and the platelet-derived completion September than two lines of systemic growth factor receptor. Erdafitinib purportedly blocks Immune checkpoint 2019, preliminary data treatment that includes an angiogenesis, proliferation, and survival pathways in inhibitors (eg, reported June 2018 immune checkpoint inhibitor urothelial cancer cells by inhibiting constitutive ligand- atezolizumab, avelumab, independent FGFR signaling. In some urothelial cancers, durvalumab, nivolumab, the presence of activating FGFR gene alterations, pembrolizumab) including point mutations and gene rearrangements, Platinum agents (eg, lead to uncontrolled cell proliferation. Testing for carboplatin, cisplatin) FGFR mutation status will require use of a companion diagnostic. In clinical trials, erdafitinib is administered Taxanes (eg, docetaxel, orally at a starting daily dose of 8 mg on each 21-day nab-paclitaxel, paclitaxel) cycle until disease progression or intolerable toxicity. Developer(s): Janssen Pharmaceutical, LLC (Horsham, Pennsylvania), a subsidiary of Johnson & Johnson, Inc (Horsham, PA), in collaboration with Astex Pharmaceuticals, Inc (Cambridge, UK)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or HSV-TK T-cell therapy (Zalmoxis) is an allogeneic stem Chemotherapy Disease-free survival FDA designation(s): Orphan older with acute cell therapy comprised of lymphocytes from haploidentical Drug lymphoblastic leukemia (half match) donors for graft-versus-leukemia treatment. Hematopoietic stem cell Overall survival (ALL) or acute myeloid A haploidentical donor is typically a parent or child, or, transplant Clinical trial(s): Phase III Chronic GVHD- TK008 primary completion leukemia (AML) in complete in some cases, a sibling. Donor peripheral blood Targeted therapy free/relapse-free survival response (first, second, or mononuclear cells are cultured with leukemic cells in the March 2021 subsequent), relapse (first presence of cytokines to select for T cells with reactivity Immune reconstitution or second), or primary against leukemic cells. Reactive T cells are then Engraftment rate refractory transduced with a retrovirus vector containing the herpes simplex virus tyrosine kinase gene (HSV-TK) and a Cumulative incidence of truncated rat low-affinity receptor for the nerve growth acute or chronic GVHD factor gene (LNGFR) for selection. HSV-TK expression in Cumulative incidence of T cells acts as a suicide gene to prevent the cell therapy relapse from causing graft-versus-host disease (GVHD). HSV-TK phosphorylates the prodrug ganciclovir into its active Incidence and duration form, which will kill cells expressing HSV-TK only. of infections Treatment is intended to provide antileukemia activity, promote early and sustained reconstitution of the immune Quality of life system, and reduce transplant-related mortality. Zalmoxis might also help prevent disease relapse and protect from opportunistic infections. In clinical trials, Zalmoxis is administered as an intravenous infusion between days 21 and 49 after haploidentical hematopoietic stem cell transplant. At the first sign of symptoms suggestive of GVHD, patients are treated with ganciclovir to prevent GVHD from developing. Developer(s): MolMed SpA (Milan, Italy)

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Adults aged 18 years or Idasanutlin (RG7388) is a nutlin-class small molecule Chemotherapy with one Overall survival FDA designation(s): Orphan older with relapsed/ drug that blocks the interaction between the mouse or more of the following: Drug refractory acute myeloid double minute 2 homolog protein (MDM2) and p53. Progression-free survival Anthracyclines (eg, Clinical trial(s): Phase III leukemia (AML) whose Idasanutlin has a novel mechanism of action that might Quality of life condition has failed to improve patient health outcomes. In some AML cases, daunorubicin, idarubicin) MIRROS primary completion December 2019 respond and has relapsed MDM2 is thought to negatively regulate p53 by promoting Antibody-drug conjugate after one or two induction p53’s degradation through the ubiquitin-proteasome (eg, gemtuzumab regimens system and by negatively regulating p53’s transcriptional ozogamicin) activation activity. No FDA-approved agents restore p53 tumor suppressor activity. Idasanutlin is a second- Antimetabolites (eg, generation MDM2 inhibitor with superior potency, cladribine, clofarabine, selectivity, and oral bioavailability compared with cytarabine, fludarabine) imidazoline Nutlin-3, the first-generation MDM2 Cytokine (eg, antagonist. Idasanutlin targets a small hydrophobic granulocyte colony- pocket on MDM2, to which p53 normally binds, causing stimulating factor) activation of the p53 pathway. Idasanutlin purportedly stabilizes p53 by blocking the MDM2-p53 interaction, DNA synthesis inhibitors potentially upregulating downstream transcriptional (eg, etoposide, targets involved in arrest and programed cell mitoxantrone) death. In clinical trials, idasanutlin is administered orally FLT3 inhibitor (eg, twice daily at a dose of 300 mg in combination with gilteritinib) cytarabine (1000 mg/m2) for the first 5 days of a 28-day cycle, until complete remission or disease Hypomethylating agents progression. (eg, azacitidine, decitabine) Developer(s): IDH inhibitors (eg,, Genentech, Inc (South San Francisco, California), a enasidenib, ivosidenib) subsidiary of F. Hoffman La-Roche, Ltd (Basel, Switzerland) Multikinase inhibitor (eg, sorafenib)

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Adults aged 18 years or Idecabtagene vicleucel (Ide-cel) is a chimeric antigen Chemotherapy with one Overall survival Submission date: Biologics older with relapsed and receptor (CAR) T-cell therapy that has been engineered or more of the following: License Application refractory multiple myeloma to target the B-cell maturation antigen (BCMA) using Progression-free survival anticipated in 2020 Alkylating agents (eg, (RRMM) who have had 3 or autologous T cells isolated from a patient's blood sample. Quality of life more lines of treatment that Ide-cel has potential to improve health outcomes by bendamustine, FDA designation(s): Orphan included a protease providing a novel, but expensive, personalized therapy for cyclophosphamide) Drug, Breakthrough Therapy inhibitor, an patients who generally have poor prognosis. The Anthracyclines (eg, Clinical trial(s): Phase II immunomodulatory agent, collected T cells are transduced with a lentiviral vector doxorubicin) KarMMa primary completion and an anti-CD38 antibody encoding CARs with a unique anti-BCMA single-chain November 2024; phase III variable fragment (BB2121) fused to the hinge and Glucocorticoids (eg, KarMMa-3 primary transmembrane domains of CD8α, the costimulatory dexamethasone) completion June 2025 domain (4-1BB) of CD137, and the signaling domains of Immunomodulatory CD3ζ. The BB2121 CAR-transduced T cells that comprise agents (eg, lenalidomide, Ide-cel are proliferated and then reintroduced into the pomalidomide, patient. Ide-cell purportedly targets malignant BCMA- thalidomide) expressing plasma cells in patients with multiple myeloma cells and promotes robust cellular activity against these Monoclonal antibodies cells as a treatment for multiple myeloma. BCMA has (eg, daratumumab, been proposed as a biomarker for targeting multiple elotuzumab) myeloma because it is highly expressed in malignant Proteasome inhibitors plasma cells. In clinical trials, Ide-cel is administered as (eg, bortezomib, a single intravenous infusion of anti-BCMA CAR-T cells carfilzomib, ixazomib) at a dose ranging from 1.5 × 108 to 4.5 × 108 T cells. Topoisomerase inhibitors Developer(s): (eg, etoposide) bluebird bio, Inc. (Cambridge, Massachusetts), in collaboration with Celgene Corp (Summit, New Jersey)

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Adults aged 75 years or Ivosidenib (Tibsovo) is a small-molecule inhibitor of a Low-intensity therapy Complete remission rate Approval date: May 2, 2019 older with untreated acute mutated form of the enzyme isocitrate dehydrogenase 1 (azacitidine and myeloid leukemia (AML) (IDH1) known to occur in about 6% to 10% of AMLs decitabine) Overall survival FDA Designation(s): Orphan Drug, Breakthrough therapy harboring an ivosidenib- Ivosidenib has a novel mechanism that might improve Quality of life susceptible mutation in the patient health outcomes in the first- line setting. This alone or in combination with Clinical trial(s): Phase I isocitrate dehydrogenase 1 mutant form of IDH1 causes accumulation of the primary completion May gene, IDH1, who have oncometabolite D-2-hydroxyglutarate and a decrease in azacitidine or low-dose cytarabine 2020, data presented comorbidities that preclude the levels of IDH1's normal metabolite alpha- December 2018; phase III the use of intensive ketoglutarate, and these shifts purportedly have multiple in combination AGILE primary completion induction chemotherapy effects (eg, histone modification, DNA methylation) that with low-dose cytarabine April 2022; phase III retain cells in a dedifferentiated (ie, leukemic) state. By HOVON150AML primary inhibiting the mutated form of IDH1, ivosidenib Low-dose cytarabine completion February 2023 purportedly leads to differentiation of AML cells. Gemtuzumab Note(s): FDA approved Ivosidenib is administered orally (500 mg/day) as a ozogamicin monotherapy. ivosidenib for treating elapsed or refractory AML Developer(s): with a susceptible IDH1 Agios Pharmaceuticals (Cambridge, Massachusetts) mutation in July 2018, and it received supplemental New Drug Application approval as monotherapy for newly diagnosed IDH1 mutant AML patients, aged 75 years or older, ineligible for intensive chemotherapy in May 2019

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Lifileucel (LN-144) is an autologous T-cell therapy that Chemotherapy with one Overall survival FDA designation(s): Orphan older with unresectable or uses cells isolated from the patient's melanoma tumor. or more of the following: Drug, Fast Track, metastatic melanoma who Lifileucel uses a novel personalized therapy strategy that Progression-free survival Regenerative Medicine Alkylating agents (eg, have progressed after one is likely to increase treatment-related costs but might Quality of life Advanced Therapy or more lines of systemic improve patient health outcomes. Lifileucel relies on dacarbazine, therapy. Treatment includes naturally occurring T cells that can penetrate cancerous temozolomide) Clinical trial(s): Phase II C- an immune checkpoint tumors, which are referred to as tumor infiltrating 144-01 primary completion BRAF inhibitors (eg, March 2020, safety and inhibitor (ICI) for patients lymphocytes (TILs). The extracted TILs are expanded in dabrafenib, ) with BRAF mutation– culture until reaching a count of billions of cells. Lifileucel efficacy data reported negative melanoma or an is intended as a tumor-specific therapy that can overcome Immunotherapy (eg, November 2018 ICI and a BRAF inhibitor the tumor's immune-suppressive environment and , nivolumab, alone or in combination with promote its elimination. In clinical trials, lifileucel is pembrolizumab) a MEK inhibitor for patients administered as an intravenous infusion followed by up to MEK inhibitors (eg, with BRAF V600 mutation- 6 doses of to support growth and activation trametinib) positive melanoma of TILs. Platinum-based agents Developer(s): (eg, carboplatin) Iovance Biotherapeutics, Inc (San Carlos, California), in Taxane agents (eg, collaboration with the National Cancer Institute at the paclitaxel) National Institutes of Health (Bethesda, Maryland)

Children aged 12 years or LOXO-292 is a novel, highly selective, ATP-competitive Chemotherapy with one Overall survival FDA designation(s): older and adults with locally small molecule rearranged during transfection (RET) or more of the following: Breakthrough Therapy advanced or metastatic inhibitor. Unlike multikinase inhibitors that target specific Progression-free survival agents Clinical trial(s): Phase I/II RET-mutant medullary alterations, LOXO-292 has been designed to inhibit Quality of life thyroid cancer (MTC) that diverse RET fusions, activating mutations, and acquired- (eg, 5-fluorouracil) LIBRETTO-001 primary has progressed after resistance mutations with nanomolar potency, which completion August 2019, Anthracyclines (eg, preliminary data presented treatment with cabozantinib might improve patient health outcomes. LOXO-292 doxorubicin) and/or purportedly prolongs survival of patients with MTC by October 2018 targeting and inhibiting RET-mutant tumor cells. Even Tyrosine kinase though the receptor tyrosine kinase RET can be inhibitors (eg, oncogenically activated by gene fusions or point cabozantinib, mutations, activating RET point mutations affect about vandetanib) 60% of MTCs. Patients are required to undergo genetic Tyrosine kinase testing before initiating LOXO-292 treatment. In clinical inhibitors (off-label; eg, trials, LOXO-292 is administered orally at an lenvatinib, , undetermined dose. sunitinib) Developer(s): Loxo Oncology, Inc (Stamford, Connecticut), a subsidiary of Eli Lilly and Co, Inc (Indianapolis, Indiana)

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Adults aged 18 years or MDNA55 is a cytokine that specifically targets the Chemotherapy with one Overall survival FDA designation(s): Orphan older with recurrent interleukin-4 receptor (IL4R), a surface receptor reported or more of the following: Drug, Fast Track malignant gliomas, including to be overexpressed in different types of cancer stem Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase II astrocytoma and cells comprising the tumor. MDNA55 offers a novel Quality of life glioblastoma multiforme approach for treating IL4R-expressing tumors. Because carmustine, MDNA55-05 primary (GBM) GBM does not respond well to standard therapy, cyclophosphamide, completion December 2019, MDNA55 might improve health outcomes and change lomustine, nitrosourea, interim data reported patient management. MDNA55 is a genetically procarbazine, February 2019 engineered fusion protein composed of a circularly temozolomide) permuted interleukin-4 molecule fused to the catalytic Angiogenesis inhibitors domain of the bacterial pseudomonas exotoxin A (PE) (eg, bevacizumab) protein. The fusion protein functions like a molecular decoy by binding IL4R and triggering receptor-mediated mTOR inhibitors (eg, endocytosis to deliver the cytotoxic PE payload into the everolimus) cytoplasm. MDNA55 purportedly has high specificity and Platinum agents (eg, affinity for IL4R-expressing tumors to deliver cell-killing carboplatin, cisplatin) payloads to cancer stem cells and immunosuppressive cells of the tumor microenvironment. MDNA55 has Vinca alkaloids (eg, potential to not only kill the tumor cells, but also unblind vincristine) the immune system to cancer. In clinical trials, MDNA55 is administered as a single infusion via convection- enhanced delivery (CED) at an unspecified dose. CED purportedly provides a safer, targeted delivery by using a pressure gradient at the infusion catheter’s tip to push the therapeutic agent across the blood-brain-barrier, through the brain’s interstitial spaces, and to the delivery site. Developer(s): Medicenna Therapeutics Corp (Toronto, Ontario, Canada)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 4 years or NY-ESO-1 T-cells (SPEAR T-cells) comprise an Chemotherapy with one Overall survival FDA designation(s): older and adults with autologous T-cell therapy engineered from the patient's or more of the following: Breakthrough Therapy unresectable, metastatic, peripheral-blood mononuclear cells (PBMCs). Patients Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase I/II progressive, or recurrent with synovial sarcoma have limited treatment options; Quality of life synovial sarcoma who have thus, NY-ESO-1 T-cells represent a novel therapy that dacarbazine, NY-ESO-1 primary had treatment with might improve health outcomes but might also increase temozolomide) completion May 2020 ifosfamide- or doxorubicin- treatment-related costs. After PBMCs are collected, the Anthracyclines (eg, based chemotherapy cells are transduced with a retroviral vector encoding a doxorubicin, epirubicin, T-cell receptor that recognizes a specific peptide from liposomal doxorubicin) NY-ESO, a testicular cancer antigen expressed in up to 80% of synovial sarcomas. Successfully transduced cells Antimetabolites (eg, are activated, expanded, and then cryopreserved until gemcitabine, ifosfamide) ready to be used. NY-ESO-1 T-cells purportedly DNA synthesis inhibitors strengthen the patient's natural T-cell responses against (eg, ) cancer cells expressing the NY-ESO antigen. In clinical trials, patients are infused intravenously with an initial Microtubule inhibitors dose ranging from 1 × 109 to 6 × 109 NY-ESO-1 T-cells. (eg, eribulin, vinorelbine) Patients who have a confirmed response or stable Multikinase inhibitors disease for 3 or more months may receive a second (eg, pazopanib, NY-ESO-1 T-cell infusion. regorafenib, sorafenib) Developer(s): Tropomyosin receptor GlaxoSmithKline plc (Brentford, UK) after program was kinase inhibitor (eg, transferred from Adaptimmune LLC (Oxford, UK) in July larotrectinib) 2018

