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 may 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 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; March 2019.

HORIZON SCANNING STATUS REPORT ● MARCH 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 first 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 ● MARCH 2019 ii

Table of Contents

Statement of Funding and Purpose ...... i Financial Disclosure Statement ...... i Public Domain Notice ...... i Introduction ...... 1 Status Reports ...... 1 Horizon Scanning Process Overview ...... 1 Reporting Period Summary ...... 2 Section 1. Currently Monitored Topics: 73 Topics ...... 3 Table 1. Alzheimer’s Disease and Other Dementias: 4 Topics ...... 3 Table 2. Cancer: 37 Topics ...... 5 Table 3. Cardiovascular: 8 Topics ...... 29 Table 4. Mental and Behavioral Health: 10 Topics...... 35 Table 5. Rare Diseases: 14 Topics ...... 42 Section 2. Topics Added Since Last Status Report: 0 Topics ...... 50 Table 6. Alzheimer’s Disease and Other Dementias: 0 Topics ...... 50 Table 7. Cancer: 0 Topics ...... 50 Table 8. Cardiovascular: 0 Topics ...... 50 Table 9. Mental and Behavioral Health: 0 Topics ...... 50 Table 10. Rare Diseases: 0 Topics ...... 50 Section 3. Topics Archived Since Last Status Report: 0 Topics ...... 51 Table 11. Alzheimer’s Disease and Other Dementias: 0 Topics ...... 51 Table 12. Cancer: 0 Topics ...... 51 Table 13. Cardiovascular: 0 Topics ...... 51 Table 14. Mental and Behavioral Health: 0 Topics ...... 51 Table 15. Rare Diseases: 0 Topics ...... 51

HORIZON SCANNING STATUS REPORT ● MARCH 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. Note that because this is the first PCORI HCHSS Status Report, all topics are reported in Section 1; in subsequent reports, new topics added since the previous Status Report will be reported in Section 2. 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, 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 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,

HORIZON SCANNING STATUS REPORT ● MARCH 2019 1

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. To date, the HCHSS team has reviewed more than 700 leads that led to identification of 73 topics, which are reported in this Status Report. Topics are presented in alphabetic order according to intervention name (ie, 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 product. The topics included in this report represent 50 diseases/conditions and span the PCORI-defined priority areas as follows: • Alzheimer’s disease and other dementias: 4 topics (5%) • Cancer: 37 topics (51%) • Cardiovascular: 8 topics (11%) • Mental and behavioral health: 10 topics (14%) • Rare diseases: 14 topics (19%)

Across all priority areas, topics in this report represent the following therapeutic classes: • Biotechnology: 19 topics (26%) • Device: 3 topics (4%) • Implant: 3 topics (4%) • Pharmaceutical: 48 topics (66%)

HORIZON SCANNING STATUS REPORT ● MARCH 2019 2

Section 1. Currently Monitored Topics: 73 Topics

Table 1. Alzheimer’s Disease and Other Dementias: 4 Topics

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

Adults aged 50-85 years Aducanumab (BIIB037) is a recombinant human Gantenerumab Progression of AD Clinical trial(s): Phase III with prodromal to mild against beta amyloid (Abeta) EMERGE primary Alzheimer’s disease (AD) intended as a disease-modifying therapy for AD. Tau aggregation Survival completion January 2020; inhibitors (eg, LMTX) Purportedly, aducanumab preferentially binds neurotoxic Quality of life phase III ENGAGE primary oligomeric forms of Abeta, inhibits new Abeta Cromolyn/ibuprofen completion January 2020 aggregation, and promotes the disaggregation of existing (ALZT-OP1) Abeta aggregates, including plaques. In clinical trials, aducanumab is administered intravenously at 1 of 2 unspecified doses. Developer(s): Biogen (Cambridge, Massachusetts), in collaboration with Neurimmune AG (Schlieren-Zurich, Switzerland)

Adults aged 55-91 years Brexpiprazole (Rexulti), an atypical antipsychotic, is a Caregiver intervention Agitation (as measured Clinical trial(s): Phase III with Alzheimer’s disease serotonin-dopamine activity modulator that purportedly and environmental by accepted rating primary completion (AD)-associated agitation reduces agitation in patients with AD. AD-associated modification (removed or scales and inventories) November 2020; phase III agitation may be the result of reduced serotonin levels alleviated stressors) open-label extension and increased levels of noradrenaline and dopamine. Quality of life primary completion May Anti-anxiety drugs According to the manufacturer, brexpiprazole may be a Adverse events 2021; phase III extension partial agonist of serotonin 5-HT1A and dopamine D2 Antidepressants primary completion August receptors and an antagonist of serotonin 5-HT2A 2021; phase II/III primary receptors. Brexpiprazole may also bind to noradrenaline Antipsychotics (eg, completion November 2021 α1B/2C receptors. In clinical trials, brexpiprazole is haloperidol) administered orally, once daily, for 10 to 14 weeks at a Atypical antipsychotics dose of 1 to 3 mg. (eg, aripiprazole) Developer(s): Beta-adrenergics Otsuka Holdings Co, Ltd (Tokyo, Japan), in collaboration Synthetic with H. Lundbeck A/S (Valby, Denmark) tetrahydrocannabinol

Section 1. Currently Monitored Topics 3

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

Adults aged 50-95 years Gantenerumab (anti-Abeta, RG1450) is a fully human Aducanumab Progression of AD Clinical trial(s): Phase III with prodromal to mild monoclonal antibody against beta amyloid (Abeta) primary completion August Alzheimer’s disease (AD) intended as a disease-modifying treatment for AD. Cromolyn/ibuprofen Survival 2020; phase III completion (ALZT-OP1) According to the manufacturer, gantenerumab Quality of life November 2020; phase III preferentially binds neurotoxic oligomeric forms of Abeta, Tau aggregation completion May 2022; phase inhibits new Abeta aggregation, and promotes the inhibitors (eg, LMTX) III completion May 2022 disaggregation of existing Abeta aggregates, including plaques. In clinical trials, gantenerumab is administered subcutaneously at a dose of 105 to 225 mg every 4 weeks for 104 weeks. Developer(s): MorphoSys AG (Planegg, Germany), in collaboration with Genentech Inc (South San Francisco, California), a subsidiary of F. Hoffmann-La Roche Ltd (Basel, Switzerland)

Adults up to 90 years of age Leuco-methylthioninium (LMTX) is a tau aggregation Anti-Abeta monoclonal Disease progression Clinical trial(s): Phase II/III with mild to moderate inhibitor intended as a disease-modifying treatment for antibodies (eg, LUCIDITY primary Alzheimer’s disease (AD) AD. According to the manufacturer, LMTX reduces levels aducanumab, Morbidity and mortality completion June 2020 of aggregated or misfolded tau proteins, which contribute gantenerumab) Quality of life to AD disease pathology. In clinical trials, LMTX is administered orally, twice daily, at a dose of 8 to 16 mg Cromolyn/ibuprofen per day. (ALZT-OP1) Developer(s): TauRx Pharmaceuticals Ltd (Singapore, Republic of Singapore)

Section 1. Currently Monitored Topics 4

Table 2. Cancer: 37 Topics

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

Adults aged 18-70 years ATIR101 is an allogeneic T-lymphocyte 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 leukemia, acute donor’s peripheral blood. The immune cells from the methoxypsoralen Progression-free survival Medicine Advanced Therapy lymphoblastic leukemia, or partially matched donor also undergo a photodepletion Quality of life myelodysplastic syndrome procedure that eliminates T cells responsible for causing Therapy with one or Clinical trial(s): Phase III for whom allogeneic graft-versus-host disease (GVHD). ATIR101 is intended more HATCY primary completion hematopoietic stem cell as an immunotherapy adjunct to allogeneic HSCT that immunosuppressants: February 2021 transplantation (HSCT) is offers immunity against infectious agents, while Alkylating agent (eg, being considered maintaining patients at low risk for GVHD. In clinical trials, cyclophosphamide) ATIR101 is delivered as intravenous infusion at a single dose of 2 x 106 cells/kg administered between 28 and 32 Antibodies (eg, days after allogeneic HSCT. , anti- thymocyte globulin) Developer(s): Calcineurin inhibitors Kiadis Pharma NV (Amsterdam, the Netherlands) (eg, cyclosporine, tacrolimus) Corticosteroids (eg, methotrexate, mycophenolate mofetil, prednisone) mTOR inhibitor (eg, sirolimus)

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 Avelumab (Bavencio) is an immune checkpoint inhibitor Active surveillance Overall survival FDA designation(s): Orphan older with unresectable, consisting of a fully human, monoclonal antibody specific Drug locally advanced, or for programmed death-ligand 1 (PD-L1). Immune Maintenance Progression-free survival Clinical trial(s): Phase III metastatic adenocarcinoma tolerance is a hallmark of cancer and may be mediated by Quality of life of the stomach or binding of PD-L1 to its receptor, programmed cell death 1 JAVELIN Gastric 100 gastroesophageal junction (PD-1), which inhibits T cells and anticancer immune primary completion responses. Preventing interaction between PD-L1 and November 2019 PD-1 by binding of avelumab purportedly inhibits this immune checkpoint, potentially leading to an anticancer immune response. In clinical trials in gastric cancer, avelumab (10 mg/kg infusion once every 2 weeks until disease progression or development of unacceptable toxicity) is being studied in the maintenance setting after completion of an induction phase of cytotoxic chemotherapy. Developer(s): Pfizer Inc (New York, New York)

Women aged 18 years or Axalimogene filolisbac (AXAL) is an immunotherapy External beam radiation Overall survival FDA designation(s): Orphan older with surgically comprising live, attenuated Listeria monocytogenes (Lm) therapy alone or with Drug, Fast Track resected squamous cell, bacteria engineered to express the E7 protein of human one or more of the Disease-free survival Clinical trial(s): Phase III adenocarcinoma, or papilloma virus (HPV) type 16, which has a crucial role in following: Quality of life adenosquamous carcinoma cervical oncogenesis. The E7 gene is cloned in a plasmid AIM2CERV primary of the cervix who have containing a truncated fragment of listeriolysin O (tLLO) Antimetabolites (eg, 5- completion June 2020; completed adjuvant gene that is introduced into Lm, which will express and fluorouracil) designed under Special Protocol Assessment treatment with cisplatin and secrete the tLLO-E7 fusion protein. Although E7 peptides Platinum-based agents radiation presented on the surface of antigen-presenting cells (eg, carboplatin, stimulate CD4+ and CD8+ T cells, tLLO modulates cells cisplatin) involved in immune suppression. AXAL purportedly reduces a patient’s 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 x 109, 3.3 x 109, or 1 x 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 6

