- Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI.
An intervention that potentially meets inclusion criteria might not appear in this report simply because the horizon scanning system has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions.
A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the horizon scanning system. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions.
Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflicts with the material presented in this report.
Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated.
All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. This publication was developed through a contract to support PCORI's work. Questions or comments may be sent to PCORI at [email protected] or by mail to Suite 900, 1828 L Street, NW, Washington, DC 20036. ©2019 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org.
Suggested citation: Hulshizer R, Carlson D, Cuevas C, et al. 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; September 2019.
HORIZON SCANNING STATUS REPORT ● SEPTEMBER 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. The goal of PCORI HCHSS is not to predict future utilization and costs of any health care intervention; rather, the reports are intended to help inform and guide planning and prioritization of research resources. This edition of the Status Report is the third 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].
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Table of Contents
Statement of Funding and Purpose ...... i Financial Disclosure Statement ...... i Public Domain Notice ...... i Preface ...... ii Introduction ...... 1 Section 1. Currently Monitored Topics: 151 Topics ...... 4 Table 1. Alzheimer’s Disease and Other Dementias: 6 Topics ...... 4 Table 2. Cancer: 67 Topics ...... 7 Table 3. Cardiovascular: 16 Topics ...... 64 Table 4. Mental and Behavioral Health: 13 Topics ...... 76 Table 5. Rare Diseases: 49 Topics ...... 85 Section 2. Topics Added Since Last Status Report: 66 Topics ...... 129 Table 6. Alzheimer’s Disease and Other Dementias: 2 Topics ...... 129 Table 7. Cancer: 19 Topics ...... 131 Table 8. Cardiovascular: 7 Topics ...... 149 Table 9. Mental and Behavioral Health: 6 Topics ...... 156 Table 10. Rare Diseases: 32 Topics ...... 161 Section 3. Topics Archived Since Last Status Report: 7 Topics ...... 193 Table 11. Cancer: 7 Topics ...... 193 Section 4. Potentially Disruptive Trends: 13 Trends ...... 200 Table 12. Potentially Disruptive Trends: 13 Trends ...... 200
HORIZON SCANNING STATUS REPORT ● SEPTEMBER 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 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 4 sections, titled as follows: (1) Currently Monitored Topics, (2) Topics Added Since Last Status Report, (3) Topics Archived Since Last Status Report, and (4) Potential Disruptive Trends. For Sections 1 through 3, each section contains a table for each of the 5 initial PCORI- defined priority areas for which topics exist: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health, and rare diseases. (If no topics exist within a given priority area for a given section, no table will be included for that priority area in that section.) PCORI may choose, upon future consideration, to modify or expand its list of priority areas. The tables in Sections 1 and 2 summarize information in each row, as shown in the following columns: potential patient population; intervention description (including names and locations of developers/manufacturers); potential comparators; patient-oriented outcome measures (limited to those reported in clinical trials); and regulatory information. Information in the first 4 columns is collectively referred to as PICO (patient population, intervention, comparators, and outcomes) information. In Section 3 (archived topics), the regulatory information column is replaced by the reason for archiving the topic. Within each table, topics are sorted alphabetically by intervention name (ie, the second column, intervention description). In addition to the topics included in the sections detailed above, the PCORI HCHSS identifies and monitors disruptive trends (ie, large, high-level disruptions) occurring across clinical areas or within a clinical area from a combination of factors that, taken together, create a paradigm shift in health care. Identification of these trends is not limited to PCORI’s initially defined priority areas. These trends are summarized in a single table in Section 4 and sorted alphabetically by title.
Horizon Scanning Process Overview The PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual (hereafter referred to as the Protocol) details the criteria we use to select topics and trends. We briefly describe our process below. 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 or shift) in one or more key dimensions of health care in the United States. Examples
HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2019 1
of these dimensions include patient health outcomes, access to care, care setting and delivery processes, disparities, and costs of care. In addition, we scan broadly in all areas of health care for high-level, potentially disruptive trends. Analysts review leads to discover potential topics and trends, and if they meet inclusion criteria, create topic records encompassing the PICO information and key regulatory information or trend records briefly describing the trend and its potential threats and opportunities. Analysts present potential topics at topic nomination meetings and trends at trends nomination meetings. After a brief presentation and discussion of each topic or trend, the HCHSS team votes to include or exclude the topic based on criteria as described in the Protocol. All included topics and trends 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 that asks the commenter to rate—on a scale of 1 (low disruption potential) to 4 (high disruption potential)—the intervention’s potential to disrupt several 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 the clinical research environment for longer than 1 year.
Reporting Period Summary The PCORI HCHSS began operating in December 2018. Since then, review of about 1200 leads has led to the identification of about 300 potential topics across the 5 PCORI priority areas and 13 high-level trends occurring in all areas of health care. After subjecting the potential topics to our inclusion criteria and nomination process, 224 topics have been selected and are being actively monitored in the system, or were being monitored but have been archived within the past 3 months. Likewise, after subjecting the potential trends to our inclusion criteria and nomination process, 13 trends have been selected and are being actively monitored in the system. These 224 topics and 13 trends are reported in this Status Report. Topics are presented in alphabetical order according to intervention name (ie, the second column, intervention description) within each priority area’s table. As topics advance in development, their names often change from a research name to a generic name to the brand-
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name product. The 224 topics included in this report represent 123 diseases/conditions and span the PCORI-defined priority areas as follows:
• Alzheimer’s disease and other dementias: 8 topics (4%) • Cancer: 93 topics (42%) • Cardiovascular diseases: 23 topics (10%) • Mental and behavioral health: 19 topics (8%) • Rare diseases: 81 topics (36%)
Across all priority areas, topics in this report represent the following therapeutic classes:
• Biotechnology: 75 topics (33%) • Device (nonimplantable): 11 topics (5%) • Implant: 6 topics (3%) • Pharmaceutical: 132 topics (59%)
Trends are presented in alphabetical order according to title. Title and descriptions of trends will change over time as new information becomes available. Among the 13 trends presented in this report, 2 themes have emerged:
• Artificial intelligence and machine learning: 4 trends (31%) • Proteomics, genomics, and personalized medicine: 3 trends (23%)
HORIZON SCANNING STATUS REPORT ● SEPTEMBER 2019 3
Section 1. Currently Monitored Topics: 151 Topics
Table 1. Alzheimer’s Disease and Other Dementias: 6 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 55 to 91 years Brexpiprazole (Rexulti) is an atypical antipsychotic Antianxiety drugs Agitation, as measured Clinical trial(s): Phase III who have Alzheimer’s medication that purportedly reduces agitation in patients by accepted clinical primary completion disease (AD)–associated with AD by modulating serotonin-dopamine. Although Antidepressants ratings and scales November 2020; phase III agitation antipsychotics are sometimes used off-label to treat this open-label extension Antipsychotics (eg, Quality of life condition, they carry an increased risk of death in patients haloperidol) primary completion May with dementia. Brexpiprazole might have a better safety 2021; phase III extension profile than other antipsychotics. According to the Atypical antipsychotics primary completion manufacturer, brexpiprazole is a partial agonist of (eg, aripiprazole) August 2021; phase II/III serotonin 5-HT1A and dopamine D2 receptors and an Beta-adrenergics primary completion antagonist of serotonin 5-HT2A receptors. Brexpiprazole November 2021 might also bind to noradrenaline α1B/2C receptors. In Caregiver intervention clinical trials, brexpiprazole is given orally, once daily, for and environmental Note(s): Brexpiprazole is 10 to 14 weeks, at a dose of 1 to 3 mg. modification (ie, removed approved by FDA to treat or alleviated stressors) schizophrenia and as an Developer(s): adjunctive treatment for Synthetic major depressive Otsuka Holdings Co Ltd (Tokyo, Japan), in collaboration tetrahydrocannabinol disorder. with H. Lundbeck A/S (Valby, Denmark)
Adults aged 55 to 80 years COR388 is a bacterial protease inhibitor that targets the Cholinesterase inhibitors Cognitive performance, Clinical trial(s): Phase II/III who have mild to moderate infectious pathogen Porphyromonas gingivalis gingipains, (eg, donepezil, measured by Alzheimer’s GAIN primary completion Alzheimer’s disease (AD) a bacterium purportedly linked to periodontal disease and galantamine, Disease Assessment December 2021 AD and linked to the production of amyloid beta (Aβ) in rivastigmine) Scale-Cognitive preclinical and clinical models. P. gingivalis gingipains is Subscale 11 found in the brain tissue and cerebral spinal fluid of Memantine (off-label) people with AD. COR388 purportedly could be the first Progression of AD disease-modifying treatment to reduce brain infection, Quality of life block Aβ production, reduce neuroinflammation, and impart neuroprotection for patients with mild to moderate AD. In clinical trials, COR388 is given orally in 40- or 80- mg capsules, twice daily. Developer(s): Cortexyme Inc (San Francisco, California)
Section 1. Currently Monitored Topics 4
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 55 to 79 years Cromolyn and ibuprofen (ALZT-OP1) is a combination Cholinesterase inhibitors Disease progression Clinical trial(s): Phase III who have evidence of early therapy intended to modify disease in AD. It is intended to (eg, donepezil, COGNITE primary Alzheimer’s disease (AD) slow or reverse cognitive and functional decline in galantamine, Morbidity completion December patients with early-stage AD. Cromolyn acts as an rivastigmine) Mortality 2020, designed under amyloid beta (Aβ) polymerization inhibitor to purportedly Special Protocol block the development and spread of Aβ plaques. The Supportive care Quality of life Assessment ibuprofen component is intended to reduce neuronal inflammation caused by existing plaques. In clinical trials, Cromolyn is inhaled and ibuprofen is given orally (dosage and treatment duration are unspecified for both components). Developer(s): AZTherapies Inc (Boston, Massachusetts)
Adults aged 50 to 90 years Deuterated dextromethorphan hydrobromide and Antianxiety medications Agitation, as measured FDA designation(s): Fast who have Alzheimer’s quinidine sulfate in combination (AVP-786) is being (eg, alprazolam, by accepted clinical Track disease (AD)–associated developed to treat AD-associated agitation. AD- buspirone, lorazepam, ratings and scales agitation associated agitation is thought to result from reduced oxazepam) Clinical trial(s): Phase III serotonin levels and increased noradrenaline and Quality of life study completed January dopamine levels. AVP-786 is intended to modulate Antidepressants (eg, 2019, topline data citalopram, fluoxetine, reported March 2019; neurotransmitter levels and decrease AD-associated agitation with fewer side effects than available treatments. nortriptyline, paroxetine, phase III primary Dextromethorphan hydrobromide acts as an sertraline) completion September 2019; phase III primary uncompetitive N-methyl-D-aspartate receptor antagonist, Antipsychotics (eg, sigma receptor agonist, and serotonin and norepinephrine completion June 2021; aripiprazole, phase III long-term inhibitor. Quinidine sulfate is a CYP2D6 inhibitor that brexpiprazole, purportedly enhances dextromethorphan’s treatment extension primary haloperidol, olanzapine, completion June 2022 effects. In clinical trials, AVP-786 is given orally, twice quetiapine, risperidone, daily, at 1 of 3 unspecified doses, for up to 52 weeks. ziprasidone) Developer(s): Caregiver intervention Avanir Pharmaceuticals Inc (Aliso Viejo, California), a and environmental wholly owned subsidiary of Otsuka Holdings Co Ltd modification (ie, removed (Tokyo, Japan) or alleviated stressors) Synthetic tetrahydrocannabinol
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 up to 90 years Leuco-methylthioninium dihydromethanesulfonate (LMTX) Cholinesterase inhibitors Brain atrophy rate Clinical trial(s): Phase II/III who have early Alzheimer’s is a tau aggregation inhibitor being developed as a (eg, donepezil, LUCIDITY primary disease (AD) disease-modifying treatment for AD. It is intended to galantamine, Cognition and memory, completion December reduce levels of aggregated or misfolded tau proteins in rivastigmine) as measured by 2020 the brain, which are believed to contribute to AD disease accepted clinical ratings pathology. In clinical trials, LMTX is given orally, twice Supportive care and scales daily, at a dose of 8 to 16 mg per day. Quality of life
Developer(s): TauRx Pharmaceuticals Ltd (Singapore, Republic of Singapore)
Adults aged 50 to 85 years Troriluzole (BHV-4157) is a third-generation, tripeptide Cholinesterase inhibitors Bioavailability, safety, Clinical trial(s): Phase II/III who have mild to moderate prodrug conjugate of riluzole being developed as a (eg, donepezil, and dosing T2 Protect AD primary Alzheimer’s disease (AD) disease-modifying treatment for AD. In patients with AD, galantamine, completion January 2020 damaged brain cells are susceptible to cellular injury by rivastigmine) Disease progression Note(s): Troriluzole is also overactivity of the excitatory neurotransmitter glutamate. Quality of life Riluzole is a sodium channel blocker and glutamate Memantine (off-label) in phase III clinical modulator approved by FDA to treat amyotrophic lateral Symptom severity, as development to treat sclerosis. It purportedly reduces glutamate-mediated measured by accepted spinocerebellar ataxia. excitotoxicity and nerve cell deterioration by promoting clinical ratings and glutamate’s reuptake into nerve cells. Troriluzole scales purportedly has the same mechanism of action as riluzole but with improved bioavailability and tolerability. These factors could reduce adverse events typically associated with riluzole, such as fatigue, weakness, dizziness, and hepatotoxicity. Troriluzole purportedly decreases glutamate-mediated neuronal damage to reduce symptoms in patients with AD and delay AD progression by preventing the loss of synapses. In clinical trials, patients receive 280 mg of troriluzole orally at bedtime, once daily, for 48 weeks. Developer(s): Biohaven Pharmaceuticals Inc (New Haven, Connecticut)
Section 1. Currently Monitored Topics 6
Table 2. Cancer: 67 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Alpelisib (Piqray) is a selective small-molecule inhibitor of One or more of the Overall survival Approval date: May 24, who have locally advanced or the phosphoinositide-3-kinase (PI3K) signaling pathway following: 2019 metastatic estrogen receptor that specifically targets PI3Kα, the catalytic subunit of Progression-free (ER)–positive, human PI3K encoded by the phosphatidylinositol-4,5- Alkylating agents (eg, survival Clinical trial(s): Phase III cyclophosphamide) SOLAR-1 primary epidermal growth factor bisphosphate 3-kinase catalytic subunit alpha gene, Quality of life receptor 2 (HER2)–negative PIK3CA. Patients with breast cancer who have PIK3CA completion June 2018, Anthracyclines (eg, topline data published May breast cancer that harbors gene alterations have limited treatment options after doxorubicin, epirubicin) PIK3CA gene alterations, developing resistance to endocrine therapy. Alpelisib 2019 including point mutations and targets mutated PI3K in these patients. Upon binding to Antimetabolites (eg, 5- PIK3CA amplification, and PI3Kα, alpelisib prevents the enzyme from fluorouracil, capecitabine, whose disease has phosphorylating phosphatidylinositol, thus preventing pemetrexed) progressed during or after activation of downstream serine-threonine kinases Immune checkpoint one line of treatment with an associated with cell growth and proliferation. Alpelisib inhibitors (eg, aromatase inhibitor purportedly prevents the uncontrolled proliferation of atezolizumab) breast cancer cells with constitutive PI3Kα activity, which makes the disease resistant to endocrine therapy. Microtubule inhibitors (eg, Determining PIK3CA mutation status requires use of a eribulin, ixabepilone) companion diagnostic test. In clinical trials, alpelisib is mTOR inhibitors (eg, given orally, once daily, at a dose of 300 mg in everolimus) combination with intramuscular fulvestrant at a dose of 500 mg, injected on days 1 and 15 of cycle 1 and then on Platinum agents (eg, day 1 of each 28-day cycle until disease progression or carboplatin, cisplatin) intolerable toxicity. Poly adenosine Developer(s): diphosphate-ribose polymerase (PARP) Novartis AG (Basel, Switzerland) inhibitors (eg, olaparib, talazoparib) Taxanes (eg, docetaxel, paclitaxel) Vinca alkaloids (eg, vinorelbine)