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Males aged 18 to 99 years Olaparib (Lynparza) is a small molecule drug intended to Abiraterone Overall survival Clinical trial(s): Phase III with metastatic, castration- inhibit poly adenosine diphosphate-ribose polymerase PROpel primary completion resistant prostate cancer (PARP), which functions in a DNA-repair pathway. Docetaxel Progression-free survival April 2021 who have received no Olaparib might provide a novel and potentially synergistic Enzalutamide Quality of life cytotoxic chemotherapy or mechanism of action for treating patients with this new hormonal agent (ie, indication, which has poor overall outcomes. Cancers are abiraterone or often deficient in a DNA repair pathway, and when PARP enzalutamide) at the is also inhibited, the loss of two types of DNA repair metastatic castration- results in cancer cell death in response to DNA damage. resistant disease stage and Preclinical studies have indicated that cross-talk might who are candidates exist between androgen receptor signaling pathways and abiraterone treatment PARP. In clinical trials, olaparib is being studied in combination with the hormone synthesis inhibitor abiraterone. Olaparib is administered orally, 300 mg, twice daily until disease progression or intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, UK), in collaboration with Merck & Co, Inc (Kenilworth, New Jersey)

Males aged 18 years or Olaparib (Lynparza) is a small molecule drug intended to Abiraterone Overall survival FDA designation(s): older with metastatic, inhibit poly adenosine diphosphate-ribose polymerase Breakthrough Therapy castration-resistant prostate (PARP), which functions in a DNA-repair pathway. Progression-free survival Clinical trial(s): Phase III cancer who have received Olaparib might provide a novel and potentially synergistic Docetaxel Quality of life treatment with one or more mechanism of action for treating patients with this PROfound primary new hormonal agents (ie, indication, which has poor overall outcomes. Cancers are Enzalutamide completion March 2020 abiraterone and/or often deficient in a DNA repair pathway, and when PARP Pembrolizumab for Note(s): Myriad Genetics, enzalutamide) and whose is also inhibited, the loss of two types of DNA repair tumors that are Inc (Salt Lake City, Utah), tumor harbors a mutation in results in cancer cell death in response to DNA damage. microsatellite instability has expanded its one of 15 genes involved in Olaparib purportedly induces cell death in prostate tumors high or mismatch repair collaboration with the homologous recombination that harbor germline mutations in one of several genes deficient developers and will work to repair involved in homologous recombination repair, providing a identify germline mutations way of treating tumors for patients with limited options. In in men enrolled in clinical trials, olaparib is administered orally, 300 mg, PROfound study twice daily until disease progression or development of intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, UK), in collaboration with Merck & Co, Inc (Kenilworth, New Jersey)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 or older with ONC201 is a small-molecule imipridone (a class of Chemotherapy with one Overall survival FDA Designation(s): Fast recurrent high-grade glioma anticancer compounds) that acts as an antagonist of or more of the following: Track harboring a histone H3 the G-protein coupled receptor dopamine receptor Progression-free survival Alkylating agents (eg, Clinical Trial(s): Phase II K27M mutation D2 (DRD2). ONC201 has a novel mechanism of action Quality of life that might improve health outcomes in patients who have carmustine, lomustine, primary completion few effective treatment options and poor prognosis after procarbazine, November 2019; unphased recurrence. ONC201-mediated antagonism of DRD2 temozolomide) Expanded Access Program available purportedly inactivates the ras pathway, a driver of cell Angiogenesis inhibitors growth and proliferation, and activates the integrated (eg, bevacizumab) stress response, which can activate cell death pathways. Gliomas harboring K27M mutations in the histone gene, Vinca alkaloids (eg, H3, have a poor prognosis, and preclinical data have vincristine) indicated these gliomas might be susceptible to treatment with a DRD2 antagonist. Testing for H3 K27M mutation status requires use of a companion diagnostic. In clinical trials, ONC201 is administered orally at an unspecified dose. Developer(s): Oncoceutics, Inc (Philadelphia, Pennsylvania)

Section 2. Topics Added Since Last Status Report 78

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that Chemotherapy with one Overall survival Clinical trial(s): Phase III older with stage IV or M1 targets the programmed death-1 (PD-1) co-inhibitory or more of the following: KEYNOTE-119 primary metastatic triple-negative receptor expressed by activated T cells. Because TNBC Progression-free survival completion April 2019 Alkylating agents (eg, breast cancer (TNBC) is not amenable to endocrine therapy or targeted Quality of life whose disease has therapies, pembrolizumab might improve health cyclophosphamide) Note(s): FDA approved progressed after one or two outcomes, change patient management, and increase pembrolizumab for treating Anthracyclines (eg, melanoma in September lines of systemic treatment-related costs. A hallmark of cancer is its ability doxorubicin) chemotherapy to evade an immune response. Several types of cancer 2014, for non–small cell cells, including TNBC, activate an immune-checkpoint Antimetabolites (eg, lung cancer in October pathway in T cells by overexpressing the programmed fluorouracil, gemcitabine, 2015, for head and neck death-ligand 1 (PD-L1), which binds to PD-1 to limit the pemetrexed) cancer in August 2016, for activation cancer-specific T cells. Pembrolizumab Hodgkin lymphoma in March PARP inhibitors (eg, 2017, for urothelial purportedly prevents the interaction between PD-1 and olaparib) PD-L1 to inhibit the immune-checkpoint pathway. carcinoma in May 2017, for Treatment with pembrolizumab might overcome the Taxanes (eg, docetaxel, microsatellite instability-high immune tolerance of TNBC by enhancing cancer-specific nab-paclitaxel, paclitaxel) solid tumors in May 2017, T-cell responses. In clinical trials, pembrolizumab is for gastric or Vinca alkaloid (eg, administered as an intravenous infusion at a dose of gastroesophageal junction vinorelbine) 200 mg, once every 3 weeks, until disease progression cancer in September 2017, or intolerable toxicity. for cervical cancer in June 2018, for mediastinal large Developer(s): B-cell lymphoma in June 2018, for hepatocellular Merck & Co, Inc (Kenilworth, New Jersey) carcinoma in November 2018, for Merkel cell carcinoma in December 2018, and for advanced in April 2019

Section 2. Topics Added Since Last Status Report 79

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that Chemotherapy with one Overall survival Approval date: June 11, older with untreated targets the programmed death-1 (PD-1) co-inhibitory or more of the following: 2019 recurrent or metastatic head receptor expressed by activated T cells. Because most Progression-free survival Antimetabolites (eg, 5- Clinical trial(s): Phase III and neck squamous cell patients with HNSCC have disease recurrence after Quality of life carcinoma (HNSCC) whose treatment with standard platinum-based chemotherapy, fluorouracil, KEYNOTE-048 primary primary tumor is located in pembrolizumab might improve health outcomes, change capecitabine, completion February 2019, the oral cavity, larynx, patient management, and increase treatment-related gemcitabine, interim data reported hypopharynx, or oropharynx costs. A hallmark of cancer is its ability to evade an methotrexate) October 2018 immune response. Several types of cancer cells, EGFR inhibitor (eg, Note(s): FDA approved including HNSCC, activate an immune-checkpoint cetuximab) pembrolizumab for treating pathway in T cells by overexpressing the programmed melanoma in September death-ligand 1 (PD-L1), which binds to PD-1 and limits Platinum-based drugs 2014, for non–small cell the activation of cancer-specific T cells. Pembrolizumab (eg, carboplatin, lung cancer in October purportedly prevents the interaction between PD-1 and cisplatin) 2015, for head and neck PD-L1 to inhibit the immune-checkpoint pathway. Taxanes (eg, docetaxel, cancer (second-line) in Treatment with pembrolizumab might overcome the paclitaxel) August 2016, for Hodgkin immune tolerance of HNSCC by enhancing cancer- lymphoma in March 2017, specific T-cell responses. In clinical trials, pembrolizumab for urothelial carcinoma in is administered as an intravenous infusion at a dose of May 2017, for microsatellite 200 mg, once every 3 weeks, for up to 24 months. instability-high solid tumors Pembrolizumab is being studied as monotherapy or in in May 2017, for gastric or combination with intravenous cisplatin (100 mg/m2) or gastroesophageal junction carboplatin (AUC 5) plus 5-fluorouracil (1000 mg/m2). cancer in September 2017, Developer(s): for cervical cancer in June 2018, for mediastinal large Merck & Co., Inc (Kenilworth, New Jersey) B-cell lymphoma in June 2018, for hepatocellular carcinoma in November 2018, for Merkel cell carcinoma in December 2018, and for advanced renal cell carcinoma in April 2019

Section 2. Topics Added Since Last Status Report 80

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that Chemotherapy with one Overall survival FDA designation(s): older with untreated targets the programmed death-1 (PD-1) co-inhibitory or more of the following: Breakthrough Therapy microsatellite instability-high receptor expressed by activated T cells. Pembrolizumab Progression-free survival Angiogenesis inhibitors Clinical trial(s): Phase III (MSI-H) or mismatch repair might improve health outcomes in patients with dMMR Quality of life deficient (dMMR) Stage IV colorectal cancers, which make up 15% to 20% of (eg, bevacizumab) KEYNOTE-177 primary completion August 2019 colorectal cancer nonhereditary cases and most hereditary cases. It might Antimetabolites (eg, 5- also change patient management and increase treatment- fluorouracil, Note(s): FDA approved related costs. A hallmark of cancer is its ability to evade capecitabine) pembrolizumab for treating an immune response. Several types of cancer cells, melanoma in September including colorectal cancer, activate an immune- EGFR antibodies (eg, 2014, for non–small cell checkpoint pathway in T cells by overexpressing the cetuximab, lung cancer in October programmed death-ligand 1 (PD-L1), which binds to panitumumab) 2015, for head and neck PD-1 and limits the activation of cancer-specific T cells. FOLFIRI (leucovorin, 5- cancer (second-line) in Pembrolizumab purportedly prevents the interaction fluorouracil, irinotecan) August 2016, for Hodgkin between PD-1 and PD-L1 to inhibit the checkpoint lymphoma in March 2017, pathway. Treatment with pembrolizumab might overcome FOLFOX (leucovorin, 5- for urothelial carcinoma in the immune tolerance of colorectal cancer by enhancing fluorouracil, oxaliplatin) May 2017, for MSI-H solid cancer-specific T-cell responses. Tumors with MSI-H or Multikinase inhibitors tumors in May 2017, for dMMR are also purported to be more susceptible to (eg, regorafenib) gastric or gastroesophageal pembrolizumab than tumors with low MSI. In clinical trials, junction cancer in pembrolizumab is administered as an intravenous Platinum-based agents September 2017, for infusion at a dose of 200 mg, once every 3 weeks, for up (eg, oxaliplatin) cervical cancer in June to 24 months. 2018, for mediastinal large Topoisomerase inhibitors B-cell lymphoma in June Developer(s): (eg, irinotecan) 2018, for hepatocellular Merck & Co, Inc (Kenilworth New Jersey) carcinoma in November 2018, for Merkel cell carcinoma in December 2018, and for advanced renal cell carcinoma in April 2019

Section 2. Topics Added Since Last Status Report 81

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that Chemotherapy with one Overall survival Clinical trial: Phase III older with unresectable, targets the programmed death-1 (PD-1) co-inhibitory or more of the following: PROMISE-meso primary advanced, or metastatic receptor expressed by activated T cells. Frontline therapy Progression-free survival completion December 2020 Antimetabolites (eg, malignant pleural for MPM relies on platinum-based chemotherapy, but Quality of life mesothelioma (MPM), because response rates are low and no second-line gemcitabine, Note(s): FDA approved whose disease has therapies are available, pembrolizumab might improve pemetrexed, ) pembrolizumab for treating melanoma in September progressed after systemic health outcomes, change patient management, and Platinum agents (eg, cisplatin therapy and increase treatment-related costs. A hallmark of cancer is 2014, for non–small cell carboplatin, cisplatin, lung cancer in October pemetrexed chemotherapy its ability to evade an immune response. Several types of oxaliplatin) cancer cells, including MPM, activate an immune- 2015, for head and neck checkpoint pathway in T cells by overexpressing the cancer (second-line) in programmed death-ligand 1 (PD-L1), which binds to (eg, irinotecan) August 2016, for Hodgkin PD-1 and limits the activation of cancer-specific T cells. lymphoma in March 2017, Vinca alkaloid (eg, for urothelial carcinoma in Pembrolizumab purportedly prevents the interaction vinorelbine) between PD-1 and PD-L1 to inhibit the immune- May 2017, for microsatellite checkpoint pathway. Treatment with pembrolizumab instability-high solid tumors might overcome the immune tolerance of MPM by in May 2017, for gastric or enhancing cancer-specific T-cell responses. In clinical gastroesophageal junction trials, pembrolizumab is administered as an intravenous cancer in September 2017, infusion at a dose of 200 mg, once every 3 weeks, for up for cervical cancer in June to 24 months. 2018, for mediastinal large B-cell lymphoma in June Developer(s): 2018, for hepatocellular carcinoma in November Merck & Co, Inc (Kenilworth, New Jersey) 2018, for Merkel cell carcinoma in December 2018, and for advanced renal cell carcinoma in April 2019

Section 2. Topics Added Since Last Status Report 82

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that Chemotherapy with one Overall survival Approval date: April 19, older with untreated, locally targets the programmed death-1 (PD-1) co-inhibitory or more of the following: 2019 advanced or metastatic receptor expressed by activated T cells. Pembrolizumab Progression-free survival Angiogenesis inhibitors Clinical trial(s): Phase III renal cell carcinoma (RCC) might improve health outcomes, change patient Quality of life management, and increase treatment-related costs. (eg, bevacizumab) KEYNOTE-426 primary A hallmark of cancer is its ability to evade an immune completion October 2018 , Cytokines (eg, - pivotal data reported response. Several types of cancer cells with poor alpha, interleukin-2) treatment responses, including RCC, activate an immune- October 2018, data checkpoint pathway in T cells by overexpressing the Immunotherapy (eg, published February 2019 programmed death-ligand 1 (PD-L1), which binds to PD-1 ipilimumab, nivolumab) Note(s): FDA approved and limits the activation of cancer-specific T cells. mTOR inhibitors (eg, pembrolizumab for treating Pembrolizumab purportedly prevents the interaction everolimus, melanoma in September between PD-1 and PD-L1 to inhibit the immune- ) 2014, for non–small cell checkpoint pathway. Treatment with pembrolizumab lung cancer in October might overcome the immune tolerance of RCC by Tyrosine kinase 2015, for head and neck enhancing cancer-specific T-cell responses. In clinical inhibitors (eg, , cancer (second-line) in trials, pembrolizumab is administered as an intravenous cabozantinib, lenvatinib, August 2016, for Hodgkin infusion at a dose of 200 mg, once every 3 weeks, plus pazopanib, sorafenib, lymphoma in March 2017, axitinib 5 mg orally twice daily, for up to 24 months. sunitinib) for urothelial carcinoma in Developer(s): May 2017, for microsatellite instability-high solid tumors Merck & Co, Inc (Kenilworth, New Jersey) in May 2017, for gastric or gastroesophageal junction cancer in September 2017, for cervical cancer in June 2018, for mediastinal large B-cell lymphoma in June 2018, for hepatocellular carcinoma in November 2018, and for Merkel cell carcinoma in December 2018

Section 2. Topics Added Since Last Status Report 83

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that Chemotherapy with one Overall survival Clinical trial(s): Phase III older with untreated, targets the programmed death-1 (PD-1) co-inhibitory or more of the following: KEYNOTE-590 primary unresectable, locally receptor expressed by activated T cells. Frontline therapy Progression-free survival completion August 2021 Antimetabolites (eg, advanced or metastatic for esophageal carcinoma relies on platinum-based Quality of life esophageal carcinoma or chemotherapy, but because response rates are low and 5-fluorouracil, Note(s): FDA approved esophagogastric junction no second-line therapies are available, pembrolizumab capecitabine) pembrolizumab for treating (EGJ) carcinoma might improve health outcomes, change patient melanoma in September Anthracyclines (eg, 2014, for non–small cell management, and increase treatment-related costs. epirubicin) A hallmark of cancer is its ability to evade an immune lung cancer in October response. Several types of cancer cells, including HER2 antibodies (eg, 2015, for head and neck esophageal and EGJ carcinomas, activate an immune- trastuzumab) cancer (second-line) in August 2016, for Hodgkin checkpoint pathway in T cells by overexpressing the Platinum agents (eg, programmed death-ligand 1 (PD-L1), which binds to lymphoma in March 2017, carboplatin, cisplatin, for urothelial carcinoma in PD-1 and limits the activation of cancer-specific T cells. oxaliplatin) Pembrolizumab purportedly prevents the interaction May 2017, for microsatellite between PD-1 and PD-L1 to inhibit the immune- Taxanes (eg, docetaxel, instability-high solid tumors checkpoint pathway. Treatment with pembrolizumab paclitaxel) in May 2017, for gastric or might overcome the immune tolerance of esophageal gastroesophageal junction and EGJ carcinomas by enhancing cancer-specific cancer in September 2017, T-cell responses. In clinical trials, pembrolizumab is for cervical cancer in June administered as an intravenous infusion at a dose of 2018, for mediastinal large 200 mg, once every 3 weeks, for up to 24 months. B-cell lymphoma in June 2018, for hepatocellular Developer(s): carcinoma in November 2018, for Merkel cell Merck & Co, Inc (Kenilworth, New Jersey) carcinoma in December 2018, and for advanced renal cell carcinoma in April 2019.