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

Children and adults aged 12 is a human/mouse chimeric monoclonal Overall survival FDA designation(s): Orphan years or older with an antibody specific for the protein endoglin (CD105). Drug angiosarcoma that is Endoglin is a transforming growth factor β coreceptor that Pazopanib Progression-free survival Clinical trial(s): Phase III surgically unresectable is required for angiogenesis, is highly expressed by Sorafenib Quality of life proliferating endothelial and tumor cells, and is TAPPAS ongoing primary upregulated following hypoxia induced by vascular Sunitinib completion September 2019 endothelial growth factor (VEGF) pathway inhibition. Taxanes Therefore, carotuximab may function as an antiangiogenic and antineoplastic drug, particularly when Vinorelbine used in combination with VEGF pathway inhibitors. In clinical trials, carotuximab is being used in combination with the VEGF pathway inhibitor pazopanib. Carotuximab is administered intravenously once weekly at 10 mg/kg for 4 treatments, then biweekly infusions at 15 mg/kg until disease progression or development of unacceptable toxicity. Developer(s): Tracon Pharmaceuticals Inc (San Diego, California)

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 18-70 years DCVax-L is an autologous immunotherapy that consists Fractionated external Overall survival Clinical trial(s): Phase III with surgically resected of activated dendritic cells loaded with patient-derived beam radiation therapy GBM primary completion glioblastoma multiforme tumor antigens. DCVax-L is manufactured using Progression-free survival November 2016; interim Chemotherapy with one who have completed monocytes obtained from the patient through Quality of life results published May 2018; adjuvant radiation therapy leukapheresis. The monocytes are differentiated into or more of the following: updated interim results and chemotherapy dendritic cells in vitro and then activated and loaded with Alkylating agents (eg, reported November 2018 patient-derived antigens from the patient’s tumor tissue carmustine, after surgical resection. The purified DCVax-L is then cyclophosphamide, administered to elicit adaptive immunity from T cells and lomustine, procarbazine, B cells. DCVax-L purportedly reduces a patient’s risk for temozolomide) disease recurrence by promoting an immune response against residual glioblastoma cells. In clinical trials, Angiogenesis inhibitors DCVax-L containing 2.5 x 106 tumor lysate–pulsed (eg, bevacizumab) dendritic cells is administered as an intradermal injection mTOR inhibitors (eg, in the upper arm at days 0, 10, and 20 and at weeks 8, everolimus) 16, 32, 48, 72, 96, and 120. Patient treatment involves total or near total surgical resection of the tumor followed Platinum-based agents by conventional external beam radiation therapy and (eg, carboplatin, concurrent temozolomide chemotherapy at least 2 weeks cisplatin) before treatment with the first course of DCVax-L. Vinca alkaloids (eg, Developer(s): vincristine) 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 18-75 years or Devimistat is a first-in-class, lipoate analogue, small Chemotherapy with one Overall survival FDA designation(s): Orphan older with distant metastatic molecule that inhibits the activity of the mitochondrial or more of the following: Drug pancreatic adenocarcinoma enzymes α-ketoglutarate dehydrogenase (KGDH) and Progression-free survival Antimetabolites (eg, 5- Clinical trial(s): Phase III who have not received first- pyruvate dehydrogenase (PDH) by mimicking catalytic Quality of life line therapy intermediates for these enzymes. KGDH and PDH are fluorouracil, AVENGER 500 primary responsible for converting glutamate to α-ketoglutarate capecitabine, completion October 2021 and pyruvate to acetyl coenzyme A (acetyl-CoA), gemcitabine) respectively, processes that are essential for generating Chemoprotectant (eg, energy through the tricarboxylic acid cycle (TCA) cycle. leucovorin) Pancreatic adenocarcinoma cells overexpress several enzymes involved in the mitochondrial TCA cycle. As a DNA synthesis inhibitor result, the metabolic activity of cancer cells is greatly (eg, irinotecan) increased compared with that of noncancerous cells. EGFR inhibitor (eg, Devimistat purportedly downregulates metabolic erlotinib) pathways in cancer cells that depend on α-ketoglutarate and acetyl-CoA, which may cause them to become Platinum-based agents particularly sensitive to first-line chemotherapy regimens. (eg, cisplatin, oxaliplatin) In clinical trials, devimistat is administered intravenously Taxanes (eg, albumin- at a dose of 500 mg/m2, on days 1 and 3 of a 14-day bound paclitaxel, cycle, followed immediately by intravenous modified docetaxel) 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 that Chemotherapy with one Overall survival FDA designation(s): Orphan older with recurrent causes N7 DNA alkylation. Resistance to temozolomide is or more of the following: Drug, Fast Track malignant gliomas, including common in patients with glioblastomas because of the Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase III glioblastoma multiforme high expression of the enzyme O6-methylguanine-DNA- Quality of life methyltransferase (MGMT), which possesses DNA repair carmustine, STAR-3 primary completion activity. VAL-083’s N7 DNA alkylation activity purportedly cyclophosphamide, June 2019 overcomes MGMT-mediated resistance. In clinical trials, lomustine, nitrosourea, VAL-083 is administered as an intravenous infusion at a procarbazine, dose of 40 mg/m2 on days 1, 2, and 3 of a 21-day temozolomide) treatment cycle, for up to twelve 21-day treatment cycles. Angiogenesis inhibitors Developer(s): (eg, bevacizumab) DelMar Pharmaceuticals Inc (Vancouver, British mTOR inhibitors (eg, Columbia, Canada) everolimus) Platinum-based drugs (eg, carboplatin, cisplatin) Vinca alkaloids (eg, vincristine)

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 Durvalumab (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 head It is a monoclonal antibody against programmed death-1 completion December 2018 receptor ligand (PD-L1), which is frequently expressed in Antimetabolites (eg, 5- and neck squamous cell fluorouracil, Quality of life Note: FDA approved carcinoma tumor microenvironments and downregulates T cells via activation of the programmed death-1 (PD-1) immune capecitabine, durvalumab for treating checkpoint. Advanced head and neck cancer has a poor gemcitabine, bladder cancer in May 2017 prognosis and a high recurrence rate, suggesting the methotrexate) and for nonsmall cell lung cancer in February 2018. need for new treatments. A hallmark of cancer is its ability EGFR inhibitor (eg, to evade an immune response. Durvalumab, a checkpoint ) inhibitor, purportedly limits activation of the immune checkpoint by preventing the interaction between PD-L1 Platinum-based drugs and its receptor, PD-1. In clinical trials, durvalumab is (eg, carboplatin, being tested as monotherapy or in combination with cisplatin) tremelimumab. It is administered intravenously every 2 Taxanes (eg, docetaxel, weeks from day 1 for a maximum of 12 months or paclitaxel) development of intolerable toxicity. Developer(s): MedImmune LLC (Gaithersburg, Maryland), a subsidiary of AstraZeneca plc (Cambridge, United Kingdom)

Adults aged 18 years or Dusquetide (SGX942) is a synthetic water-soluble, 5- Lidocaine Incidence of bacterial FDA designation(s): Fast older who develop oral amino-acid peptide with anti-inflammatory and anti- infection Track mucositis while receiving infective properties. It is a member of a novel drug class Narcotics Duration of severe Special award(s): NIH cancer therapy (commonly called innate defense regulators that targets the innate Supportive care with oropharyngeal cancer) immune system. Dusquetide binds to an intracellular mucositis selected SGX942 for its adaptor protein, sequestosome-1, or p62, which has a Small Business Innovation Incidence of severe Research/Small Business pivotal function in signal transduction during activation mucositis and control of the innate immune system. In clinical trials, Technology Transfer it is administered intravenously at a dose of 1.5 mg/mL as Pain Commercialization Accelerator Program a 4-minute IV infusion, twice weekly, starting within 3 Ability to eat and drink days after initiating radiation therapy and continuing September 2018 through 2 weeks after completing radiation therapy. Cancer treatment Clinical trial(s): Phase III adherence Developer(s): DOM-INNATE primary Quality of life completion March 2019 Soligenix Inc (Princeton, New Jersey)

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 Eflornithine plus sulindac (CPP-1X/sul) combines Surgical resection of Delay in time to onset of FDA designation(s): Orphan older with phenotypic eflornithine with sulindac. Eflornithine, a therapy for polyps or colectomy first FAP-related event Drug, Fast Track classical familial hirsutism and African trypanosomiasis, irreversibly binds adenomatous polyposis to ornithine decarboxylase and prevents ornithine from Clinical trial(s): Phase III (FAP) with disease interacting with the active site of the enzyme, and primary completion April involvement of the sulindac is a nonsteroidal anti-inflammatory drug. Both 2019 duodenum and/or colon, agents purportedly reduced the growth of colon polyps in rectum, or pouch early studies and are being developed for reducing the risk of occurrence or recurrence of problematic polyps and tumors associated with FAP. In a late-stage clinical trial, patients are given eflornithine, three 250 mg tablets, and 150 mg sulindac, orally, once daily, for 2 years. Developer(s): Cancer Prevention Pharmaceuticals Inc (Tucson, Arizona)

Adults aged 18 years or Etirinotecan pegol (Onzeald) is a novel formulation of the Chemotherapy with one Overall survival FDA designation(s): Fast older with advanced breast topoisomerase I inhibitor irinotecan. Etirinotecan pegol is or more of the following: Track cancer and a history of a modified version of irinotecan in which the drug is linked Progression-free survival Alkylating agents (eg, Clinical trial(s): Phase III stable brain metastases to a macromolecule core. The linkage purportedly renders Quality of life who have been treated with the drug inert in the bloodstream and allows its slow cyclophosphamide) BEACON completed; pivotal 1 or 2 prior cytotoxic release as the linkages are metabolized. Slow release results published November Anthracyclines (eg, 2015; quality of life results regimens extends the time that the patient’s disease is exposed to doxorubicin) therapeutic levels of the drug and limits exposure to high published May 2017; phase drug levels during infusion. Additionally, the large drug- Antimetabolites (eg, III ATTAIN primary polymer conjugate may preferentially accumulate in tumor fluorouracil, gemcitabine, completion July 2020 tissues because of the increased permeability of tumor pemetrexed) vasculature. In clinical trials, etirinotecan pegol is PARP inhibitors (eg, administered as an intravenous infusion at a dose of 145 2 niraparib, olaparib, mg/m once every 21 days. rucaparib) Developer(s): Taxanes (eg, docetaxel, Nektar Therapeutics Inc (San Francisco, California) nab-paclitaxel, paclitaxel) Vinca alkaloid (eg, vinorelbine)

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 Lefitolimod (MGN1703) is a DNA molecule developed to Chemotherapy with one Overall survival FDA designation(s): Orphan older with metastatic be an agonist of Toll-like receptor 9 (TLR9), a component or more of the following: Drug colorectal cancer whose of the innate immune system. Activating TLR9 signaling Progression-free survival Angiogenesis inhibitors Clinical trial(s): Phase III disease has responded to promotes immune system activation, possibly through Quality of life first-line chemotherapy dendritic cell maturation or differentiation of B cells into (eg, bevacizumab, IMPALA primary completion antibody-secreting plasma cells or both. Many patients ) March 2019 with metastatic colorectal cancer respond to first-line Antimetabolites (eg, 5- chemotherapy, but disease ultimately progresses in most fluorouracil, patients. Immune-response activation by lefitolimod might capecitabine) overcome immune tolerance to tumor-associated antigens, potentially leading to an anticancer immune EGFR antibodies (eg, response. Lefitolimod purportedly prevents or delays cetuximab, disease recurrence by stimulating cancer-specific immune ) responses in the maintenance setting. In clinical trials, FOLFIRI (leucovorin, 5- lefitolimod solution is administered in an unspecified way fluorouracil, irinotecan) at a dose of 60 mg twice weekly until disease progression. FOLFOX (leucovorin, 5- fluorouracil, oxaliplatin) Developer(s): Multikinase inhibitors MOLOGEN AG (Berlin, Germany) (eg, regorafenib) Platinum-based agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)