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 years or older Atezolizumab (Tecentriq) is a monoclonal antibody that One or more of the Overall survival Approval date: March 18, who have newly diagnosed targets the programmed death-ligand 1 (PD-L1), an following: 2019 extensive-stage small cell inhibitory surface molecule expressed by cells to Progression-free lung cancer (SCLC) and have modulate immune responses. Front-line therapy for SCLC Platinum-based agents (eg, survival Clinical trial(s): Phase III carboplatin, cisplatin) IMpower133 primary had no previous systemic relies on platinum-based chemotherapy, but because Quality of life therapy response rates are low, additional treatment options are completion April 2018, Topoisomerase inhibitors pivotal data published needed. A hallmark of cancer is its ability to evade an (eg, etoposide, topotecan) immune response. Several types of cancer cells, December 2018, data including SCLC, activate an immune checkpoint pathway published July 2019 in T cells by overexpressing PD-L1, which binds to the Note(s): FDA approved programmed death-1 (PD-1) co-inhibitory receptor and atezolizumab to treat limits the activation of cancer-specific T cells. urothelial carcinoma in May Atezolizumab purportedly prevents the interaction 2016, for non-SCLC in between PD-1 and PD-L1 to inhibit the immune October 2016, and triple- checkpoint pathway. Treatment with atezolizumab is negative breast cancer in intended to overcome SCLC’s immune tolerance by March 2019. enhancing cancer-specific T-cell responses. In clinical trials, atezolizumab is given as an intravenous infusion at a dose of 1200 mg, once every 3 weeks for up to 24 months, in combination with etoposide (100 mg/m2) plus carboplatin (AUC 5). Developer(s): Genentech Inc (South San Francisco, California), a subsidiary of F Hoffman-La Roche AG (Basel, Switzerland)
Section 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 years or older Atezolizumab (Tecentriq) is a monoclonal antibody that One or more of the Overall survival Approval date: March 11, who have PD-L1-positive, targets programmed death-ligand 1 (PD-L1), an inhibitory following: 2019 locally advanced or surface molecule expressed by cells to modulate immune Progression-free metastatic triple-negative responses. A hallmark of cancer is its ability to evade an Alkylating agents (eg, survival Clinical trial(s): Phase III cyclophosphamide) IMpassion131 primary breast cancer (TNBC) and immune response. Several types of cancer cells, Quality of life have had no previous including TNBC, activate an immune checkpoint pathway completion January 2020; Anthracyclines (eg, phase III IMpassion132 systemic therapy in T cells by overexpressing PD-L1, which binds to the doxorubicin) programmed death-1 (PD-1) co-inhibitory receptor and primary completion July limits the activation of cancer-specific T cells. Antimetabolites (eg, 2019; phase III Atezolizumab purportedly prevents the interaction fluorouracil, pemetrexed) IMpassion130 primary completion April 2020, between PD-1 and PD-L1 to inhibit the immune Poly adenosine checkpoint pathway. Treatment with atezolizumab is pivotal data published diphosphate-ribose November 2018; phase III intended to overcome TNBC’s immune tolerance by polymerase (PARP) enhancing cancer-specific T-cell responses. In clinical IMpassion031 primary inhibitors (eg, niraparib, completion September trials, atezolizumab is given as an intravenous infusion at olaparib) a dose of 840 mg on days 1 and 15 of a 4-week cycle for 2020; phase III up to 24 months, until disease progression or Taxanes (eg, docetaxel, IMpassion030 primary unacceptable toxicity, in combination with nab-paclitaxel paclitaxel) completion January 2022 (100 mg/m2), paclitaxel (90 mg/m2), or gemcitabine (1000 Vinca alkaloid (eg, Note(s): FDA approved mg/m2) plus capecitabine (1000 mg/m2) and carboplatin vinorelbine) atezolizumab to treat (AUC 2). urothelial carcinoma in May Developer(s): 2016, for non–small cell lung cancer in October Genentech Inc (South San Francisco, California), a 2016, and for small cell subsidiary of F Hoffman-La Roche AG (Basel, lung cancer in March 2019. Switzerland)
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 to 70 years ATIR101 is a T-lymphocyte immunotherapy derived from Photopheresis alone or Overall survival FDA designation(s): who have acute myeloid mature immune cells from a haploidentical (half match; combined with 8- Orphan Drug, leukemia, acute eg, parent, child, sibling) donor’s peripheral blood. methoxypsoralen Progression-free Regenerative Medicine lymphoblastic leukemia, or ATIR101 is intended as an immunotherapy adjunct to survival Advanced Therapy One or more of the myelodysplastic syndrome allogeneic HSCT to provide immediate immunity against Quality of life and have received an infectious agents and residual cancer during the 6 to following: Clinical trial(s): Phase III allogeneic hematopoietic 12 months after HSCT. During this time the patient’s HATCY primary completion Alkylating agent (eg, February 2021 stem cell transplantation immune system is repopulating, and ATIR101 is intended cyclophosphamide) (HSCT) to minimize patient risk for graft-versus-host disease (GVHD). Because patients receiving ATIR101 purportedly Antibodies (eg, do not require a perfect donor match, it might enable alemtuzumab, rapid access to HSCT and eliminate the need for antithymocyte globulin) prophylactic immune suppression. The donor’s immune Calcineurin inhibitors (eg, cells also undergo a proprietary photodepletion procedure cyclosporine, tacrolimus) that eliminates T cells responsible for causing GVHD. In clinical trials, ATIR101 is delivered as an intravenous Corticosteroids (eg, infusion at a single dose of 2 × 106 cells/kg given between methotrexate, prednisone) 28 and 32 days after allogeneic HSCT. mTOR inhibitor (eg, Developer(s): sirolimus) Kiadis Pharma NV (Amsterdam, the Netherlands)
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 older Avapritinib (BLU-285) is purportedly a potent and Tyrosine kinase inhibitors Overall survival PDUFA date: February 4, who have locally advanced, selective oral type 1 kinase inhibitor of mutated KIT and (eg, imatinib, regorafenib) 2020, Priority Review unresectable, or metastatic platelet-derived growth factor receptor A (PDGFRA) Progression-free gastrointestinal stromal tumor kinases. Avapritinib is intended to treat GIST in patients survival FDA designation(s): Fast Track, Breakthrough (GIST) that has been treated with KIT- or PDGFRA-driven disease whose treatment Quality of life previously with imatinib and 1 options are limited and whose disease is likely to develop Therapy or 2 other tyrosine kinase resistance. Avapritinib has broad inhibition against Clinical trial(s): Phase III inhibitors activating mutations in KIT and PDGFRA, which drive VOYAGER primary GIST proliferation. Avapritinib is also designed to act completion April 2021; against activation loop mutations in KIT and PDGFRA, phase I NAVIGATOR which currently approved multikinase inhibitors do not primary completion inhibit. Avapritinib purportedly selectively inhibits KIT and December 2020, topline PDGFRA to prevent GIST cell proliferation, spread, and data reported November survival without off-target activity on other cells. A 2018, updated data companion diagnostic test will be used to determine presented June 2019 patients’ KIT and PDGFRA mutation status. In clinical trials, avapritinib is given orally, once daily, at a dose of Note(s): FDA designations 300 mg, until disease progression or intolerable toxicity. are specific for treating patients harboring the Developer(s): PDGFRA D842V mutation. Blueprint Medicines Corp (Cambridge, Massachusetts)
Adults aged 18 years or older Avapritinib (BLU-285) is purportedly a potent and Tyrosine kinase inhibitors Overall survival FDA designation(s): who have advanced systemic selective oral type 1 kinase inhibitor of mutated KIT and (eg, imatinib, midostaurin) Breakthrough Therapy mastocytosis that includes platelet-derived growth factor receptor A (PDGFRA) Progression-free aggressive systemic kinases. It also purportedly binds and inhibits the KIT survival Clinical trial(s): Phase II PATHFINDER primary mastocytosis, indolent D816V mutation, the primary driver of disease in up to Quality of life systemic mastocytosis, or 95% of patients with systemic mastocytosis. Because no completion December smoldering systemic FDA-approved treatments exist for this patient population, 2020; phase II PIONEER mastocytosis patients need new treatment options. Avapritinib broadly primary completion inhibits activating mutations in KIT and PDGFRA, which December 2020; phase I drive tumor cell division. Avapritinib is designed to act EXPLORER primary against activation loop mutations in KIT and PDGFRA, completion November which approved multikinase inhibitors do not inhibit. In 2021, topline data reported clinical trials, 300 mg of avapritinib is given orally, once December 2018, updated daily, until disease progression or intolerable toxicity. results reported June 2019 Developer(s): Blueprint Medicines Corp (Cambridge, Massachusetts)
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 Avelumab (Bavencio) is an immune checkpoint inhibitor Maintenance therapy with Overall survival FDA designation(s): or older who have consisting of a fully human, monoclonal antibody specific one or more of the Orphan Drug unresectable, locally for programmed death-ligand 1 (PD-L1). It is proposed for following: Progression-free advanced, or metastatic use as maintenance therapy to delay disease progression survival Clinical trial(s): Phase III Anthracyclines (eg, JAVELIN Gastric 100 adenocarcinoma of after primary chemotherapy. Immune tolerance is a Quality of life the stomach or cancer hallmark that might be mediated by binding PD-L1 epirubicin) primary completion November 2019 gastroesophageal junction to its receptor, programmed death-1 (PD-1), which inhibits Antimetabolites (eg, 5- T cells and anticancer immune responses. Preventing fluorouracil, capecitabine) PD-L1/PD-1 interaction by binding of avelumab purportedly inhibits this immune checkpoint, potentially Human epidermal growth leading to an anticancer immune response. Patients are factor receptor 2 (HER2) given avelumab ongoing after completing one line of antibodies (eg, induction-phase cytotoxic chemotherapy. In clinical trials, trastuzumab) avelumab is given intravenously at a dose of 10 mg/kg Platinum-based agents (eg, infusion once every 2 weeks, until disease progression or carboplatin, cisplatin, unacceptable toxicity. oxaliplatin) Developer(s): Taxanes (eg, docetaxel, Pfizer Inc (New York, New York), in collaboration with paclitaxel) Merck KGaA (Darmstadt, Germany)
Adults aged 18 years or older Avisopasem manganese (GC4419) is a small-molecule One or more of the Cancer treatment FDA designation(s): who are at risk for oral superoxide dismutase mimetic drug intended to detoxify following: adherence Breakthrough Therapy, mucositis (OM) after reactive oxygen species. GC4419 is intended to treat Fast Track chemoradiation therapy with patients who are likely to develop OM and have no Localized therapy (eg, low- Incidence of severe cisplatin and image- treatment options to prevent the condition. No effective level laser therapy, oral mucositis Clinical trial(s): Phase III modulated radiation therapy treatments are available for OM, a common side effect of cryotherapy) ROMAN primary Quality of life completion October 2020 for locally advanced, anticancer therapies (eg, chemotherapy and radiation). Supportive care (eg, oral nonmetastatic head and neck Reactive oxygen species are overproduced during hygiene protocols) cancer chemoradiation therapy, overwhelming endogenous superoxide dismutase enzymes and resulting in oxidative tissue damage that contributes to OM. Exogenous administration of a superoxide dismutase, such as GC4419, purportedly reduces chemoradiation-induced toxicity. In clinical trials, GC4419 is given intravenously at an unspecified dose before initiating intensity-modulated radiation therapy. Developer(s): Galera Therapeutics Inc (Malvern, Pennsylvania)
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 older Canakinumab (ACZ885) is a human monoclonal antibody One or more of the Overall survival Clinical trial(s): Phase III who have locally advanced or that binds and neutralizes the immune mediator activity of following: CANOPY-2 primary metastatic non–small cell human interleukin-1β (IL-1β), a member of the interleukin- Progression-free completion March 2021; lung cancer (NSCLC) of 1 (IL-1) family of cytokines. Canakinumab is intended as ALK inhibitors (eg, survival phase III CANOPY-1 alectinib, crizotinib) if ALK squamous or nonsquamous an addition to the standard of care and is designed to be Quality of life primary completion May origin that has not been a selective antibody that binds with high affinity to IL-1β, rearrangement positive 2021 treated for locally advanced but not to any other member of the IL-1 family or ALK inhibitors (eg, ceritinib, or metastatic disease or that IL-1β from another species. Canakinumab purportedly Note(s): FDA approved crizotinib) if ROS1 canakinumab to treat has been previously treated elicits an anti-inflammatory response in the tumor rearrangement positive with an immune checkpoint microenvironment that blocks tumor proliferation and new cryopyrin-associated inhibitor in combination with blood vessel formation (ie, angiogenesis). Under specific Angiogenesis inhibitors periodic syndromes in June or after platinum-based conditions, IL-1β and other inflammatory cytokines, which (eg, bevacizumab, 2009, for active systemic chemotherapy are produced primarily by tumor-associated ramucirumab) juvenile idiopathic arthritis macrophages, play a role in growth, vascularization, in May 2013, and for tumor Anthracyclines (eg, necrosis factor receptor– progression, and spread of cancer cells. In clinical trials, doxorubicin) canakinumab is given as a subcutaneous injection at an associated periodic unspecified dose in combination with intravenous Antimetabolites (eg, syndrome, docetaxel at a dose of 75 mg/m2 or intravenous gemcitabine, pemetrexed) hyperimmunoglobulin D pembrolizumab at a dose of 200 mg plus platinum-based syndrome/mevalonate Epidermal growth factor chemotherapy every 3 weeks until disease progression or kinase deficiency, and receptor (EGFR) inhibitors intolerable toxicity. familial Mediterranean (eg, afatinib, erlotinib) if fever in September 2016. Developer(s): EGFR mutation positive Novartis AG (Basel, Switzerland) Immune checkpoint inhibitors (eg, nivolumab, pembrolizumab) Platinum-based agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, paclitaxel) Tropomyosin kinase inhibitors (eg, larotrectinib) if neurotrophic tyrosine receptor kinase (NTRK) rearrangement positive Vinca alkaloids (eg, vinblastine, vinorelbine)
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 older Capmatinib (INC280) is a potent and selective, small- One or more of the Overall survival Submission date: New who have locally advanced or molecule inhibitor of the hepatocyte growth factor (HGF) following: Drug Application planned metastatic non–small cell receptor, a receptor tyrosine kinase encoded by the MET Progression-free for December 2019 lung cancer (NSCLC) gene that is normally required for tissue/organ Angiogenesis inhibitors survival (eg, bevacizumab, FDA designation(s): harboring MET gene regeneration and damage repair. The incidence of MET Quality of life alterations (MET exon 14 gene alterations in patients with NSCLC, including MET ramucirumab) Orphan Drug, Breakthrough Therapy deletion or MET exon 14 deletion and MET amplification, is about 2% to Anthracyclines (eg, amplification) that has not 4%. MET-driven NSCLC is an aggressive disease doxorubicin) Clinical trial(s): Phase II been treated or that has been associated with poor prognosis and limited treatment GEOMETRY mono-1 previously treated options. Capmatinib is a novel targeted therapy intended Antimetabolites (eg, primary completion May with 1 or 2 lines of as first-line therapy for patients harboring MET gemcitabine, pemetrexed) 2021, preliminary data chemotherapy alterations. Capmatinib is designed to interact with Immune checkpoint presented October 2018, tyrosine 1230 and a hinge motif in the HGF receptor’s inhibitors (eg, nivolumab, updated preliminary data kinase domain, which causes it to adopt a unique pembrolizumab) reported June 2019 autoinhibitory shape that prevents access to its adenosine triphosphate (ATP)-binding site. Because capmatinib is Platinum agents (eg, highly specific for the HGF receptor, it purportedly has carboplatin, cisplatin) fewer off-target effects. In NSCLC cells, capmatinib Taxanes (eg, docetaxel, purportedly blocks new blood vessel formation (ie, paclitaxel) angiogenesis), proliferation, and survival pathways by inhibiting the HGF receptor’s constitutive ligand- Vinca alkaloids (eg, independent signaling. Determining eligibility for this vinblastine, vinorelbine) therapy requires testing for MET mutation status. In clinical trials, capmatinib is given orally at a twice-daily dose of 400 mg until disease progression or intolerable toxicity. Developer(s): Novartis AG (Basel, Switzerland), licensed by Incyte Corp (Wilmington, Delaware)
Section 1. Currently Monitored Topics 14
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 70 years DCVax-L is an autologous immunotherapy comprising Fractionated external beam Overall survival Clinical trial(s): Phase III who have glioblastoma activated dendritic cells loaded with patient-derived tumor radiation therapy GBM primary completion multiforme (GBM) that has antigens. Options for GBM treatment are very limited with Progression-free November 2016, interim been surgically resected and poor outcomes, and DCVax-L is intended to improve One or more of the survival data published May 2018, following: treated with adjuvant outcomes by promoting an immune response against Quality of life 3-year survival data radiation therapy and residual glioblastoma cells after surgical resection. Alkylating agents (eg, reported November 2018 chemotherapy DCVax-L is manufactured using monocytes obtained from cyclophosphamide, the patient through a leukapheresis process. The lomustine, procarbazine) monocytes are differentiated into dendritic cells in vitro and then activated and loaded with patient-derived Angiogenesis inhibitors antigens from the patient’s tumor tissue after surgical (eg, bevacizumab) resection. The purified DCVax-L is then given to elicit mTOR inhibitors (eg, adaptive immunity from T cells and B cells. At least 2 everolimus) weeks before the first course of DCVax-L is given, the tumor is removed (ie, total or near total resection) and Platinum agents (eg, conventional external beam radiation therapy with carboplatin, cisplatin) concurrent temozolomide chemotherapy is delivered. In Vinca alkaloids (eg, clinical trials, DCVax-L containing 2.5 × 106 tumor lysate- vincristine) pulsed dendritic cells is given as an intradermal injection in the upper arm at days 0, 10, and 20 and at weeks 8, 16, 32, 48, 72, 96, and 120. Developer(s): Northwest Biotherapeutics Inc (Bethesda, Maryland)
Section 1. Currently Monitored Topics 15