Section 2. Topics Added Since Last Status Report 84

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that Chemotherapy with one Overall survival PDUFA date: Priority older with extensive-stage targets the programmed death-1 (PD-1) co-inhibitory or more of the following: Review June 17, 2019 small cell lung cancer receptor expressed by activated T cells. Frontline therapy Progression-free survival Platinum-based agents Clinical trial(s): Phase III (SCLC) whose disease has for SCLC relies on platinum-based chemotherapy, but Quality of life progressed after two or because response rates are low and disease becomes (eg, carboplatin, KEYNOTE-604 primary more lines of systemic resistant to subsequent lines of treatment, pembrolizumab cisplatin) completion December 2019; phase II KEYNOTE-158 chemotherapy might improve health outcomes, change patient Topoisomerase inhibitors management, and increase treatment-related costs. primary completion August (eg, etoposide, 2023, interim data reported A hallmark of cancer is its ability to evade an immune topotecan) response. Several types of cancer cells, including SCLC, June 2018; phase I activate an immune-checkpoint pathway in T cells by KEYNOTE-28 primary overexpressing the programmed death-ligand 1 (PD-L1), completion December 2020, which binds to PD-1 and limits the activation cancer- data published December specific T-cells. Pembrolizumab purportedly prevents the 2017 interaction between PD-1 and PD-L1 to inhibit the Note(s): FDA approved immune-checkpoint pathway. Treatment with pembrolizumab for treating pembrolizumab might overcome the immune tolerance of melanoma in September SCLC by enhancing cancer-specific T-cell responses. In 2014, for non–small cell clinical trials, pembrolizumab is administered as an lung cancer in October intravenous infusion at a dose of 200 mg, once every 2015, for head and neck 3 weeks for up to 24 months, in combination with cancer (second-line) in etoposide (100 mg/m2) plus carboplatin (AUC 5) or August 2016, for Hodgkin cisplatin (75 mg/m2). lymphoma in March 2017, Developer(s): for urothelial carcinoma in May 2017, for microsatellite Merck & Co, Inc (Kenilworth, New Jersey) instability-high solid tumors in May 2017, for gastric or gastroesophageal junction cancer in September 2017, for cervical cancer in June 2018, for mediastinal large B-cell lymphoma in June 2018, for hepatocellular carcinoma in November 2018, for Merkel cell carcinoma in December 2018, and for advanced renal cell carcinoma in April 2019

Section 2. Topics Added Since Last Status Report 85

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (Polivy) is a monoclonal antibody Chemotherapy with one Overall survival Approval date: June 10, older with relapsed or conjugated with a chemotherapy drug (vedotin) that has or more of the following: 2019 accelerated approval refractory diffuse large B- been designed to bind the surface receptor CD79b, a Progression-free survival Alkylating agents (eg, FDA designation(s): Orphan cell lymphoma (DLBCL) protein highly expressed in most cases of DLBCL. The Quality of life most common type of non-Hodgkin lymphoma, DLBCL bendamustine, Drug, Breakthrough Therapy has a 40% relapse rate, and polatuzumab vedotin might cyclophosphamide, ifosfamide, procarbazine) Clinical trial(s): Phase III improve health outcomes in patients with this condition. POLARIX primary The drug is a synthetic auristatin with cytotoxic activity completion December 2019; that blocks the formation of microtubules. Polatuzumab (eg, lenalidomide) phase I/II GO29365 primary vedotin is purported to bind to CD79b and trigger completion January 2020, internalization of the drug into the cells. This increases Anthracyclines (eg, long-term data reported the likelihood of vedotin targeting and killing malignant doxorubicin) December 2018 cells while minimizing cytotoxicity on normal cells. In Antimetabolites (eg, clinical trials, polatuzumab vedotin is administered cytarabine, gemcitabine) intravenously at a dose of 1.8 mg/kg once every 21 days for 6 cycles, in combination with rituximab (375 mg/m2) Glucocorticoid (eg, plus bendamustine (90 mg/m2). Rituximab monotherapy dexamethasone, is administered in cycles 7 and 8. methylprednisolone, prednisone) Developer(s): Kinase inhibitor (eg, Genentech, Inc (South San Francisco, California), a ) subsidiary of F. Hoffman-La Roche AG (Basel, Switzerland), in collaboration with Monoclonal antibodies Seattle Genetics, Inc (Bothell, Washington) (eg, , rituximab) Platinum-based agents (eg, carboplatin, cisplatin, oxaliplatin) Topoisomerase inhibitors (eg, etoposide, mitoxantrone) Vinca alkaloid (eg, vincristine, vinorelbine)

Section 2. Topics Added Since Last Status Report 86

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or ProTmune is a next-generation allogeneic hematopoietic Standard hematopoietic Overall survival FDA designation(s): Orphan older with a hematologic cell transplantation (HCT) developed from donor-sourced, cell transplantation Drug, Fast Track malignancy (acute mobilized, peripheral blood T cells that have been Progression-free survival Clinical trial(s): Phase I/II lymphoblastic leukemia cultured ex vivo in the presence of FT1050 and FT4145 Quality of life [ALL], acute myeloid (2 small-molecule stem cell modulators that guide cell fate PROTECT primary leukemia [AML], chronic for use as HCT). ProTmune might reduce disease completion September myelogenous leukemia recurrence and improve patient survival. Many patients 2019, initial data reported [CML], or myelodysplastic with hematologic malignancies seek curative therapy March 2018, expanded syndrome) who are through HCT; however, about 50% of patients undergoing enrollment May 2019 considering allogeneic HCT die or experience disease recurrence within the first hematopoietic peripheral 2 years because they develop graft-versus-host disease blood cell transplantation (GVHD). ProTmune purportedly decreases the incidence and severity of acute GVHD while maintaining therapeutic activity against hematologic malignancies. Clinical trials do not specify ProTmune's delivery route; however, similar to standard HCT, it is likely administered as an intravenous infusion. Developer(s): Fate Therapeutics, Inc (San Diego, California)

Section 2. Topics Added Since Last Status Report 87

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or PVS-RIPO is a Sabin type 1 strain of poliovirus Fractionated external Overall survival FDA designation(s): Orphan older with recurrent genetically engineered to not harm or kill normal cells. beam radiation therapy Drug, Breakthrough Therapy malignant glioma (eg, PVS-RIPO uses a novel oncolytic virus approach that Progression-free survival Chemotherapy with one Clinical trial(s): Phase II glioblastoma multiforme might change patient management and improve health Quality of life [GBM], anaplastic outcomes in patients who do not respond to standard or more of the following: Pro00077024 primary completion May 2021 astrocytoma) who have therapy. It selectively infects and replicates tumor cells Alkylating agents (eg, undergone surgical that express the poliovirus receptor nectin-like protein 5 carmustine, resection and completed (CD155), which is expressed in most types of solid tumor cyclophosphamide, adjuvant radiation and cancers. Because CD155 is also expressed in other lomustine, procarbazine, temozolomide therapy immune cells, including dendritic cells and macrophages, temozolomide) PVS-RIPO infection of immune cells facilitates induction of an antitumor immune response that does not kill or limit Angiogenesis inhibitors immune function of dendritic cells. Although immune cells (eg, bevacizumab) infected by PVS-RIPO initiate a type I interferon mTOR inhibitors (eg, response, this will not destroy the oncolytic virus. PVS- everolimus) RIPO purportedly targets and destroys cells in brain tumors and activates tumor-specific immune responses Platinum agents (eg, by stimulating dendritic cell activity and immune function. carboplatin, cisplatin) In clinical trials, PVS-RIPO is administered as a single Vinca alkaloids (eg, intratumoral injection at a dose ranging from 7 × 106 to 7 vincristine) × 109 plaque- forming units. Developer(s): Istari Oncology, Inc (Durham, North Carolina), in collaboration with the Preston Robert Tisch Brain Tumor Center at Duke University (Durham, North Carolina)

Section 2. Topics Added Since Last Status Report 88

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 12 years or Relatlimab (BMS-986016) is a novel human Chemotherapy with one Overall survival Clinical trial(s): Phase II/III older and adults with immunoglobulin G4 (IgG4) monoclonal antibody against or more of the following: primary completion July unresectable or metastatic lymphocyte-activator gene-3 (LAG-3), a co-inhibitor Progression-free survival 2020 Alkylating agents (eg, melanoma who have not receptor primarily expressed on exhausted tumor- Quality of life had systemic therapy infiltrating lymphocytes (TILs). Relatlimab is a novel dacarbazine, immunotherapy that might improve patient outcomes by temozolomide) enhancing immune checkpoint inhibitors and stimulating BRAF inhibitors (eg, TILs. As an adjunct to a checkpoint inhibitor, relatlimab dabrafenib, , might also increase treatment-related costs. The binding vemurafenib) of relatlimab to LAG-3 prevents inhibitory T-cell responses of TILs via interaction with major Immune checkpoint histocompatibility complex class-II (MHC-II) on dendritic inhibitors (eg, cells and melanoma cells. Relatlimab purportedly ipilimumab, nivolumab, promotes innate immune responses and FAS-mediated pembrolizumab) apoptosis in melanoma cells expressing high MHC-II. MEK inhibitors (eg, Relatlimab also synergizes with programmed death- 1 , , immune checkpoint inhibitors that might encourage trametinib) melanoma-specific immune responses. In clinical trials, relatlimab is administered intravenously at a dose of Platinum agents (eg, 160 mg in combination with intravenous nivolumab at a carboplatin) dose of 480 mg on day 1 of each 28-day cycle until Taxane agents (eg, disease progression or intolerable toxicity. paclitaxel) Developer(s): Bristol-Myers Squibb Co (New York, New York)

Section 2. Topics Added Since Last Status Report 89

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Females aged 18 years or Robotically assisted mastectomy using the da Vinci Open surgical Patient satisfaction Clinical trial(s): Phase II older for whom total system off-label has been pioneered by a few European mastectomy MARCI primary completion mastectomy with immediate investigators to improve cosmesis and patient satisfaction Tissue necrosis (nipple- November 2019, preliminary breast reconstruction is compared with open surgical mastectomy. Shifting areola complex) data published September recommended to treat mastectomies from open surgery to robotically assisted Local tumor recurrence 2018; unphased comparing invasive breast cancer or procedures might be disruptive because robotic robotic-assisted and open ductal carcinoma in situ, procedures cost more than open surgeries and require Distant tumor recurrence mastectomy primary or in whom prophylactic personnel training and shifts in infrastructure. Compared Overall survival completion December 2019 mastectomy with to open surgery, da Vinci robotically assisted mastectomy reconstruction is requested purportedly facilitates the performance of technically Disease-free survival Note(s): FDA issued a due to high-risk breast challenging laparoscopic procedures, enhances safety communication on Quality of life cancer–related genetic cosmesis, and improves patient satisfaction. In clinical February 28, 2019 mutations trials, surgeons performing robotically assisted mastectomy avoid the nipple-areola tissue by removing the target breast cancer tissue through a small incision under the arm (axillary access). After the robotically assisted steps, a surgeon manually reconstructs the breast using a conventional breast implant and standard subcutaneous and cutaneous suturing techniques. Developer(s): Clinical investigators at the European Institute of Oncology (Milan, Italy) and Gustave Roussy Cancer Centre (Villejuif, France)

Section 2. Topics Added Since Last Status Report 90

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 55 years or Romyelocel-L (CLT-008) is an allogeneic bone marrow Therapy with one of the Overall survival FDA designation(s): older with untreated, de hematopoietic stem cell-derived, differentiated, expanded, following: Regenerative Medicine novo acute myeloid cryopreserved, myeloid progenitor cell therapy prepared Progression-free survival Advanced Therapy Growth factors (eg, leukemia (AML) for whom from samples obtained from screened and tested healthy Quality of life induction therapy with donors. Romyelocel-L might improve patient health filgrastim, granulocyte- Clinical trial(s): Phase II cytarabine alone or outcomes; however, it might also increase treatment colony stimulating factor) CLT008-03 primary combined with other costs. It is intended to treat chemotherapy-induced completion date September antileukemic agents (eg, in patients with AML, which can lead to 2017, key data reported anthracyclines, opportunistic infections. Romyelocel-L comprises June 2018, updated data daunorubicin, etoposide, multipotent progenitors (CD34+, CD90+), common reported November 2018 idarubicin, purine myeloid progenitors, granulocyte macrophage nucleoside inhibitors) is progenitors, megakaryocyte erythroid progenitors, and being considered few or undetectable levels of B lymphocytes or T lymphocytes. Romyelocel-L purportedly prevents opportunistic infections by introducing a population of myeloid progenitor cells able to produce granulocytes, neutrophils, monocytes, macrophages, red blood cells, and platelets, while unable to produce lymphoid cells and permanently engraft in the bone marrow. In clinical trials, patients receive a single intravenous infusion of romyelocel-L at an unspecified dose. Developer(s): Cellerant Therapeutics, Inc (San Carlos, California)

Section 2. Topics Added Since Last Status Report 91

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (DS-8201) is a monoclonal Chemotherapy with one Overall survival Clinical trial(s): Phase III older with unresectable or antibody conjugated with a chemotherapy drug or more of the following: DESTINY-Breast04 primary metastatic, hormone (deruxtecan) designed to bind the surface receptor Progression-free survival completion January 2022 Alkylating agents (eg, receptor (HR)-positive or human receptor 2 (HER2), a Quality of life HR-negative, human protein commonly associated in some subtypes of breast cyclophosphamide) epidermal growth factor cancer. Frontline therapy for breast cancers expressing Anthracyclines (eg, receptor 2 (HER2)-low low HER2 levels relies on single-agent chemotherapy, but doxorubicin, epirubicin, breast cancer, who have because of limited treatment options and no approved liposomal doxorubicin) received one or two lines of therapies for low- HER2-expressing tumors, trastuzumab treatment deruxtecan might improve health outcomes, disrupt Antimetabolites (eg, 5- patient management, and increase treatment-related fluorouracil, costs. Deruxtecan inhibits the activity of topoisomerase I, capecitabine, an enzyme that relieves DNA supercoiling, leading cells gemcitabine, to arrest their cell cycle and die because of replication- methotrexate, dependent, site-selective, DNA double-strand breaks. pemetrexed) Trastuzumab deruxtecan purportedly binds to HER2 and Immune checkpoint triggers internalization of the drug into the cells. This inhibitors (eg, increases the likelihood that deruxtecan will target and kill atezolizumab) malignant cells while minimizing cytotoxicity on normal cells. In clinical trials, trastuzumab deruxtecan is Microtubule inhibitors administered intravenously at a dose of 5.4 mg/kg once (eg, eribulin, ixabepilone) every 21 days until disease progression or intolerable PARP inhibitors (eg, toxicity. olaparib, talazoparib) Developer(s): Platinum agents (eg, Daiichi Sankyo Co, Ltd (Tokyo, Japan), in collaboration carboplatin, cisplatin) with AstraZeneca (Cambridge, UK Taxanes (eg, docetaxel, nab-paclitaxel, paclitaxel) Vinca alkaloids (eg, vinorelbine)