Adults aged 18 years or Lurbinectedin (PM01183) is a synthetic, marine-derived Chemoradiation therapy Overall survival FDA designation(s): Orphan older with unresectable compound that selectively inhibits transactivated RNA Drug small cell lung cancer polymerase II transcription, selectively blocking the Platinum-based agents Progression-free survival (eg, carboplatin, Clinical trial(s): Phase III refractory to one prior elongation phase of mRNA synthesis. The manufacturer Quality of life platinum-containing regimen asserts that lurbinectedin does not inhibit RNA cisplatin) ATLANTIS primary completion February 2020 polymerase I, mitochondrial RNA polymerase, or basal Topoisomerase inhibitors transcription. Lurbinectedin is administered intravenously (eg, etoposide, to patients every 3 weeks at a dose of 4 mg in topotecan) combination with doxorubicin. Developer(s): Pharma Mar S.A. (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 monoclonal antibody that Chemotherapy with one Overall survival Submission planned: older with metastatic or binds to HER2 to inhibit tumor cell growth. In contrast to or more of the following: Biologics License locally advanced, relapsed, other HER2-specific antibodies (eg, , Progression-free survival Application, second half Alkylating agents (eg, or refractory, HER2-positive ), margetuximab has an optimized Fc region Quality of life 2019 breast cancer, who have with higher affinity for the Fc-gamma receptor on cyclophosphamide) received at least 2 prior macrophages. This increases their recruitment and FDA designation(s): Fast Anthracyclines (eg, Track lines of anti-HER2 targeted enhances antibody-dependent cellular cytotoxicity of the doxorubicin) therapy tumor. Additionally, macrophages that have Clinical trial(s): Phase III phagocytosed and processed a tumor cell will present Antimetabolites (eg, SOPHIA primary completion tumor antigens to prime T cells, which then elicit antigen- fluorouracil, gemcitabine, March 2020; pivotal results specific immune responses against the tumor. In clinical pemetrexed) reported February 2019 trials, margetuximab is administered intravenously once HER2-targeted every 3 weeks, at a dose of 15 mg/kg, in combination with antibodies (eg, ado- 2 2 capecitabine (1000 mg/m ), eribulin (1.4 mg/m ), trastuzumab emtansine, gemcitabine (1000 mg/m2), and vinorelbine (25-30 pertuzumab, mg/m2). Treatment continues until disease progression or trastuzumab) development of unacceptable toxicity. HER2-targeted kinase Developer(s): tyrosine inhibitors (eg, afatinib, lapatinib) MacroGenics Inc (Rockville, Maryland) Taxanes (eg, docetaxel, Green Cross Corp (Yongin, South Korea), regional nab-paclitaxel, partner paclitaxel) Vinca alkaloid (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 18-74 years Metformin is a biguanide drug indicated for treating Active surveillance Overall survival Clinical trial(s): Phase III without diabetes who have diabetes. Retrospective studies of patients with diabetes MA32 primary completion localized breast cancer and taking metformin and window-of-opportunity studies in the Progression-free survival February 2022 have undergone surgical neoadjuvant breast cancer setting have indicated that Quality of life resection and completed metformin may have anticancer effects. Metformin may neoadjuvant or adjuvant exert its anticancer effects by activating AMP-activated chemotherapy protein kinase, which functions to limit downstream components of the mTOR pathway. Additionally, metformin’s actions in reducing circulating insulin levels and improving insulin resistance in nondiabetic patients may be antineoplastic because of the potential growth- stimulating activity of insulin. In treating breast cancer, 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)

Adults aged 18 years or Napabucasin is a small-molecule, first-in-class inhibitor of Irinotecan-based Overall survival Clinical trial(s): Phase III older with metastatic the mitogenic STAT-3 pathway intended to target and kill chemotherapy with or CanStem303C primary colorectal cancer who have cancer stem cells within tumors—tumor growth, treatment without antiangiogenic or Progression-free survival completion June 2020; undergone 1 previous resistance, metastasis, and poor prognosis are attributed anti-epidermal growth Quality of life phase III primary completion systemic chemotherapy to these cells. In clinical trials, napabucasin is factor receptor targeted November 2021 regimen of fluoropyrimidine administered orally, at a dose of 240 mg twice daily, in therapy and oxaliplatin combination with the multiagent cytotoxic chemotherapy regimen FOLFIRI (leucovorin, fluorouracil, and irinotecan) Immune checkpoint with or without bevacizumab. Patients receive inhibitors (for patients napabucasin until disease progression or development of with defects in mismatch unacceptable toxicity. repair or microsatellite instability) Developer(s): Boston Biomedical Inc (Cambridge, Massachusetts), a subsidiary of Sumitomo Dainippon Pharma Co Ltd (Osaka, Japan)

Section 1. Currently Monitored Topics 15

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

Children and adults aged NiCord is an allogeneic stem cell therapy that uses Allogeneic bone marrow Overall survival FDA designation(s): Orphan 12-65 years with a umbilical cord blood that has been modified using transplant Drug, Breakthrough Therapy hematologic malignancy proprietary nicotinamide (NAM) technology as an Bone marrow (acute lymphoblastic alternative to hematopoietic stem cell transplantation. Pooled unexpanded cord engraftment rate Clinical trial(s): Phase III leukemia, acute NAM prevents umbilical cord blood cells from blood transplant primary completion Neutrophil recovery rate December 2019 myelogenous leukemia, differentiating rapidly in culture, resulting in increased Unexpanded cord blood chronic myelogenous stem cells (CD34+CD38-Lin-). Continuous growth in the transplant Platelet recovery rate leukemia, or presence of NAM enhances stem cell functionality, which Quality of life myelodysplastic syndrome) includes migration, homing, and engraftment in the bone and for whom an allogeneic marrow. NiCord is intended as a curative approach for stem cell transplant is being high-risk blood cancers in patients with no fully matched considered donor available. NiCord might have the potential of restoring blood and immune cell function, improving resistance to infections and related complications. In clinical trials, NiCord is administered as a single intravenous infusion (dose was unspecified). 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 16

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

Adults aged 18 years or (Opdivo) is an immune checkpoint inhibitor Radiation therapy plus Overall survival FDA designation(s): Orphan older with newly diagnosed consisting of a fully human, monoclonal antibody specific temozolomide with or Drug glioblastoma who have for the cell surface receptor programmed death 1 (PD-1). without alternating Progression-free survival Clinical trial(s): Phase III undergone only surgical Immune tolerance is a hallmark of cancer and may be electrical fields therapy Quality of life resection mediated by binding of PD-1 by its ligands (programmed CheckMate 498 ongoing cell death ligand 1 and programmed cell death ligand 2), primary completion March which inhibits T cells and anticancer immune responses. 2019; phase III Prevention PD-1 interaction with its ligands by nivolumab CheckMate548 primary purportedly inhibits this immune checkpoint, potentially completion February 2022 leading to an anticancer immune response. In clinical trials treating newly diagnosed glioblastoma, nivolumab is administered intravenously at a dose of 240 mg every 2 weeks for 16 weeks and then 480 mg every 4 weeks until disease progresses or development of unacceptable toxicity. It is being studied in combination with radiation therapy with or without temozolomide. Developer(s): Bristol-Myers Squibb (New York, New York)

Adults aged 22 years or NovoTTF-100L is a device that delivers tumor-treating Docetaxel Overall survival Clinical trial(s): Phase III older with metastatic fields therapy to solid tumors by exposing them to low- primary completion nonsmall cell lung cancer intensity, intermediate-frequency, alternating electric Immune checkpoint Progression-free survival December 2021 inhibitors (, (NSCLC) that has fields (ie, tumor-treating fields). These fields purportedly Quality of life progressed after first-line, disrupt cell division through effects on charged nivolumab, platinum-based macromolecules and organelles within cancer cells, ) chemotherapy potentially limiting tumor growth. The NovoTTF-100L device consists of a battery-powered field generator coupled to an electrode array that is attached to the skin of the patient’s torso. Tumor-treating fields therapy is 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, New 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 18-99 years Olaparib (Lynparza) is a small molecule intended to inhibit Chemotherapy with one Overall survival FDA designation(s): Orphan with germline BRCA1 poly (ADP-ribose) polymerase (PARP), which functions in or more of the following: Drug and/or BRCA2 mutation- a DNA repair pathway. Cancers are often deficient in a Progression-free survival Antimetabolites (eg, 5- Clinical trial(s): Phase III positive metastatic DNA repair pathway, and when PARP is also inhibited, Quality of life pancreatic cancer whose the loss of 2 types of DNA repair results in cancer cell fluorouracil, POLO primary completion disease has not progressed death in response to DNA damage. Only about 5% of capecitabine, January 2019; initial data during first-line platinum- patients with pancreatic cancer respond to the standard of gemcitabine) reported February 2019 based chemotherapy care (gemcitabine chemotherapy), and the prognosis for Folic acid derivatives Note: FDA approved these patients is poor. Olaparib purportedly induces cell (eg, leucovorin) olaparib for treating ovarian death in pancreatic tumors that harbor germline mutations cancer in December 2014 in the BRCA1 and/or BRCA2 genes. In clinical trials, Multikinase inhibitors and for breast cancer in olaparib is administered orally, 300 mg, twice daily until (eg, erlotinib) January 2018. disease progression or intolerable toxicity. Platinum-based agents Developer(s): (eg, cisplatin, oxaliplatin) AstraZeneca plc (Cambridge, United Kingdom), in Taxanes (eg, docetaxel, collaboration with Merck & Co Inc (Kenilworth, New nab-paclitaxel, Jersey) paclitaxel)

Adults aged 18 years or Oportuzumab monatox (Vicinium) is an antibody-drug Cystectomy Overall survival Clinical trial(s): Phase III older with non-muscle conjugate consisting of a humanized monoclonal antibody VISTA primary completion invasive bladder cancer fragment specific for the epithelial cell adhesion molecule Intravesicular Progression-free survival December 2018 chemotherapy whose disease is refractory (EpCAM) linked to a truncated form of Pseudomonas Time to cystectomy to or relapsed after aeruginosa exotoxin A (ETA). ETA is a cytotoxic agent (gemcitabine, mitomycin- intravesicular treatment with that acts by inhibiting protein synthesis through C, valrubicin) Quality of life bacillus Calmette-Guérin inactivation of elongation factor-2. EpCAM is highly expressed by bladder cancer cells; therefore, oportuzumab monatox may preferentially deliver the linked exotoxin to these cells. In treating non-muscle invasive bladder cancer, 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)