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 60 years Devimistat (CPI-613) is a small-molecule lipoate analog One or more of the Overall survival FDA designation(s): or older who have drug intended to target the altered energy metabolism following: Orphan drug relapsed/refractory acute unique to many cancers, including AML. Patients with Progression-free myeloid leukemia (AML) relapsed AML have limited treatment options and poor Anthracyclines (eg, survival Clinical trial(s): Phase III outcomes. New therapies are needed. The altered energy daunorubicin, idarubicin) primary completion Quality of life October 2022 metabolism of cancer cells frequently depends on the Antibody–drug conjugate activity of the pyruvate dehydrogenase complex and the (eg, gemtuzumab α-ketoglutarate dehydrogenase complex. Devimistat ozogamicin) purportedly inhibits the catalytic and regulatory functions of these key cancer pathways, leading to tumor cell Antimetabolites (eg, death. In clinical trials, devimistat is being tested in cladribine, fludarabine) combination with a standard induction regimen of Cytokine (eg, granulocyte high-dose cytarabine and mitoxantrone. Devimistat colony-stimulating factor) 2000 mg/m2 is given intravenously on days 1 to 5 of the induction regimen. DNA synthesis inhibitors (eg, etoposide, Developer(s): mitoxantrone) Rafael Pharmaceuticals Inc (Cranbury, New Jersey) FLT3 inhibitor (eg, gilteritinib) Hypomethylating agents (eg, azacitidine, decitabine) IDH inhibitors (eg, enasidenib, ivosidenib) Multikinase inhibitor (eg, sorafenib)
Section 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 to 75 years Devimistat (CPI-613) is a small-molecule lipoate analog One or more of the Overall survival FDA designation(s): who have pancreatic drug intended to target the altered energy metabolism of following: Orphan Drug adenocarcinoma with distant many cancers, including pancreatic adenocarcinomas. Progression-free metastases that has not been Only about 5% of patients with pancreatic cancer respond Antimetabolites (eg, 5- survival Clinical trial(s): Phase III treated to the standard of care (gemcitabine chemotherapy), and fluorouracil, gemcitabine) AVENGER 500 primary Quality of life completion October 2021 patient outcomes are poor. Devimistat is intended as first- Chemoprotectant (eg, line therapy. The altered energy metabolism of cancer leucovorin) cells frequently depends on the activity of the pyruvate dehydrogenase complex and the α-ketoglutarate DNA synthesis inhibitor dehydrogenase complex. Devimistat purportedly (eg, irinotecan) downregulates metabolic pathways in cancer cells that Epidermal growth factor depend on α-ketoglutarate and acetyl-CoA. In clinical receptor (EGFR) inhibitor trials, devimistat is given by intravenous injection at a (eg, erlotinib) dose of 500 mg/m2, on days 1 and 3 of a 14-day cycle, followed immediately by intravenous modified Platinum-based agents (eg, FOLFIRINOX (leucovorin [folinic acid] at 400 mg/m2, 5- cisplatin, oxaliplatin) fluorouracil at 400 mg/m2, irinotecan at 140 mg/m2, and Taxanes (eg, docetaxel, oxaliplatin at 65 mg/m2). paclitaxel) Developer(s): Rafael Pharmaceuticals Inc (Cranbury, New Jersey)
Adults aged 18 years or older Dianhydrogalactitol (VAL-083) is a small-molecule drug One or more of the Overall survival FDA designation(s): who have recurrent malignant that causes N7 DNA alkylation. It is intended to treat following: Orphan Drug, Fast Track glioma (GBM) recurrent malignant gliomas, which often become Progression-free resistant to the standard-of-care temozolomide therapy Alkylating agents (eg, survival Clinical trial(s): Phase III carmustine, STAR-3 primary because the tumor expresses high levels of an enzyme Quality of life (O6-methylguanine-DNA-methyltransferase [MGMT]) that cyclophosphamide, completion August 2019 helps repair DNA. Patients need better treatment options; procarbazine) VAL-083’s novel N7 DNA alkylation activity is intended to Angiogenesis inhibitors overcome MGMT-mediated resistance. In clinical trials, (eg, bevacizumab) VAL-083 is given as an intravenous infusion at a dose of 40 mg/m2 on days 1, 2, and 3 of a 21-day treatment cycle, mTOR inhibitors (eg, for up to twelve 21-day treatment cycles. everolimus) Developer(s): Platinum-based drugs (eg, carboplatin, cisplatin) DelMar Pharmaceuticals Inc (Vancouver, British Columbia, Canada) Vinca alkaloids (eg, vincristine)
Section 1. Currently Monitored Topics 17
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Durvalumab (Imfinzi) is a novel immunotherapy intended One or more of the Overall survival Clinical trial(s): Phase III who have recurrent or to prevent the immune tolerance of cancer cells. following: KESTREL primary metastatic head and neck Advanced head and neck cancers have a poor prognosis Progression-free completion September squamous cell carcinoma and high recurrence rate, suggesting the need for new Antimetabolites (eg, 5- survival 2019 fluorouracil, capecitabine) (HNSCC) that has not been treatments. Durvalumab is a monoclonal antibody against Quality of life treated programmed death-ligand 1 (PD-L1) and is intended as a Note(s): FDA approved EGFR inhibitors (eg, durvalumab to treat first-line therapy. Durvalumab is being studied as a cetuximab) monotherapy or in combination with tremelimumab. bladder cancer in May Frequently expressed in tumor microenvironments, PD-L1 Platinum agents (eg, 2017 and for non–small downregulates T cells via activation of the programmed carboplatin, cisplatin) cell lung cancer in February 2018. death-1 (PD-1) immune checkpoint. Durvalumab Taxanes (eg, docetaxel, purportedly limits activation of the immune checkpoint by paclitaxel) preventing the interaction between PD-L1 and its receptor, PD-1. In clinical trials, durvalumab is given intravenously every 2 weeks from day 1 for up to 12 months or until intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, United Kingdom)
Adults aged 18 years or older Dusquetide (SGX942) is a novel synthetic, water-soluble, One or more of the Cancer treatment FDA designation(s): who are at risk for oral 5-amino-acid peptide with anti-inflammatory and anti- following: adherence Orphan Drug, Fast Track mucositis (OM) during infective properties intended to treat OM. No effective chemoradiation therapy with treatments are available for OM, a common side effect of Analgesics (eg, lidocaine, Duration of severe Clinical trial(s): Phase III cisplatin and image- anticancer therapies (eg, chemotherapy and radiation) narcotics) mucositis DOM-INNATE primary completion March 2020 modulated radiation therapy that affects about 80% of patients with oropharyngeal Localized therapy (eg, low- Incidence of bacterial for locally advanced, cancer. Dusquetide is a member of a novel drug class level laser therapy, oral infection Note(s): The US National nonmetastatic squamous cell called innate defense regulators that targets the innate cryotherapy) Institutes of Health (NIH) carcinoma of the oral cavity immune system and binds to an intracellular adaptor Incidence of severe selected SGX942 for its or oropharynx protein, sequestosome-1. Also called p62, this protein has Supportive care (eg, oral mucositis Small Business Innovation hygiene protocols) a pivotal function in signal transduction during activation Pain Research/Small Business and control of the innate immune system. In clinical trials, Technology Transfer dusquetide is given at a dose of 1.5 mg/mL as a 4-minute Quality of life Commercialization intravenous infusion, twice weekly, starting within 3 days Accelerator Program in after initiating radiation therapy and continuing through 2 September 2018. weeks after completing radiation therapy. Developer(s): Soligenix Inc (Princeton, New Jersey)
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 older Enfortumab vedotin (Adcetris) is a monoclonal antibody One or more of the Overall survival Submission date: Biologics who have metastatic or conjugated to a chemotherapy drug (vedotin), designed to following: License Application July surgically unresectable bind to the surface receptor nectin 4. Patients with Progression-free 16, 2019 urothelial cancer that has metastatic or unresectable urothelial cancer that has not Alkylating agents (eg, survival been previously treated responded to standard of care have poor outcomes and ifosfamide) FDA designation(s): Quality of life Breakthrough Therapy with 2 lines of systemic need better treatment options. Vedotin is a synthetic Antimetabolites (eg, treatment, including platinum- auristatin with cytotoxic activity that blocks the formation gemcitabine, pemetrexed) Clinical trial(s): Phase III based therapy followed by an of microtubules. The adhesion protein nectin 4 is highly EV-301 primary completion immune checkpoint inhibitor expressed in various types of solid tumors, including Immune checkpoint September 2021; phase II urothelial cancer. Enfortumab vedotin purportedly binds to inhibitors (eg, EV-201 primary completion nectin 4 and triggers internalization of the drug into the atezolizumab, durvalumab) November 2020, topline cells. This increases vedotin’s likelihood of targeting and Platinum agents (eg, data presented June 2019 killing malignant cells while minimizing cytotoxicity on carboplatin, cisplatin) normal cells. In clinical trials, enfortumab vedotin is given intravenously at an unspecified dose on days 1, 8, and 15 Taxanes (eg, docetaxel, of each 28-day cycle until disease progression or paclitaxel) intolerable toxicity. Developer(s): Seattle Genetics Inc (Bothell, Washington), in collaboration with Astellas Pharma Inc (Tokyo, Japan)
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 older Erdafitinib (Balversa) is a novel, highly selective, small- One or more of the Overall survival Approval date: April 12, who have metastatic or molecule inhibitor of 4 members of the FGFR family (1, 2, following: 2019 surgically unresectable 3, and 4). Erdafitinib is intended to treat unresectable Progression-free urothelial cancer that harbors urothelial FGFR-positive cancer after first- and second- Antimetabolites (eg, survival FDA designation(s): gemcitabine, pemetrexed) Breakthrough Therapy fibroblast growth factor line treatment options have failed. Erdafitinib is designed Quality of life receptor (FGFR) genomic to target FGFRs and not bind to similar signaling domains Immune checkpoint Clinical trial(s): Phase III alterations and has been in the vascular endothelial growth factor receptor and the inhibitors (eg, nivolumab, BLC3001 primary previously treated with a platelet-derived growth factor receptor. Erdafitinib pembrolizumab) completion November single line of systemic purportedly blocks blood vessel formation, cell 2020; phase II BLC2001 chemotherapy or no more proliferation, and cell survival pathways in urothelial Platinum agents (eg, primary completion than 2 lines of systemic cancer cells by inhibiting constitutive ligand-independent carboplatin, cisplatin) September 2019, data treatment, including an FGFR signaling. In some urothelial cancers, the presence Taxanes (eg, docetaxel, published June 2019 immune checkpoint inhibitor of activating FGFR gene alterations, including point paclitaxel) mutations and gene rearrangements, leads to uncontrolled cell proliferation. Eligibility for the therapy will require testing for FGFR mutation status. In clinical trials, erdafitinib is given orally at a starting daily dose of 8 mg on each 21-day cycle until disease progression or intolerable toxicity. Developer(s): Janssen Pharmaceutical LLC (Titusville, New Jersey), a subsidiary of Johnson & Johnson Inc (New Brunswick, New Jersey), in collaboration with Astex Pharmaceuticals Inc (Cambridge, United Kingdom)
Section 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 older Etirinotecan pegol (Onzeald), a novel drug-polymer form One or more of the Overall survival FDA designation(s): Fast who have advanced breast of the topoisomerase I inhibitor irinotecan, is intended to following: Track cancer with stable brain reduce treatment-related adverse events in patients with Progression-free metastases that has been breast cancer and brain metastases. Etirinotecan pegol Alkylating agents (eg, survival Clinical trial(s): Phase III cyclophosphamide) BEACON completed June treated with 1 or 2 cytotoxic links to a macromolecule core. This linkage purportedly Quality of life regimens renders the drug inert in the bloodstream and allows its 2016, pivotal data Anthracyclines (eg, published November 2015, slow release as the linkages are metabolized by the doxorubicin) patient’s body. Slow release extends the time the cancer quality-of-life data is exposed to therapeutic levels of the drug and limits high Antimetabolites (eg, published May 2017; levels of drug exposure during infusion. Additionally, the fluorouracil, gemcitabine, phase III ATTAIN primary large drug-polymer conjugate might preferentially pemetrexed) completion July 2020 accumulate in tumor tissues because of the increased Poly adenosine permeability of tumor vasculature. In clinical trials, diphosphate-ribose etirinotecan pegol is given as an intravenous infusion at a 2 polymerase (PARP) dose of 145 mg/m , once every 21 days until disease inhibitors (eg, niraparib, progression or intolerable toxicity. olaparib, rucaparib) Developer(s): Taxanes (eg, docetaxel, Nektar Therapeutics Inc (San Francisco, California) nab-paclitaxel, paclitaxel) Vinca alkaloid (eg, vinorelbine)
Section 1. Currently Monitored Topics 21
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years Idasanutlin (RG7388) is a nutlin-class small-molecule One or more of the Overall survival FDA designation(s): or older who have drug that blocks interactions between the mouse double following: Orphan Drug relapsed/refractory acute minute 2 homolog protein (MDM2) and p53, a tumor Progression-free myeloid leukemia (AML) that suppressor protein thought to be involved in up to half of Anthracyclines (eg, survival Clinical trial(s): Phase III daunorubicin, idarubicin) MIRROS primary has not responded to AML cases. No FDA-approved agents exist for restoring Quality of life or has relapsed after 1 or p53 activity. Standard AML chemotherapy lacks completion December Antibody–drug conjugate 2019 2 induction regimens specificity, leading to a range of side effects and disease (eg, gemtuzumab relapse over time, as well as poor responses in elderly ozogamicin) patients. In some AML cases, MDM2 is thought to reduce the amount of p53 by promoting its destruction through Antimetabolites (eg, the ubiquitin-proteasome system and by turning off p53’s cladribine, fludarabine) transcriptional activation. Idasanutlin purportedly targets a Cytokine (eg, granulocyte small hydrophobic pocket on MDM2 that normally binds to colony-stimulating factor) p53. Idasanutlin purportedly stabilizes p53 by blocking the MDM2–p53 interaction, potentially activating downstream DNA synthesis inhibitors transcriptional targets that keep AML cells from dividing (eg, etoposide, and initiates programed cell death. In clinical trials, mitoxantrone) idasanutlin is given orally twice daily at a dose of 300 mg FLT3 inhibitor (eg, in combination with cytarabine (1000 mg/m2) for the first gilteritinib) 5 days of a 28-day cycle, until complete remission or disease progression. Hypomethylating agents (eg, azacitidine, decitabine) Developer(s): IDH inhibitors (eg, Genentech Inc (South San Francisco, California), a enasidenib, ivosidenib) subsidiary of F Hoffman-La Roche Ltd (Basel, Switzerland) Multikinase inhibitor (eg, sorafenib)
Section 1. Currently Monitored Topics 22
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Idecabtagene vicleucel (ide-cel) is a chimeric antigen One or more of the Overall survival Submission date: Biologics who have relapsed and receptor T cell (CAR-T) therapy that has been engineered following: License Application refractory multiple myeloma to target the B-cell maturation antigen (BCMA) using Progression-free planned for fourth-quarter that has been treated with 3 autologous T cells isolated from a patient’s blood sample. Alkylating agents (eg, survival 2020 bendamustine, or more lines of Patients whose disease has progressed after 3 prior Quality of life chemotherapy that included a treatment lines have a very poor prognosis and no cyclophosphamide) FDA designation(s): protease inhibitor, an options, so they need new and better options. The Orphan Drug, Anthracyclines (eg, Breakthrough Therapy immunomodulatory agent, collected T cells are genetically modified with a lentiviral doxorubicin) and an anti-CD38 antibody vector (transduction) encoding CARs with a unique anti- Clinical trial(s): Phase II BCMA single-chain variable fragment (BB2121) fused to Glucocorticoids (eg, KarMMa primary the hinge and transmembrane domains of CD8α, the dexamethasone) completion November costimulatory domain (4-1BB) of CD137, and the Immunomodulatory agents 2024; phase III KarMMa-3 signaling domains of CD3ζ. The BB2121 CAR-transduced (eg, lenalidomide, primary completion June T cells that compose ide-cel are proliferated and then pomalidomide, thalidomide) 2025 reintroduced into the patient. Ide-cell purportedly targets malignant BCMA-expressing plasma cells in patients with Monoclonal antibodies (eg, multiple myeloma cells and promotes robust cellular daratumumab, elotuzumab) activity against these cells to treat multiple myeloma. Proteasome inhibitors (eg, BCMA has been proposed as a biomarker for targeting bortezomib, carfilzomib, multiple myeloma because it is highly expressed in ixazomib) malignant plasma cells. In clinical trials, ide-cel is given as a single intravenous infusion at a dose ranging from 1.5 × Topoisomerase inhibitors 108 to 4.5 × 108 anti-BCMA CAR-T cells. (eg, etoposide) Developer(s): bluebird bio Inc (Cambridge, Massachusetts), in collaboration with Celgene Corp (Summit, New Jersey)
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 75 years or older Ivosidenib (Tibsovo) is a small-molecule inhibitor of a Antibody–drug conjugate Complete remission Approval date: May 2, who have untreated AML that mutated form of the enzyme isocitrate dehydrogenase 1 (eg, gemtuzumab rate 2019 harbors an ivosidenib- (IDH1) known to occur in about 6% to 10% of AMLs. ozogamicin) susceptible mutation in the Ivosidenib provides a novel treatment option in the first- Overall survival FDA Designation(s): Glasdegib in combination Orphan Drug, isocitrate dehydrogenase 1 line setting for older patients who are unable to tolerate Quality of life gene, IDH1, and who cannot standard induction therapy. This mutant form of IDH1 with low-dose cytarabine Breakthrough therapy tolerate intensive induction causes an accumulation of the oncometabolite D-2- Low-dose cytarabine Clinical trial(s): Phase I chemotherapy hydroxyglutarate and a decrease in the levels of IDH1’s primary completion May normal metabolite, α-ketoglutarate. These shifts Low-intensity therapy (ie, 2020, data presented purportedly have multiple effects (eg, histone azacitidine and decitabine) December 2018, updated modification, DNA methylation) that keep cells in a Venetoclax alone or in results presented May dedifferentiated (ie, leukemic) state. Inhibiting the mutated combination with 2019; phase III AGILE form of IDH1 with ivosidenib purportedly causes azacitidine or low-dose primary completion April differentiation in AML cells, reducing malignancy. cytarabine 2022; phase III Ivosidenib is taken orally as a 500-mg/day daily tablet. HOVON150AML primary
Developer(s): completion February 2023 Agios Pharmaceuticals (Cambridge, Massachusetts) Note(s): FDA approved ivosidenib to treat relapsed or refractory AML with a susceptible IDH1 mutation in July 2018, and it granted a supplemental New Drug Application approval as monotherapy for patients with newly diagnosed IDH1-mutant AML, aged 75 years or older, ineligible for intensive chemotherapy in May 2019; safety data released February 2019.