Section 2. Topics Added Since Last Status Report 92

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 75 years Uproleselan (GMI-1271) is an inhibitor of E-selectin, a Chemotherapy with one Complete remission rate FDA Designation(s): Orphan with relapsed/refractory transmembrane glycoprotein that functions as a cell or more of the following: Drug, Breakthrough adhesion molecule. Uproleselan has a novel mechanism Overall survival Therapy, Fast Track Anthracyclines (eg, (AML) of action that might improve health outcomes in patients Quality of life with AML, who typically have poor treatment outcomes. In daunorubicin, idarubicin) Clinical trial(s): Phase III particular, E-selectin retains AML cells within the vascular primary completion Antibody-drug conjugate December 2020 niches of the bone marrow where these cells are less (eg, gemtuzumab susceptible to cytotoxic chemotherapy. Uproleselan ozogamicin) purportedly antagonizes E-selectin's cell adhesion activity, mobilizing AML cells out of bone marrow and into Antimetabolites (eg, the bloodstream and rendering them more sensitive to cladribine, clofarabine, chemotherapy. In clinical trials, uproleselan is being cytarabine, fludarabine) administered in combination with standard induction Cytokine (eg, chemotherapy regimens (ie, mitoxantrone, etoposide, granulocyte colony- and cytarabine [MEC] or fludarabine, cytarabine, and stimulating factor) idarubicin [FAI]). Uproleselan is administered intravenously at a dose of 10 mg/kg of body weight. DNA synthesis inhibitors (eg, etoposide, Developer(s): mitoxantrone) GlycoMimetics, Inc (Rockville, Maryland) FLT3 inhibitor (eg, gilteritinib) Hypomethylating agents (eg, azacitidine, decitabine) IDH inhibitors (eg, enasidenib, ivosidenib) Multikinase inhibitor (eg, sorafenib)

Section 2. Topics Added Since Last Status Report 93

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Females aged 18 to 99 (ABT-888) is a small-molecule inhibitor of poly Chemotherapy with one Overall survival Clinical trial(s): Phase III years with untreated, stage adenosine diphosphate-ribose polymerase (PARP), an or more of the following: M13-694 primary completion III or IV, high-grade, enzyme involved in DNA repair. Veliparib is the first Progression-free survival April 2019 Angiogenesis inhibitors serious, epithelial ovarian, PARP inhibitor studied in the first-line setting that might Quality of life fallopian tube, or primary improve patient health outcomes. It might also disrupt (eg, bevacizumab) peritoneal carcinoma, patient management by delaying disease progression in Anthracyclines (eg, whose disease harbors the maintenance setting. By inhibiting PARP's DNA doxorubicin, pegylated germline BRCA mutations repair, veliparib might potentiate the anticancer activity of liposomal doxorubicin) cytotoxic chemotherapy drugs whose mechanism of action induces DNA damage. Additionally, PARP Platinum agents (eg, inhibition might exhibit synthetic lethality with cells carboplatin, cisplatin) harboring loss-of-function mutations in the breast cancer Taxanes (eg, docetaxel, 1 gene, BRCA1, and/or the breast cancer 2 gene, BRCA2 nab-paclitaxel, paclitaxel) (an predisposition gene that is also involved in DNA repair); ovarian cancers frequently harbor such mutations. Testing for BRCA mutation status will require use of a companion diagnostic test. In clinical trials, veliparib is administered daily, orally, at an unspecified dose in combination with carboplatin and paclitaxel for 6 cycles of 21 days. Veliparib maintenance therapy is given for up to 30 additional 21-day cycles. Developer(s): AbbVie, Inc (North Chicago, Illinois)

Section 2. Topics Added Since Last Status Report 94

Table 8. Cardiovascular: 8 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 85 years Bempedoic acid is a small-molecule prodrug converted to Bile-acid-binding resins Major adverse PDUFA Date: February 21, with atherosclerotic an active drug primarily in the liver and designed to inhibit cardiovascular events 2020 cardiovascular disease, citrate (ACL), a key enzyme Ezetimibe (MACE) Clinical trial(s): Phase III including coronary artery involved in cholesterol and fatty acid synthesis in the liver. Fibrates disease, symptomatic As an oral drug that might replace statins as a primary Mortality CLEAR Outcomes primary peripheral arterial disease, cholesterol-lowering agent, bempedoic acid might be Niacin completion December 2021 or cerebrovascular disease more cost-effective and more widely accepted than Proprotein convertase and low-density lipoprotein injectable proprotein convertase subtilisin kexin 9 subtilisin kexin 9 level of 100 (2.6 mmol/L) or (PCSK9) inhibitors for managing patients who cannot (PCSK9)- inhibiting higher who are at high risk tolerate statins. By inhibiting ACL, bempedoic acid monoclonal antibodies of an adverse purportedly reduces cholesterol synthesis, thereby cardiovascular event and upregulating low-density lipoprotein (LDL) receptors who have a history of and increasing clearance of LDL cholesterol from the intolerance to two or more bloodstream. In clinical trials, bempedoic acid is taken statin drugs as a 180 mg oral tablet, once daily. Developer(s): Esperion Therapeutics, Inc (Ann Arbor, Michigan)

Section 2. Topics Added Since Last Status Report 95

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

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

Section 2. Topics Added Since Last Status Report 96

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 21 to 80 years CLBS14 is an autologous CD34+ cell therapy intended to Beta blockers Angina incidence FDA designation(s): with Canadian reduce angina by stimulating growth of new Regenerative Medicine Cardiovascular Society microvasculature (angiogenesis) in ischemic myocardial Calcium channel Exercise capacity Advanced Therapy class III or IV chronic tissue. CLBS14 might improve medical therapy for blockers Major adverse coronary Clinical trial(s): Phase III refractory angina who have patients with refractory angina for whom conventional Nitrates events obstructive coronary revascularization is ineffective or unsuitable. During the RENEW completed disease unsuitable for proprietary process, patients receive granulocyte colony- Ranolazine Mortality November 2015, pivotal data published August 2016 conventional stimulating factor (5 mg/kg subcutaneous injection) for Enhanced external Quality of life revascularization about 4 days to mobilize CD34+ cells before apheresis on counterpulsation day 5 to collect cells from peripheral blood. Clinicians ship peripheral blood to a processing laboratory to isolate Spinal cord stimulation CD34+ cells and prepare the cell therapy product for Transmyocardial laser transport back to the treating facility. After about 3 to revascularization 4 days, clinicians administer the cell product into ischemic heart muscle via catheter-based intramyocardial injection. Developer(s): Caladrius Biosciences, Inc (Basking Ridge, New Jersey) acquired exclusive worldwide license from Shire plc (Dublin, Ireland), which is now part of Takeda Pharmaceutical Co, Ltd (Osaka, Japan)

Adults aged 18 years or Inclisiran is an RNA interference therapeutic designed to Bile-acid sequestrants Major adverse Clinical trial(s): Phase III older with atherosclerotic target and reduce the expression of proprotein convertase cardiovascular events ORION-10 primary cardiovascular disease subtilisin kexin type 9 (PCSK9) to treat Fibrates completion October 2019 Mortality (coronary, peripheral, or hypercholesterolemia. Inhibiting PCSK9 production Niacin other arteries) and elevated purportedly increases the number of low-density low-density lipoprotein lipoprotein (LDL) receptors that are recycled and are PCSK9 -inhibiting cholesterol (greater than available on the surface of cells to remove LDL particles monoclonal antibodies 70 mg/dL) despite optimal from extracellular fluid. Inclisiran might enable improved Statins dose of statins or other lipid- dosing as subcutaneous injections every 3 to 6 months lowering therapies if statin- compared with every 2 to 4 weeks for and intolerant . In clinical trials, clinicians administer inclisiran 300 mg subcutaneously on days 1 and 90 and then every 6 months. Developer(s): The Medicines Company (Parsippany, New Jersey), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)

Section 2. Topics Added Since Last Status Report 97

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Inclisiran is an RNA interference therapeutic designed to Bile-acid sequestrants Major adverse Clinical trial(s): Phase III older with a diagnosis of target and reduce the expression of proprotein convertase cardiovascular events ORION-9 primary heterozygous familial subtilisin kexin type 9 (PCSK9) to treat Fibrates completion September 2019 Mortality hypercholesterolemia and hypercholesterolemia. Inhibiting PCSK9 production Niacin elevated low-density purportedly increases the number of LDL receptors that lipoprotein (LDL) cholesterol are recycled and are available on the surface of cells to Proprotein convertase level despite maximal lipid- remove LDL particles from extracellular fluid. Inclisiran subtilisin kexin 9 lowering therapies might enable improved dosing as subcutaneous injections (PCSK9) inhibiting every 3 to 6 months compared with every 2 to 4 weeks for monoclonal antibodies alirocumab and evolocumab. In clinical trials, clinicians Statins administer inclisiran 300 mg subcutaneously on days 1 and 90 and then every 6 months. Developer(s): The Medicines Company (Parsippany, New Jersey) in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)

Adults aged 18 to 85 years (Tegsedi) is an antisense oligonucleotide being Liver transplant Cardiac function FDA designation(s): Orphan with cardiomyopathy of developed for use in patients with hATTR amyloidosis– Drug hereditary transthyretin- associated cardiomyopathy, a progressive disease Small interfering RNAs mediated (hATTR) caused by a mutation in the transthyretin gene, TTR. (siRNAs) Clinical trial(s): Phase II primary completion June amyloidosis Because inotersen is intended to treat the underlying TTR tetramer stabilizers disease process, it might improve patient health 2021 outcomes. In patients with hATTR amyloidosis, misfolded and wild-type TTR proteins, which are made in the liver, accumulate as amyloid deposits in the heart, central and peripheral nerves, and . These deposits block normal organ functions and cause symptoms such as autonomic dysfunction, cardiomyopathy, and polyneuropathy. Tegsedi purportedly reduces production of wild-type and mutant TTR and thus reduces or prevents amyloid deposit accumulation. It is approved by FDA for use in patients with polyneuropathy caused by hATTR amyloidosis. In clinical trials, Tegsedi 300 mg is administered subcutaneously, once weekly, for 24 months. Developer(s): Akcea Therapeutics (Cambridge, Massachusetts), an affiliate of Ionis Pharmaceuticals (Carlsbad, California)

Section 2. Topics Added Since Last Status Report 98

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 80 years RT-100 (Ad5.hAC6) is an adenovirus-based gene therapy Aldosterone receptor Exercise tolerance FDA designation(s): Fast with a diagnosis of New product intended to improve heart function in chronic antagonists Track York Heart Association heart failure by increasing expression of the adenylyl Heart failure–related functional class II to IV heart cyclase type 6 (AC6) protein. RT-100 might disrupt the Angiotensin-converting hospitalizations Clinical trial(s): Phase III failure and left ventricular standard office-based medical management for the enzyme (ACE) inhibitors FLOURISH primary Mortality completion June 2020 ejection fraction between majority of patients with heart failure. AC6 helps regulate Angiotensin II receptor 10% and 35% who remain heart function but is underexpressed in heart muscle cells blockers (ARBs) New York Heart symptomatic despite of patients with heart failure. RT-100 is an adenovirus Association heart failure guideline-directed optimal vector (human adenovirus 5 encoding human AC6 Beta blockers functional class medical therapy [Ad5.hAC6 ), modified to prevent it from replicating, Digoxin Quality of life designed to enter heart cells to deliver the gene encoding for AC6. A physician uses standard cardiac Diuretics catheterization techniques to administer a single dose Hydralazine/nitrate of RT-100 into the coronary arteries using an infusion catheter. In a phase II trial, patients received 1 of Ivabradine 5 ascending doses from 3.2 × 109 to 1012 virus particles. Dose levels in the phase III trial have not yet been Sacubitril/valsartan reported. Developer(s): Renova Therapeutics (San Diego, California)

Section 2. Topics Added Since Last Status Report 99

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 22 years or Woven EndoBridge (WEB) Aneurysm Embolization Balloon-assisted or Stroke Approval date: December older with saccular, wide- System is designed to treat wide-necked, bifurcated stent-assisted 31, 2018 necked, bifurcated intracranial aneurysms by preventing blood flow into the endovascular coiling Mortality Clinical trial(s): WEB-IT intracranial aneurysms at aneurysm sac. This first-in-class intrasaccular aneurysm Device-related adverse the middle cerebral artery embolization device might provide more complete Flow-diverting stents single-arm IDE study (no events/complications phase reported) ongoing bifurcation, internal carotid aneurysm occlusion than that achieved with flow- Surgical clipping artery terminus, anterior diversion stents, while reducing the need for long-term primary completion communicating artery antiplatelet therapy. Further, WEB implantation requires September 2017, pivotal complex, or basilar artery only a single delivery catheter, unlike stent-assisted or data published April 2019 apex, with aneurysm dome balloon-assisted coiling procedures. Physicians use diameter from 3 mm to 10 standard neurointerventional techniques to place the self- mm and either an aneurysm expanding, metallic mesh device into the aneurysm sac neck size of 4 mm or with a compatible delivery catheter. Over time, greater, or a dome-to-neck thromboses develop within the device to fill the space, ratio greater than 1 and less purportedly blocking blood flow into the aneurysm and than 2 preventing aneurysm rupture. The device is composed of nitinol and platinum braided wires and is available in 2 shapes, barrel or sphere, both offered in 3 sizes (4-7 mm diameter, 8-9 mm diameter, 10-11 mm diameter) to accommodate different aneurysm anatomies. Developer(s): Sequent Medical, Inc (Aliso Viejo, California) developed the technology but was subsequently acquired and become part of MicroVention, Inc (Aliso Viejo, California), a Terumo Corp (Tokyo, Japan) company

Section 2. Topics Added Since Last Status Report 100

Table 9. Mental and Behavioral Health: 5 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adolescent females aged Brexanolone (ZULRESSO) purportedly produces a rapid Psychotherapy Depression symptoms Approval date: March 15 years or older and and sustained reduction in depression symptoms and and severity 19,2019 adult females aged up to severity in women with PPD. Its mechanism of action in Antidepressants 45 years with diagnosed treating PPD is not fully understood but is thought to be FDA designation(s): Priority postpartum depression related to its positive allosteric modulation of both Review, Breakthrough (PPD) synaptic and extrasynaptic GABA-A receptors, which Therapy mimics . Falling levels of progesterone after Clinical trials: Phase III childbirth contribute to postpartum depression. primary completion June Brexanolone might improve patient health outcomes by 2020; phase III completed rapidly alleviating these symptoms. The most common October 2017 (moderate adverse events are excessive sedation and somnolence, PPD); phase III completed loss of consciousness, dry mouth, and flushing. Because October 2017 (severe PPD); of the risk of serious harm resulting from excessive pivotal integrated data sedation or sudden loss of consciousness, brexanolone is published September 2018, available only through enrollment in a restricted program additional data presented under a Risk Evaluation and Mitigation Strategy (REMS) October 2018 called the ZULRESSO REMS. Sage Therapeutics has set brexanolone price at $34 000 per course of treatment. Note(s): ZULRESSO is Brexanolone is a one-time treatment, given by continuous expected to be available in intravenous infusion for a total of 60 hours (2.5 days). late June 2019 Developer(s): Sage Therapeutics, Inc (Cambridge, Massachusetts)

Section 2. Topics Added Since Last Status Report 101

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Patients of all ages with Cranial electrotherapy stimulator (Cervella) transmits a Pharmacotherapy (eg, Anxiety symptoms and Clearance date: FDA 510(k) generalized anxiety disorder low-level, constant electrical current to the brain through selective serotonin severity March 15, 2019 (GAD) the patient's skin via a pair of conductive electrodes reuptake inhibitors placed bilaterally on the mastoid process. Because the [SSRIs], serotonin and Quality of life device is portable and can be used discreetly, it might norepinephrine reuptake improve patient adherence to therapy and might improve inhibitors [SNRIs], patient health and quality of life outcomes. Use of the benzodiazepines) device purportedly reduces anxiety levels. Unlike previously cleared cranial electrotherapy stimulation Psychotherapy (eg, (CES) devices, Cervella incorporates conductive cognitive behavioral electrodes into ear cushions of Bluetooth-enabled noise- therapy [CBT]) canceling stereo headphones controlled by a smartphone app. The app allows patients to adjust intensity level, frequency, and duration of the treatment, and the device records data, sends reminders, and provides analytics intended to improve treatment outcomes. CES devices have been in use for several decades and are cleared by the FDA for treating , depression, and anxiety. Cervella's price is set at $695. Developer(s): Innovative Neurological Devices LLC (Carmel, Indiana)

Children aged 8 to 12 years External trigeminal nerve stimulation (eTNS; Monarch) is Behavior therapy (eg, ADHD symptoms and Clearance date: FDA 510(k) with a DSM-5 diagnosis of a noninvasive medical device that stimulates the applied behavior severity April 19, 2019 attention deficit/hyperactivity trigeminal nerve via an external conductive patch to treat analysis [ABA], cognitive disorder (ADHD) children with ADHD. The eTNS system is a novel behavioral therapy Global functioning Clinical trial(s): Unphased 5- week open extension nonpharmacologic approach to treating ADHD that [CBT]) Anxiety symptoms purportedly improves ADHD symptoms and cognition. completed May 2018, data The eTNS system is a cell phone–sized electrical pulse Stimulant medications Depression symptoms reported April 2019; (eg, , unphased completed May generator that delivers mild electrical signals via 2 wires Executive function connected to a small single-use electric patch that , 2018; unphased 12-month adheres to the forehead. The external electrical nerve lisdexamfetamine) open extension completed May 2018 stimulation purportedly changes the neuronal activity in Nonstimulant key regions of the brain—the brainstem, thalamus, and medications (eg, cortex—increasing activity in regions that are underactive. guanfacine, clonidine, The eTNS system is self-administered at home and is ) typically used daily, for 8 hours at a time, while sleeping. Developer(s): Neurosigma (Los Angeles, California), in collaboration with University of California (Los Angeles, California)