Section 1. Currently Monitored Topics 18

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

Adults aged 18 years or Pegargiminase (ADI-PEG 20) is a pegylated preparation Cisplatin and Overall survival FDA designation(s): Orphan older with malignant pleural of the enzyme arginine deiminase, which catalyzes the pemetrexed Drug mesothelioma exhibiting low hydrolysis of arginine, depleting the supply of this Progression-free survival Clinical trial(s): Phase II/III argininosuccinate essential amino acid from the bloodstream. Cells of many Quality of life synthetase 1 expression tumor types are unable to autonomously synthesize ATOMIC primary completion who have undergone no arginine and therefore may be sensitive to arginine October 2020 prior systemic therapies for depletion. In particular, tumor cells that express low levels mesothelioma of the arginosuccinate synthetase 1 (ASS1) gene involved in cellular arginine synthesis may depend on exogenous arginine. In treating patients with pleural malignant mesothelioma exhibiting low levels of ASS1 expression, pegargiminase is administered weekly by intramuscular injection at a dose of 36 mg/m2 in combination with standard chemotherapy with cisplatin and pemetrexed. Developer(s): Polaris Group (San Diego, California)

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

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 Pexastimogene devacirepvec (Pexa-Vec) is a Wyeth High-intensity focused Overall survival FDA designation(s): Orphan older with advanced strain of vaccinia virus that has had its viral thymidine ultrasound Drug hepatocellular carcinoma kinase (TK) gene disrupted to selectively infect and Progression-free survival Locoregional treatment Clinical trial(s): Phase III who have had no previous replicate in tumor cells, which commonly express high Quality of life systemic therapy levels of TK. Pexa-Vec has also been engineered to with one of the following: Phocus primary completion July 2019; designed under express human granulocyte macrophage colony- Ablation (eg, stimulating factor (GM-CSF) and β-galactosidase. Special Protocol radiofrequency, Assessment Although GM-CSF induces an antitumor immune cryoablation, response and disrupts the tumor’s vascularization, percutaneous alcohol presentation of β-galactosidase peptides stimulates T-cell injection, microwave) responses. Pexa-Vec purportedly targets and destroys cells in liver tumors and in tumor-associated blood Arterially directed vessels as well as activating tumor-specific immune therapies (eg, responses. In clinical trials, Pexa-Vec is administered as transarterial 3 biweekly intratumoral injections at a dose of 1 x 109 embolization, plaque forming units on day 1 and weeks 2 and 4. At transcatheter arterial week 6 after the first dose of Pexa-Vec, sorafenib chemoembolization) (Nexavar, Bayer AG, Leverkusen, Germany) treatment Radiation therapy (eg, begins at a dose of 400 mg twice daily. external beam radiation Developer(s): therapy, stereotactic body radiation therapy) SillaJen Inc (Busan, South Korea) Chemotherapy with one Green Cross Corp (Yongin, South Korea), regional or more of the following: partner Angiogenesis inhibitors Transgene S.A. (Strasbourg, France), regional partner (eg, lenvatinib) Lee’s Pharmaceutical Holdings Ltd (Sha Tin, Hong Kong), Anthracyclines (eg, regional partner doxorubicin) Antimetabolites (eg, 5- fluorouracil, gemcitabine) DNA synthesis inhibitors (eg, mitomycin C) Multikinase inhibitors (eg, cabozantinib, regorafenib, sorafenib) Platinum-based agents (eg, cisplatin, oxaliplatin)

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 Pexidartinib is a small-molecule multikinase inhibitor with Radiation therapy Overall survival PDUFA date: August 2019, older with a tenosynovial activity against several receptor tyrosine kinases including priority review giant cell tumor (TGCT) that CSF1R, FLT3, and KIT. TGCTs typically overexpress Off-label imatinib Progression-free survival FDA designation(s): cannot be surgically colony-stimulating factor 1 (CSF1), which is an activating Quality of life resected ligand for CSF1R. TGCT-expressed CSF1 leads to Breakthrough Therapy recruitment of CSF1R-expressing cells such as Clinical trial(s): Phase III osteoclasts, macrophages, and mast cells, which initiate ENLIVEN primary an inflammatory reactive process that contributes to completion date December TGCT pathogenesis. Therefore, inhibiting CSF1R by 2019 pexidartinib may 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 (Tokyo, Japan)

Men aged 18 years or older ProstAtak, a gene-mediated, cytotoxic immunotherapy, Radiation therapy with or Overall survival Clinical trial(s): Phase III with localized prostate consists of an adenovirus vector containing a herpes without androgen PrTK03 primary completion cancer undergoing radiation simplex virus thymidine kinase gene (aglatimagene deprivation therapy Progression-free survival December 2021 under therapy who have besadenovec) that is injected into the tumor and leads to Quality of life Special Protocol intermediate-risk or high- infected cells expressing thymidine kinase. After injection, Assessment risk disease with a single a low dose of a synthetic guanosine analogue (eg, high-risk feature valacyclovir) that is activated by thymidine kinase is administered, potentially killing tumor cells expressing the transgene. Release of tumor-associated antigens by dying tumor cells purportedly leads to an antitumor immune response. ProstAtak is administered in 3 rounds of treatment with intratumoral injection of aglatimagene besadenovec and systemic valacyclovir. Patients also receive standard radiation therapy with or without androgen deprivation therapy. Developer(s): Advantagene Inc (Auburndale, Massachusetts)

Section 1. Currently Monitored Topics 21

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

Infants and children aged 2 Remestemcel-L, an allogeneic mesenchymal precursor Photopheresis alone or Overall survival Submission planned: months to 17 years with cell therapy, uses a donor’s bone marrow and selectively combined with 8- Biologics License steroid-refractory acute expands mesenchymal stem cells. GVHD is an immune methoxypsoralen Progression-free survival Application, fourth quarter graft-versus-host disease disorder that is a frequent complication of allogeneic Quality of life 2019 (GVHD) hematopoietic cell transplantation. GVHD affects many Therapy with one or organ systems and arises when donor T cells recognize more FDA designation(s): Orphan host cells as foreign, by virtue of their expression of immunosuppressants: Drug, Fast Track alloantigens, and mount an immune response. Alkylating agent (eg, Clinical trial(s): Phase III Remestemcel-L purportedly secretes growth factors and cyclophosphamide) MSB0GVHD001 primary anti-inflammatory cytokines that facilitate tissue repair by completion January 2018 downregulating immune and inflammatory responses of Antibodies (eg, and completed April 2018; immunocompetent T cells contained in the graft. In clinical alemtuzumab, anti- topline results reported trials, remestemcel-L is delivered by an intravenous thymocyte globulin) February 2018; 100-day 6 infusion, at a dose of 2 x 10 cells/kg twice a week for 4 Calcineurin inhibitors survival results reported consecutive weeks. (eg, cyclosporine, June 2018; 180-day survival Developer(s): tacrolimus) results reported September 2018 Mesoblast Ltd (Melbourne, Australia, and New York, New Corticosteroids (eg, York) methotrexate, mycophenolate mofetil, prednisone) mTOR inhibitor (eg, sirolimus)

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 18-81 years Rigosertib (Estybon) is a small-molecule, multikinase Lenalidomide Overall survival FDA designation(s): Orphan with myelodysplastic inhibitor with activity against both the alpha and beta Drug syndrome that exhibited isoforms of phosphoinositide 3 kinase (PI3K) and polo- Overall response rate Clinical trial(s): Phase III primary resistance to like kinase 1 (PLK1). Inhibiting PI3K may disrupt cell Quality of life hypomethylating agents (ie, signaling that promotes cell growth and survival, and INSPIRE ongoing primary disease progression before inhibiting PLK1 may disrupt mitosis, leading to cell-cycle completion March 2019 attaining a complete or arrest in transformed cells. A previous randomized partial response, or controlled trial suggested that rigosertib was most hematologic improvement) effective in a subgroup of patients who had not responded to first-line therapy with hypomethylating agents. In clinical trials, rigosertib is administered intravenously at 1800 mg daily for 3 days. This regimen is administered every 2 weeks for 8 cycles, then every 4 weeks until disease progression or development of unacceptable toxicity. Developer(s): Onconova Therapeutics Inc (Newtown, Pennsylvania)

Section 1. Currently Monitored Topics 23

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: April 6, 2019, older with refractory or inhibitor of nuclear export that specifically binds with and or more of the following: priority review relapsed multiple myeloma inhibits the nuclear export protein XPO1 (also called Progression-free survival Alkylating agents (eg, FDA designation(s): Orphan after 3 or more therapies CRM1). This binding purportedly restores nuclear Quality of life composed of alkylating localization, or the accumulation of tumor suppressor bendamustine, Drug, Fast Track cyclophosphamide) agents, angiogenesis proteins in the cell nucleus, thereby restoring and Clinical trial(s): Phase II inhibitors, anti-CD38 amplifying their tumor suppressor function. Selinexor Angiogenesis inhibitors STORM primary completion monoclonal antibody, might also activate the selective induction of apoptosis in (eg, lenalidomide, April 2018; top-line results glucocorticoids, and/or cancer cells, while largely sparing normal cells. Clinical pomalidomide, reported April 2018; phase proteasome inhibitors trials are testing selinexor in combination with various thalidomide) III BOSTON primary multiple myeloma treatments. Selinexor is administered completion June 2020 orally, 60 to 80 mg twice weekly or 100 mg once weekly. Anthracycline (eg, doxorubicin) Developer(s): Glucocorticoid (eg, Karyopharm Therapeutics Inc (Newton, Massachusetts) dexamethasone) Monoclonal antibodies (eg, , ) Proteasome inhibitors (eg, bortezomib, carfilzomib) Topoisomerase inhibitor (eg, etoposide)

Adults aged 18-80 years Seviprotimut-L (POL-103A) is a polyvalent vaccine that is Active surveillance Overall survival FDA designation(s): Orphan with stage IIB, IIC, or III generated by isolating peptides secreted by 3 human Drug who have melanoma cell lines grown in culture. The isolated BRAF/MEK inhibitors Progression-free survival undergone surgical peptides are combined with an adjuvant (aluminum Clinical trial(s): Phase III Immune checkpoint Quality of life MAVIS ongoing primary resection of the primary skin hydroxide) to generate the vaccine. The polyvalent nature inhibitors lesion of the vaccine purportedly allows its use in all patients completion January 2019 irrespective of tumor and/or human leukocyte antigen genotypes. In clinical trials, seviprotimut-L is being administered intradermally as adjuvant therapy after surgical resection. Developer(s): Polynoma LLC (San Diego, California)

Section 1. Currently Monitored Topics 24

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

Children aged 1 month to Sodium thiosulfate (Pedmark) is a proprietary formulation Cisplatin chemotherapy Ototoxity Submit date: Rolling New 18 years with localized, of sodium thiosulfate that inactivates the metabolic alone (without adjuvant Drug Application initiated nonmetastatic, solid tumors byproducts of systemic platinum-based (cisplatin) preventive therapy) Hearing ability December 2018 eligible for cisplatin chemotherapy to reduce the risk of cisplatin-induced Quality of life chemotherapy ototoxicity, which can damage hearing. Pedmark FDA designation(s): Orphan purportedly acts only on cisplatin metabolites in general Drug, Fast Track, circulation and does not interfere with cisplatin Breakthrough Therapy effectiveness within targeted tumor cells. In clinical trials, Clinical trial(s): Phase III Pedmark is administered intravenously, 16 g/m2 or 533 completed April 2015; data mg/kg, 6 hours after receiving cisplatin-based published January 2017; chemotherapy. Pedmark treatment continues until phase III SIOPEL6 completion of cisplatin treatment. completed February 2018; Developer(s): data published June 2018 Fennec Pharmaceuticals Inc (Research Triangle Park, North Carolina)