Section 1. Currently Monitored Topics 24
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Lifileucel (LN-144) is an autologous cell therapy that uses One or more of the Overall survival FDA designation(s): who have locally advanced or T cells isolated from the patient’s melanoma tumor. following: Orphan Drug, Fast Track, metastatic melanoma that Lifileucel uses a novel personalized therapy strategy that Progression-free Regenerative Medicine has progressed after one or relies on naturally occurring T cells that can penetrate Alkylating agents (eg, survival Advanced Therapy dacarbazine, more previous lines of cancerous tumors and are called tumor-infiltrating Quality of life standard systemic therapy lymphocytes (TILs). The extracted TILs are expanded in temozolomide) Clinical trial(s): Phase II C- culture until reaching a count of billions of cells. Lifileucel 144-01 primary completion BRAF inhibitors (eg, March 2020, safety and is intended as a tumor-specific therapy to overcome the dabrafenib, vemurafenib) tumor’s immune-suppressive environment and promote efficacy data reported May its elimination. In clinical trials, lifileucel is given as an Immunotherapy (eg, 2019 intravenous infusion followed by up to 6 doses of ipilimumab, nivolumab, interleukin 2 to support the growth and activation of TILs. pembrolizumab) Developer(s): MEK inhibitors (eg, trametinib) Iovance Biotherapeutics Inc (San Carlos, California), in collaboration with the National Cancer Institute at the Platinum-based agents (eg, National Institutes of Health (Bethesda, Maryland) carboplatin) Taxane agents (eg, paclitaxel)
Children aged 12 years or LOXO-292 is a novel, highly selective, ATP-competitive One or more of the Overall survival FDA designation(s): older and adults who have small-molecule RET inhibitor intended to provide a following: Breakthrough Therapy locally advanced or targeted treatment option to patients with recurrent Progression-free metastatic medullary thyroid disease and a RET gene alteration. Unlike multikinase Anthracyclines (eg, survival Clinical trial(s): Phase I/II doxorubicin) LIBRETTO-001 primary cancer that harbors an inhibitors that target specific alterations, LOXO-292 has Quality of life alteration in the RET been designed to inhibit diverse RET fusions, activating completion March 2022, Antimetabolite agents (eg, preliminary data presented (rearranged during mutations, and acquired-resistance mutations with 5-fluorouracil) transfection) gene and has nanomolar potency. LOXO-292 targets and purportedly October 2018 progressed after treatment inhibits RET-mutant tumor cells. The receptor tyrosine Tyrosine kinase inhibitors with cabozantinib and/or kinase RET can be oncogenically activated by gene (eg, cabozantinib, vandetanib fusions or point mutations, and activating RET point vandetanib) mutations affect about 60% of metastatic medullary Tyrosine kinase inhibitors thyroid cancers. Eligibility for the therapy will require (off-label; eg, lenvatinib, testing for a RET gene alteration. In clinical trials, LOXO- pazopanib, sunitinib) 292 is given orally at an undetermined dose and time frame. Developer(s): Loxo Oncology Inc (Stamford, Connecticut), a subsidiary of Eli Lilly and Co Inc (Indianapolis, Indiana)
Section 1. Currently Monitored Topics 25
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Lurbinectedin (Zepsyre) is a synthetic, marine-derived Chemoradiation therapy Overall survival Submission date: New who have extensive-stage compound that selectively inhibits transactivated RNA Drug Application planned small-cell lung cancer polymerase II transcription. Patients with SCLC that is Platinum-based agents (eg, Progression-free for fourth-quarter 2019 (SCLC) refractory to a single refractory to platinum chemotherapy have limited carboplatin, cisplatin) survival platinum-containing regimen treatment options and poor prognosis, and they need new FDA designation(s): Topoisomerase inhibitors Quality of life Orphan Drug therapy options. Lurbinectedin selectively inhibits RNA (eg, etoposide, topotecan) polymerase (Pol) II activity during the elongation phase of Clinical trial(s): Phase III messenger RNA (mRNA) synthesis. Although ATLANTIS primary lurbinectedin interacts with RNA Pol II, it does not affect completion February 2020; the activity of RNA Pol I, mitochondrial RNA Pol, or basal phase II PM1183-B-005-14 transcription machinery. Lurbinectedin’s binding to RNA primary completion Pol II and inhibition of mRNA synthesis purportedly January 2020, data induces cancer cell death by reducing the expression of presented June 2019 cellular factors involved in tumor progression. In clinical trials, lurbinectedin is given intravenously at a dose of 4 mg once every 3 weeks in combination with doxorubicin until disease progression or intolerable toxicity. Developer(s): Pharma Mar SA (Madrid, Spain)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Margetuximab (MGAH22) is a monoclonal antibody that One or more of the Overall survival Submission date: Biologics who have metastatic or binds to HER2 to inhibit tumor cell growth. Margetuximab following: License Application locally advanced, relapsed, is intended as an option for patients whose cancer no Progression-free planned for fourth-quarter or refractory human longer responds to HER2-targeted therapies. In contrast Alkylating agents (eg, survival 2019 cyclophosphamide) epidermal growth factor to other HER2-specific antibodies (eg, pertuzumab, Quality of life receptor 2 (HER2)-positive trastuzumab), margetuximab has an optimized fragment FDA designation(s): Fast Anthracyclines (eg, Track breast cancer that has been crystallizable (Fc) region with higher affinity for the Fc- doxorubicin) treated with at least 2 lines of gamma receptor on macrophages. This increases their Clinical trial(s): Phase III anti-HER2 targeted therapy recruitment and enhances the tumor’s antibody- Antimetabolites (eg, SOPHIA primary dependent cellular cytotoxicity. Additionally, macrophages fluorouracil, pemetrexed) completion March 2020, that have consumed (ie, phagocytosed) and processed a HER2-targeted antibodies pivotal data reported tumor cell present tumor antigens to prime T cells, which (eg, ado-trastuzumab February 2019, updated then elicit antigen-specific immune responses against the emtansine, pertuzumab) data reported May 2019 tumor. In clinical trials, margetuximab is given intravenously once every 3 weeks, at a dose of 15 mg/kg, Taxanes (eg, docetaxel, in combination with capecitabine (1000 mg/m2), eribulin paclitaxel) (1.4 mg/m2), gemcitabine (1000 mg/m2), and vinorelbine Tyrosine kinase inhibitors (25-30 mg/m2). Treatment continues until disease (eg, afatinib, lapatinib) progression or intolerable toxicity. Vinca alkaloids (eg, Developer(s): vinorelbine) MacroGenics Inc (Rockville, Maryland), in collaboration with Green Cross Corp (Yongin, South Korea)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older MDNA55 is a cytokine that specifically targets the One or more of the Overall survival FDA designation(s): who have a recurrent interleukin-4 receptor (IL4R), a surface receptor reported following: Orphan Drug, Fast Track malignant glioma (eg, to be overexpressed in different types of cancer stem Progression-free astrocytoma, glioblastoma cells in the tumor. MDNA55 offers a novel approach for Alkylating agents (eg, survival Clinical trial(s): Phase II cyclophosphamide, MDNA55-05 primary multiforme [GBM]) treating IL4R-expressing tumors because GBM does not Quality of life respond well to standard therapy, and patients need temozolomide) completion December better therapy options. MDNA55 is a genetically 2019, preliminary data Angiogenesis inhibitors reported June 2019 engineered fusion protein composed of a circularly (eg, bevacizumab) permuted interleukin-4 molecule fused to the catalytic domain of the bacterial pseudomonas exotoxin A (PE) mTOR inhibitors (eg, protein. The fusion protein functions as a molecular decoy everolimus) by binding IL4R and triggering receptor-mediated Platinum agents (eg, endocytosis to deliver the cytotoxic PE payload into the carboplatin, cisplatin) cytoplasm. MDNA55 purportedly has high specificity and affinity for IL4R-expressing tumors to deliver cell-killing Vinca alkaloids (eg, payloads to cancer stem cells and immunosuppressive vincristine) cells of the tumor microenvironment. MDNA55 has the potential to not only kill the tumor cells but also “unblind” the immune system to cancer. MDNA55 is given as an infusion via convection-enhanced delivery (CED). Purportedly providing a safer, targeted delivery, CED uses a pressure gradient at the infusion catheter’s tip to push the therapeutic agent across the blood–brain barrier, through the brain’s interstitial spaces, and to the delivery site. In clinical trials, MDNA55 is infused as a single, unspecified dose. Developer(s): Medicenna Therapeutics Corp (Toronto, Ontario, Canada)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 74 years Metformin is a biguanide drug (a class of drugs that Active surveillance Disease-free survival Clinical trial(s): Phase III without diabetes mellitus who prevents glucose production in the liver) often used to MA32 primary completion have localized breast cancer treat type 2 diabetes mellitus. Some researchers think the Overall survival February 2022 that has been treated with drug might benefit patients with breast cancer because Quality of life surgical resection and retrospective studies of patients with diabetes taking neoadjuvant or adjuvant metformin and window-of-opportunity studies in the chemotherapy neoadjuvant breast cancer setting have shown that metformin might have anticancer effects. Metformin purportedly exerts its anticancer effects by activating AMP-activated protein kinase, which limits downstream components of the mTOR pathway. Additionally, metformin’s actions in reducing circulating insulin levels and improving insulin resistance in patients without diabetes might be antineoplastic because of insulin’s potential growth-stimulating activity. In clinical trials, metformin (850 mg) is being given orally, twice daily, for up to 5 years in the absence of disease progression. Developer(s): Canadian Cancer Trials Group (Kingston, Ontario, Canada)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Napabucasin (BBI608) is a small-molecule inhibitor of the One or more of the Overall survival Clinical trial(s): Phase III who have metastatic mitogenic signal transducer and activator of the following: CanStem303C primary colorectal cancer that has transcription 3 (STAT-3) pathway. Napabucasin’s novel Progression-free completion June 2020; been treated with a single mechanism of action is intended to treat colorectal cancer Angiogenesis inhibitors survival phase III primary (eg, bevacizumab, systemic chemotherapy that does not respond to second-line chemotherapy by Quality of life completion November regimen based on purportedly targeting and killing cancer stem cells in ramucirumab) 2021 fluoropyrimidine and tumors. Cancer stem cells are associated with treatment Antimetabolites (eg, 5- oxaliplatin resistance, metastasis, and poor prognosis. In clinical fluorouracil, capecitabine) trials, napabucasin is given orally at a dose of 240 mg twice daily in combination with the multiagent cytotoxic epidermal growth factor chemotherapy regimen FOLFIRI (leucovorin [folinic acid], receptor (EGFR) antibodies fluorouracil, and irinotecan) with or without the addition of (eg, cetuximab, bevacizumab, until disease progression or intolerable panitumumab) toxicity. FOLFIRI (ie, 5-fluorouracil, Developer(s): leucovorin) Boston Biomedical Inc (Cambridge, Massachusetts), a FOLFOX (ie, 5-fluorouracil, subsidiary of Sumitomo Dainippon Pharma Co Ltd leucovorin, oxaliplatin) (Osaka, Japan) Immune checkpoint inhibitors (eg, nivolumab, pembrolizumab) for patients with defects in mismatch repair or microsatellite instability Multikinase inhibitors (eg, regorafenib) Platinum agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Nivolumab (Opdivo) is an immune checkpoint inhibitor Fractionated external beam Overall survival FDA designation(s): who have newly diagnosed consisting of a fully human, monoclonal antibody that is radiation therapy with or Orphan Drug glioblastoma that has been specific to the cell surface receptor known as without alternating Progression-free surgically resected programmed death-1 (PD-1). Nivolumab uses a novel electrical fields plus survival Clinical trial(s): Phase III CheckMate-498 primary immune approach and is intended as adjuvant therapy for chemotherapy with one or Quality of life glioblastoma after surgical resection. Immune tolerance is more of the following: completion January 2019, a hallmark of cancer and might be mediated by binding of topline data reported May PD-1 by its ligands (programmed cell death ligand 1 and Alkylating agents (eg, 2019; phase III programmed cell death ligand 2), which inhibit T cells and cyclophosphamide, CheckMate-548 primary anticancer immune responses. Using nivolumab to procarbazine) completion February 2022 prevent PD-1 interaction with its ligands purportedly Angiogenesis inhibitors inhibits this immune checkpoint, potentially releasing the (eg, bevacizumab) brakes of anticancer immune responses. In clinical trials, nivolumab is given intravenously at a dose of 240 mg mTOR inhibitors (eg, every 2 weeks for 16 weeks and then 480 mg every everolimus) 4 weeks until disease progression or intolerable toxicity. Platinum agents (eg, Nivolumab is being studied in combination with radiation carboplatin, cisplatin) therapy with or without temozolomide. Vinca alkaloids (eg, Developer(s): vincristine) Bristol-Myers Squibb (New York, New York), in collaboration with Ono Pharmaceutical Co Ltd (Osaka, Japan)
Adults aged 22 years or older NovoTTF-100L is a device intended to treat solid tumors Systemic therapy with one Overall survival Clinical trial(s): Phase III who have metastatic non– by exposing them to low-intensity, intermediate- or more of the following: LUNAR primary completion small cell lung cancer frequency, alternating electric fields (ie, tumor-treating Progression-free December 2021 (NSCLC) that has progressed fields [TTF]). TTF disrupts cell division through effects on Immune checkpoint survival inhibitors (eg, after first-line, platinum-based charged macromolecules and organelles within cancer Quality of life therapy cells, potentially limiting tumor growth. NovoTTF-100L is a atezolizumab, nivolumab) battery-powered field generator coupled with an electrode Taxanes (eg, docetaxel) array that is attached to the skin of the patient’s torso as a noninvasive device. The patient applies TTF therapy in the home setting 24 hours a day, 7 days a week. The therapy is intended for use in combination with standard systemic therapies for metastatic NSCLC. Developer(s): NovoCure Ltd (St. Helier, Jersey)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 4 years or NY-ESO-1 SPEAR T-cell (GSK3377794) therapy is an One or more of the Overall survival FDA designation(s): older and adults who have autologous cell therapy engineered from T cells collected following: Breakthrough Therapy locally advanced or from a patient’s peripheral blood. Patients with synovial Progression-free metastatic synovial sarcoma sarcoma have limited treatment options, and NY-ESO-1 Alkylating agents (eg, survival Clinical trial(s): Phase I/II dacarbazine, 208466 primary completion that has not been previously SPEAR T cells could represent a new option. In this Quality of life treated or has progressed or therapy, T cells are genetically modified with a retroviral temozolomide) December 2019, data recurred after one line of vector (transduction) encoding a T-cell receptor that reported August 2018; Anthracyclines (eg, phase II 208467 primary chemotherapy recognizes a specific antigen in New York esophageal doxorubicin, epirubicin) squamous cell carcinoma-1 (NY-ESO-1), a protein with completion January 2022 restricted expression in testis and ovaries that is re- Antimetabolites (eg, expressed in up to 80% of synovial sarcomas. gemcitabine, ifosfamide) Successfully transduced cells are activated, expanded, DNA synthesis inhibitors and then frozen until use. NY-ESO-1 SPEAR T cells (eg, mitomycin C) purportedly strengthen the patient’s natural T-cell responses against cancer cells expressing NY-ESO-1. In Microtubule inhibitors (eg, clinical trials, after thawing, NY-ESO-1 SPEAR T cells are eribulin, vinorelbine) given as an intravenous infusion at an initial dose ranging Multikinase inhibitors (eg, from 1 × 109 to 6 × 109 cells. Patients who have a pazopanib, sorafenib) confirmed response or stable disease for 3 or more months might receive a second NY-ESO-1 SPEAR T-cell Tropomyosin receptor infusion. kinase inhibitor (eg, larotrectinib) Developer(s): GlaxoSmithKline plc (Brentford, United Kingdom)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Men aged 18 to 99 years who Olaparib (Lynparza) is a small-molecule drug intended to Abiraterone alone Overall survival Clinical trial(s): Phase III have metastatic, castration- inhibit poly adenosine diphosphate-ribose polymerase PROpel primary completion resistant prostate cancer (PARP), which functions in a DNA repair pathway. Docetaxel Progression-free April 2021 (mCRPC) that is being Olaparib might provide a novel and potentially synergistic survival Enzalutamide Note(s): FDA approved treated with androgen mechanism of action when used with abiraterone to treat Quality of life deprivation therapy but has newly diagnosed mCRPC. Cancers are often deficient in olaparib to treat ovarian not yet been treated with a DNA repair pathway, and when PARP is also inhibited, cancer in December 2014 chemotherapy or a new the loss of 2 types of DNA repair results in cancer cell and for breast cancer in hormonal agent (ie, death in response to DNA damage. Preclinical studies January 2018. abiraterone or enzalutamide) have indicated that cross-talk might exist between androgen receptor signaling pathways and PARP. In clinical trials, olaparib is being studied in combination with the hormone synthesis inhibitor abiraterone. Olaparib is given orally, 300 mg, twice daily, in addition to abiraterone, until disease progression or intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, United Kingdom), in collaboration with Merck & Co Inc (Kenilworth, New Jersey)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 99 years Olaparib (Lynparza) is a small-molecule drug intended to One or more of the Overall survival FDA designation(s): who have germline BRCA1 inhibit poly adenosine diphosphate-ribose polymerase following: Orphan Drug and/or BRCA2 mutation- (PARP), which functions in a DNA repair pathway. Progression-free positive metastatic pancreatic Cancers are often deficient in a DNA repair pathway, and Antimetabolites (eg, survival Clinical trial(s): Phase III gemcitabine) POLO primary completion cancer that has not when PARP is also inhibited, the loss of 2 types of DNA Quality of life progressed during first-line, repair results in cancer cell death in response to January 2019, data Platinum-based agents (eg, published July 2019 platinum-based DNA damage. Only about 5% of patients with pancreatic cisplatin, oxaliplatin) chemotherapy cancer respond to the standard of care (gemcitabine plus Note(s): FDA approved chemotherapy), and the prognosis for these patients is Taxanes (eg, docetaxel, olaparib to treat ovarian poor. Olaparib purportedly induces cell death in nab-paclitaxel, paclitaxel) cancer in December 2014 pancreatic tumors that harbor germline mutations in the and for breast cancer in breast cancer genes BRCA1 and/or BRCA2. In clinical January 2018; Myriad trials, olaparib is given orally, 300 mg, twice daily, until Genetics (Salt Lake City, disease progression or intolerable toxicity. Utah) plans to file for a Developer(s): Supplemental Premarket Approval application for a AstraZeneca plc (Cambridge, United Kingdom), in companion diagnostic test collaboration with Merck & Co Inc (Kenilworth, New for germline BRCA Jersey) mutations in patients with metastatic pancreatic cancer.