Section 2. Topics Added Since Last Status Report 102

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children and adolescents HCl extended-release (SPN-810) is an indole Antidepressants Impulse aggression Submission date: New Drug aged 12 to 17 years with derivative and a dopamine D2 receptor antagonist that ( [Wellbutrin] or behaviors (self-reported) Application anticipated attention deficit/hyperactivity purportedly modulates dopamine and serotonin pathways [Effexor]) fourth quarter 2020 disorder (ADHD) and and reduces impulse aggression in patients with ADHD. Quality of life impulse aggression No medication is approved by FDA specifically to treat Off-label antipsychotics FDA designation(s): Fast impulse aggression, a maladaptive form of aggression Track that is reactive, overt, and occurs outside of an Clinical trial(s): Phase II acceptable social context. Impulse aggression is often completed October 2012, refractory to primary ADHD therapy and has been shown data published April 2016; to increase negative outcomes. In ongoing trials, flexibly- phase III CHIME 2 primary dosed (12 to 36 mg) extended-release SPN-810 is completion May 2018; phase administered orally in combination with standard ADHD III primary completion July treatment. 2019; phase III CHIME 1 Developer(s): primary completion October 2019 Supernus Pharmaceuticals, Inc (Rockville, Maryland)

Children and adolescents HCl (SPN-812) is a novel nonstimulant Atomoxetine (Strattera) ADHD symptoms Submission date: New Drug aged 6 to 17 years with selective norepinephrine reuptake inhibitor with selective (hyperactivity, Application anticipated diagnosed attention- serotonin modulation activity for treating ADHD. With a Stimulants (eg, mixed impulsivity, fourth quarter 2019 deficit/hyperactivity disorder novel mechanism of action, viloxazine might improve salts inattentiveness) (ADHD) patient health outcomes. Viloxazine purportedly produces dextroamphetamine, Clinical trial(s): Phase III a stimulant effect similar to that of , without lisdexamfetamine, Functional impairment completed November 2018 methylphenidate, (child, high dose); phase III the risk of dependence. Viloxazine has an extensive Adverse events safety record in Europe, where it was marketed for many dexmethylphenidate) completed October 2018 years as an antidepressant. In trials, viloxazine is Suicidality (child, low dose); phase III Extended-release completed February 2019 administered orally once a day for 5 to 7 weeks at a guanfacine dose of 100, 200, or 400 mg. (adolescent, high dose); phase III completed October Developer(s): Extended-release 2018 (adolescent, low dose) Supernus Pharmaceuticals, Inc (Rockville, Maryland) clonidine Note(s): Combined topline Behavior therapy study results reported March 2019

Section 2. Topics Added Since Last Status Report 103

Table 10. Rare Diseases: 36 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

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

Section 2. Topics Added Since Last Status Report 104

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 6 months to ABO-102 is a recombinant adeno-associated viral vector Supportive care Cognitive and motor FDA designation(s): Orphan 2 years or children older carrying a wild-type copy of the SGSH gene intended for function, as measured Drug, Fast Track, Rare than 2 years with Sanfilippo treating patients with Sanfilippo syndrome type A Bone marrow transplant by accepted clinical Pediatric Disease, syndrome type A (MPSIIIA), a childhood-onset, progressive, inherited ratings and scales Regenerative Medicine (mucopolysaccharidosis metabolic disorder caused by a mutation in the N- Advanced Therapy type III A [MPSIIIA]) and a sulfoglucosamine sulfohydrolase gene, SGSH. Patients Sulfamidase enzyme minimum cognitive with the disorder cannot break down the polysaccharide activity Clinical trial(s): Phase I/II primary completion developmental quotient of heparan sulfate, the process of which is normally Heparan sulfate levels 60 or above mediated by the SGSH-encoded enzyme sulfamidase. December 2019 Buildup of heparan sulfate in cells of the central nervous system causes degeneration that manifests as behavioral problems, sleeplessness, loss of speech and cognitive skills, mental retardation, heart problems, seizures, and loss of mobility. Sanfilippo syndrome type A (about 60% of all Sanfilippo syndrome cases) has no cure, and patients typically do not survive past their 20s. In patients with Sanfilippo syndrome type A, ABO-102 purportedly restores sulfamidase enzyme function, blocks central nervous system degeneration, and reduces disease-related symptoms. In clinical trials, ABO-102 is administered in viral genomes (vg) at a low dose (0.5 × 1013 vg/kg), mid dose (1 × 1013 vg/kg), or high dose (3 × 1013 vg/kg), intravenously via a peripheral limb vein, once. Developer(s): Abeona Therapeutics, Inc (Dallas, Texas)

Section 2. Topics Added Since Last Status Report 105

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Males aged younger than 5 AT132 is an adeno-associated virus vector that delivers Supportive care Children's Hospital of FDA designation(s): Orphan years with chromosome a functional copy of the myotubularin gene, MTM1, Philadelphia Infant Test drug, Rare Pediatric X–linked myotubular which encodes a phosphatase enzyme called of Neuromuscular Disease, Fast Track, myopathy myotubularin thought to be involved in the development Disorders Regenerative Medicine and maintenance of muscle cells. No cure is available for Advanced Therapy X-linked myotubular myopathy, and affected children Motor function Clinical trial(s): Phase I/II exhibit muscle weakness and tone, which can be Respiratory function observed as early as birth. AT132 is intended to increase (ASPIRO) primary levels of myotubularin and thereby reduce disease Ventilator use completion March 2019, interim data presented at symptoms. In clinical trials, AT132 is administered in Survival viral genomes (vg) at a dose of 1.0 × 1014 vg/kg, the 22nd American Society 3.0 × 1014 vg/kg, or 5.0 × 1014 vg/kg, once intravenously. Quality of life of Gene and Cell Therapy Meeting May 2019 Developer(s): Audentes Therapeutic, Inc (San Francisco, California)

Children aged 10 years or CAP-1002 is a cell-based therapy intended for treating Corticosteroids (eg, Upper limb function, as FDA designation(s): Orphan older and adults with DMD, an inherited, X-linked genetic disorder caused by deflazacort) measured by accepted Drug, Rare Pediatric genetically confirmed mutations or deletions in the dystrophin gene, DMD. DMD-specific ratings Disease, Regenerative Duchenne muscular DMD encodes dystrophin, a protein that helps keep Supportive care and scales Medicine Advanced dystrophy (DMD) who can muscle cells intact. The absence of wild-type dystrophin Therapy be either ambulatory or protein causes progressive muscle fiber necrosis and Muscle strength, as nonambulatory and are eventual widespread muscle weakness. No cure is measured by accepted Clinical trial(s): Phase II receiving stable doses of available for DMD, and first-line corticosteroid treatment DMD-specific ratings HOPE-2 primary completed systemic glucocorticoids (eg, Emflaza; PTC Therapeutics, Inc, South Plainfield, and scales December 2019 New Jersey) manages symptoms but does not prevent 6-minute walk test disease progression and has significant side effects. FDA approved a gene therapy for patients who have a Quality of life specific mutation in DMD (eg, in exon 51); however, patients who have other DMD mutations do not qualify. CAP-1002 might help fill this gap and improve patient health outcomes. CAP-1002 contains cardiosphere- derived cells (CDCs) derived from donor heart tissue. The CDCs in CAP-1002 purportedly secrete growth factors and exosomes that promote cellular regeneration and improve muscle function in patients with DMD. In clinical trials, a solution of CAP-1002 containing 150 million CDCs is administered intravenously, once every 3 months, 4 times. Developer(s): Capricor Therapeutics, Inc (Beverly Hills, California)

Section 2. Topics Added Since Last Status Report 106

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 7 years or FCX-007 is an autologous cell therapy consisting of the Supportive care for pain Change in wound size FDA designation(s): Orphan older and adults with patient's dermal fibroblasts transduced in vitro with a and infection risk from baseline Drug, Fast Track, Rare recessive dystrophic functional copy of the VIIA1 gene, COL7A1, to Pediatric Disease epidermolysis bullosa restore expression of type VII collagen in patients with Time to wound closure (RDEB) RDEB. This rare genetic disease is caused by mutations from baseline Clinical trial(s): Phase I/II FI- in the collagen COL7A1 protein, which is needed for EB-001 primary completion proper skin integrity. Loss of COL7A1 expression in December 2018, interim RDEB leads to widespread blistering, resulting in severe data reported May 2018; scarring, vision loss, disfigurement, and other serious phase III planned medical problems. FCX-007 is intended to prevent blistering and promote wound healing without heavy scarring by delivering transduced COL7A1-expressing fibroblasts into poorly healing lesions. The therapy is thought to form anchoring fibrils that hold the layers of skin together to prevent RDEB-caused wounds. In clinical trials, FCX-007 was injected directly at an unspecified dose into the papillary dermis of blisters and wounds. Developer(s): Fibrocell Technologies, Inc (Exton, Pennsylvania), in collaboration with Castle Creek Pharmaceuticals LLC (Parsippany-Troy Hills, New Jersey)

Section 2. Topics Added Since Last Status Report 107

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 2 to 8 years Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, Monthly convulsive Submission date: New Drug and adults with Dravet amphetamine derivative intended as an adjunctive valproate, , seizure frequency Application February 2019 syndrome who are taking therapy for Dravet syndrome, a rare, severe, infantile- clobazam, stiripentol) (MCSF) one or more antiepileptic onset form of epilepsy usually caused by a mutation in FDA designation(s): Orphan drugs the sodium voltage-gated channel alpha subunit 1 gene, Plant-derived Convulsive seizure Drug, Breakthrough SCN1A. Fintepla might improve health outcomes in cannabidiol duration Therapy, Fast Track patients with Dravet syndrome who have prolonged Ketogenic diet Seizure-free interval Clinical trial(s): Phase III seizures difficult to control with currently available completed June 2018, data antiepileptic drugs. In addition, patients typically presented December 2018; experience cognitive impairment, behavioral problems, phase III primary completion muscle weakness, and sleep disorders. FDA has June 2019, data presented approved cannabidiol (Epidiolex; GW Pharmaceuticals December 2017; phase III plc, Cambridge, UK) for treating the disease, but it might open-label extension cause hepatic impairment, especially when used in primary completion conjunction with certain antiepileptics; the drug might December 2019, data also cause sleepiness, sedation, and suicidal behavior. presented December 2018; In patients with Dravet syndrome, Fintepla purportedly phase III primary completion promotes serotonin release and stabilizes nerve activity January 2020, data in the brain, which might decrease seizure frequency presented December 2017; and duration. In clinical trials, patients or caregivers phase III long-term follow- orally administer Fintepla at a dose of 0.2 0.4 or up primary completion April 0.8 mg/kg/day (up to a maximum of 20 mg/day) for 2023 up to 156 weeks. Note(s): FDA issued a Developer(s): Refusal to File letter on April Zogenix, Inc (Emeryville, California) 8, 2019, citing missing and incorrect data

Section 2. Topics Added Since Last Status Report 108

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 2 years or Fenfluramine hydrochloride low-dose (Fintepla) is an Anti-epileptics (e.g., Frequency of seizures FDA designation(s): Orphan older and adults aged up to amphetamine derivative intended as an adjunctive valproate, topiramate, that result in drops Drug 35 years with Lennox- therapy for Lennox-Gastaut syndrome, a rare, severe, clobazam, stiripentol) Gastaut syndrome who are infantile- or childhood-onset form of epilepsy. Fintepla Duration of seizures that Clinical trial(s): Phase III taking 1 to 4 antiepileptic might improve health outcomes in patients with Lennox- Plant-derived result in drops primary completion drugs Gastaut syndrome, who often experience multiple types cannabidiol December 2019; phase III Seizure-free interval long-term follow-up study of seizures (eg, atonic, tonic, atypical absence, drop Ketogenic diet attacks) difficult to control with FDA-approved primary completion April antiepileptic drugs. In addition, patients typically 2023 experience cognitive impairment, intellectual disability, behavioral problems, delayed development, and muscle weakness. FDA has approved cannabidiol (Epidiolex; GW Pharmaceuticals plc, Cambridge, UK) for treating the disease, but it might cause hepatic impairment, especially when used in conjunction with certain antiepileptics; the drug might also cause sleepiness, sedation, and suicidal behavior. In patients with Lennox- Gastaut syndrome, Fintepla purportedly promotes serotonin release and stabilizes nerve activity in the brain, which might decrease seizure frequency and duration. In clinical trials, patients or caregivers orally administer Fintepla at a dose of 0.2 or 0.8 mg/kg/day (up to a maximum of 20 mg/day) for up to 52 weeks. Developer(s): Zogenix, Inc (Emeryville, California)

Section 2. Topics Added Since Last Status Report 109

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 13 years or Gaboxadol, also known as OV101 or THIP, is a small- Supportive care (eg, Motor function, as FDA designation(s): Orphan older and adults aged up to molecule derivative of muscimol, a compound found in physical therapy, measured by accepted Drug, Fast Track 49 years with genetically the mushroom Amanita muscaria. It is intended for occupational therapy, clinical ratings and confirmed Angelman treating Angelman syndrome, a rare, noninherited, speech/language scales Clinical trial(s): Phase II syndrome chromosome X–linked neurodevelopmental disorder therapy, assistive completed June 2018 caused by a mutation in the ubiquitin protein E3a devices, Time to sleep onset (children and adults), data presented October 2018, gene, UBE3A. UBE3A encodes the UB3A protein, which anticonvulsants, Total sleep time mediates cellular protein degradation and is expressed benzodiazepines for data reported May 2019; in both excitatory and inhibitory neurons in the brain. sleep disturbances) Behavioral disturbances, phase II ELARA open-label Normally, the brain can differentiate between excitatory as measured by extension primary and inhibitory signals, a process called tonic inhibition, accepted clinical ratings completion July 2020 and is partially mediated by gamma-aminobutyric acid and scales (children and adults); phase (GABA) receptors. In a mouse model of Angelman III planned for the second syndrome in which the animals lacked UBE3A and UBA3 half of 2019 (children only) expression, loss of tonic inhibition disrupted nerve cell Note: Gaboxadol is also in function and normal brain activity, resulting in motor phase II clinical dysfunction. Patients with Angelman syndrome development for treating experience severe developmental delays, intellectual fragile X syndrome disability, impaired speech and motor function, behavioral and sleep disturbances, and seizures. No cure is available, and treatment consists of supportive care. If effective, gaboxadol could decrease symptom severity in patients with the disease. Because the drug is a delta-selective, GABA-A receptor agonist that activates GABA-A receptors, it purportedly restores the process of tonic inhibition and normalizes brain activity in patients with Angelman syndrome. In clinical trials, patients receive gaboxadol 10 to 25 mg, once or twice daily, for up to 52 weeks. Developer(s): Ovid Therapeutics, Inc (New York, New York)

Section 2. Topics Added Since Last Status Report 110

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults with episodic cluster -gnlm (Emgality) is a humanized Off-label topiramate Weekly cluster Approval date: June 4, 2019 headache monoclonal antibody against gene–related headache frequency peptide (CGRP) approved to treat migraine headache Off-label verapamil FDA designation(s): Cluster headache Breakthrough Therapy and then studied to prevent chronic or episodic cluster Corticosteroids headache. However, in the FDA approval granted in severity, as measured (episodic cluster headache) June 2019, the labeled indication pertains to “treating by accepted clinical ratings and scales Clinical trial(s): Phase III episodic cluster headache in adults.” Galcanezumab completed February 2018; thus became the first biologic to be approved for patients phase III open-label who experience these headaches. CGRP is a extension primary thought to contribute to pain signaling of completion July 2021 the trigeminal sensory nerve, leading to headache (episodic, chronic cluster development. Galcanezumab purportedly prevents headache) CGRP from binding to its receptor, which might reduce cluster headache frequency. For episodic cluster headache, the recommended dosage of galcanezumab is 300 mg, which patients self-administer subcutaneously as 3 consecutive injections of 100 mg each, at the onset of the cluster period and then monthly until the end of the same cluster period. Developer(s): Eli Lilly and Co (Indianapolis, Indiana)