Adults aged 18 years or Synthetic hypericin (SGX301) is a photosensitizing agent Chemotherapy Overall survival FDA designation(s): Orphan older in whom for use with visible light, potentially avoiding the Drug, Fast Track patch/plaque–phase complications associated with ultraviolet light. Standard Ultraviolet A Damage to tumor- cutaneous T-cell lymphoma care for CTCL often requires photodynamic therapy with phototherapy with adjacent tissue Clinical trial(s): Phase III (CTCL) has been diagnosed ultraviolet light, which can damage surrounding tissue and psoralen FLASH primary completion Progression-free survival December 2019 lead to skin burns, increased pigmentation, or secondary Ultraviolet B skin cancer. SGX301 purportedly clears CTCL lesions phototherapy Quality of life without increasing the patient’s risk for skin burns. In clinical trials, SGX301 is applied topically to the CTCL lesion twice weekly (covered with an opaque bandage for 12-24 hours) followed by fluorescent light activation of the compound. Developer(s): Soligenix Inc (Princeton, New Jersey)

Section 1. Currently Monitored Topics 25

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

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

Adults aged 18 years or Tesetaxel is an orally administered taxane, a class of Anthracyclines (eg, Overall survival Clinical trial(s): Phase III older with HER2-negative, antineoplastic drugs that inhibits mitosis. Taxanes (eg, doxorubicin, liposomal CONTESSA primary hormone receptor-positive, docetaxel, nab-paclitaxel, paclitaxel) are frequently used doxorubicin) Progression-free survival completion September 2020 locally advanced or in treating breast cancer; however, available taxanes Quality of life metastatic breast cancer must be administered intravenously and are frequently Antimetabolites (eg, previously treated with a associated with hypersensitivity reactions, which can be capecitabine, taxane in the neoadjuvant serious or even life threatening and can necessitate gemcitabine) or adjuvant setting stopping the taxane-based chemotherapy regimen. Microtubule inhibitors Additionally, tesetaxel has demonstrated antineoplastic (eg, eribulin, vinorelbine) activity in tumors that have previously been exposed to other taxanes. In metastatic breast cancer, tesetaxel (27 PARP Inhibitors (eg, mg/m2 once daily every 21 days) is being used in an all- olaparib, talazoparib) for oral regimen in combination with low-dose capecitabine. BRCA 1/2 mutated breast cancer Developer(s): Odonate Therapeutics Inc (San Diego, California) Taxanes (eg, docetaxel, paclitaxel)

Section 1. Currently Monitored Topics 26

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

Patients of any age with Varlitinib is a small-molecule inhibitor of the epidermal Fluoropyrimidine-based Overall survival FDA designation(s): Orphan advanced, unresectable growth factor receptor (EGFR) family of receptor tyrosine chemotherapy Drug biliary tract cancer (eg, kinases, including EGFR (HER1), HER2, and HER4. Progression-free survival Immune checkpoint Clinical trial(s): Phase II/III cholangiocarcinoma, gall EGFR signaling promotes biliary tract cell growth and Quality of life bladder cancer, carcinoma proliferation, and most biliary tract cancers overexpress inhibitors for tumors with TreeTopp primary of ampulla of Vater) who EGFR; therefore, inhibiting the EGFR family of receptor deficiency in mismatch completion July 2019 have received one prior tyrosine kinases may have therapeutic efficacy in these repair or microsatellite round of gemcitabine-based cancers. In clinical trials, varlitinib (300 mg) is instability chemotherapy administered orally twice daily in combination with fluoropyrimidine-based chemotherapy (capecitabine) until disease progression or development of unacceptable toxicity. Developer(s): Aslan Pharmaceuticals (Singapore, Republic of Singapore), in collaboration with Array BioPharma Inc (Boulder, Colorado)

Women aged 18 years or VGX-3100 is a DNA-based immunotherapy vaccine Colposcopy followed by Rates of cervical HSIL Clinical trial(s): Phase III older with cervical high- comprising plasmids that contain expression cassettes for one of the following REVEAL 1 primary grade squamous HPV proteins E6 and E7. Once VGX-3100’s optimized procedures to remove Rates of infection with completion August 2019; intraepithelial lesion (HSIL) DNA is delivered into cells, it is translated into the E6 and cervical lesions: HPV-16 and/or HPV-18 phase III REVEAL 2 primary and confirmed infection with E7 proteins, which act as antigens to induce targeted T- Adverse events completion December 2020 human papillomavirus cell and antibody responses. VGX-3100 purportedly uses Carbon dioxide laser (HPV) type 16 and/or 18 the immune system to clear HPV-16 and HPV-18 ablation infections and precancerous lesions, enabling patients to Cold knife cone biopsy avoid the risks associated with surgery, such as loss of reproductive health and negative psychosocial impacts. In Laser cone biopsy clinical trials, VGX-3100 is administered as an Loop electrosurgical intramuscular injection, followed by electroporation with excision 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)

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 18-75 years Vocimagene amiretrorepvec (Toca 511) is a cancer- Fractionated external Overall survival FDA designation(s): Orphan with recurrent high-grade selective gene therapy 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 received first-line surgery enzyme that converts the orally administered antifungal Toca5 primary completion Alkylating agents (eg, December 2019; first interim followed by temozolomide prodrug Toca FC (5-fluorocytosine) to the anticancer carmustine, and radiation agent 5-fluorouracil (5-FU) in cells. Toca 511 purportedly analysis reported August cyclophosphamide, 2018 generates high levels of 5-FU in replicating glioma cells to lomustine, procarbazine, cause cell death, which may improve patient survival. In temozolomide) clinical trials, 4 mL of Toca 511 is injected into the wall of the resected tumor cavity on day 1 (about 40 injections of Angiogenesis inhibitors 0.1 mL). At least 6 weeks after resection, Toca FC is (eg, bevacizumab) administered orally at a dose of 220 mg/kg/day, for 7-day mTOR inhibitors (eg, courses, and repeated about every 6 weeks. everolimus) Developer(s): Platinum-based agents Tocagen Inc (San Diego, California) (eg, carboplatin, cisplatin) Vinca alkaloids (eg, vincristine)

Section 1. Currently Monitored Topics 28

Table 3. Cardiovascular: 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 selective inhibitor of bromodomain Bile-acid-binding resins Major adverse cardiac Clinical trial(s): Phase III older with high-risk coronary extra-terminal (BET) proteins. By blocking BET proteins at events BETonMACE primary artery disease, defined as the transcription level, apabetalone purportedly slows the Ezetimibe completion June 2019 All-cause mortality acute coronary syndrome abnormally increased production of dysregulated disease- Fibrates (myocardial infarction or associated proteins, moving them closer to normal levels. Kidney function unstable angina) within the Apabetalone purportedly may reduce incidence of major Niacin past 90 days, low high- cardiovascular events by reducing various mediators that Statins density lipoprotein promote vascular inflammation; calcium deposition; cholesterol level, and type 2 coagulation cascade; and other mechanisms, including diabetes mellitus metabolism, cholesterol transport, and the complement cascade. Developer(s): Resverlogix Corp (Calgary, Alberta, Canada)

Section 1. Currently Monitored Topics 29

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

Adults aged 18 years or Cardiac contractility modulation (CCM) with the Aldosterone receptor NYHA heart failure Circulatory System Devices older with New York Heart implantable Optimizer device delivers nonexcitatory antagonists functional class Panel vote: December 4, Association (NYHA) electrical pulses during the myocardial absolute refractory 2018 functional class III or IV period to improve systolic contraction. CCM purportedly Angiotensin-converting Exercise tolerance heart failure, who remain normalizes phosphorylation of regulatory proteins to enzyme inhibitors FDA designation(s): Heart failure–related Breakthrough Device symptomatic despite improve calcium handling, ultimately interrupting the Angiotensin II receptor hospitalization guideline-directed medical remodeling cascade to reverse left ventricular remodeling blockers Clinical trial(s): FIX-HF-5C therapy and are in normal and improve left ventricular contractile strength. Mortality pivotal completed Beta blockers sinus rhythm with left Physicians place the implantable pulse generator Quality of life September 2017; pivotal ventricular ejection fraction subcutaneously in the right pectoral region, similar to Coronary artery bypass data published October between 25% and 45% placement of standard pacemakers and defibrillators; 2 graft surgery 2018; FIX-HF-5C2 standard pacemaker leads are placed through the blood confirmatory trial of 2-lead vessels into the right ventricle on the right ventricular Digoxin configuration Optimizer septum to sense local electrical activity and deliver CCM. Diuretics device, primary completion An optional atrial lead may be placed in the right atrium November 2019; FIX-HF- for additional electrical sensing. The device delivers Hydralazine/nitrate 5CA continued access study pulses at regular intervals during the day, purportedly of 3-lead configuration Implantable cardioverter- unnoticed by patients. Patients recharge the pulse Optimizer device, primary defibrillators generator weekly at home for about 1 hour using a completion January 2020 noninvasive charging system placed over the implant. Ivabradine The Optimizer Smart model replaced all earlier Optimizer versions (II, III, IV) in clinical trials since 2016. Sacubitril/valsartan Developer(s): Impulse Dynamics (USA) Inc (Orangeburg, New York)

Section 1. Currently Monitored Topics 30

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

Adults aged 21-90 years CardiAMP therapy delivers autologous bone marrow– Aldosterone receptor NYHA heart failure Clinical trial(s): Phase III with New York Heart derived mononuclear cells to damaged heart muscle, with antagonists functional class primary completion June Association (NYHA) the goal of improving heart function and exercise 2020 functional class II or III heart capacity. The treatment purportedly improves heart Angiotensin-converting Quality of life enzyme inhibitors failure who have chronic function through 2 mechanisms: direct and indirect Exercise tolerance ischemic left ventricular regeneration. In direct regeneration, the transplanted cells Angiotensin II receptor dysfunction secondary to purportedly travel to injured myocardium and differentiate blockers Heart failure–related myocardial infarction, with into new functional heart cells. In indirect regeneration, hospitalizations Beta blockers ventricular ejection fraction the transplanted cells purportedly secrete stimulatory Mortality between 20% and 40% on cytokines to instruct resident stem cells to initiate tissue Cardiac stable, guideline-directed regeneration. Clinicians first collect about 15 cc of bone resynchronization medical and device therapy marrow aspirate from the patient and send to a partner therapy for heart failure laboratory for proprietary molecular analysis to estimate a candidate’s likelihood of successful cell therapy. If assay Coronary artery bypass results are positive, patients return to the cardiac graft surgery catheterization laboratory after 3 or more days to undergo Digoxin the procedure. Clinicians collect about 60 cc of bone marrow aspirate from an eligible patient to concentrate a Diuretics sufficient dose of autologous cells at the point of care and inject the prepared cell product into the myocardium using Hydralazine/nitrate a proprietary needle-injection catheter. Patients are Implantable cardioverter- discharged the same day or the next day. defibrillators Developer(s): Ivabradine BioCardia Inc (San Carlos, California) Sacubitril/valsartan