Section 1. Currently Monitored Topics 34
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Males aged 18 years or older Olaparib (Lynparza) is a small-molecule drug intended to Abiraterone Overall survival FDA designation(s): who have metastatic, inhibit poly adenosine diphosphate-ribose polymerase Breakthrough Therapy castration-resistant prostate (PARP), which functions in a DNA repair pathway. Cabazitaxel Progression-free cancer (mCRPC) that Olaparib might provide a novel and potentially synergistic survival Clinical trial(s): Phase III Docetaxel PROfound primary harbors a mutation in one of mechanism of action for treating patients with this Quality of life 15 genes involved in indication, which has poor overall outcomes. Cancers are Enzalutamide completed June 2019, data reported August 2019 homologous recombination often deficient in a DNA repair pathway, and with the Pembrolizumab for tumors repair and has been treated addition of PARP inhibition, the loss of 2 types of DNA that are microsatellite Note(s): Myriad Genetics with 1one or more new repair results in cancer cell death in response to DNA instability-high or mismatch Inc (Salt Lake City, Utah) hormonal agents (ie, damage. Olaparib purportedly induces cell death in repair deficient has expanded its abiraterone and/or prostate tumors that harbor germline mutations in one of collaboration with the enzalutamide) several genes involved in the homologous recombination developers and will work to repair pathway, providing a way to treat tumors for identify germline mutations patients with limited options. Eligibility for treatment will in men enrolled in the require testing for specific germline gene mutations. In PROfound study; FDA clinical trials, olaparib is given orally, 300 mg, twice daily, approved olaparib to treat until disease progression or intolerable toxicity. BRCA-mutated ovarian Developer(s): cancer in December 2018. AstraZeneca plc (Cambridge, United Kingdom), in collaboration with Merck & Co Inc (Kenilworth, New Jersey)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or Omidubicel (NiCord) is an allogeneic stem cell therapy Allogeneic bone marrow Bone marrow FDA designation(s): older and adults aged up to derived from umbilical cord blood that has been multiplied transplant engraftment rate Orphan Drug, 65 years who have a in the laboratory using proprietary nicotinamide (NAM) Breakthrough Therapy hematologic malignancy technology. Omidubicel is intended as a curative Pooled unexpanded cord Neutrophil recovery (acute lymphoblastic approach for high-risk blood cancers in patients who have blood transplantation rate Clinical trial(s): Phase III leukemia, acute no fully matched donor available. The therapy is intended primary completion Unexpanded cord blood Overall survival December 2019 myelogenous leukemia, to efficiently and quickly restore blood and immune cells transplantation chronic myelogenous and improve resistance to infections and related Platelet recovery rate leukemia, or myelodysplastic complications. NAM purportedly prevents umbilical cord syndrome) blood cells from differentiating rapidly in culture, resulting in increased stem cells (CD34-+CD38-Lin-). NAM works outside the genetic coding region in the DNA (ie, epigenetic) and purportedly increases the migration, bone marrow homing, and engraftment efficiency of allogeneic blood progenitor cells. In clinical trials, omidubicel is given as a single intravenous infusion at an unspecified dose. Developer(s): Gamida Cell Ltd (Jerusalem, Israel), in collaboration with Be the Match BioTherapies LLC (Minneapolis, Minnesota), a subsidiary of the National Marrow Donor Program/Be the Match (Minneapolis, Minnesota)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older ONC201 is a small-molecule imipridone (a class of One or more of the Overall survival FDA Designation(s): Fast who have a recurrent high- anticancer compounds) that acts as an antagonist of the following: Track Progression-free grade glioma that harbors a G-protein coupled receptor dopamine receptor D2 K27M mutation in the histone (DRD2). ONC201 has a novel mechanism of action that Alkylating agents (eg, survival Clinical Trial(s): Phase II carmustine, temozolomide) ONC013 primary gene, H3 might provide an option for patients who have few Quality of life effective treatment options and poor prognosis after completion November Angiogenesis inhibitors 2019; phase II ONC006 recurrence. ONC201-mediated antagonism of DRD2 (eg, bevacizumab) purportedly inactivates the ras pathway, a driver of cell primary completion growth and proliferation, and activates the integrated Vinca alkaloids (eg, December 2020; unphased stress response, which can activate cell death pathways. vincristine) Expanded Access Patients with gliomas harboring K27M mutations in the Program; pooled data from histone gene, H3, have a poor prognosis, and preclinical these 3 trials presented data have indicated these gliomas might be susceptible to June 2019 treatment with a DRD2 antagonist. Eligibility for the therapy will require testing for the H3 K27M mutation. In clinical trials, ONC201 is given orally at an unspecified dose and time frame. Developer(s): Oncoceutics Inc (Philadelphia, Pennsylvania)
Section 1. Currently Monitored Topics 37
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Oportuzumab monatox (Vicinium) is an antibody–drug Cystectomy Disease-free survival Submission Date: Biologics who have non–muscle conjugate comprising a humanized monoclonal antibody License Application invasive bladder cancer that fragment specific for the epithelial cell adhesion molecule Transurethral resection of Overall survival planned for fourth-quarter bladder tumor is refractory to or has (EpCAM) linked to a truncated form of Quality of life 2019 relapsed after at least Pseudomonas aeruginosa exotoxin A (ETA). ETA is a Intravesicular 2 intravesicular treatments cytotoxic agent that acts by inhibiting protein synthesis Time to cystectomy FDA designation(s): Fast chemotherapy with one or Track with bacillus Calmette-Guérin through inactivation of elongation factor-2. EpCAM is more of the following: highly expressed by bladder cancer cells. Oportuzumab Clinical trial(s): Phase III monatox is intended to preferentially deliver the linked Anthracyclines (eg, VISTA primary completion exotoxin to these cells and delay the time to major valrubicin) December 2020, surgery (cystectomy) and associated side effects of Antimetabolites (eg, preliminary data published surgery (eg, urinary diversion). In clinical trials, gemcitabine) August 2019 oportuzumab monatox (30 mg) is given intravesically in an office setting. In a clinical trial, treatment involves a 12- DNA synthesis inhibitors week induction phase (12 twice-weekly instillations (eg, mitomycin-C) followed by 6 weekly instillations) and a maintenance phase of instillations once every 2 weeks for up to 2 years. Developer(s): Sesen Bio (Cambridge, Massachusetts)
Adults aged 18 years or older Pegargiminase (ADI-PEG 20) is a pegylated preparation One or more of the Overall survival FDA designation(s): who have malignant pleural of the enzyme arginine deiminase, which catalyzes the following: Orphan Drug mesothelioma that has not hydrolysis of arginine, depleting the supply of this Progression-free been treated with systemic essential amino acid from the bloodstream. Cells of many Antimetabolites (eg, survival Clinical trial(s): Phase II/III therapies and exhibits low tumor types cannot autonomously synthesize arginine pemetrexed) ATOMIC primary Quality of life completion October 2020 argininosuccinate synthetase and, therefore, might be sensitive to arginine depletion. In Platinum agents (eg, 1 expression particular, tumor cells that express low levels of the cisplatin) argininosuccinate synthetase 1 gene, ASS1 (involved in cellular arginine synthesis), might be dependent on exogenous arginine. This is thought to be the case in malignant pleural mesothelioma, which lacks effective treatment options. In clinical trials, pegargiminase is given weekly by intramuscular injection at a dose of 36 mg/m2 in combination with standard chemotherapy with cisplatin and pemetrexed until disease progression or intolerable toxicity. Developer(s): Polaris Group (San Diego, California)
Section 1. Currently Monitored Topics 38
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pegylated human recombinant hyaluronidase (PEGPH20) One or more of the Overall survival FDA designation(s): who have previously is a formulation of the enzyme hyaluronidase, which following: Orphan Drug, Fast Track untreated stage IV pancreatic functions to degrade the hyaluronan (HA) component of Progression-free ductal adenocarcinoma and the extracellular matrix. HA is a gel-like component of Antimetabolites (eg, 5- survival Clinical trial(s): Phase III fluorouracil, capecitabine, HALO-109-301 primary at least one metastasis normal body tissues (eg, skin, cartilage), but it also forms Quality of life a layer on the tumor surface, which might limit tumor gemcitabine) completion November 2019 exposure to therapeutic compounds. PEGPH20 is Folic acid derivatives (eg, intended to temporarily degrade HA to increase leucovorin) chemotherapy efficacy and immune cells in metastatic pancreatic cancer. Only about 5% of patients with Multikinase inhibitors (eg, pancreatic cancer respond to the standard of care erlotinib) (gemcitabine chemotherapy), and these patients’ Platinum-based agents (eg, prognosis is poor, so more effective treatment options are cisplatin, oxaliplatin) needed. In clinical trials, PEGPH20 is given intravenously in combination with standard chemotherapy drugs nab- Taxanes (eg, docetaxel, paclitaxel and gemcitabine at a dose of 3 μg/kg twice nab-paclitaxel, paclitaxel) weekly for weeks 1 to 3 of the first 28-day cycle, then once weekly for weeks 1 to 3 of subsequent 28-day cycles. Nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) are given once weekly for weeks 1 to 3 of all 28-day cycles. Developer(s): Halozyme Therapeutics Inc (San Diego, California)
Section 1. Currently Monitored Topics 39
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Approval date: April 19, who have locally advanced or targets the programmed death-1 (PD-1) co-inhibitory following: 2019 metastatic renal cell receptor expressed by activated T cells. Malignant Progression-free carcinoma (RCC) that has cancers, including RCC, can often effectively evade Angiogenesis inhibitors survival Clinical trial(s): Phase III (eg, bevacizumab) KEYNOTE-426 primary not been treated immune responses, causing poor treatment responses. Quality of life The cancer cells trigger an immune checkpoint pathway completed October 2018, Cytokines (eg, interferon- pivotal data reported in T cells by overexpressing the programmed death- alpha, interleukin-2) ligand 1 (PD-L1), which binds to PD-1. This limits October 2018, data activation of cancer-specific T cells and the body’s Immunotherapy (eg, published February 2019 immune response. Pembrolizumab purportedly prevents ipilimumab, nivolumab) Note(s): FDA approved the interaction between PD-1 and PD-L1 in an effort to mTOR inhibitors (eg, pembrolizumab to treat overcome the immune tolerance of RCC by enhancing everolimus, temsirolimus) melanoma in September cancer-specific T-cell responses. In clinical trials, 2014, for non–small cell pembrolizumab is given as an intravenous infusion at a Tyrosine kinase inhibitors lung cancer in October dose of 200 mg, once every 3 weeks, plus 5 mg of axitinib (eg, axitinib, cabozantinib, 2015, for head and neck orally twice daily, for up to 24 months. sunitinib) cancer (second-line) in Developer(s): August 2016, for Hodgkin lymphoma in March 2017, Merck & Co Inc (Kenilworth, New Jersey) for urothelial carcinoma in May 2017, for microsatellite instability-high solid tumors in May 2017, for gastric or gastroesophageal junction cancer in September 2017, for cervical cancer in June 2018, for mediastinal large B-cell lymphoma in June 2018, for hepatocellular carcinoma in November 2018, for Merkel cell carcinoma in December 2018, for advanced esophageal squamous cell cancer (second-line) in June 2019, and for recurrent or metastatic head and neck squamous cell carcinoma (first-line) in June 2019.
Section 1. Currently Monitored Topics 40
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Clinical trial(s): Phase III who have locally advanced or targets the programmed death-1 (PD-1) co-inhibitory following: PROMISE-meso primary metastatic malignant pleural receptor expressed by activated T cells. Front-line Progression-free completion December mesothelioma (MPM) that therapy for MPM relies on platinum-based chemotherapy, Antimetabolites (eg, survival 2020 gemcitabine, pemetrexed, has progressed or recurred but response rates are low and no second-line therapies Quality of life after one previous line of exist, so effective options are needed. A hallmark of raltitrexed) Note(s): FDA approved pembrolizumab to treat systemic cisplatin plus cancer is its ability to evade an immune response. Platinum agents (eg, pemetrexed chemotherapy Several types of cancer cells, including MPM, activate an melanoma in September carboplatin, cisplatin, 2014, for non–small cell immune checkpoint pathway in T cells by overexpressing oxaliplatin) programmed death-ligand 1 (PD-L1), which binds to PD-1 lung cancer in October and limits the activation of cancer-specific T cells. Topoisomerase inhibitor 2015, for head and neck Pembrolizumab purportedly prevents the interaction (eg, irinotecan) cancer (second-line) in between PD-1 and PD-L1 in an effort to overcome the August 2016, for Hodgkin Vinca alkaloid (eg, lymphoma in March 2017, immune tolerance of MPM by enhancing cancer-specific vinorelbine) T-cell responses. In clinical trials, pembrolizumab is given for urothelial carcinoma in as an intravenous infusion at a dose of 200 mg, once May 2017, for microsatellite every 3 weeks, for up to 24 months. instability-high solid tumors in May 2017, for gastric or Developer(s): gastroesophageal junction cancer in September 2017, Merck & Co Inc (Kenilworth, New Jersey) for cervical cancer in June 2018, for mediastinal large B-cell lymphoma in June 2018, for hepatocellular carcinoma in November 2018, for Merkel cell carcinoma in December 2018, for advanced renal cell carcinoma in April 2019, for advanced esophageal squamous cell cancer (second-line) in June 2019, and for recurrent or metastatic head and neck squamous cell carcinoma (first-line) in June 2019.
Section 1. Currently Monitored Topics 41
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival FDA designation(s): who have stage IV colorectal targets the programmed death-1 (PD-1) co-inhibitory following: Breakthrough Therapy cancer that is microsatellite receptor expressed by activated T cells. Pembrolizumab Progression-free instability-high (MSI-H) or is intended to provide a targeted option for patients with Angiogenesis inhibitors survival Clinical trial(s): Phase III mismatch repair deficient MSI-H or dMMR colorectal cancers, which make up 15% (eg, bevacizumab) KEYNOTE-177 primary Quality of life completion August 2019 (dMMR) and has not been to 20% of nonhereditary cases and most hereditary Antimetabolites (eg, 5- previously treated cases. A hallmark of cancer is its ability to evade an fluorouracil, capecitabine) Note(s): FDA approved immune response. Several types of cancer cells, pembrolizumab to treat including colorectal cancer, activate an immune EGFR antibodies (eg, melanoma in September checkpoint pathway in T cells by overexpressing cetuximab, panitumumab) 2014, for non–small cell programmed death-ligand 1 (PD-L1), which binds to PD-1 FOLFIRI (ie, 5-fluorouracil, lung cancer in October and limits the activation of cancer-specific T cells. irinotecan, leucovorin) 2015, for head and neck Pembrolizumab purportedly prevents the interaction cancer (second-line) in between PD-1 and PD-L1 in an effort to overcome the FOLFOX (ie, 5-fluorouracil, August 2016, for Hodgkin immune tolerance of colorectal cancer by enhancing leucovorin, oxaliplatin) lymphoma in March 2017, cancer-specific T-cell responses. Tumors with MSI-H or Multikinase inhibitors (eg, for urothelial carcinoma in dMMR are also purportedly more susceptible to regorafenib) May 2017, for MSI-H solid pembrolizumab than tumors with low MSI. In clinical trials, tumors in May 2017, for pembrolizumab is given as an intravenous infusion at a Platinum-based agents (eg, gastric or dose of 200 mg, once every 3 weeks, for up to oxaliplatin) gastroesophageal junction 24 months. cancer in September 2017, Topoisomerase inhibitors for cervical cancer in June Developer(s): (eg, irinotecan) 2018, for mediastinal large Merck & Co Inc (Kenilworth, New Jersey) B-cell lymphoma in June 2018, for hepatocellular carcinoma in November 2018, for Merkel cell carcinoma in December 2018, for advanced renal cell carcinoma in April 2019, for advanced esophageal squamous cell cancer (second-line) in June 2019, and for recurrent or metastatic head and neck squamous cell carcinoma (first-line) in June 2019.
Section 1. Currently Monitored Topics 42
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Approval date: June 11, who have recurrent or targets the programmed death-1 (PD-1) co-inhibitory following: 2019 metastatic head and neck receptor expressed by activated T cells. Because most Progression-free squamous cell carcinoma patients with HNSCC have disease recurrence after Antimetabolites (eg, 5- survival Clinical trial(s): Phase III fluorouracil, capecitabine, KEYNOTE-048 primary (HNSCC) that has not been treatment with standard platinum-based chemotherapy, Quality of life previously treated and the pembrolizumab might improve health outcomes, change gemcitabine, methotrexate) completion February 2019, data presented May 2019 primary tumor is located in patient management, and increase treatment-related Epidermal growth factor the oral cavity, larynx, costs. A hallmark of cancer is its ability to evade an receptor (EGFR) inhibitor Note(s): FDA approved hypopharynx, or oropharynx immune response. Several types of cancer cells, (eg, cetuximab) pembrolizumab to treat including HNSCC, activate an immune checkpoint melanoma in September pathway in T cells by overexpressing the programmed Platinum-based drugs (eg, 2014, for non–small cell death-ligand 1 (PD-L1), which binds to PD-1 and limits carboplatin, cisplatin) lung cancer in October the activation of cancer-specific T cells. Pembrolizumab Taxanes (eg, docetaxel, 2015, for head and neck purportedly prevents the interaction between PD-1 and paclitaxel) cancer (second-line) in PD-L1 in an effort to overcome the immune tolerance of August 2016, for Hodgkin HNSCC by enhancing cancer-specific T-cell responses. lymphoma in March 2017, In clinical trials, pembrolizumab is given as an for urothelial carcinoma in intravenous infusion at a dose of 200 mg, once every May 2017, for microsatellite 3 weeks, for up to 24 months. Pembrolizumab is being instability-high solid tumors studied as monotherapy or in combination with in May 2017, for gastric or intravenous cisplatin (100 mg/m2) or carboplatin (AUC 5) gastroesophageal junction plus 5-fluorouracil (1000 mg/m2). cancer in September 2017, Developer(s): for cervical cancer in June 2018, for mediastinal large Merck & Co Inc (Kenilworth, New Jersey) B-cell lymphoma in June 2018, for hepatocellular carcinoma in November 2018, for Merkel cell carcinoma in December 2018, for advanced renal cell carcinoma in April 2019, and for advanced esophageal squamous cell cancer (second-line) in June 2019.
Section 1. Currently Monitored Topics 43
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Clinical trial(s): Phase III who have locally advanced or targets the programmed death-1 (PD-1) co-inhibitory following: KEYNOTE-590 primary metastatic esophageal receptor expressed by activated T cells. Front-line Progression-free completion August 2021 carcinoma or therapy for esophageal carcinoma relies on platinum- Anthracyclines (eg, survival epirubicin) Note(s): FDA approved esophagogastric junction based chemotherapy, but response rates are low and no Quality of life (EGJ) carcinoma that is second-line therapies exist. Pembrolizumab might pembrolizumab to treat Antimetabolites (eg, 5- melanoma in September unsuited for surgery and has improve health outcomes, change patient management, fluorouracil, capecitabine) not been previously treated and increase treatment-related costs. A hallmark of 2014, for non–small cell cancer is its ability to evade an immune response. Human epidermal growth lung cancer in October Several types of cancer cells, including esophageal and factor receptor 2 (HER2) 2015, for head and neck EGJ carcinomas, activate an immune checkpoint pathway antibodies (eg, cancer (second-line) in in T cells by overexpressing the programmed death- trastuzumab) August 2016, for Hodgkin lymphoma in March 2017, ligand 1 (PD-L1), which binds to PD-1 and limits the Platinum agents (eg, activation of cancer-specific T cells. Pembrolizumab for urothelial carcinoma in carboplatin, cisplatin, May 2017, for microsatellite purportedly prevents the interaction between PD-1 and oxaliplatin) PD-L1 in an effort to overcome the immune tolerance of instability-high solid tumors esophageal and EGJ carcinomas by enhancing cancer- Taxanes (eg, docetaxel, in May 2017, for gastric or specific T-cell responses. In clinical trials, pembrolizumab paclitaxel) gastroesophageal junction is given as an intravenous infusion at a dose of 200 mg, cancer in September 2017, once every 3 weeks, for up to 24 months. for cervical cancer in June 2018, for mediastinal large Developer(s): B-cell lymphoma in June 2018, for hepatocellular Merck & Co Inc (Kenilworth, New Jersey) carcinoma in November 2018, for Merkel cell carcinoma in December 2018, for advanced renal cell carcinoma in April 2019, for advanced esophageal squamous cell cancer (second-line) in June 2019, and for recurrent or metastatic head and neck squamous cell carcinoma (first-line) in June 2019.