Section 2. Topics Added Since Last Status Report 111

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 12 years or Givosiran (ALN-AS1) is an RNAi therapeutic that Hemin injection (acute) Rate of attacks Submission date: Rolling older and adults with acute reduces the expression of synthase 1 submission of New Drug hepatic porphyrias (APH), (ALAS1) to treat AHP. AHPs are a group of rare Carbohydrate perfusion Rate of hemin Application initiated end of including acute intermittent metabolic disorders caused by genetic mutations (acute) administration 2018; complete filing of New porphyria, variegate (usually autosomal dominant) in enzymes that are Supportive therapy Pain score change from Drug Application expected porphyria, and hereditary involved in heme biosynthesis in the liver and converge (acute) baseline mid-2019 coproporphyria in their respective metabolic pathways on the ALAS1 enzyme, which is thought to increase the production Trigger avoidance score change FDA designation(s): Orphan neurotoxic heme intermediates in the liver, contributing (acute) from baseline Drug, Breakthrough Therapy the development of AHP. The manifestations include Fatigue score change intermittent porphyria, aminolevulinic acid dehydratase- from baseline Clinical trial(s): Phase III deficiency porphyria, hereditary coproporphyria, and ENVISION primary variegate porphyria. Common symptoms from these completed January 2019, manifestations can include confusion, fatigue, nausea, data reported April 2019 weakness, blisters on sun-exposed skin, and severe, diffuse abdominal pain. The disorders are chronic and are associated with serious morbidity. Acute flares can be life-threatening. No treatments are FDA-approved to prevent attacks or treat chronic manifestations of these disorders. Givosiran is designed to reduce the expression of ALAS1 enzyme in the liver and reduce buildup of neurotoxic heme intermediates and prevent or reduce recurrent AHP attacks. It is administered as a subcutaneous injection. Developer(s): Alnylam Pharmaceuticals, Inc (Cambridge, Massachusetts)

Section 2. Topics Added Since Last Status Report 112

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 7 to 13 years (SRP-4053) is a phosphorodiamidate Corticosteroids (eg, Ambulatory capacity, as PDUFA date: Priority with Duchenne muscular morpholino oligomer (DNA analogue) intended for deflazacort measured by accepted Review August 19, 2019 dystrophy (DMD) who have treating DMD, an inherited, chromosome X–linked clinical ratings and a deletion in the DMD gene genetic disorder caused by mutations or deletions in the Supportive care scales FDA designation(s): Orphan Drug that is amenable to exon 53 dystrophin gene, DMD. DMD encodes dystrophin, a skipping and who are on a protein that helps keep muscle cells intact. The absence 6-minute walk test distance Clinical trial(s): Phase III stable dose of of wild-type dystrophin protein causes progressive ESSENCE primary corticosteroids muscle fiber necrosis and eventual widespread muscle Quality of life completion May 2022 weakness. DMD has no cure, and first-line corticosteroid treatment (eg, Emflaza; PTC Therapeutics, Inc, South Plainfield, New Jersey) manages symptoms but does not prevent disease progression and has significant side effects. FDA approved a gene therapy for patients with a specific mutation in DMD (eg, in exon 51), but patients who have other DMD mutations do not qualify for these therapies. Therefore, additional therapies are needed. Golodirsen purportedly binds exon 53 of dystrophin pre-mRNA (precursor RNA composed of introns and exons) and promotes skipping of exon 53 during mRNA processing, which allows for synthesis of an internally truncated but functional dystrophin protein. Therefore, golodirsen treatment might promote skeletal muscle function and prevent or delay disease progression in patients who have mutations in DMD exon 53. In clinical trials, golodirsen 30 mg/kg is administered intravenously, once weekly, for up to 96 weeks. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts)

Section 2. Topics Added Since Last Status Report 113

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 2 to 6 years GT-AADC (formerly known as AGIL-AADC and AAV2- Dopamine (eg, Motor function, as Submission date: Biologics with genetically confirmed, hAADC) is an adeno-associated viral vector containing , measured by accepted License Application planned symptomatic aromatic L- a functional copy of the human dopa decarboxylase pramipexole, ropinirole, clinical ratings and for 2019 amino acid decarboxylase gene, DDC, intended for treating patients with AADCD, rotigotine) scales deficiency (AADCD) a childhood-onset, progressive, inherited FDA designation(s): Orphan neurometabolic disorder. AADCD is caused by a Monoamine oxidase Developmental delays Drug, Rare Pediatric mutation in DDC that results in the loss of the gene's inhibitors (eg, , Disease tranylcypromine) Dyskinesia encoded enzyme, aromatic L-amino acid decarboxylase Clinical trial(s): Phase I/II Quality of life (AADC), which is critical for converting neurotransmitter Vitamin B6 primary completion precursors into dopamine, epinephrine, norepinephrine, December 2020, data or serotonin. Patients with AADCD experience published December 2017; symptoms including severe developmental delays, weak phase II MIND primary muscle tone, involuntary movements of the arms completion December 2018, and legs, and painful seizures. Existing treatments only pooled data published May manage symptoms and do not prevent disease 2018 progression. Delivery of a functional copy of DDC by GT-AADC treatment might enhance neurotransmitter production, restore motor function, and delay or prevent other disease symptoms. In clinical trials, 1.8 × 1011 viral genome (vg) or 2.4 × 1011 vg of GT-AADC is administered intracerebrally into the bilateral putamen via stereotactic surgery, once. Developer(s): PTC Therapeutics, Inc (South Plainfield, New Jersey)

Section 2. Topics Added Since Last Status Report 114

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or jCell is an allogeneic stem cell therapy that uses human Vitamin and nutritional Best corrected visual FDA designation(s): Orphan older with retinitis retinal progenitor cells that have been cultured and supplementation acuity Drug, Regenerative pigmentosa (RP) who have expanded under clinical-grade conditions. No effective Medicine Advanced undergone genetic testing treatments are available for RP, so jCell could be the first Supportive care Contrast sensitivity Therapy to identify the causative nonsurgical therapy to delay RP progression or reverse Functional vision mutation vision loss through the release of Clinical trial(s): Phase II JC- (assessed by visual 02 primary completion that might rescue diseased retinal cells and possibly quality of life evaluation) differentiate into new rod cells in the retina. In clinical August 2019 trials, jCell has been administered 3.0 × 106 or 6.0 × 106 Microperimetry change human retinal progenitor cells suspended in clinical from baseline grade medium injected intravitreally under local Mobility (maze testing) anesthesia into the eye with the poorest visual acuity or, if vision is comparable in both eyes, the nondominant Spectral domain optical eye. coherence tomography Developer(s): Visual fields jCyte, Inc (Newport Beach, California), in collaboration with California Institute of Regenerative Medicine (Oakland, California)

Section 2. Topics Added Since Last Status Report 115

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or Lenabasum is a novel synthetic anti-inflammatory and Combined autologous Disease progression FDA designation(s): Orphan older with diffuse antifibrotic medication under investigation for treating the hematopoietic stem cell Drug, Fast Track cutaneous systemic rare, incurable, autoimmune, connective tissue disease transplant and high-dose Mortality sclerosis systemic sclerosis. Conventional immunosuppressive immunosuppressive Clinical trial(s): Phase III Skin fibrosis and primary completion March therapy has limited efficacy in preventing disease therapy inflammation progression or reducing mortality rates. The disease is 2020, primary endpoint marked by vasculopathy, skin thickening due to collagen Low-dose Quality of life changed April 2019 accumulation, autoantibody formation, and inflammation immunosuppressive therapy leading to fibrosis in skin and internal organs. Patients with limited cutaneous systemic sclerosis have fairly high Symptom-based survival rates but are at increased risk of pulmonary palliative arterial hypertension. Patients with diffuse cutaneous pharmacotherapy systemic sclerosis have worse survival rates. Preclinical (nonsteroidal anti- studies suggest that lenabasum is a preferential agonist inflammatory drugs of immune cell cannabinoid receptors (CB2). Lenabasum [NSAIDs], angiotensin- purportedly binds CB2 receptors and triggers converting enzyme inflammation resolution, a multifaceted process that [ACE] inhibitors) reduces immune-mediated inflammation and tissue injury to improve systemic sclerosis symptoms. In clinical trials, lenabasum is administered orally, at 5 or 20 mg doses, twice daily. Developer(s): Corbus Pharmaceuticals Holdings, Inc (Norwood, Massachusetts)

Children aged 12 years or LentiGlobin (BB305) consists of patient-derived Hydroxyurea Frequency of vaso- FDA designation(s): Orphan older and adults aged up to hematopoietic stem cells transduced with a functional occlusive crises and Drug, Regenerative 50 years with severe sickle copy of the human beta-globin gene, which are then Pharmaceutical-grade L- hospitalizations Medicine Advanced cell disease reintroduced to the patient. LentiGlobin has a unique glutamine Therapy Number of blood amino acid substitution in the beta-globin gene that Blood transfusion promotes antisickling of red blood cells. By replacing transfusions required Clinical trial(s): Phase I/II primary completion January dysfunctional human beta-globin genes, LentiGlobin Hematopoietic stem cell Quality of life might address sickle cell disease's underlying cause, transplant 2021, interim data rather than just reduce symptoms. Physicians administer presented at the 60th LentiGlobin by intravenous infusion as a single dose Annual Meeting of the after myeloablative conditioning with busulfan. American Society of Hematology December Developer(s): 2018 bluebird bio, Inc (Cambridge, Massachusetts)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 8 years or Livoletide (AZP-531) is a first-in-class analogue of Hormone therapy Hyperphagia (abnormal FDA designation(s): Orphan older and adults with unacylated ghrelin, a naturally occurring hormone (human growth appetite) drug Prader-Willi syndrome thought to counteract the effects of acylated ghrelin, hormone) (PWS) who have commonly called the "hunger hormone," which Rate of comorbidities Clinical trial(s): Phase IIb/III abnormally increased stimulates food-seeking behavior. No effective or Cognitive and behavioral (cardiovascular disease, ZEPHYR pivotal primary appetite (hyperphagia) approved treatments for PWS-associated abnormal therapy diabetes mellitus, completion June 2020 obesity) eating behaviors exist. If livoletide is effective for treating Controlled diet abnormal eating in PWS, it might reduce obesity-related Caregiver burden complications and improve quality of life for patients. Exercise programs Mortality Livoletide is under development to treat hyperphagia -like peptide 1 associated with PWS, a rare genetic disease (about (GLP-1) receptor agonist Quality of life 8000 to 11 000 estimated US patients) caused by lack ( or ; of expression of several genes on chromosome 15. In off-label) addition to having intellectual disability and short stature, patients with PWS often die by about age 40 years, mainly from obesity-related comorbidities, including cardiovascular and respiratory (eg, sleep apnea) complications and type 2 diabetes mellitus. In clinical trials, patients receive daily subcutaneous injections at dosages between about 60 mcg/kg and 120 mcg/kg. Developer(s): Millendo Therapeutics (Ann Arbor, Michigan)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 years or (Ofev) is a kinase inhibitor and antifibrotic Other antifibrotic drugs Annual rate of forced Submission date, New Drug older with systemic drug approved by FDA for treating idiopathic pulmonary (eg, pirfenidone, D- vital capacity (FVC) Application March 18, 2019 sclerosis–associated fibrosis (IPF) and being developed for treating SSc-ILD. penicillamine) decline interstitial lung disease Patients with SSc (also known as ) have FDA designation(s): Orphan (SSc-ILD) thickening and scarring of connective tissue in multiple Anti-inflammatory drugs Time to all-cause Drug, Fast Track organs. Most will develop ILD, which is the leading (eg, nonsteroidal anti- mortality inflammatory drugs Clinical trial(s): Phase III cause of death in these patients. No cure is available for Skin thickness, as SENSCIS completed SSc-ILD, and existing treatments such as corticosteroids [NSAIDs], cyclooxygenase-2 measured by accepted October 2018, data and immunosuppressants manage symptoms but do not clinical ratings and published May 2019; phase prevent disease progression, and they have significant [COX-2] inhibitors, corticosteroids) scales III open-label extension side effects. Ofev purportedly binds to and blocks primary completion intracellular signaling of the receptor tyrosine kinases Immunosuppressants Quality of life, as July 2021 (RTKs) platelet-derived growth factor receptor (PDGFR) measured by accepted α and β, fibroblast growth factor receptor (FGFR) 1-3, Supportive care clinical ratings and and vascular endothelial growth factor receptor scales (VEGFR) 1-3, which are thought to contribute to lung tissue fibrosis in both IPF and ILD. Therefore, nintedanib might be effective in preventing SSc-ILD disease progression. In clinical trials, patients orally self- administer nintedanib 150 mg, twice daily, for up to 100 weeks. Developer(s): Boehringer Ingelheim International GmbH (Ingelheim, Germany)

Section 2. Topics Added Since Last Status Report 118

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Males aged 18 years or NSR-REP1 (AAV2-REP1) comprises an adeno- Low vision aids (eg, Best corrected visual FDA designation(s): Orphan older with genetically associated virus serotype 2 (AAV2) vector that delivers a telescopic and acuity (BCVA) Drug, Regenerative confirmed choroideremia recombinant human CHM-associated gene Rab effector magnifying lenses) Medicine Advanced (CHM) protein 1 (REP1) inside the eye. CHM is a rare, Color vision Therapy Supportive care degenerative, chromosome X–linked genetic retinal Contrast sensitivity disorder primarily affecting males, with no treatment Clinical trial(s): Phase III available. NSR-REP1 is intended to introduce a Microperimetry STAR primary completion functional choroideremia gene, CHM, designed to March 2020 enhance expression of REP1. This is thought to reduce accumulation of waste products in retinal cells and slow or stop vision decline. REP1's enhanced expression might also slow or reverse early stages of cell death in damaged retinal cells, possibly improving visual acuity in some patients. In clinical trial trials, NSR-REP1 was administered surgically by injection into the subretinal space, which is between the retina's outer layers at a low (1 × 1010) or high (1 × 1011) vector dose. Developer(s): Biogen (Cambridge, Massachusetts), in collaboration with Nightstar Therapeutics, plc (London, UK), which was acquired by Biogen in June 2019

Section 2. Topics Added Since Last Status Report 119

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Males aged 18 years or NSR-RPGR is a recombinant adeno-associated viral Vitamin and nutritional Best corrected visual Clinical trial(s): Phase II/III older with retina specialist– vector that delivers a codon-optimized form of the wild- supplementation acuity (BCVA) XIRIUS primary completion confirmed chromosome X– type RPGR-ORF 15 (retinitis pigmentosa GTPase August 2020, preliminary linked retinitis pigmentosa regulator-open reading frame 15) gene, RPGR, which Supportive care Microperimetry change safety and efficacy data (XLRP) and RPGR-ORF 15 encodes a full-length functional protein for treating from baseline reported September 2018 gene mutations XLRP. No effective treatments are approved for this rare Spectral domain optical condition, and NSR-RPGR could become the first retinal coherence tomography gene therapy to delay XLRP or reverse vision loss. XLRP is the most common form of retinitis pigmentosa Visual fields caused by mutations in the eye-specific form of the RPGR gene called RPGR-ORF 15. NSR-RPGR is intended to express a full-length RPGR-ORF 15 protein in retinal cells that will restore the function of cones and rods. In clinical trials, a single dose is administered via subretinal injection into the eye. Developer(s): Biogen (Cambridge, Massachusetts), in collaboration with Nightstar Therapeutics, plc (London, UK), which was acquired by Biogen in June 2019