Section 1. Currently Monitored Topics 31

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

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

Section 1. Currently Monitored Topics 32

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

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

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

Section 1. Currently Monitored Topics 33

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 NYHA heart failure Clinical trial(s): IDE pivotal older with heart failure and Resynchronization Therapy (WiSE-CRT) purportedly antagonists functional class trial (SOLVE CRT) primary a class I or IIa guideline improves on conventional CRT devices by replacing completion September 2019 indication for conventional epicardial left ventricular pacing stimulation from an Angiotensin-converting Exercise tolerance enzyme inhibitors cardiac resynchronization electrode lead placed within the coronary sinus vein along Heart failure–related therapy (CRT) and who are the left ventricular wall with endocardial left ventricular Angiotensin II receptor hospitalizations either nonresponders to pacing from a wireless electrode implanted inside the left blockers CRT or who are previously ventricle. A conventional pacemaker implanted Mortality Beta blockers untreatable, defined as subcutaneously in the chest senses and paces the right Quality of life having an implanted CRT ventricle with a conventional right atrial lead and a right Conventional system turned off because ventricular lead. A wireless electrode (16.3 mm long, 2.7 biventricular of electrode lead failure or mm wide) anchored in the left ventricular wall paces the pacing/cardiac relative contraindications to left ventricle. A wireless transmitter placed resynchronization an implanted lead subcutaneously in the chest senses the right ventricular therapy with epicardial pacing and sends ultrasound energy to the implant to left ventricular lead generate endocardial left ventricular pacing in synchrony with right-sided pacing. A battery pack placed Coronary artery bypass subcutaneously along the ribs and under the arm powers graft surgery the wireless transmitter via a thin cable tunneled under Digoxin the skin. Diuretics Developer(s): Hydralazine/nitrate EBR Systems Inc (Sunnyvale, California) Implantable cardioverter- defibrillators Ivabradine Sacubitril/valsartan

Section 1. Currently Monitored Topics 34

Table 4. Mental and Behavioral Health: 10 Topics

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

Adults aged 18-55 years Dasotraline is a dual-acting dopamine and norepinephrine Lisdexamfetamine Binge days per week Clinical trial(s): Phase II/III with moderate to severe reuptake inhibitor. Inhibiting the reuptake increases the (Vyvanse) completed October 2016; binge eating disorder (BED) concentration of neurotransmitters in the brain. The slow BED severity phase III completed May absorption and long elimination half-life of dasotraline Off-label 2018; phase III extension pharmacotherapies (eg, Health-related quality of purportedly results in stable plasma concentrations over life primary completion June 24 hours. In a trial, dasotraline was given to participants antiepileptics, 2019 twice a day (4 or 6 mg per day) for 12 weeks. norepinephrine reuptake inhibitors, serotonin- Developer(s): norepinephrine reuptake inhibitors) Sunovion (Marlborough, Massachusetts), a subsidiary of Sumitomo Dainippon Pharma (Osaka, Japan)

Adults aged 22-68 years Deep transcranial magnetic stimulation (TMS) is Off-label use of rTMS PTSD severity and Clinical trial(s): Phase I/II with moderate to severe noninvasive outpatient treatment delivered with a device symptoms completed July 2011; data post-traumatic stress that uses directed electromagnetic fields to target and Psychotherapy (cognitive published May 2013; disorder (PTSD) stimulate the prefrontal cortex in the brain. It purportedly behavior therapy, Depression severity and unphased primary reduces PTSD symptoms and severity. In an ongoing prolonged exposure symptoms completion June 2019 therapy, eye movement trial, the treatment is given in 20-minute sessions, 3 times Cognitive function a week, for 4 weeks, with a booster treatment at week 5 desensitization and and another at week 9, totaling 14 treatment sessions. A reprocessing therapy) Adverse events minimum of 8 sessions is required for treatment. The Selective serotonin Health-related quality of manufacturer purports that the H1 coil used in the device reuptake inhibitors life stimulates deeper regions of the prefrontal cortex than the (sertraline [Zoloft], figure-8 coil used in repetitive TMS. The treatment is paroxetine [Paxil]) intended as an adjunct to pharmacologic or psychological treatment. Developer(s): BrainsWay Ltd (Hackensack, New Jersey)

Section 1. Currently Monitored Topics 35

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

Adults aged 18-64 years Esketamine intranasal (Spravato) is the S(+) enantiomer Deep brain stimulation Depression symptoms Approval date: March 5, with treatment-resistant of ketamine, a general anesthetic and dissociative and severity 2019 Electroconvulsive major depressive disorder hallucinogen that acts as an N-methyl-D-aspartate therapy Function and disability FDA designation(s): (MDD) that has not receptor antagonist and glutamate receptor modulator. Breakthrough Therapy responded to 2 or more The drug purportedly restores synaptic connections in Monoamine oxidase Health-related quality of currently available brain cells in patients with treatment-resistant MDD and inhibitors life Clinical trial(s): Phase III trial antidepressants of has rapid and sustained antidepressant effects. This (SUSTAIN-2) completed adequate dose and duration occurs through the direct activation of glutamate, while Off-label intravenous October 2017; phase III trial in the current moderate to traditional antidepressants affect glutamate through first ketamine (TRANSFORM-2) completed severe episode of increasing serotonin activity in multiple parts of the brain, Off-label intranasal November 2017; phase III depression a process that takes 2 to 4 weeks. The nasal spray is self- ketamine trial (TRANSFORM-1) administered by patients, under the supervision of a completed February 2018; health care professional, twice a week for 4 weeks. In the Psychotherapy phase III trial (SUSTAIN-1) induction phase (weeks 1-4), patients receive a single Selective serotonin completed February 2018; starting dose of 56 mg, and subsequent doses of 56 mg reuptake inhibitors phase III trial (SUSTAIN-3) or 84 mg, twice weekly. In the first part of the primary study completion maintenance phase (weeks 5-8), patients receive doses Serotonin- August 2021 of 56 mg or 84 mg, once weekly, and in weeks 9 and norepinephrine reuptake beyond, patients receive doses of 56 mg or 84 mg, once inhibitors every week to every 2 weeks. Dosing frequency should Tricyclic antidepressants be as limited as possible while still maintaining response. Intranasal esketamine is used in combination with oral Transcranial magnetic antidepressants (SSRIs [selected serotonin reuptake stimulation inhibitors] or SNRIs [serotonin and norepinephrine reuptake inhibitors]). Vagal nerve stimulation Developer(s): Janssen Research & Development LLC, unit of Johnson & Johnson (New Brunswick, New Jersey)

Section 1. Currently Monitored Topics 36

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

Adults aged 18-75 years To treat patients with PTSD, external trigeminal nerve Off-label use of repetitive PTSD severity and Clinical trial(s): Phase I with post-traumatic stress stimulation (eTNS) sends electrical stimulation to the transcranial magnetic symptoms completed January 2012 disorder (PTSD) trigeminal nerve through a patch placed on the forehead. stimulation (published data); unphased The eTNS system is a cell-phone-sized electrical pulse Depression severity and primary completion generator that delivers mild electrical signals via 2 wires Psychotherapy (cognitive symptoms September 2019 behavior therapy, connected to the small single-use electric patch. The Cognitive function eTNS system is self-administered at home and is typically prolonged exposure used for 8 hours at a time while the patient is sleeping. therapy, eye movement Adverse events The external electrical nerve stimulation purportedly desensitization and reprocessing therapy) Health-related quality of changes the neuronal activity in key regions of the brain— life the brainstem, thalamus, and cortex—increasing activity Selective serotonin in regions that are underactive. It is used in conjunction reuptake inhibitors with pharmacotherapy. (sertraline [Zoloft], Developer(s): paroxetine [Paxil]) Neurosigma (Los Angeles, California) in collaboration with University of California, Los Angeles

Adults aged 18-65 years Ketamine is an N-methyl-D-aspartate receptor antagonist Off-label use of repetitive PTSD severity and Clinical trial(s): Phase II/III who fulfill Diagnostic and and glutamate receptor modulator that purportedly transcranial magnetic symptoms primary completion Statistical Manual of Mental restores synaptic connections in brain cells and may have stimulation December 2018 (repeated Depression severity and Disorders (DSM-5) criteria a rapid and sustained therapeutic effect for patients with dose); phase II completed Psychotherapy (cognitive symptoms for current civilian or PTSD. In the most recent clinical trial, participants receive September 2013 (single behavior therapy, combat-related post- 0.5 mg/kg doses of ketamine intravenously 3 times a dose); results published prolonged exposure Cognitive function traumatic stress disorder week for 2 weeks, for 6 total doses. The active control is June 2014 therapy, eye movement (PTSD) midazolam, a similar acute anesthetic that has not been Adverse events desensitization and shown to be effective in treating PTSD. After treatment, reprocessing therapy) Health-related quality of patients must be monitored for at least 4 hours before life discharge. Selective serotonin reuptake inhibitors Developer(s): (sertraline [Zoloft], VA Office of Research and Development (Washington, paroxetine [Paxil]) DC)

Section 1. Currently Monitored Topics 37

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

Adolescents aged 12-17 NaBen is a prescription-strength formulation of sodium Antidepressants Positive and negative FDA designation(s): Orphan years with a confirmed benzoate, a common food preservative that is also the (selective serotonin schizophrenia symptoms Drug, Breakthrough Therapy Diagnostic and Statistical sodium salt of naturally occurring benzoic acid. A key reuptake inhibitors and Health-related quality of Clinical trial(s): Phase IIb/III Manual of Mental Disorders factor in schizophrenia pathophysiology is N-methyl-D- serotonin and life primary completion (DSM-IV or DSM-5) aspartate receptor (NMDAR) hypofunctioning. NaBen norepinephrine reuptake diagnosis of schizophrenia inhibitors) December 2018 (estimated inhibits D-amino acid oxidase (DAAO) metabolism, completion June 2019) who are clinically stable with increasing DAAO activity, leading to the production of residual symptoms Antipsychotics (oral and more D-serine, which increases NMDA activity in the injectable) hypothalamus region of the brain. Increasing NMDA activity has been shown to affect both positive and Mood stabilizers negative schizophrenia symptoms. In an ongoing phase Psychotherapy (cognitive IIb trial, 500 mg NaBen oral tablets are administered twice behavior therapy) daily at a total dose of 1000 mg/day for 6 weeks. Participants’ current antipsychotic regimens Combination therapy remained unchanged for at least 8 weeks before study screening and will remain unchanged during the study. A phase III trial will continue treatment for a randomized sample of these participants for an unspecified length of time. Developer(s): SyneuRx International (Taiwan) Corp (Taipei, Taiwan)