Section 1. Currently Monitored Topics 44
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years Pexidartinib (Turalio) is a small-molecule multikinase Off-label imatinib Patient-reported pain Approval date: August 2, or older who have a inhibitor with activity against several receptor tyrosine and stiffness 2019 tenosynovial giant cell tumor kinases, including colony-stimulating factor 1 receptor Radiation therapy Patient-reported FDA designation(s): (TGCT) that is unsuited for (CSF1R), FMS-like tyrosine kinase 3, and KIT. No FDA- surgery approved interventions are available to treat TGCT, and physical function Breakthrough Therapy patients need effective options. TGCTs typically (PROMIS physical function scale) Clinical trial(s): Phase III overexpress colony-stimulating factor 1 (CSF1), which is ENLIVEN primary an activating ligand for CSF1R. TGCT-expressed CSF1 Quality of life completion December leads to recruitment of CSF1R-expressing cells, such as 2019; topline data reported osteoclasts, macrophages, and mast cells, which initiate Response rate June 2018 an inflammatory reactive process that contributes to TGCT pathogenesis. Therefore, inhibiting CSF1R by pexidartinib might limit CSF1-/CSF1R-driven chemotaxis of inflammatory cells and limit the proinflammatory process underlying TGCT. In clinical trials, pexidartinib is given orally at a dose of 1000 mg/day for 2 weeks followed by 800 mg/day for 22 weeks. Developer(s): Daiichi Sankyo Inc (Tokyo, Japan)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Polatuzumab vedotin (Polivy) is a monoclonal antibody One or more of the Overall survival Approval date: June 10, who have relapsed or conjugated with a chemotherapy drug (vedotin) that has following: 2019 refractory diffuse large B-cell been designed to bind to the surface receptor CD79b, a Progression-free lymphoma (DLBCL) protein highly expressed in most cases of DLBCL. The Alkylating agents (eg, survival FDA designation(s): bendamustine, Orphan Drug, most common type of non-Hodgkin lymphoma, DLBCL Quality of life has a 40% relapse rate, and patients need effective new cyclophosphamide, Breakthrough Therapy ifosfamide, procarbazine) treatment options. The drug is a synthetic form of Clinical trial(s): Phase III auristatin with cytotoxic activity that blocks microtubule Angiogenesis inhibitor (eg, POLARIX primary formation. Polatuzumab vedotin purportedly binds to lenalidomide) completion January 2021; CD79b, allowing the drug to enter and kill malignant cells phase I/II GO29365 while minimizing toxicity to normal cells. Polatuzumab Anthracyclines (eg, primary completion vedotin is given by intravenous infusion at a dose of doxorubicin) December 2019, long-term 1.8 mg/kg once every 21 days for 6 cycles, in combination Antimetabolites (eg, data reported December 2 with rituximab (375 mg/m ) plus bendamustine (90 cytarabine, gemcitabine) 2018, updated results mg/m2). Rituximab monotherapy is given in cycles 7 reported March 2019 and 8. Glucocorticoid (eg, dexamethasone, Note(s): FDA approval was Developer(s): methylprednisolone, under the Accelerated Genentech Inc (South San Francisco, California), a prednisone) Approval pathway. subsidiary of F Hoffman-La Roche AG (Basel, Kinase inhibitor (eg, Switzerland), in collaboration with Seattle Genetics Inc ibrutinib) (Bothell, Washington) Monoclonal antibodies (eg, brentuximab vedotin, rituximab) Platinum-based agents (eg, carboplatin, cisplatin, oxaliplatin) Topoisomerase inhibitors (eg, etoposide, mitoxantrone) Vinca alkaloid (eg, vincristine, vinorelbine)
Section 1. Currently Monitored Topics 46
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Men aged 18 years or older ProstAtak is a gene-mediated cytotoxic immunotherapy Radiation therapy with or Disease-free survival Clinical trial(s): Phase III who have localized prostate consisting of an adenovirus vector containing a herpes without androgen PrTK03 primary completion cancer that is deemed to be simplex virus thymidine kinase gene (aglatimagene deprivation therapy Overall survival December 2021, designed intermediate or high risk besadenovec) that is injected intratumorally and leads to Quality of life under Special Protocol based on one factor and has infected cells expressing thymidine kinase. After viral Assessment; phase II been treated with radiation injection, a low dose of a synthetic guanosine analogue ULYSSES primary therapy (eg, valacyclovir) activated by thymidine kinase is given, completion September potentially killing tumor cells expressing the transgene (ie, 2020 aglatimagene besadenovec). The intervention is intended to provide antitumor effects while preserving critical structures around the prostate. Release of tumor- associated antigens by dying tumor cells purportedly leads to an antitumor immune response. ProstAtak is given as 3 rounds of intratumoral aglatimagene besadenovec injection/systemic valacyclovir administration in addition to standard radiation therapy with or without androgen deprivation therapy. Developer(s): Advantagene Inc (Auburndale, Massachusetts)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years ProTmune is a next-generation allogeneic hematopoietic Standard hematopoietic Overall survival FDA designation(s): or older who have a peripheral blood cell transplant (HPBCT). It is developed cell transplantation Orphan Drug, Fast Track hematologic malignancy from donor-sourced, mobilized, peripheral blood T cells Progression-free (acute lymphoblastic that have been cultured in the laboratory in the presence survival Clinical trial(s): Phase I/II PROTECT primary leukemia, acute myeloid of FT1050 and FT4145 (2 small-molecule stem cell Quality of life leukemia, chronic modulators that guide cell fate for use in HPBCT). completion September myelogenous leukemia, or ProTmune might reduce disease recurrence and improve 2019, initial data reported myelodysplastic syndrome) patient survival. Many patients with hematologic March 2018, expanded that will be treated with malignancies seek curative therapy through HPBCT; enrollment May 2019 allogeneic hematopoietic however, about 50% of patients undergoing HPBCT die peripheral blood cell or experience disease recurrence within the first 2 years transplantation because they develop graft-versus-host disease (GVHD). ProTmune purportedly decreases GVHD’s incidence and severity while maintaining therapeutic activity against hematologic malignancies. Clinical trials do not specify ProTmune’s delivery route; however, similar to standard hematopoietic cell transplant, it is likely given as an intravenous infusion. Developer(s): Fate Therapeutics Inc (San Diego, California)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older PVS-RIPO is a Sabin type 1 strain of poliovirus Fractionated external beam Overall survival FDA designation(s): who have recurrent malignant genetically engineered to not harm or kill normal cells. radiation therapy Orphan Drug, glioma (eg, glioblastoma PVS-RIPO uses a novel oncolytic virus approach Progression-free Breakthrough Therapy multiforme, anaplastic intended for patients whose cancer has recurred and who One or more of the survival following: Clinical trial(s): Phase II astrocytoma) that has been have limited options after standard therapy. It selectively Quality of life treated with surgery and infects and replicates tumor cells that express the Pro00077024 primary Alkylating agents (eg, completion May 2021 adjuvant radiation and poliovirus receptor nectin-like protein 5 (CD155), which is carmustine, temozolomide therapy expressed in most types of solid tumor cancers. Because cyclophosphamide, CD155 is also expressed in other immune cells, including lomustine, procarbazine, dendritic cells and macrophages, PVS-RIPO infection of temozolomide) immune cells facilitates induction of an antitumor immune response that does not kill or limit immune function of Angiogenesis inhibitors dendritic cells. Although immune cells infected by PVS- (eg, bevacizumab) RIPO initiate a type 1 interferon response, this will not mTOR inhibitors (eg, destroy the oncolytic virus. PVS-RIPO purportedly targets everolimus) and destroys cells in brain tumors and activates tumor- specific immune responses by stimulating dendritic cell Platinum agents (eg, activity and immune function. In clinical trials, PVS-RIPO carboplatin, cisplatin) is given as a single intratumoral injection at a dose from Vinca alkaloids (eg, 7 × 106 to 7 × 109 plaque-forming units. vincristine) Developer(s): Istari Oncology Inc (Durham, North Carolina), in collaboration with the Preston Robert Tisch Brain Tumor Center at Duke University (Durham, North Carolina)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or Relatlimab (BMS-986016) is a novel human One or more of the Overall survival Clinical trial(s): Phase II/III older and adults who have immunoglobulin G4 (IgG4) monoclonal antibody against following: primary completion July melanoma that is unsuited for lymphocyte-activator gene-3 (LAG-3), a co-inhibitor Progression-free 2020 surgery or is metastatic and receptor primarily expressed on exhausted TILs. Alkylating agents (eg, survival dacarbazine, has not been previously Relatlimab is intended to enhance activity of immune Quality of life treated with systemic therapy checkpoint inhibitors by stimulating TILs. As an adjunct to temozolomide) a checkpoint inhibitor, relatlimab might also increase BRAF inhibitors (eg, treatment-related costs. The binding of relatlimab to LAG- dabrafenib, encorafenib, 3 prevents inhibitory T-cell responses of TILs via vemurafenib) interaction with major histocompatibility complex class-II (MHC-II) on dendritic cells and melanoma cells. Immune checkpoint Relatlimab purportedly promotes innate immune inhibitors (eg, ipilimumab, responses and FAS-mediated programmed cell death nivolumab, (apoptosis) in melanoma cells expressing high MHC-II. pembrolizumab) Relatlimab also synergizes with programmed death-1 MEK inhibitors (eg, immune checkpoint inhibitors that might encourage binimetinib, cobimetinib, melanoma-specific immune responses. In clinical trials, trametinib) relatlimab is given intravenously at a dose of 160 mg in combination with intravenous nivolumab at a dose of Platinum agents (eg, 480 mg on day 1 of each 28-day cycle until disease carboplatin) progression or intolerable toxicity. Taxane agents (eg, Developer(s): paclitaxel) Bristol-Myers Squibb Co (New York, New York)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Infants and children aged 2 Remestemcel-L (Prochymal) is an allogeneic Photopheresis alone or Overall survival Submission date: Rolling months to 17 years who have mesenchymal precursor cell therapy that uses donor combined with 8- Biologics License acute GVHD that has not bone marrow and selectively expands mesenchymal stem methoxypsoralen Progression-free Application initiated May responded well to steroids cells. It is intended for graft-versus-host disease (GVHD) survival 2019 Therapy with one or more that is refractory to steroid treatment. GVHD is a life- Quality of life threatening immune disorder that is a frequent immunosuppressants: FDA designation(s): Orphan Drug, Fast Track complication of allogeneic hematopoietic stem cell Alkylating agents (eg, transplantation and affects many organ systems. It arises cyclophosphamide) Clinical trial(s): Phase III when donor T cells recognize host cells as foreign by MSB0GVHD001 completed virtue of their expression of alloantigens and mount an Antibodies (eg, April 2018, 180-day immune response. Remestemcel-L purportedly secretes alemtuzumab, anti- survival data reported growth factors and anti-inflammatory cytokines that thymocyte globulin) September 2018 facilitate tissue repair by downregulating immune and Calcineurin inhibitors (eg, inflammatory responses of immunocompetent T cells cyclosporine, tacrolimus) contained in the graft. In clinical trials, remestemcel-L is given by intravenous infusion at a dose of 2 × 106 cells/kg Corticosteroids (eg, twice a week for 4 consecutive weeks. methotrexate, mycophenolate mofetil, Developer(s): prednisone) Mesoblast Ltd (Melbourne, Australia, and New York, New mTOR inhibitors (eg, York) sirolimus)
Adults aged 18 to 81 years Rigosertib (Estybon) is a small-molecule, multikinase Immunomodulatory agents Complete remission FDA designation(s): who have myelodysplastic inhibitor with activity against both the α and β isoforms of (eg, lenalidomide) rate Orphan Drug syndrome that has exhibited phosphoinositide 3 kinase (PI3K) and polo-like kinase 1 primary resistance to (PLK1). No effective treatment is available for resistant Overall survival Clinical trial(s): Phase III INSPIRE primary hypomethylating agents (ie, myelodysplastic syndrome, and patients generally have a Quality of life disease progression without poor prognosis when the syndrome has not responded to completed March 2019, attaining a complete or partial treatment with a hypomethylating agent. Inhibiting PI3K is designed under Special response or hematologic intended to disrupt cell signaling that promotes cell growth Protocol Assessment improvement) and survival. Inhibiting PLK1 might disrupt cell division, leading to cell-cycle arrest in cancerous cells. In clinical trials, rigosertib is given intravenously at a dose of 1800 mg daily for 3 days every 2 weeks for 8 cycles, then every 4 weeks until disease progression or intolerable toxicity. Developer(s): Onconova Therapeutics Inc (Newtown, Pennsylvania)
Section 1. Currently Monitored Topics 51
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Women aged 18 years or Robotic-assisted nipple-sparing mastectomy using the Open surgical mastectomy Disease-free survival Clinical trial(s): Phase II older who have invasive da Vinci system has been pioneered by a few European MARCI primary completion breast cancer or ductal investigators to improve cosmesis and patient satisfaction Distant tumor November 2019, carcinoma in situ and are and reduce length of stay after total mastectomy recurrence preliminary data published undergoing total mastectomy compared with open surgery. Compared with open Local tumor September 2018; with immediate breast surgery, da Vinci robotic-assisted mastectomy purportedly recurrence unphased comparing reconstruction facilitates the performance of technically challenging robotic-assisted and open laparoscopic procedures, enhances cosmesis, reduces Overall survival mastectomy primary length of stay, and improves patient satisfaction. In Patient satisfaction completion December clinical trials, surgeons performing the surgery avoid the 2019 nipple-areola tissue by removing the target breast cancer Quality of life tissue through a small incision under the arm (axillary Note(s): FDA issued a Tissue necrosis access). After the robotically assisted steps, a surgeon safety communication on (nipple-areola manually reconstructs the breast using a conventional February 28, 2019. complex) breast implant and standard subcutaneous and cutaneous suturing techniques. Developer(s): Clinical investigators at the European Institute of Oncology (Milan, Italy) and Gustave Roussy Cancer Centre (Villejuif, France)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 55 years or older Romyelocel-L (CLT-008) is a myeloid progenitor cell Growth factors (eg, Overall survival FDA designation(s): who have acute myeloid therapy product. It consists of allogeneic bone marrow– filgrastim, granulocyte Regenerative Medicine leukemia (AML) that has not derived hematopoietic stem cells that are differentiated, colony-stimulating factor) Progression-free Advanced Therapy previously been treated and multiplied in the lab, and frozen for storage before use. In survival Clinical trial(s): Phase II will be treated with induction patients with AML, romyelocel-L is intended to treat Quality of life therapy with cytarabine alone chemotherapy-induced neutropenia, a side effect of CLT008-03 primary or combined with other treatment that can lead to opportunistic infections. completed September antileukemic agents (eg, Romyelocel-L purportedly prevents opportunistic 2017, key data reported anthracyclines, daunorubicin, infections by introducing a population of myeloid June 2018, updated data etoposide, idarubicin, purine progenitor cells able to produce granulocytes, neutrophils, reported November 2018 nucleoside inhibitors) monocytes, macrophages, red blood cells, and platelets that permanently engraft in the bone marrow. It does so while producing few, if any, B lymphocytes and T lymphocytes, which could lead to graft-versus-host complications. In clinical trials, patients receive a single intravenous infusion of romyelocel-L at an unspecified dose. Developer(s): Cellerant Therapeutics Inc (San Carlos, California)
Section 1. Currently Monitored Topics 53
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Selinexor (Xpovio) is a first-in-class, reversible, potent, One or more of the Overall survival Approval date: July 3, 2019 who have relapsed and/or selective inhibitor of nuclear export that specifically binds following: refractory multiple myeloma to and inhibits the nuclear export protein XPO1 (also Progression-free FDA designation(s): (MM) after 2 or more called CRM1). Selinexor’s novel mechanism of action is Alkylating agents (eg, survival Orphan Drug, Fast Track therapies that include intended to provide another treatment option for MM in bendamustine, cyclophosphamide) Quality of life Clinical trial(s): Phase III alkylating agents, heavily treated patients who have a poor prognosis. BOSTON primary angiogenesis inhibitors, anti- Selinexor’s binding to XPO1 purportedly restores nuclear Anthracyclines (eg, completion June 2020; CD38 monoclonal antibodies localization, or the accumulation of tumor suppressor doxorubicin) phase II STORM primary glucocorticoids, and/or proteins in the cell nucleus, thereby restoring and completion April 2019, proteasome inhibitors amplifying their tumor suppressor function. Selinexor Glucocorticoids (eg, topline data reported April might also activate cancer cell death (selective apoptosis) dexamethasone) 2018 while sparing normal cells. In clinical trials, selinexor is Immunomodulatory agents given orally at a dose of 60 to 80 mg twice weekly or (eg, lenalidomide, 100 mg once weekly in combination with various MM pomalidomide, thalidomide) treatments until disease progression or intolerable toxicity. Monoclonal antibodies (eg, daratumumab, elotuzumab) Developer(s): Proteasome inhibitors (eg, Karyopharm Therapeutics Inc (Newton, Massachusetts) bortezomib, carfilzomib, ixazomib) Topoisomerase inhibitors (eg, etoposide)
Adults aged 18 to 80 years Seviprotimut-L (POL-103A) is a polyvalent vaccine (ie, Active surveillance Overall survival FDA designation(s): who have stage IIb, IIc, or III targets multiple melanoma-specific peptides) intended to Orphan Drug melanoma at high risk of induce immune responses against residual melanoma One or more of the Recurrence-free recurrence that has been cells after primary surgery to improve outcomes in following: survival Clinical trial(s): Phase III treated with surgery of the patients at high risk of recurrence. Seviprotimut-L is MAVIS primary completion BRAF inhibitors (eg, January 2019 primary skin lesion generated by isolating peptides secreted by 3 human dabrafenib) melanoma cell lines grown in culture. The isolated peptides are combined with an adjuvant (aluminum Immune checkpoint hydroxide) to generate the vaccine. The vaccine’s inhibitors (eg, nivolumab, polyvalent nature purportedly allows its use in all patients pembrolizumab) irrespective of tumor and/or human leukocyte antigen MEK inhibitors (eg, genotypes. In clinical trials, seviprotimut-L is given as a trametinib) set of 4 injections (0.2 mL each) into the volar surface of the forearms and anterior upper thighs. Developer(s): Polynoma LLC (San Diego, California)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 1 month to 18 Sodium thiosulfate (Pedmark) is intended to reduce the Platinum-based Hearing ability Submission date: Rolling years who have localized, risk of cisplatin-induced ototoxicity, a common side effect chemotherapy (eg, New Drug Application nonmetastatic, solid tumors in children that can damage hearing and for which no cisplatin) alone without Ototoxicity initiated December 2018, eligible for cisplatin effective treatment is available. It is a proprietary adjuvant preventive Quality of life completion expected by chemotherapy formulation that inactivates the metabolic byproducts of therapy 2020 systemic platinum-based (cisplatin) chemotherapy. Sodium thiosulfate purportedly acts only on cisplatin FDA designation(s): metabolites in general circulation and does not interfere Orphan Drug, Fast Track, with cisplatin effectiveness within targeted tumor cells. In Breakthrough Therapy clinical trials, sodium thiosulfate is given intravenously at Clinical trial(s): Phase III a dose of 16 g/m2 or 533 mg/kg, 6 hours after receiving completed April 2015, data cisplatin-based chemotherapy. Treatment with sodium published January 2017; thiosulfate continues until completion of cisplatin phase III SIOPEL6 treatment. completed September Developer(s): 2017, data published June 2018 Fennec Pharmaceuticals Inc (Research Triangle Park, North Carolina)