Section 2. Topics Added Since Last Status Report 120

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 21 to 80 years NT-501 (Renexus) is an eye implant containing Vascular endothelial Neurodegeneration, as FDA designation(s): Orphan with macular telangiectasia genetically modified human cells that secrete the growth factor (VEGF) measured by changes in Drug, Fast Track type 2 neuropeptide ciliary neurotrophic factor (CNTF). No inhibitors macular ellipsoid zone implants are approved to carry biologics for macular Clinical trial(s): Phase III telangiectasia type 2 (MacTel), a neurodegenerative Macular thickness primary completion March 2021; phase III primary disorder that causes gradual central vision loss over a Visual acuity period of 10 to 20 years. Therefore, NT-501 might completion March 2021; represent a novel treatment option for these patients. Retinal sensitivity phase II completed April 2017, data published April NT-501 allows controlled release of biologic drugs and is Reading speed intended to slow retinal degeneration. CNTF purportedly 2019 diffuses into the retina from the cells contained within the Renexus device to stimulate retinal cell growth and protect the cells from damage. In clinical trials, Renexus is surgically implanted into the vitreous humor and contains an unspecified dose of CNTF. The implant purportedly secretes CNTF for up to 2 years after placement. Developer(s): Neurotech Pharmaceuticals (Cumberland, Rhode Island), in collaboration with Lowy Medical Research Institute (La Jolla, California)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 60 years NurOwn is an autologous, bone marrow–derived, Edaravone Disease progression, as FDA designation(s): Orphan with rapidly progressing mesenchymal stromal cell therapy intended for ALS. In measured by accepted Drug, Fast Track amyotrophic lateral patients with ALS, the presence of abnormal protein Riluzole clinical ratings and Clinical trial(s): Phase III sclerosis (ALS) aggregates in the brain causes neuronal death and Supportive care scales contributes to disease progression. The exact cause of BCT-002 primary these aggregates is unknown. FDA-approved drugs for completion July 2019 treating the disease (eg, riluzole, edaravone) decrease symptom severity in some patients, but do not block neuronal injury and ALS progression. NurOwn grows the patient's bone marrow cells in a proprietary culture media to differentiate mesenchymal stromal cells into astrocyte-like cells. The cultured cells purportedly secrete neurotrophic and growth factors, including glial-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor, and , which have immunomodulatory characteristics, intended to protect neurons and glial cells from toxins and facilitate tissue repair. Thus, NurOwn could delay or prevent neuronal injury in patients with rapidly progressing ALS. In clinical trials, an unspecified dose of NurOwn is administered intrathecally (into the spinal cord), every other month, 3 times. Developer(s): BrainStorm Cell Therapeutics (New York, New York)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 2 years or -xioi (AVXS-101, Manual chest Mortality Approval date: May 24, younger with spinal muscle Zolgensma) is an adeno-associated viral vector (AAV9) physiotherapy for 2019 atrophy (SMA) type 1 containing a functional copy of the SMN1 gene intended ineffective cough (eg, Ventilator support use FDA designation(s): Orphan (infantile-onset SMA or to restore SMN1 expression in patients with SMA type 1. Cough Assist or Nutritional support use Werdnig-Hoffmann SMA, a severe neuromuscular disorder caused by a VitalCough) Drug (all types of SMA), disease) with bi-allelic genetic defect in SMN1, results in loss of the gene’s Motor function, as Breakthrough Therapy mutations in the survival encoded SMN protein. The protein is critical for motor Noninvasive positive measured by accepted (SMA type 1), Fast Track motor neuron 1 gene, neuron function and transmission of signals from the pressure ventilation clinical ratings and (SMA type 1) (NIV) SMN1 brain to skeletal muscles. Patients with SMA experience scales Clinical trial(s): Phase I motor neuron loss, resulting in progressive muscle Muscle strength, as START completed weakness and eventual paralysis. Restoring functional measured by accepted December 2017, long-term SMN1 expression through Zolgensma could delay or halt clinical ratings and follow-up data reported May disease progression in patients with SMA type 1. In scales 2019; phase III STR1VE clinical trials, patients received either 6.7 x 1013 viral primary completion genomes (vg)/kg of body weight or 2.0 x 1014 vg /kg of Developmental November 2019, interim body weight of Zolgensma, intravenously via a peripheral milestone achievement data reported April 2019 vein, once. Hospitalization rates Developer(s): AveXis, Inc (Bannockburn, Illinois), a wholly owned subsidiary of Novartis AG (Basel, Switzerland)

Infants, children, and OTL-101 is an autologous CD34+ hematopoietic stem Bone marrow transplant Overall survival Submission date: Biologics adolescents aged 30 days cell treatment transduced with a lentiviral vector that License Application planned to 17 years with adenosine delivers the gene, ADA. ADA- Enzyme replacement Event-free survival for 2020 deaminase/severe SCID is a rare and life-threatening inherited disease of combined the immune system due to a faulty ADA gene. ADA is FDA designation(s): Orphan immunodeficiency (ADA- essential for T-cell and B-cell production (lymphocytes), Drug, Breakthrough SCID) who are ineligible for so patients with ADA-SCID produce no functional Therapy, Rare Pediatric matched family allogeneic lymphocytes, leading to susceptibility to serious and life- Disease bone marrow threatening infections. Without enzyme replacement Clinical trial(s): Phase I/II transplantation therapy, patient life expectancy is short. OTL-101 was primary completed October designed to restore lymphocyte development and 2018, initial data reported immunity in patients with ADA/SCID (bubble boy February 2019; phase I/II disease). OTL-101 is administered as a single primary completion intravenous infusion of an unspecified dose. December 2020 Developer(s): Orchard Therapeutics, Ltd (London, UK)

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Children and adults aged OTL-103 consists of patient bone marrow–derived Immunoglobulin infusion Frequency of FDA designation(s): Orphan up to 65 years with a CD34+ hematopoietic stem cells that are transduced ex immunoglobulin or Drug, Rare Pediatric diagnosis of Wiskott-Aldrich vivo with a lentiviral vector containing the human Platelet infusion platelet infusions Disease syndrome (WAS) Wiskott-Aldrich syndrome gene, WAS. The syndrome is Hematopoietic stem cell Rate of hospitalizations Clinical trial(s): Phase I/II a recessive chromosome X–linked inherited primary transplant immunodeficiency caused by mutations in the WAS for infection or bleeding TIGET-WAS completed gene, a cytoskeleton regulator expressed only in episodes October 2018, data hematopoietic cells. WAS deficiency leads to eczema, published May 2019; phase petechiae, , reduced blood clotting, II primary completion and susceptibility to infections. A bone marrow transplant February 2022 from an allogeneic donor can potentially cure WAS. OTL-103 is intended to improve WAS symptoms by repopulating the bone marrow with WAS-expressing hematopoietic stem cells that restore growth, replication, and functional capacities enabling response to infectious agents and injury. In clinical trials, the transduced OTL-103 cell product is readministered as a single intravenous infusion of an unspecified number of cells, after patients have received a myeloablative conditioning regimen with busulfan, fludarabine, and anti-CD20 antibody. Developer(s): Orchard Therapeutics, Ltd (London, UK)

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Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 4 years or Palovarotene is a selective receptor gamma Supportive care (eg, New HO formation Submission date: New Drug older and adults with (RARγ) agonist being developed for treating FOP, a rare corticosteroids, Application planned for fibrodysplasia ossificans connective tissue disorder caused by a mutation in the nonsteroidal anti- Number of body regions second half of 2019 (flare progressiva (FOP) activin A receptor type 1 gene, ACVR1, which encodes inflammatory drugs, with HO treatment indication only) for the ACVR1/ALK2 receptor. ALK2 normally regulates occupational therapy, Flare rate the bone morphogenetic protein (BMP) pathway, which assistive devices) FDA designation(s): Orphan is responsible for cartilage regulation and bone Range of motion, as Drug, Breakthrough development and growth. In patients with FOP, mutant measured by accepted Therapy, Fast Track, Rare ALK2 overactivates Smad 1/5/8 transcription factors in clinical ratings and Pediatric Disease the BMP2 pathway, leading to the abnormal growth of scales Clinical trial(s): Phase III bone in muscles, tendons, and ligaments, known as Physical function, as MOVE primary completion heterotopic ossification (HO). HO flares can occur measured by accepted September 2020; phase II spontaneously or after physical trauma (eg, injury, clinical ratings and completed May 2016, data infection). Once formed, the heterotopic bone cannot be scales presented September 2017; removed, because tissue disruption causes additional phase II long-term HO episodes. HO progressively interferes with normal extension primary body functions, including walking, bending, breathing, completion March 2021 chewing, and swallowing. Palovarotene purportedly binds to and activates RARγ, which promotes Smad Note(s): Palovarotene is degradation. Thus, palovarotene treatment might prevent also in phase II HO in patients with FOP. In clinical trials, for preventive development for treating treatment, patients or caregivers administer oral multiple osteochondromas palovarotene 5 mg, once daily for 24 months. For disease flares, patients or caregivers administer oral palovarotene 20 mg, once daily for 4 weeks, followed by palovarotene 10 mg, once daily for 8 weeks. Developer(s): Clementia, an Ipsen company (Montreal, Québec, Canada)

Section 2. Topics Added Since Last Status Report 125

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adolescents aged 16 years PBI-4050 (3-pentylbenzeneacetic acid sodium salt) is a Supportive care Change from baseline in FDA designation(s): Orphan or older and adults with first-in-class, synthetic, medium-chain fatty acid skin pathology Drug, Rare Pediatric Alström syndrome analogue, oral antifibrotic (reduces scar tissue formation) Organ transplant Disease intended to treat Alström syndrome, a rare genetic Change from baseline in syndrome. The syndrome is characterized by obesity in fasting plasma glucose Clinical trial(s): Phase II/III childhood or adolescence and type 2 diabetes mellitus, over time primary completion July often with severe insulin resistance, dyslipidemia, 2020, preliminary data Change from baseline in reported April 2018 hypertension, and severe life-threatening multiorgan plasma insulin over time fibrosis involving the bladder, kidney, liver, and heart. Progressive loss of vision and hearing, dilated Change from baseline in cardiomyopathy, and short stature may also occur. PBI- glycated hemoglobin 4050 purportedly has agonist and antagonist activity (HbA1c) over time towards the G-protein coupled receptors GPR40 and Change from baseline in GPR84, respectively, which reduce fibrotic activity in blood glucose as macrophages, fibroblasts/myofibroblasts, and epithelial measured by weekly 4- cells. PBI-4050 is intended to alleviate the development point profile of insulin resistance, dyslipidemia, and hypertension and severe multiorgan fibrosis. In clinical trials, PBI-4050 was Change from baseline in administered as four 200 mg capsules (800 mg total), liver stiffness once daily. Developer(s): Prometic Life Sciences, Inc (Laval, Québec, Canada)

Section 2. Topics Added Since Last Status Report 126

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 10 years or Plerixafor (Mozobil) is a CXC chemokine receptor 4 Granulocyte-colony Infection rate FDA designation(s): Orphan older and adults aged up to (CXCR4) antagonist, which purportedly prevents most stimulating factor (G- Drug 75 years with clinical leukocyte subsets from homing in and localizing in the CSF; infection Severity of infections Clinical trial(s): Phase III diagnosis of WHIM bone marrow, which is characteristic of WHIM syndrome prevention) Wart control syndrome (warts, and increases infection risk and other complications. primary completion hypogammaglobulinemia, WHIM syndrome is a rare primary immunodeficiency Intravenous Hematologic and November 2020 infections, and caused by several different mutations in the C-X-C motif immunoglobulin (IVIg; immunologic parameters infection prevention) Note: FDA approved myelokathexis), chemokine receptor 4 gene, CXCR4. The mutations Quality of life Plerixafor for treating heterozygous mutation in cause dysfunction of the body’s immune system, Imiquimod (warts) ovarian cancer in 2008 for the C-tail of CXCR4, resulting in many types of bacterial infections that can be use in combination with G- documented neutropenia, mild to severe with serious sequelae. Standard treatment CSF to mobilize and history of severe or involves antibiotic prophylaxis and treatment of infections hematopoietic stem cells recurrent infections and their consequences; no cure is available. Plerixafor (HSCs) to the peripheral is intended to reduce the risk of infections. In a clinical blood for collection and trial, plerixafor is administered 0.02 to 0.04 mg/kg/day subsequent autologous for 6 months. transplantation in patients Developer(s): with non-Hodgkin lymphoma and multiple Karyopharm Therapeutics, Inc (Natick, Massachusetts) myeloma

Adults aged 40 to 80 years PRM-151 (rhPTX-2) is a recombinant form of the innate Lung transplantation Exercise capacity FDA designation(s): Orphan with idiopathic pulmonary immunity protein pentraxin-2, which is active at sites of Drug, Breakthrough fibrosis (IPF) tissue damage and has demonstrated broad antifibrotic Nintedanib Respiratory function Therapy activity in preclinical models. Unlike available therapies Pirfenidone Mortality that only slow the rate of disease progression, PRM-151 Clinical trial(s): Phase III is an agonist that purportedly reverses IPF pathology. Quality of life planned; phase II primary PRM-151 purportedly turns off the proliferation pathway completion May 2018, data mediated by proinflammatory and profibrotic published June 2018 macrophages that leads to fibrosis and helps activate the healing resolution pathway by directing the differentiation of monocytes into proresolution macrophages. In clinical trials, PRM-151 was administered as an intravenous infusion 10 mg/kg over 60 minutes on days 1, 3, and 5, then 1 infusion every 4 weeks. Developer(s): Promedior, Inc (Lexington, Massachusetts)

Section 2. Topics Added Since Last Status Report 127

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 65 years (AXS-12) is a selective norepinephrine Amphetamines Weekly FDA designation(s): Orphan with narcolepsy, excessive reuptake inhibitor (NRI) intended for treating cataplexy attacks Drug daytime sleepiness (EDS), and EDS in patients with narcolepsy, a chronic Antidepressants (eg, and cataplexy neurologic sleep disorder. Narcolepsy is caused by tricyclic antidepressants, EDS severity, as Clinical trial(s): Phase II impaired production of hypocretin, an excitatory selective serotonin measured by accepted CONCERT primary neuropeptide that regulates sleep-wake cycles. About reuptake inhibitors) clinical ratings and completion June 2019 scales 60% to 70% patients with narcolepsy also experience Nonamphetamine Note: Reboxetine is cataplexy, which is characterized by sudden, stimulants (eg, Maintenance of approved for treating major uncontrollable muscle weakness or paralysis that occurs , ) wakefulness, as depressive disorder in a during the daytime and is often triggered by a strong measured by accepted number of countries outside emotion (eg, crying, excitement, laughter). Reboxetine clinical ratings and of the United States purportedly promotes wakefulness and reduces EDS Sodium oxybate scales and cataplexy by increasing the activity of the excitatory neurotransmitter norepinephrine. In clinical trials, patients orally self-administer an unspecified dose of reboxetine twice daily for 3 weeks. Developer(s): Axsome Therapeutics, Inc (New York, New York)

Section 2. Topics Added Since Last Status Report 128

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 4 months to RGX-121 is a recombinant, adeno-associated viral Supportive care Cognitive, behavioral FDA designation(s): Orphan 5 years with Hunter vector serotype 9 carrying the human iduronate and adaptive function, Drug, Fast Track, Rare syndrome 2-sulfatase gene, IDS, and is intended to treat Hunter as measured by Pediatric Disease (mucopolysaccharidosis syndrome (MPSII). This childhood-onset, progressive, accepted MPSII-specific type II; MPSII) inherited metabolic disorder is caused by a mutation in clinical ratings and Clinical trial(s): Phase I/II IDS. Patients with the disorder cannot break down the scales RGX-121-101 primary polysaccharides dermatan sulfate and heparan sulfate, completion August 2019 the process of which is normally mediated by the IDS- Quality of life encoded enzyme iduronate 2-sulfatase. Buildup of dermatan sulfate and heparan sulfate in cells of the central nervous system causes degeneration that manifests as behavioral problems, sleeplessness, loss of speech and cognitive skills, mental retardation, heart problems, seizures, and loss of mobility. No cure is available for Hunter syndrome, and standard-of-care treatment consists of weekly enzyme replacement infusions. RGX121 is a gene therapy intended to deliver a functional copy of the IDS gene to the central nervous system. It purportedly restores iduronate 2-sulfatase function, blocks central nervous system degeneration, and reduces disease-related symptoms with a single injection, thereby eliminating the need for weekly enzyme replacement therapy. In clinical trials, RGX 1.3 × 1010 genome copies per gram (GC/g) of brain mass or 6.5 x 1010 GC/g brain mass is injected intracisternally (into the cerebrospinal fluid), once. Developer(s): Regenxbio, Inc (Rockville, Maryland)

Section 2. Topics Added Since Last Status Report 129

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Infants and children with RVT-802 is an allogeneic, donor thymus-derived, cell- Thymus transplant Survival Submission date: Rolling complete DiGeorge based therapy for treating primary immune deficiency Biologics License syndrome (DGS) from congenital athymia (lack of a thymus) arising from Supportive care T-cell proliferation Application initiated 2018 complete DiGeorge genetic anomaly. Patients with DGS have a high risk of death (often by 24 months of age) FDA designation(s): Orphan due a chromosomal mutation that causes T cell Drug, Rare Pediatric lymphopenia; the resulting absence of functional mature Disease, Breakthrough T cells or B cells offers little to no protective immunity in Therapy, Regenerative patients. RVT-802 is intended to restore the patient's Medicine Advanced ability to produce naïve T cells with a broad T-cell Therapy receptor repertoire, conferring effective immune Clinical trial(s): Phase II responses. Isolated thymocytes are cultured ex vivo for primary completed March 14 to 21 days. In clinical trials, RVT-802 is administered 2008; phase II primary by placing a cultured thymus slice into a small hole in the completed August 2010 quadriceps muscle that is then pulled over the slice using an insoluble stitch. The dose is 4 g/m2 to 18 g/m2 of thymus tissue per patient body weight in kilograms. Developer(s): Enzyvant Therapeutics GmbH (Basel, Switzerland), a subsidiary of Roivant Sciences GmbH (Basel, Switzerland)