Section 1. Currently Monitored Topics 38

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

Adults aged 18-55 years NaBen is a prescription-strength formulation of sodium Antidepressants Positive and negative FDA designation(s): with a confirmed Diagnostic benzoate, a common food preservative that is also the (selective serotonin schizophrenia symptoms Breakthrough Therapy and Statistical Manual of sodium salt of naturally occurring benzoic acid. A key reuptake inhibitors and Health-related quality of Clinical trial(s): Phase IIb/III Mental Disorders (DSM-5) factor in schizophrenia pathophysiology is N-methyl-D- serotonin and life primary completion diagnosis of schizophrenia aspartate receptor (NMDAR) hypofunctioning. NaBen norepinephrine reuptake for the past 2 years who are inhibitors) December 2018, estimated inhibits D-amino acid oxidase (DAAO) metabolism, completion June 2019 clinically stable with residual increasing DAAO activity, leading to the production of symptoms Antipsychotics (oral and more D-serine, which increases NMDA activity in the injectable) hypothalamus region of the brain. Increasing NMDA activity has been shown to affect both positive and Electroconvulsive negative schizophrenia symptoms. In an ongoing phase therapy IIb trial, 500 mg NaBen oral tablets are administered twice Mood stabilizers daily, at a total dose of 1000 mg/day for up to 8 weeks, adjunct to standard antipsychotic . Psychotherapy (cognitive Participants’ current antipsychotic medication regimens behavior therapy) remained unchanged for at least 8 weeks before study Combination therapy screening and will remain unchanged during the study. After the 8-week treatment, treatment will continue for 52 weeks as a phase III open-label extension study. Developer(s): SyneuRx International (Taiwan) Corp (Taipei, Taiwan)

Section 1. Currently Monitored Topics 39

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

Adults aged 18-55 years NaBen is a prescription-strength formulation of sodium Last-line antipsychotic Positive and negative FDA designation(s): Orphan with treatment-refractory benzoate, a common food preservative that is also the (clozapine) schizophrenia symptoms Drug, Breakthrough Therapy schizophrenia sodium salt of naturally occurring benzoic acid. A key Health-related quality of Clinical trial(s): Phase IIb/III factor in schizophrenia pathophysiology is N-methyl-D- life primary completion June aspartate receptor (NMDAR) hypofunctioning. NaBen 2019 inhibits D-amino acid oxidase (DAAO) metabolism, increasing DAAO activity, leading to the production of more D-serine, which increases NMDA activity in the hypothalamus region of the brain. Increasing NMDA activity has been shown to affect both positive and negative schizophrenia symptoms. In an ongoing phase IIb trial, participants will receive either two 500 mg NaBen oral tablets administered twice daily, at a total dose of 2000 mg/day, or one 500 mg NaBen oral tablet administered twice daily, at a total dose of 1000 mg/day, for 8 weeks, adjunct to their current dose of clozapine. Participants’ clozapine regimens remained unchanged for at least 3 months before study screening and will remain unchanged during the study. After the 8-week treatment, a phase III study will continue treatment for a randomized sample of these participants for an unspecified length of time. Developer(s): SyneuRx International (Taiwan) Corp (Taipei, Taiwan)

Section 1. Currently Monitored Topics 40

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

Adults aged 18-65 years Oxytocin administered intranasally purportedly mitigates Antidepressants Social cognition ability Clinical trial(s): Unphased with schizophrenia negative symptoms associated with schizophrenia by (selective serotonin completed August 2012 increasing levels of oxytocin, a naturally occurring reuptake inhibitors and Negative symptoms (published data); phase II hormone that works as a neurotransmitter, in the brain. serotonin and Health-related quality of completed July 2014; phase Other antipsychotic drugs have been used successfully to norepinephrine reuptake life II completed November treat the positive symptoms of patients with schizophrenia inhibitors) 2015; unphased primary but have minimal effects on negative symptoms and completion date June 2019 cognitive deficits. Studies have shown that patients with Antipsychotics (oral and schizophrenia have lower levels of oxytocin. This injectable) hormone has been associated with increased levels of Electroconvulsive trust, empathy, and ability to interpret mental states, as therapy well as decreased cortisol release and anxiety. Oxytocin could potentially normalize social dysfunction seen in Mood stabilizers patients with schizophrenia. It has been studied as a Psychotherapy (cognitive standalone and adjunct treatment. In the most recent behavior therapy) clinical trial, it is being studied as an add-on to risperidone. In this study, oxytocin is administered Combination therapy intranasally at a dose of three 4-IU (international units) puffs per nostril for a total dose of 24 IU. Other trials used doses of 24 to 80 IU per day for 1 to 6 weeks, and a dose-ranging study compared doses of 6 to 84 IUs. Trials have studied single-dose treatments as well as daily treatment for up to 4 weeks. Developer(s): VA Greater Los Angeles Healthcare System (Los Angeles, California)

Adults aged 21-70 years Zonisamide (Zonegran) is a sulfonamide anticonvulsant Pharmacotherapy (eg, Alcohol consumption Clinical trial(s): Pilot with alcohol use disorder demonstrated to modulate GABAergic and glutamatergic acamprosate, disulfiram, unphased completed March (AUD) neurotransmission. Purportedly, zonisamide reduces naltrexone) Alcohol cravings 2009; pilot phase IV alcohol consumption in patients with heavy drinking completed May 2009; phase Psychotherapy (cognitive Alcohol withdrawal behaviors or AUD and can also ameliorate the symptoms symptoms III primary completion of alcohol withdrawal syndrome. In completed and behavior therapy) October 2019; phase III ongoing clinical trials, zonisamide is administered orally, Relapse primary completion February at doses of up to 500 mg daily. Health-related quality of 2021 Developer(s): life VA Office of Research and Development (Washington, DC)

Section 1. Currently Monitored Topics 41

Table 5. Rare Diseases: 14 Topics

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

Adults aged 50 years or Alpha AMS subretinal implant is intended to partially Argus II retinal Independent functioning Clinical trial(s): Unphased older with retinitis restore visual function in patients with blindness caused prosthesis system primary completion July pigmentosa–mediated by retinitis pigmentosa. The device has 3 components: Visual function 2025 blindness the implant itself, a receiver placed under the skin behind Quality of life the ear, and a pocket-sized external transponder and control unit. The implant, which is 3.2 mm x 4 mm in size with a height of 70 µm, contains 1600 photodiodes that convert incident light into an electrical signal. The signal 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 one eye; patients undergo 5 years of follow-up. Developer(s): Retina Implant AG (Reutlingen, Germany), in collaboration with Wills Eye Hospital (Philadelphia, Pennsylvania)

Section 1. Currently Monitored Topics 42

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

Adults aged 18 years or Apremilast purportedly inhibits phosphodiesterase type 4 Corticosteroids Visual symptoms FDA designation(s): Orphan older with active Behçet’s and increases intracellular cyclic AMP (adenosine Drug disease monophosphate), which decreases proinflammatory Immunosuppressants Pain (eg, azathioprine, Clinical trial(s): Phase III mediators such as TNF-alpha, IL-17, and IL-23 to treat Frequency and duration symptoms of Behçet’s disease. The disease is a rare cyclosporine) primary completion of oral/genital ulcers September 2017, final disorder that causes inflammation in blood vessels Nonsteroidal anti- throughout the body. Signs and symptoms may include Disease remission completion March 2021; inflammatory drugs pivotal data reported mouth sores, eye inflammation, skin rashes and lesions, Quality of life and genital sores. Blood vessel inflammation is a February 2018 characteristic of Behçet’s disease that investigators have Note: FDA approved linked to overactive Th17 cells and increased IL-17 Apremilast March 2014 for production, suggesting apremilast might alleviate treating plaque psoriasis and symptoms of Behçet’s disease. In clinical trials, the drug September 2014 for treating is administered orally at a dose of 30 mg, twice daily. psoriatic arthritis. Developer(s): Celgene Corp (Summit, New Jersey)

Adults aged 18 years or Arimoclomol is a small-molecule amine intended to Riluzole (Rilutek) Disease regression FDA designation(s): Orphan older with amyotrophic increase the expression of molecular chaperones, Drug lateral sclerosis (ALS) including heat shock proteins, which promote proper Supportive care Stable disease Clinical trial(s): Phase III protein folding and degradation of misfolded proteins. In Mortality animal models expressing copper-zinc superoxide ORARIALS-01 primary dismutase 1 (SOD1) mutations that mimic those found in Quality of life completion December 2020; ALS, arimoclomol administration alleviates oxidative planned phase III open-label stress and reduces misfolded protein aggregates extension primary containing mutant SOD1. Therefore, arimoclomol might completion July 2022 have efficacy for treating ALS in patients who harbor an SOD1 mutation (about 10% to 20% of inherited ALS cases). In clinical trials, arimoclomol is administered orally (dose, frequency, and duration unspecified). Developer(s): Orphazyme US Inc (Newton, Massachusetts)

Section 1. Currently Monitored Topics 43

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 Renal function FDA designation(s): Orphan older with biopsy-proven intended to treat IgA nephropathy, also known as Drug immunoglobulin A (IgA) Berger’s disease, which occurs when IgA antibody Immunosuppressants Time to renal function nephropathy who have complexes accumulate in the kidneys, causing local (eg, mycophenolate, decline Clinical trial(s): Phase III azathioprine, Nefigard primary completion estimated glomerular inflammation and reduced glomerular filtration, which lead Quality of life filtration rate levels between to chronic kidney disease. Budesonide is delivered to the cyclophosphamide) October 2020 45 and 90 mL/min per 1.73 Peyer patches of the small intestine, where IgA m2 (stage II-IIIA chronic complexes are thought to originate, via the kidney disease) and who manufacturer’s proprietary TARGIT delivery technology. have medically controlled Drug tolerability is purportedly optimized due to the drug’s blood pressure (receiving low bioavailability (about 90% is inactivated in the liver stable doses of angiotensin- before reaching blood circulation) compared with other converting enzyme corticosteroids used for treating IgA nephropathy. In inhibitors or angiotensin clinical trials, Nefecon is administered 16 mg orally, once receptor blockers) daily, for 9 months. Developer(s): Calliditas Therapeutics AB (Stockholm, Sweden)

Adults aged 18 years or Caplacizumab-yhdp (Cablivi) is a highly potent and Antiplatelet therapy aTTP recurrence Approval date: February 6, older with acquired selective bivalent antibody fragment targeting von 2019 thrombotic Willebrand factor and designed to treat aTTP. In patients Corticosteroids Thromboembolic events FDA designation(s): Orphan thrombocytopenic purpura with aTTP, the spleen produces antibodies against the Cyclosporine A Mortality (aTTP) ADAMTS13 enzyme (ie, von Willebrand factor–cleaving Drug, Priority Review protease), which is involved in blood clotting. Daily plasmapheresis Quality of life Clinical trial(s): Phase III Caplacizumab purportedly inhibits the interaction between (plasma exchange) HERCULES completed von Willebrand factor and platelets by targeting von Rituximab August 2017; pivotal data Willebrand factor A1 domain, potentially blocking ultra- published January 2019; large von Willebrand factor–mediated platelet interactions Splenectomy (to phase III post-HERCULES and the formation of string-like blood clots. The eliminate production of long-term safety and efficacy recommended first dose is an 11 mg bolus intravenous antibodies to follow-up, primary injection at least 15 minutes before plasma exchange, ADAMTS13) completion October 2020 with an 11 mg subcutaneous injection after completing Vincristine 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), a Sanofi company

Section 1. Currently Monitored Topics 44

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

Children and adults aged 12 Crizanlizumab (SEG101) is a humanized immunoglobulin Analgesia (eg, morphine, Intravenous opioid use Submission planned: 2019 years or older with sickle G2 (IgG2) antibody intended to treat SCD. Sickled red nonsteroidal anti- cell disease (SCD) who blood cells are more susceptible to oxidative damage and inflammatory drugs, VOC frequency FDA designation(s): Orphan Drug, Breakthrough Therapy experience a vaso-occlusive inappropriate adhesion and vascular obstruction, which paracetamol) Hospital length of stay crisis (VOC) can lead to VOC with severe pain and hospitalization. Hydration Clinical trial(s): Key phase II Patients may progress to thromboembolic events, stroke, Rehospitalization within SUSTAIN data reported organ failure, or early death. The only FDA-approved Hydroxyurea 3 days of discharge December 2018; phase III treatment for SCD, hydroxyurea, can reduce VOC Quality of life (STAND) primary completion incidence but is ineffective in about one-third of adult May 2022 patients. SEG101 is an antibody against P-selectin, which promotes inflammatory and adhesion processes involved in VOC. In clinical trials, crizanlizumab is administered by intravenous infusion at a dose of 5 or 7.5 mg/kg once every 4 weeks. Developer(s): Novartis AG (Basel, Switzerland)

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

Section 1. Currently Monitored Topics 45

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

Children aged 4 years or Diazoxide choline controlled release (DCCR) is an Cognitive and behavior Hyperphagia (abnormal FDA designation(s): Orphan older and adults with investigational proprietary crystalline salt formulation of therapy appetite) Drug, Fast Track hyperphagic Prader-Willi diazoxide, a potassium channel activator that inhibits syndrome (PWS) insulin secretion, for treating PWS. DCCR purportedly Dietary intervention and Aggression and Clinical trial(s): Phase III blocks the synthesis and secretion of the appetite close food intake behavioral problems primary completion June supervision 2019; phase III open-label stimulatory neuropeptides neuropeptide Y and agouti- PWS-associated related protein and blocks fatty acid synthesis. DCCR extension primary Exercise programs comorbidities completion December 2019 may also potentiate the action of GABA receptors, which (cardiovascular disease, are thought to be disrupted in patients with PWS who diabetes, obesity) experience behavioral problems such as aggression. Thus, DCCR might address hyperphagic and behavioral Mortality PWS symptoms and decrease body fat and circulating Quality of life lipid levels. Often, PWS is managed with off-label diazoxide (Proglycem), which is approved for treating hypoglycemia; however, PWS patients require lower doses of diazoxide than the current formulation, with hyperglycemia 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)

Adults aged 18 years or Eculizumab (Soliris) is a recombinant humanized Azathioprine Functional impairments Submit date: 2018 older with a confirmed monoclonal antibody that binds to the complement protein (vision, mobility, bowel or submission announced diagnosis of neuromyelitis C5 with high affinity. This binding inhibits its cleavage to Intravenous bladder incontinence) February 2019 optica or neuromyelitis C5a and C5b and prevents the downstream generation corticosteroids optica spectrum disorder and activation of the terminal complement complex C5b- Relapse rate FDA designation(s): Orphan Mycophenolate mofetil Drug who have experienced at 9. Preventing C5b-9 production is thought to directly Quality of life least 2 relapses in the past affect the symptoms and progression of diseases that rely Plasmapheresis Clinical trial(s): Phase III 12 months or 3 relapses in on uncontrolled complement activation. In clinical trials, Rituximab PREVENT completed July the past 24 months despite patients received eculizumab intravenously, 900 mg, 2018; phase III open-label stable immunosuppressive weekly for 4 weeks, followed by 1200 mg every 2 weeks extension primary therapy for a maximum up to 4 years. completion June 2020 Developer(s): Alexion Pharmaceuticals Inc (Boston, Massachusetts)

Section 1. Currently Monitored Topics 46

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

Males aged 8 years or older Idebenone (Catena) is a small molecule with similarity to Corticosteroids Muscle degeneration FDA designation(s): Rare with Duchenne muscular coenzyme Q-10 that purportedly facilitates electron (prednisone, deflazacort rate Pediatric Disease, Fast dystrophy (DMD) transport within mitochondria and is proposed as a [Emflaza]) Track treatment for DMD. DMD is 1 of 9 types of muscular Symptoms Respiratory support Clinical trial(s): Phase III dystrophy and is a genetic disorder characterized by Overall survival progressive muscle degeneration and weakness. DMD is devices (DELOS) completed April results from the absence of dystrophin, a protein that Quality of life 2014; phase III (SIDEROS) helps keep muscle cells intact. The developer asserts that primary completion July maintaining correct electron balance is essential for 2019; phase III (SIDEROS- normal energy metabolism, particularly in nerve and E) primary completion muscle cells, which demand more energy, making them December 2021 more prone to rapid cell damage or death from Note: Company announced mitochondrial dysfunction. Preserving mitochondrial preparations for regulatory function and protecting cells from oxidative stress might filing December 2018. prevent cell damage and increase energy production within impaired respiratory nerve and muscle tissue in patients with DMD. In clinical trials, idebenone was administered 900 mg daily, as two 150 mg tablets, taken 3 times a day with meals. Developer(s): Santhera Pharmaceuticals (Pratteln, Switzerland)

Children and adults aged up LentiGlobin is an autologous CD34+ hematopoietic stem Allogeneic stem cell Transfusion FDA designation(s): Orphan to 50 years with transfusion- cell therapy intended to treat β-thalassemia, an inherited transplant independence Drug, Breakthrough Therapy dependent β-thalassemia, blood disorder caused by a mutation in the HBB gene, also known as β- which causes ineffective red blood cell production leading Long-term treatment with Organ function Clinical trial(s): Phase III blood transfusions NORTHSTAR-2 primary thalassemia major, who to severe anemia. LentiGlobin consists of cells collected Iron levels in blood have a β0/β0 genotype (no from the patient’s bone marrow and transduced ex vivo completion January 2020; β-globin expression) or a with a lentiviral vector to insert a functional copy of the Quality of life preliminary data reported β+/β0 genotype (little β- HBB gene and expanded to facilitate uptake. This June 2017; efficacy data globin expression) autologous stem cell transplant does not require reported December 2018; immunosuppressive therapy. In clinical trials, LentiGlobin phase III NORTHSTAR-3 is administered as a single intravenous infusion, at an primary completion April unspecified dose, after patients are treated with busulfan 2021; preliminary data to destroy the β-thalassemia-causing blood cells. reported December 2018 Developer(s): bluebird bio Inc (Cambridge, Massachusetts)

Section 1. Currently Monitored Topics 47

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

Children and adults aged PXT3003 is a proprietary low-dose combination of 3 FDA- Analgesics Functional mobility FDA designation(s): Orphan 16-67 years with genetically approved pharmaceuticals—(RS)-baclofen, naltrexone, Drug, Fast Track confirmed Charcot-Marie- and D-sorbitol—and is intended to treat CMT1A. CMT1A Occupational therapy Pain Clinical trial(s): Phase II Tooth disease type 1A is an inherited neurologic disorder that affects peripheral Orthopedic foot surgery Quality of life (CMT1A) nerves and causes weakness and muscle wasting in the completed December 2012; lower legs starting in adolescence; hand weakness and Orthotic devices phase III PLEO-CMT completed September 2018; sensory loss may develop later. PXT3003 purportedly Physical therapy inhibits overexpression of peripheral myelin protein 22 phase III PLEO-CMT-FU (PMP22). In patients with CMT1A, PMP22 degrades the follow-up extension primary protective myelin sheath on nerve fibers, leading to completion September 2019 peripheral nerve dysfunction and eventual loss of nerve conduction. Thus, PXT3003 may reduce nerve dysfunction in patients with CMT1A. In clinical trials, PXT3003 is administered orally as a liquid solution containing 1 of 2 unspecified doses, taken twice daily with food for 15 months. Developer(s): Pharnext SA (Paris, France)

Section 1. Currently Monitored Topics 48

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

Children and adults aged 6 Rivipansel is a synthetic glycomimetic, pan-selectin Analgesia (eg, morphine, Intravenous opioid use FDA designation(s): Orphan years or older 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, VOC frequency Clinical trial(s): Phase III experiencing a vaso- reduce the duration of VOC and hospital stays. In SCD, paracetamol) Hospital length of stay occlusive crisis (VOC) sickled red blood cells are more susceptible to oxidative primary completion June damage and inappropriate adhesion, which can lead to Hydration Rehospitalizations within 2019; phase III primary completion September 2021 VOCs with severe pain and hospitalization. VOC Hydroxyurea 3 days of discharge complications can include thromboembolic events, stroke, Quality of life organ failure, or early death. The only FDA-approved treatment for SCD, hydroxyurea, can reduce VOC incidence but is ineffective in about one-third of adult patients. In clinical trials, Rivipansel is infused intravenously every 12 hours for up to 15 doses. 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 6-12 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)

Children aged 6 months or Triheptanoin (UX007) is a purified synthetic triglyceride High-carbohydrate, fat- Exercise tolerance FDA designation(s): Orphan older and adults with a that purportedly treats fatty-acid oxidation disorders restricted diet to maintain measured using cycle Drug confirmed diagnosis of a (FAODs) by providing supplemental, medium-length, odd- constant energy supply ergometry, and 12- long-chain fatty acid chain fatty acids that can be metabolized into ketones to minute and 6-minute Clinical trial(s): Phase II disorder, including carnitine increase intermediates used in Krebs cycle energy Intravenous glucose walk distance single-arm long-term safety palmitoyltransferase (CPT) generation and improve energy production. Triheptanoin administration (if oral and efficacy primary deficiency (CPT1 or CPT2), purportedly can also be converted into glucose when feeding not tolerated) Symptoms completion September 2021; very-long-chain acyl-CoA patients’ glucose levels are low. In clinical trials for unphased retrospective Disease-related observational clinical dehydrogenase deficiency, treating FAODs, triheptanoin is administered as an orally hospitalization, long-chain 3-hydroxy-acyl- ingested oil with food or by gastronomy tube, at dosages outcomes study in patients emergency department treated under expanded CoA dehydrogenase equivalent to 25% to 35% of individual patients’ caloric or acute care visits, or deficiency, trifunctional requirements. access, primary completion other unscheduled September 2019 protein deficiency, or emergency interventions carnitine-acylcarnitine Developer(s): translocase deficiency Ultragenyx Pharmaceutical Inc (Novato, California); Quality of life licensed rights to UX007 from Baylor Scott & White Research Institute (Dallas, Texas)

Section 1. Currently Monitored Topics 49

Section 2. Topics Added Since Last Status Report: 0 Topics

Table 6. Alzheimer’s Disease and Other Dementias: 0 Topics

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

Table 7. Cancer: 0 Topics

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

Table 8. Cardiovascular: 0 Topics

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

Table 9. Mental and Behavioral Health: 0 Topics

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

Table 10. Rare Diseases: 0 Topics

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

Section 2. Topics Added Since Last Status Report 50

Section 3. Topics Archived Since Last Status Report: 0 Topics

Table 11. Alzheimer’s Disease and Other Dementias: 0 Topics

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

Table 12. Cancer: 0 Topics

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

Table 13. Cardiovascular: 0 Topics

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

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

Table 15. Rare Diseases: 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 51