Section 2. Topics Added Since Last Status Report 130

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 5 years or SB-913 is a adenovirus vector–based gene-editing Idursulfase Change from baseline in FDA designation(s): Orphan older and adults with technology that uses zinc-finger endonucleases (ZFNs) IDS activity (clinical Drug, Rare Pediatric Hunter syndrome designed to insert a functional copy of the iduronate-2- laboratory Disease, Fast Track (mucopolysaccharidosis sulfatase gene, IDS, into a precise location in the DNA of measurement) type II; MPS II) hepatocytes to treat Hunter syndrome (MPSII), a Clinical trial(s): Phase I/II childhood-onset, progressive, inherited metabolic Change from baseline in primary completion disorder caused by a mutation in IDS. IDS encodes a urine GAG levels (in February 2021 lysosomal enzyme of the same name that metabolizes ratio to creatinine) glycosaminoglycans (GAGs), preventing accumulation, Change from baseline in toxicity, and widespread tissue and organ damage. No frequency of idursulfase cure is available for Hunter syndrome, and the current administration required standard-of-care treatment is weekly infusions of replacement enzyme. SB-913 is intended to enable the patient's liver to sustainably produce sufficient functional IDS to relieve disease symptoms after a single treatment, thereby eliminating the need for weekly infusions. In a clinical trial, SB-913 was administered as a single intravenous infusion of viral genomes (vg) containing 5 × 1013 vg/kg containing each of the 3 components of SB-913: ZFN1, ZFN2, and hIDS donor gene. Developer(s): Sangamo Therapeutics (Richmond, California)

Section 2. Topics Added Since Last Status Report 131

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 18 to 75 years Solriamfetol (JZP-110, Sunosi) is a selective Amphetamines Excessive daytime Approval date: March 20, with narcolepsy and norepinephrine and dopamine reuptake inhibitor (NDRI) sleepiness, as 2019 excessive daytime approved by FDA for treating EDS in patients with Antidepressants (eg, measured by accepted sleepiness (EDS) narcolepsy, a chronic neurologic sleep disorder. tricyclic antidepressants, clinical ratings and FDA designation(s): Orphan Narcolepsy is caused by impaired production of selective serotonin scales Drug reuptake inhibitors) hypocretin, an excitatory neuropeptide that regulates Clinical trial(s): Phase III sleep-wake cycles. Sodium oxybate (Xyrem) is a gamma Nonamphetamine study completion February hydroxybutyrate (GHB) derivative approved by FDA for stimulants (eg, 2017, results published treating EDS in patients with narcolepsy, but the drug modafinil, armodafinil) March 2019; phase III open- causes central nervous system depression and has label extension study potential for abuse and misuse. Patients might also Sodium oxybate completion December 2017 receive amphetamines, antidepressants, or nonamphetamine stimulants, which have the potential to Note(s): FDA also approved cause significant side effects. Solriamfetol purportedly solriamfetol for treating promotes wakefulness and reduces EDS by increasing patients who have the activity of the excitatory neurotransmitters obstructive sleep apnea norepinephrine and dopamine. Patients self-administer oral solriamfetol 75 or 150 mg, once daily. Developer(s): Jazz Pharmaceuticals plc (Dublin, Ireland)

Section 2. Topics Added Since Last Status Report 132

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children and adults aged Tasimelteon (Hetlioz) is a melatonin receptor agonist Daytime light therapy Sleep quality and Submission date: 16 to 65 years with Smith- approved by FDA for treating non–24 hour sleep- wake duration Supplemental New Drug Magenis syndrome (SMS) disorder and is being developed for treating sleep Nighttime melatonin Application planned for third and a history of sleep disturbances in patients with SMS, a developmental supplementation Quality of life quarter of 2019 disturbances disorder caused by a mutation in the retinoic acid Beta-blockers (eg, Clinical trial(s): Phase II/III induced 1 gene, RAI1. Patients with SMS typically have acebutolol) intellectual disabilities and behavioral problems and primary completion July experience sleep disturbances due to disrupted 2017, data reported melatonin production. Sleep disturbances decrease December 2018 quality of life in patients with SMS. No established guidelines exist for melatonin use in patients with SMS, so dosage might be difficult to optimize, and daytime sleepiness might increase as a result of excess melatonin levels. Therefore, additional therapies to help regulate sleep are needed for patients with SMS. Hetlioz is intended to improve sleep quality and overall quality of life by increasing melatonin levels at night. In clinical trials, patients orally self-administer an unspecified dose of Hetlioz, once daily at bedtime, for 21 weeks. Developer(s): Vanda Pharmaceuticals, Inc (Washington, DC)

Section 2. Topics Added Since Last Status Report 133

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 5 years or (NNZ-2566) is a novel synthetic analogue of Supportive care (eg, Symptom frequency and FDA designation(s): Orphan older and adults aged to 45 the amino‐terminal tripeptide of insulin-like growth factor physical therapy, severity, as measured Drug, Fast Track years with genetically 1 (IGF-1) intended for treating . A rare, occupational therapy, by accepted clinical Clinical trial(s): Phase II confirmed Rett syndrome postnatal, progressive neurologic disorder, Rett speech/language ratings and scales Rett-001 study (enrolling syndrome is caused by a mutation in the methyl CpG therapy, nutritional Motor function, as adolescents aged 16 to 17 binding protein 2 gene, MECP2. MECP2, which is support, assistive measured by accepted years and adults aged 18 to located on the X chromosome, encodes the MeCP2 devices, oxygen clinical ratings and 45 years) completed protein that normally mediates gene expression in treatment, noninvasive scales September 2014, data neuronal and glial cells. Loss of MeCP2 function results ventilation, reported November 2017; in nerve cell dysfunction, which is thought to be anticonvulsants) phase II Rett-002 study reversible. Patients with Rett syndrome develop typically (enrolling children aged 5 to until 6 to 18 months of age, but subsequently experience developmental delays and regression of previously 15 years) completed January 2017, data reported learned motor and verbal skills. The disease eventually April 2019; phase III causes additional symptoms, such as repeated hand (enrolling children aged 5 to movements, impaired gait, slowed head growth, disordered breathing, and seizures. Symptom severity 17 years and adults aged 18 to 20 years) planned for varies by patient and depends on the individual's specific the second half of 2019 MECP2 mutation and the amount of mutant MeCP2 protein expression. No cure is available for Rett syndrome, and treatment generally consists of supportive care for managing symptoms. Trofinetide, because of its homology with the amino-terminal peptide tripeptide of IGF-1, which promotes neuronal and glial function, is intended to decrease symptom severity and disease progression in patients with Rett syndrome. In clinical trials, patients receive trofinetide at a dose of 35, 50, 70, 100, or 200 mg/kg, either orally or via a gastrostomy tube, twice daily for 40 to 56 days. Developer(s): Acadia Pharmaceuticals, Inc (San Diego, California), in collaboration with Neuren Pharmaceuticals, Ltd (Camberwell, Australia) and Rettsyndrome.org (Cincinnati, Ohio)

Section 2. Topics Added Since Last Status Report 134

Potential Patient Intervention Description Potential Comparators Patient-Oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures

Children aged 12 or older Voxelotor is intended as a disease-modifying agent for Analgesia (eg, Opioid use Submission date: New Drug and adults with sickle cell treating SCD, which currently has no cure. Voxelotor morphine, nonsteroidal Application anticipated disease (SCD) purportedly binds mutated hemoglobin and prevents anti-inflammatory drugs Frequency of vaso- second half of 2019 it from sickling and aggregating, increasing native [NSAIDs], occlusive crises FDA designation(s): Orphan hemoglobin's affinity for oxygen. Because oxygenated acetaminophen) Hemolysis markers sickle hemoglobin does not polymerize, voxelotor Drug, Rare Pediatric purportedly blocks polymerization and the resultant Hydration Hospitalized days Disease, Breakthrough Therapy, Fast Track sickling and destruction of red blood cells. With the Hydroxyurea Rehospitalizations potential to improve hemolytic anemia and oxygen Clinical trial(s): Phase III delivery, voxelotor might modify the underlying SCD Quality of life GBT HOPE primary disease process, rather than merely decrease disease completion October 2019; symptoms. In a clinical trial, the drug is administered phase III primary completion orally, 900 or 1500 mg, once daily. December 2019 Developer(s): Global Blood Therapeutics, Inc (South San Francisco, California)

Section 2. Topics Added Since Last Status Report 135

Section 3. Topics Archived Since Last Status Report: 6 Topics

Table 11. Alzheimer’s Disease and Other Dementias: 2 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 50 to 85 years (BIIB037) is a recombinant human Cholinesterase inhibitors AD progression Developers announced with prodromal to mild monoclonal antibody against amyloid beta (Aβ) intended (eg, donepezil, discontinuation of their Alzheimer's disease (AD) as a disease-modifying therapy for AD. According to the galantamine, Overall survival phase III clinical trials of the manufacturer, aducanumab preferentially binds rivastigmine) Quality of life drug, stating that neurotoxic oligomeric forms of Aβ, inhibits new Aβ aducanumab was unlikely to aggregation, and promotes the disaggregation of Supportive care meet its primary endpoints. existing Aβ aggregates, including plaques. In clinical trials, aducanumab was administered intravenously, at 1 of 2 unspecified doses.

Developer(s): Biogen (Cambridge, Massachusetts), in collaboration with Neurimmune AG (Schlieren-Zurich, Switzerland) and Eisai Global (Tokyo, Japan)

Adults aged 50 to 95 years (RG1450) is a fully human monoclonal Cholinesterase inhibitors AD progression Gantenerumab failed to with prodromal to mild antibody against amyloid beta (Aβ) intended as a (eg, donepezil, meet endpoints in 2 phase Alzheimer's disease (AD) disease-modifying treatment for AD. According to the galantamine, Overall survival III trials (NCT01224106, manufacturer, gantenerumab preferentially binds rivastigmine) Quality of life NCT02051608), and neurotoxic oligomeric forms of Aβ, inhibits new Aβ developers discontinued aggregation, and promotes the disaggregation of Supportive care these trials. Although existing Aβ aggregates, including plaques. In clinical developers continue to trials, gantenerumab was administered subcutaneously pursue gantenerumab in 2 at a dose of 105 to 225 mg every 4 weeks for 104 weeks. new phase III clinical trials (NCT03443973, Developer(s): NCT03444870), the MorphoSys AG (Planegg, Germany) in collaboration with expected primary completion Genentech, Inc (South San Francisco, California), a dates are May, 2022, which subsidiary of F. Hoffmann-La Roche, Ltd (Basel, falls outside of the time Switzerland) scope for the PCORI HCHSS. This topic will be reconsidered for inclusion if or when new data warrant.

Section 3. Topics Archived Since Last Status Report 136

Table 12. Cancer: 2 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures

Children and adolescents is a human/mouse chimeric monoclonal Bevacizumab Overall survival After the phase III TAPPAS aged 12 years or older and antibody specific for the protein endoglin (CD105). trial failed to demonstrate adults with an Endoglin is a transforming growth factor β coreceptor that Pazopanib Progression-free survival efficacy in patients with angiosarcoma that is not is required for angiogenesis, is highly expressed by Sorafenib Quality of life angiosarcoma treated with amenable to surgery proliferating endothelial and tumor cells, and is TRC105 (carotuximab), the upregulated after hypoxia induced by vascular endothelial Sunitinib developer terminated all growth factor (VEGF) pathway inhibition. Carotuximab Taxanes trials of TRC105. was intended to act as an antiangiogenic and antineoplastic drug, particularly when used in combination Vinorelbine with VEGF pathway inhibitors. In clinical trials, carotuximab was being used in combination with the VEGF pathway inhibitor pazopanib, administered intravenously once weekly at 10 mg/kg for 4 treatments, then biweekly infusions at 15 mg/kg until disease progression or unacceptable toxicity. Developer(s): Tracon Pharmaceuticals, Inc (San Diego, California)

Adults aged 18 years or Eflornithine plus sulindac (CPP-1X/sul) is a therapy for Surgical resection of Time to onset of first After the phase III CCP older with phenotypic hirsutism and African trypanosomiasis. It irreversibly polyps or colectomy FAP-related event FAP-310 trial failed to meet classical familial binds to ornithine decarboxylase and prevents ornithine its primary endpoint or adenomatous polyposis from interacting with the of the enzyme; reduce time to first (FAP), with disease sulindac is a nonsteroidal anti-inflammatory drug recurrence in patients with involvement of the (NSAID). Both agents purportedly reduced the growth of FAP, the developer decided duodenum and/or colon, colon polyps in early studies and were being developed not to pursue rectum, or pouch for reducing the risk of occurrence or recurrence of commercialization. problematic polyps and tumors associated with FAP. In a late-stage clinical trial, patients received eflornithine, three 250-mg tablets, and sulindac, 150 mg, orally, once daily, for 2 years. Developer(s): Cancer Prevention Pharmaceuticals, Inc, (Tucson, Arizona) in collaboration with Mallinckrodt Pharmaceuticals (Surrey, UK)

Section 3. Topics Archived Since Last Status Report 137

Table 13. Cardiovascular: 1 Topic

Potential Patient Intervention Description Potential Comparators Patient-Oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 22 to 85 years ROX Coupler is a stent-like shunt implanted between the Alpha blockers Blood pressure According to the clinical trial with mean 24-hour iliac artery and iliac vein to treat hypertension that is record (NCT02895386), the ambulatory systolic blood refractory to optimal medical therapy. The nitinol scaffold Alpha-beta blockers Cardiovascular adverse device manufacturer, ROX events pressure of 140 mmHg or supports a permanent anastomosis between these Alpha-2 receptor Medical, has ceased higher despite optimal 2 major peripheral vessels, purportedly reducing systemic agonists Mortality business operations. antihypertensive therapy blood pressure by diverting a modest amount of arterial blood to the venous system. Physicians selectively Angiotensin-converting Quality of life choose either the right or left iliac vessels, but not both. enzyme (ACE) inhibitors A physician creates the anastomosis and implants the Angiotensin II receptor coupler using 2 catheters inserted in the upper thigh at blockers (ARBs) the femoral artery and femoral vein, respectively, and advanced to the iliac artery and vein in the groin. Beta blockers Physicians perform the procedure in a cardiac Calcium channel catheterization laboratory, interventional suite, or hybrid blockers operating room under fluoroscopic guidance with patients under local anesthesia. Central agonists Developer(s): Diuretics ROX Medical (San Clemente, California) Peripheral adrenergic inhibitors Note: Developer's website is no longer active. See "Reason for Archive." Vasodilators

Table 14. Mental and Behavioral Health: 0 Topics

Potential Patient Intervention Description Potential Comparators Patient-Oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures

Section 3. Topics Archived Since Last Status Report 138

Table 15. Rare Diseases: 1 Topic

Potential Patient Intervention Description Potential Comparators Patient-Oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures

Adults aged 50 years Alpha AMS subretinal implant is intended to partially Argus II retinal Visual function Developer ceased or older with retinitis restore visual function in patients with blindness caused prosthesis system operations, citing an pigmentosa–mediated by retinitis pigmentosa. The device has 3 components: Quality of life innovation-hostile climate in blindness the implant itself, a receiver placed under the skin behind Independence the EU, rigid regulatory and the ear, and a pocket-size external transponder and health systems, and control unit. The implant, which is 3.2 × 4 mm in size unimpressive clinical with a height of 70 µm, contains 1600 photodiodes that results. Also see this news convert incident light into an electrical signal. The signal release. is amplified and transmitted via electrodes to the patient's functional retinal signal- processing layers; it is then relayed to the brain via the optic nerve. According to the manufacturer, a theoretical maximum visual acuity of 0.07 (20/280) with a horizontal visual field of 13° is possible after Alpha AMS implantation. In clinical trials, the device is surgically implanted into 1 eye; patients undergo 5 years of follow-up. Developer(s): Retina Implant AG (Reutlingen, Germany), in collaboration with Wills Eye Hospital (Philadelphia, Pennsylvania)

Section 3. Topics Archived Since Last Status Report 139