Adults aged 18 years or older Synthetic hypericin (SGX301) is a photosensitizing agent Chemotherapy Damage to tumor- FDA designation(s): who have newly diagnosed for use with visible light to treat CTCL. Standard care for adjacent tissue Orphan Drug, Fast Track patch/plaque-phase CTCL often requires photodynamic therapy with Ultraviolet A phototherapy cutaneous T-cell lymphoma ultraviolet light, which can damage surrounding tissue and with psoralen Overall survival Clinical trial(s): Phase III (CTCL) that has not been lead to skin burns, increased pigmentation, or secondary FLASH primary completion Ultraviolet B phototherapy Progression-free December 2019 treated with systemic therapy skin cancer. SGX301 purportedly clears CTCL lesions survival without increasing the patient’s risk for skin burns. In clinical trials, SGX301 is applied topically to the CTCL Quality of life 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 55
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Children and adults of all Tabelecleucel (Tab-cel) is a chimeric antigen receptor One or more of the Overall survival Submission date: Biologics ages who received an (CAR) T-cell immunotherapy engineered to provide following: License Application allogeneic hematopoietic cell specific immune responses against EBV using unrelated Progression-free planned for the second half transplant or solid organ and haploidentical (half-match) cytotoxic T lymphocytes Adrenocortical steroid (eg, survival of 2020 transplant and developed (CTLs). Haploidentical CTLs are typically obtained from a prednisolone) Quality of life FDA designation(s): Epstein-Barr virus– parent or child or, in some cases, a sibling. Tabelecleucel Alkylating agent (eg, associated posttransplant purportedly provides immunity against EBV-associated Orphan Drug, cyclophosphamide, Breakthrough Therapy lymphoproliferative disorder cancers in patients who have received a hematopoietic dacarbazine) (EBV+PTLD) that does not cell transplant or organ transplant. EBV+PTLD can be Clinical trial(s): Phase III respond to rituximab hard to treat with standard therapies, and treatment is Anthracyclines (eg, MATCH primary associated with many comorbidities. CAR genes are doxorubicin) completion November delivered to the CTLs with an adenovirus vector (AdE1- Antitumor antibiotic (eg, 2020; phase III ALLELE LMPpoly), which targets specific regions of the EBV bleomycin) primary completion nuclear antigen 1, latent membrane protein 1, and latent November 2020 membrane protein 2A. AdE1-LMPpoly also encodes for a Vinca alkaloid (eg, PD-1-dominant negative receptor to shield the CAR CTLs vinblastine, vincristine) from being downregulated (checkpoint inhibition). The EBV-specific CAR-transduced CTLs are proliferated and frozen until treatment, and then thawed. In clinical trials, tabelecleucel is given as an intravenous infusion at a dose of 2 × 106 cells/kg on days 1, 8, and 15 of a 35-day cycle until maximal response or unacceptable toxicity. Developer(s): Atara Biotherapeutics Inc (South San Francisco, California), in collaboration with Memorial Sloan Kettering Cancer Center (New York, New York)
Section 1. Currently Monitored Topics 56
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Tesetaxel is being developed as the only orally given drug One or more of the Overall survival Clinical trial(s): Phase III who have human epidermal in the taxane class (eg, docetaxel, nab-paclitaxel, following: CONTESSA primary growth factor receptor 2 paclitaxel). Taxanes inhibit mitosis (duplicative cell Progression-free completion September (HER2)-negative, hormone division) and are frequently used to treat breast cancer. Anthracyclines (eg, survival 2020 doxorubicin, liposomal receptor–positive, locally However, available taxanes are formulated only as Quality of life advanced, or metastatic intravenous infusions and are frequently associated with doxorubicin) breast cancer previously hypersensitivity reactions because of additives needed as Antimetabolites (eg, treated with a taxane in the part of the taxane infusion solution. Breast cancer also capecitabine, gemcitabine) neoadjuvant or adjuvant develops resistance over time to these infused taxanes, setting but oral tesetaxel has demonstrated anticancer activity in Microtubule inhibitors (eg, tumors that have previously been exposed to other eribulin, vinorelbine) taxanes and developed resistance. Thus, oral tesetaxel Poly adenosine might provide a more convenient and comfortable diphosphate-ribose administration route that improves adherence, as well as polymerase (PARP) a treatment option when other taxanes become Inhibitors (eg, olaparib, 2 ineffective. In clinical trials, tesetaxel (27 mg/m once talazoparib) for BRCA 1/2 every 21 days on day 1 of each cycle) is being used in mutated breast cancer an all-oral regimen in combination with low-dose capecitabine until disease progression or intolerable Taxanes (eg, docetaxel, toxicity. paclitaxel) Developer(s): Odonate Therapeutics Inc (San Diego, California)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Trastuzumab deruxtecan (DS-8201) is a monoclonal One or more of the Overall survival Clinical trial(s): Phase III who have locally advanced or antibody conjugated with a chemotherapy drug following: DESTINY-Breast04 metastatic, hormone receptor (deruxtecan) designed to bind to the surface receptor Progression-free primary completion (HR)–positive or HR- HER2, a protein commonly associated with certain Alkylating agents (eg, survival January 2023 cyclophosphamide) negative, human epidermal subtypes of breast cancer. Front-line therapy for breast Quality of life growth factor receptor 2 cancers expressing low HER2 levels relies on single- Anthracyclines (eg, (HER2)–low breast cancer agent chemotherapy, but no therapies are approved doxorubicin, epirubicin, that has progressed or specifically for low HER2–expressing tumors, and liposomal doxorubicin) recurred after 1 or 2 previous trastuzumab deruxtecan might provide a new option for lines of systemic therapy these patients. Deruxtecan inhibits the activity of Antimetabolites (eg, 5- topoisomerase I, an enzyme that relieves DNA fluorouracil, capecitabine, supercoiling, leading cells to cease their cell cycle and gemcitabine, methotrexate, die because of replication-dependent, site-selective, pemetrexed) DNA double-strand breaks. Trastuzumab deruxtecan Immune checkpoint purportedly binds to HER2 and triggers internalization of inhibitors (eg, the drug into the cells. This increases the likelihood that atezolizumab) deruxtecan will target and kill malignant cells while minimizing toxicity on normal cells. In clinical trials, Microtubule inhibitors (eg, trastuzumab deruxtecan is given intravenously at a dose eribulin, ixabepilone) of 5.4 mg/kg once every 21 days until disease Poly adenosine progression or intolerable toxicity. diphosphate-ribose Developer(s): polymerase (PARP) inhibitors (eg, olaparib, Daiichi Sankyo Co Ltd (Tokyo, Japan), in collaboration talazoparib) with AstraZeneca (Cambridge, United Kingdom) Platinum agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, nab-paclitaxel, paclitaxel) Vinca alkaloids (eg, vinorelbine)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 75 years Uproleselan (GMI-1271) inhibits E-selectin, a One or more of the Complete remission FDA Designation(s): who have relapsed or transmembrane glycoprotein that functions as a cell following: rate Orphan Drug, refractory acute myeloid adhesion molecule. Uproleselan might provide a new Breakthrough Therapy, leukemia (AML) treatment option for a population of patients with typically Anthracyclines (eg, Overall survival Fast Track poor prognosis and outcomes. E-selectin retains daunorubicin, idarubicin) Quality of life Clinical trial(s): Phase III AML cells within the vascular niches of the bone marrow, Antibody–drug conjugate where these cells are less susceptible to cytotoxic primary completion (eg, gemtuzumab December 2020 chemotherapy. Uproleselan purportedly inhibits ozogamicin) E-selectin’s cell adhesion activity, mobilizing AML cells out of bone marrow and into the bloodstream and Antimetabolites (eg, rendering them more sensitive to chemotherapy. In cladribine, clofarabine, clinical trials, uproleselan is being given in combination cytarabine, fludarabine) with standard induction chemotherapy regimens (ie, Cytokine (eg, granulocyte mitoxantrone, etoposide, and cytarabine or fludarabine, colony-stimulating factor) cytarabine, and idarubicin). Uproleselan at a dose of 10 mg/kg is given intravenously. DNA synthesis inhibitors (eg, etoposide, Developer(s): mitoxantrone) GlycoMimetics Inc (Rockville, Maryland) FLT3 inhibitor (eg, gilteritinib) Hypomethylating agents (eg, azacitidine, decitabine) IDH inhibitors (eg, enasidenib, ivosidenib) Multikinase inhibitor (eg, sorafenib)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Patients of any age who have Varlitinib (ASLAN001) is a small-molecule inhibitor of the One or more of the Overall survival FDA designation(s): locally advanced or epidermal growth factor receptor (EGFR) family of following: Orphan Drug metastatic biliary tract cancer receptor tyrosine kinases, including human EGFR human Progression-free (eg, cholangiocarcinoma, gall epidermal growth factor receptor 1 (HER1), HER2, and Antimetabolites (eg, 5- survival Clinical trial(s): Phase II/III fluorouracil, capecitabine, TreeTopp primary bladder cancer, carcinoma of HER4. Because no EGFR inhibitors have been approved Quality of life ampulla of Vater) that has for biliary tract cancer, this might offer an option for these gemcitabine) completion July 2019 previously been treated with patients, who have few effective treatments, particularly in Immune checkpoint one line of gemcitabine- the second-line setting. EGFR signaling promotes biliary inhibitors (eg, nivolumab, based systemic therapy tract cell growth and proliferation, and most biliary tract pembrolizumab) for cancers overexpress EGFR. Therefore, inhibiting the patients with defects in EGFR family of receptor tyrosine kinases might have mismatch repair or efficacy in these cancers. In clinical trials, varlitinib is microsatellite instability given orally at a dose of 300 mg twice daily in combination with capecitabine until disease progression Platinum agents (eg, or intolerable toxicity. cisplatin, oxaliplatin) Developer(s): Aslan Pharmaceuticals (Singapore, Republic of Singapore), in collaboration with Array BioPharma Inc (Boulder, Colorado)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Women aged 18 to 99 years Veliparib (ABT-888) is a small-molecule inhibitor of poly One or more of the Overall survival Clinical trial(s): Phase III who have stage III or IV, adenosine diphosphate-ribose polymerase (PARP), an following: M13-694 primary high-grade, epithelial ovarian, enzyme involved in DNA repair. Veliparib is the first Progression-free completion July 2019 fallopian tube, or primary PARP inhibitor studied in the first-line treatment setting Angiogenesis inhibitors survival (eg, bevacizumab) peritoneal carcinoma that and is intended to delay disease progression in the Quality of life harbors germline mutations in maintenance setting. By inhibiting PARP’s DNA repair, Anthracyclines (eg, the breast cancer gene, veliparib might potentiate the anticancer activity of doxorubicin, pegylated BRCA, and has not cytotoxic chemotherapy drugs whose mechanism of liposomal doxorubicin) previously been treated action induces DNA damage. Additionally, PARP inhibition might exhibit synthetic lethality with cells Platinum agents (eg, harboring loss-of-function mutations in the breast cancer carboplatin, cisplatin) 1 gene, BRCA1, and/or the breast cancer 2 gene, BRCA2 Taxanes (eg, docetaxel, (an ovarian cancer predisposition gene that is also nab-paclitaxel, paclitaxel) involved in DNA repair); ovarian cancers frequently harbor such mutations. Eligibility for treatment will require testing for BRCA mutation status. In clinical trials, veliparib is given orally each day at an unspecified dose in combination with carboplatin and paclitaxel for 6 cycles of 21 days. Veliparib maintenance therapy is given for up to 30 additional 21-day cycles. Developer(s): AbbVie Inc (North Chicago, Illinois)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Women aged 18 years or VGX-3100 is a DNA-based immunotherapy vaccine Colposcopy followed by Incidence of cervical Clinical trial(s): Phase III older who have cervical high- containing plasmids that include expression cassettes for one of the following HSIL REVEAL 1 primary grade squamous HPV proteins E6 and E7. It is intended to offer a procedures to remove completion April 2020; intraepithelial lesion (HSIL) nonsurgical approach to treat certain precancerous cervical lesions: Incidence of infection phase III REVEAL 2 and confirmed infection with cervical lesions that are typically treated surgically. As a with HPV 16 and/or primary completion April human papillomavirus (HPV) noninvasive intervention, once VGX-3100’s optimized Carbon dioxide laser HPV 18 2021 type 16 and/or 18 DNA is delivered into cells, it is translated into the E6 and ablation Quality of life Note(s): VGX-3100 is also E7 proteins that act as antigens to induce targeted T-cell Cold knife cone biopsy and antibody response. VGX-3100 purportedly uses this being studied to treat immune system response to clear HPV-16 and HPV-18 Laser cone biopsy vulvar and anal HSIL. infections and precancerous lesions, enabling patients to Loop electrosurgical avoid the risks associated with surgery, such as loss of excision reproductive health and negative psychosocial impacts. In clinical trials, VGX-3100 is given as an intramuscular injection followed by electroporation with the Cellectra- 5PSP device on day 0, week 4, and week 12 to introduce the plasmid DNA into cells. Developer(s): Inovio Pharmaceuticals Inc (Plymouth Meeting, Pennsylvania)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 75 years Vocimagene amiretrorepvec (Toca 511) is a cancer- Fractionated external beam Overall survival FDA designation(s): who have recurrent high- selective gene therapy containing a retroviral replicating radiation therapy Orphan Drug, grade glioma (eg, vector that stably inserts itself into the genome of dividing Progression-free Breakthrough Therapy, glioblastoma multiforme cells. Toca 511 has been genetically modified to encode One or more of the survival Fast Track following: [GBM], anaplastic (create) the enzyme cytosine deaminase, a prodrug Quality of life astrocytoma) that has been activator enzyme that converts the orally given antifungal Clinical trial(s): Phase II/III Alkylating agents (eg, Toca5 primary completion treated with surgery and prodrug Toca FC (5-fluorocytosine) to the anticancer carmustine, adjuvant radiation and agent 5-fluorouracil (5-FU) in cells. Toca 511 is intended December 2019, interim cyclophosphamide, data reported August 2018 temozolomide to improve outcomes by generating high levels of 5-FU in lomustine, procarbazine, replicating glioma cells to cause cell death. In clinical temozolomide) 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) given orally at a dose of 220 mg/kg/day for 7-day courses mTOR inhibitors (eg, and repeated about every 6 weeks. everolimus) Developer(s): Platinum agents (eg, Tocagen Inc (San Diego, California) carboplatin, cisplatin) Vinca alkaloids (eg, vincristine)
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Table 3. Cardiovascular: 16 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Apabetalone is a novel epigenetic selective inhibitor of Guideline-directed drug All-cause mortality Clinical trial(s): Phase III who have type 2 diabetes bromodomain extra-terminal (BET) proteins intended to therapy (eg, aspirin, beta BETonMACE primary mellitus (T2DM) and high-risk reduce incidence of major adverse cardiac events blockers, calcium Kidney function completion November coronary artery disease (ie, (MACE) in high-risk patients with T2DM. By blocking channel blockers, MACE 2019 acute coronary syndrome BET proteins at the transcription level, apabetalone nitrates, ranolazine) with myocardial infarction or purportedly slows the abnormally increased production of unstable angina within the dysregulated, disease-associated proteins, moving them past 90 days) and a low level closer to normal levels. Apabetalone is intended to reduce of high-density lipoprotein MACE by reducing various mediators that promote cholesterol vascular inflammation, calcium deposition, coagulation cascade, and other mechanisms, including metabolism, cholesterol transport, and the complement cascade. In clinical trials, apabetalone is given as a 100-mg capsule, twice daily. Developer(s): Resverlogix Corp (Calgary, Alberta, Canada)
Adults aged 18 to 85 years Bempedoic acid is a small-molecule prodrug converted to Bile-acid-binding resins MACE PDUFA date: February 21, who have atherosclerotic an active drug primarily in the liver and designed to inhibit 2020 coronary artery disease, adenosine triphosphate citrate lyase (ACL), a key enzyme Ezetimibe Survival Clinical trial(s): Phase III symptomatic peripheral involved in cholesterol and fatty acid synthesis in the liver. Fibrates arterial disease, or As an oral drug that might replace statins as a primary CLEAR Outcomes primary cerebrovascular disease; cholesterol-lowering agent, bempedoic acid might be Niacin completion December 2021 low-density lipoprotein level more cost-effective and more widely accepted than Proprotein convertase of 100 (2.6 mmol/L) or higher; injectable proprotein convertase subtilisin kexin 9 subtilisin kexin 9 a high risk of an adverse (PCSK9) inhibitors for managing disease in patients who (PCSK9)–inhibiting cardiovascular event; and a cannot tolerate statins. By inhibiting ACL, bempedoic acid monoclonal antibodies history of intolerance to 2 or purportedly reduces cholesterol synthesis, thereby more statin drugs upregulating low-density lipoprotein (LDL) receptors and increasing clearance of LDL cholesterol from the bloodstream. In clinical trials, bempedoic acid is taken as a 180-mg oral tablet, once daily. Developer(s): Esperion Therapeutics Inc (Ann Arbor, Michigan)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 21 to 90 years CardiAMP cell therapy is a regenerative medicine therapy Guideline-directed Exercise tolerance Clinical trial(s): Phase III who have New York Heart that transplants a patient’s own bone marrow–derived optimal drug therapy (eg, CardiAMP primary Association (NYHA) mononuclear cells to damaged heart muscle. It is angiotensin-converting HF-related completion June 2020 functional class II or III heart intended to improve heart function and exercise capacity enzyme [ACE] inhibitors, hospitalizations failure (HF) with chronic through 2 mechanisms: direct and indirect regeneration. diuretics, hydralazine, NYHA HF functional ischemic left ventricular In direct regeneration, the transplanted cells purportedly ivabradine, class dysfunction secondary to travel to the injured heart muscle (myocardium) and sacubitril/valsartan) myocardial infarction and transform it into new functional heart cells. In indirect Quality of life ventricular ejection fraction regeneration, the transplanted cells purportedly secrete Survival between 20% and 40% that stimulatory cytokines to instruct resident stem cells to is stable and being treated regenerate heart tissue. Clinicians first collect about 15 cc with guideline-directed of bone marrow and send it to a partner laboratory for medical and device therapy proprietary molecular analysis to estimate a candidate’s likelihood of successful cell therapy. If test results are positive, patients return to the cardiac catheterization laboratory after 3 or more days to undergo the procedure. Clinicians collect about 60 cc of bone marrow from the patient to concentrate a sufficient dose of autologous cells at the point of care and inject the prepared cell product into the myocardium, using a proprietary needle-injection catheter. Patients are discharged the same or next day. Developer(s): BioCardia Inc (San Carlos, California)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 21 to 80 years CardiAMP cell therapy is a regenerative medicine therapy Enhanced external Angina incidence Clinical trial(s): Phase III who have Canadian that transplants a patient’s own bone marrow–derived counterpulsation CardiAMP CMI primary Cardiovascular Society class mononuclear cells to damaged heart muscle to improve Coronary adverse events completion December Guideline-directed drug III or IV chronic refractory heart function and exercise capacity. The developer Exercise tolerance 2022 angina from obstructive asserts that improving heart function could also reduce therapy (eg, aspirin, beta coronary artery disease that angina incidence in patients who are not candidates for blockers, calcium Quality of life channel blockers, is unsuited for conventional conventional revascularization procedures for ischemic Survival revascularization coronary artery disease. CardiAMP therapy purportedly nitrates, ranolazine) improves heart function through 2 mechanisms: direct and indirect regeneration. In direct regeneration, the transplanted cells purportedly travel to the injured heart muscle (myocardium) and transform it into new functional heart cells. In indirect regeneration, the transplanted cells purportedly secrete stimulatory cytokines to instruct resident stem cells to regenerate heart tissue. Clinicians first collect about 15 cc of bone marrow and send it to a partner laboratory for proprietary molecular analysis to estimate a candidate’s likelihood of successful cell therapy. If test results are positive, patients return to the cardiac catheterization laboratory after 3 or more days to undergo the procedure. Clinicians collect about 60 cc of bone marrow from the patient to concentrate a sufficient dose of autologous cells at the point of care and inject the prepared cell product into the myocardium, using a proprietary needle-injection catheter. Patients are discharged the same or next day. Developer(s): BioCardia Inc (San Carlos, California)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 21 to 80 years CLBS14 is an autologous CD34+ cell therapy intended to Enhanced external Angina incidence FDA designation(s): who have Canadian reduce angina by stimulating the growth of new counterpulsation Regenerative Medicine Cardiovascular Society class microvasculature (angiogenesis) in ischemic myocardial Exercise capacity Advanced Therapy III or IV chronic refractory tissue. CLBS14 is intended to improve medical therapy Guideline-directed optimal drug therapy (eg, Major adverse cardiac Clinical trial(s): Phase III angina and obstructive for patients with drug-resistant angina for whom events (MACE) coronary disease unsuited for conventional revascularization is ineffective or unsuitable. aspirin, beta blockers, RENEW completed conventional During the proprietary process, patients receive calcium channel Quality of life November 2015, pivotal blockers, nitrates, data published August revascularization granulocyte colony-stimulating factor (5-mg/kg Survival subcutaneous injection) for about 4 days to mobilize their ranolazine) 2016 own CD34+ cells before apheresis (plasma exchange) on day 5 to collect cells from peripheral blood. Clinicians ship peripheral blood to a processing laboratory to isolate CD34+ cells and prepare the cell therapy product for transport back to the treating facility. After about 3 to 4 days, clinicians administer the cell product into ischemic heart muscle via catheter-based intramyocardial injection. Developer(s): Caladrius Biosciences Inc (Basking Ridge, New Jersey) acquired exclusive worldwide license from Shire plc (Dublin, Ireland), which is now part of Takeda Pharmaceutical Co Ltd (Osaka, Japan)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 45 years or older Dalcetrapib is an inhibitor of cholesteryl ester transfer Guideline-directed Major adverse cardiac Clinical trial(s): Phase III who have a confirmed AA protein (CETP), a plasma protein responsible for lipid optimal drug therapy (eg, events (MACE), dal-GenE primary polymorphism at the transport. Dalcetrapib was originally intended to raise ACE inhibitors, aspirin, including cardiovascular completion August 2020 rs1967309 location in the high-density lipoprotein levels by modulating CETP beta blockers, calcium death, myocardial adenylate cyclase type 9 activity and lower cardiovascular risk by helping to lower channel blockers, infarction, and stroke gene, ADCY9, and were levels of harmful low-density lipoproteins. However, statins) recently hospitalized for although dalcetrapib failed to reduce cardiovascular acute coronary syndrome events in large phase III trials, patients treated with Proprotein convertase dalcetrapib who carried the AA polymorphism at the subtilisin kexin 9 rs1967309 location in the ADCY9 gene showed a 39% (PCSK9) inhibitors drop in cardiovascular adverse events. DalCor licensed dalcetrapib and the AA allele genetic marker from Roche for use in a genetically defined subpopulation that has an increased cardiovascular risk. Roche is developing a companion diagnostic test to identify potential candidates for dalcetrapib therapy in a phase III trial, which is also testing the drug. Dalcetrapib is given orally, 600 mg, once daily. Developer(s): DalCor Pharmaceuticals (Montreal, Québec, Canada), in collaboration with F Hoffmann-La Roche Ltd (Basel, Switzerland)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Inclisiran is an RNA interference (RNAi) therapeutic Bile-acid sequestrants Major adverse cardiac Clinical trial(s): Phase III who have heterozygous designed to target and reduce the expression of events (MACE) ORION-9 primary familial hypercholesterolemia proprotein convertase subtilisin kexin type 9 (PCSK9) to Fibrates completion September Survival and an elevated low-density treat hypercholesterolemia. Inhibiting PCSK9 production Niacin 2019 lipoprotein (LDL) cholesterol purportedly increases the number of LDL receptors that level despite maximum lipid- are recycled and are available on cell surfaces to remove Proprotein convertase lowering therapies LDL particles from extracellular fluid. Inclisiran is intended subtilisin kexin 9 to simplify the dosing regimen as a subcutaneous (ie, (PCSK9)–inhibiting under the skin) injection every 3 to 6 months rather than monoclonal antibodies an injection of alirocumab or evolocumab every 2 to Statins 4 weeks. In clinical trials, 300 mg of inclisiran is given subcutaneously on days 1 and 90 and then every 6 months. Developer(s): The Medicines Company (Parsippany, New Jersey), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)
Adults aged 18 years or older Inclisiran is an RNAi therapeutic designed to target and Bile-acid sequestrants Major adverse cardiac Clinical trial(s): Phase III who have atherosclerotic reduce the expression of proprotein convertase subtilisin events (MACE) ORION-10 primary cardiovascular disease kexin 9 PCSK9 to treat hypercholesterolemia (high Fibrates completion October 2019 Survival (coronary, peripheral, or cholesterol). Inhibiting PCSK9 production purportedly Niacin other arteries) and elevated increases the number of LDL receptors that are recycled low-density lipoprotein (LDL) and are available on cell surfaces to remove LDL particles Proprotein convertase cholesterol (greater than 70 from extracellular fluid. Inclisiran is intended to simplify subtilisin kexin 9 mg/dL) despite an optimal the dosing regimen as a subcutaneous (ie, under the (PCSK9)–inhibiting dose of statins or other lipid- skin) injection every 3 to 6 months rather than an injection monoclonal antibodies lowering therapies if statin- of alirocumab or evolocumab every 2 to 4 weeks. In Statins intolerant clinical trials, 300 mg of inclisiran is given subcutaneously on days 1 and 90 and then every 6 months. Developer(s): The Medicines Company (Parsippany, New Jersey), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 85 years Inotersen (Tegsedi) is an antisense oligonucleotide being Liver transplant Cardiac function FDA designation(s): who have cardiomyopathy developed for use in patients with hATTR amyloidosis– Orphan Drug from hereditary transthyretin- associated cardiomyopathy, a progressive disease Small interfering RNAs Clinical trial(s): Phase II mediated (hATTR) caused by a mutation in the transthyretin gene, TTR. TTR tetramer stabilizers amyloidosis Inotersen is intended to treat the underlying disease primary completion process, rather than the symptoms. In patients with January 2022 hATTR amyloidosis, misfolded and wild-type TTR Note(s): FDA has approved proteins, which are made in the liver and accumulate as this drug for use in patients amyloid deposits in the heart, central and peripheral with polyneuropathy nerves, and gastrointestinal tract. These deposits block caused by hATTR normal organ functions and cause symptoms such as amyloidosis. autonomic dysfunction, cardiomyopathy, and polyneuropathy. Inotersen purportedly reduces production of mutant (ie, caused by a genetic variant in the transthyretin gene) and wild-type (ie, not caused by any known genetic variant) TTR, and thus reduces or prevents amyloid deposit accumulation. In clinical trials, 300 mg of inotersen is given subcutaneously, once weekly, for 24 months. Developer(s): Akcea Therapeutics (Cambridge, Massachusetts), a subsidiary of Ionis Pharmaceuticals (Carlsbad, California)
Adults aged 18 to 85 years Omecamtiv mecarbil is a cardiac myosin activator Guideline-directed Heart failure–related Clinical trial(s): Phase III who have chronic heart intended to increase the duration of cardiac muscle optimal drug therapy (eg, hospitalization GALACTIC-HF primary failure, New York Heart contractility and improve cardiac muscle performance. angiotensin-converting completion February 2021, Association (NYHA) The mechanism of action purportedly improves cardiac enzyme [ACE] inhibitors, Improved exercise designed under Special functional class II to IV; left muscle performance without increasing cellular calcium diuretics, hydralazine, tolerance Protocol Assessment; ventricular ejection fraction of concentrations that can occur with other common heart ivabradine, NYHA heart failure phase III METEORIC-HF 35% or less despite failure drugs, thereby avoiding risk of increasing heart sacubitril/valsartan) functional class primary completion maximally tolerated, rate, blood pressure, and arrhythmias. In clinical trials, February 2021 guideline-directed medical omecamtiv mecarbil is given orally at 25 to 50 mg, twice Quality of life therapy; and elevated levels daily. Survival of B-type natriuretic peptide or N-terminal pro B-type Developer(s): natriuretic peptide Cytokinetics Inc (South San Francisco, California), in collaboration with Amgen Inc (Thousand Oaks, California)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Optimizer is a cardiac implant that uses a process called Guideline-directed Exercise tolerance Approval date: March 21, who have New York Heart cardiac contractility modulation (CCM) to deliver optimal drug therapy (eg, 2019 Association (NYHA) nonexcitatory electrical pulses during the myocardial angiotensin-converting Heart failure–related functional class III heart absolute refractory period to improve systolic contraction. enzyme [ACE] inhibitors, hospitalization FDA designation(s): Breakthrough Device failure and are symptomatic CCM purportedly normalizes phosphorylation of diuretics, hydralazine, NYHA heart failure with left ventricular ejection regulatory proteins to improve calcium handling— ivabradine, functional class Clinical trial(s): Unphased fraction of 25% to 45% ultimately interrupting the remodeling cascade (ie, sacubitril/valsartan) FIX-HF-5C2 primary despite guideline-directed changes in size and shape) to reverse enlargement of the Quality of life completion November medical therapy and normal left ventricle—and to improve left ventricular contractile Survival 2019; unphased FIX-HF- sinus rhythm (ie, pumping) strength. The Optimizer Smart model 5CA primary completion replaced all earlier Optimizer versions (II, III, IV) used in January 2020; unphased clinical trials since 2016. Physicians implant the pulse postapproval registry generator under the skin in the right pectoral region primary completion July similarly to standard pacemaker or defibrillator 2022 implantation. Two standard pacemaker leads are placed through major blood vessels into the right ventricle on the right ventricular septum to sense local electrical activity and deliver CCM. An optional atrial lead may be placed in the right atrium for additional electrical sensing. The device delivers pulses at regular intervals during the day, purportedly unnoticed by patients. Patients recharge the pulse generator at home for 60 to 90 minutes once a week, using a noninvasive charging system placed over the implant. Developer(s): Impulse Dynamics (USA) Inc (Orangeburg, New York)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 45 to 99 years Placental expanded cells to treat peripheral artery Guideline-directed Ischemic pain FDA designation(s): Fast who have critical limb disease (PLX-PAD) are mesenchymal-like adherent optimal drug therapy (eg, Track, Expanded Access ischemia and ischemic stromal cells derived from full-term human placentas and angiotensin-converting Major amputation Program (EAP), EAP Cost lesions with minor tissue loss cultured in a proprietary bioreactor. PLX-PAD cells enzyme [ACE] inhibitors, Wound healing in the Recovery up to the ankle level purportedly release cytokines, chemokines, and growth aspirin, cilostazol, treated leg (Rutherford category 5) and factors to promote new blood vessel growth (ie, clopidogrel, statins) Clinical trial(s): Phase III are deemed unsuitable for angiogenesis) and increase circulation in ischemic tissue, PACE primary completion peripheral artery induce muscle tissue regeneration, and modulate Proprotein convertase May 2020 revascularization by any inflammation to reduce connective tissue deposition and subtilisin kexin 9 conventional method scarring. The cell product is given by intramuscular (PCSK9) inhibitors injection to the affected leg. Developer(s): Pluristem Therapeutics Inc (Haifa, Israel)
Adults aged 18 to 80 years Rexlemestrocel-L (Revascor) is a regenerative cellular Guideline-directed Exercise tolerance Clinical trial(s): Phase III who have chronic (at least 6- therapy made from human bone marrow–derived, optimal drug therapy (eg, DREAM HF-1 primary month duration) ischemic or allogeneic adult mesenchymal precursor cells. Standard angiotensin-converting Heart failure–related completion December nonischemic New York Heart medical therapy for heart failure attempts to slow disease enzyme [ACE] inhibitors, hospitalizations 2019 Association (NYHA) progression and relieve symptoms. Rexlemestrocel-L diuretics, hydralazine, NYHA heart failure Note(s): FDA granted functional class II or III heart purportedly releases a range of factors that induce ivabradine, functional class failure while being treated functional recovery within damaged heart tissue by sacubitril/valsartan) Orphan Drug designation with maximally tolerated activating multiple pathways to induce new blood vessel Quality of life in June 2019 for preventing mucosal bleeding after left- doses of a beta blocker, an growth, reduce inflammation, reduce fibrosis and scar Survival ACE inhibitor or angiotensin- tissue formation, and regenerate heart muscle. ventricular-assist device receptor blocker, and/or an Rexlemestrocel-L is isolated from bone mononuclear cells implantation in adults with aldosterone antagonist, plus with antistromal precursor antigen (STRO)-3 antibodies, end-stage heart failure. a diuretic expanded in a laboratory, and cryopreserved until it is given. The product is intended to be an off-the-shelf therapy given as a single injection of 25 million to 150 million cells delivered into the endocardium using standard cardiac catheterization techniques. Developer(s): Mesoblast Ltd (Melbourne, Australia)
Section 1. Currently Monitored Topics 72
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 80 years RT-100 (human adenovirus 5 encoding human AC6 Guideline-directed Exercise tolerance FDA designation(s): Fast who have New York Heart [Ad5.hAC6]) is an adenovirus-based gene therapy optimal drug therapy (eg, Track Association (NYHA) product intended to improve heart function in patients with angiotensin-converting Heart failure–related functional class II to IV heart chronic heart failure by increasing expression of the enzyme [ACE] inhibitors, hospitalizations Clinical trial(s): Phase III failure and left ventricular adenylyl cyclase type 6 (AC6) protein. AC6 helps regulate diuretics, hydralazine, FLOURISH withdrawn NYHA heart failure June 2019, to reevaluate ejection fraction between heart function but is underexpressed in heart muscle cells ivabradine, functional class 10% and 35% despite of patients with heart failure. RT-100 is an adenovirus sacubitril/valsartan) product development guideline-directed optimal vector (Ad5.hAC6) modified to prevent it from replicating. Quality of life strategy medical therapy It is designed to enter heart cells to deliver the gene Survival encoding for AC6. A physician uses standard cardiac catheterization techniques to administer a single dose of RT-100 into the coronary arteries using an infusion catheter. In a phase II trial, patients received 1 of 5 ascending doses from 3.2 × 109 to 3.2 × 1012 virus particles. Dose levels in the phase III trial have not yet been reported. Developer(s): Renova Therapeutics (San Diego, California)
Section 1. Currently Monitored Topics 73
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Wireless Stimulation Endocardially for Cardiac Conventional Exercise tolerance Clinical trial(s): IDE pivotal who have heart failure and Resynchronization Therapy (WiSE-CRT) system biventricular (SOLVE CRT) primary New York Heart Association purportedly improves on conventional CRT devices. It pacing/cardiac Heart failure–related completion September (NYHA) class I or IIa replaces epicardial left ventricular pacing stimulation from resynchronization hospitalizations 2019; CT Guided WiSE- guideline indication for an electrode lead placed within the coronary sinus vein therapy with epicardial NYHA heart failure CRT primary completion conventional cardiac along the left ventricular wall with endocardial left left ventricular lead functional class December 2020 resynchronization therapy ventricular pacing from a wireless electrode implanted (CRT) and whose disease inside the left ventricle. A conventional pacemaker Guideline-directed Quality of life optimal drug therapy (eg, has not responded to CRT or implanted under the skin in the chest senses and paces Survival was previously untreatable the right ventricle with a conventional right atrial lead and angiotensin-converting (ie, had an implanted CRT a right ventricular lead. A wireless electrode (2.7 × 16.3 enzyme [ACE] inhibitors, system turned off due to mm) anchored in the left ventricular wall paces the left diuretics, hydralazine, electrode lead failure or ventricle. A wireless transmitter placed under the skin in ivabradine, relative contraindications to the chest senses the right ventricular pacing and sends sacubitril/valsartan) an implanted lead) ultrasound energy to the implant to generate endocardial left ventricular pacing synchronized with right-sided pacing. A battery pack placed under the skin along the patient’s ribs and under the arm powers the wireless transmitter via a thin cable tunneled under the skin. Developer(s): EBR Systems Inc (Sunnyvale, California)
Section 1. Currently Monitored Topics 74
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 22 years or older Woven EndoBridge (WEB) Aneurysm Embolization Balloon-assisted or Balloon-assisted or Approval date: December who have (1) a saccular, System is intended to treat wide-necked, bifurcated stent-assisted stent-assisted 31, 2018 wide-necked, bifurcated intracranial aneurysms by preventing blood flow into the endovascular coiling endovascular coiling intracranial aneurysm at the aneurysm sac, thereby averting potential rupture. This Clinical trial(s): WEB-IT middle cerebral artery first-in-class intrasaccular aneurysm embolization device Flow-diverting stents Flow-diverting stents single-arm IDE study (no phase reported) ongoing bifurcation, internal carotid is intended to provide more complete aneurysm occlusion Surgical clipping Surgical clipping artery terminus, anterior than that achieved with flow-diversion stents, while primary completion communicating artery reducing the need for long-term antiplatelet therapy. September 2017, pivotal complex, or basilar artery Further, WEB implantation requires only a single delivery data published April 2019 apex, (2) with aneurysm catheter, unlike stent-assisted or balloon-assisted coiling dome diameter from 3 to procedures. Physicians use standard neurointerventional 10 mm and (3) either an techniques to place the self-expanding, metallic mesh aneurysm neck size of 4 mm device into the aneurysm sac with a compatible delivery or larger or a dome-to-neck catheter. Over time, thromboses develop within the ratio more than 1 and less device to fill the space, purportedly blocking blood flow than 2 into the aneurysm and preventing aneurysm rupture. The device is composed of nitinol and platinum braided wires and is available in 2 shapes, barrel or sphere, both offered in 3 diameter sizes (4-7 mm, 8-9 mm, 10-11 mm) to accommodate different aneurysm anatomies. Developer(s): MicroVention Inc (Aliso Viejo, California), a Terumo Corp (Tokyo, Japan) company
Section 1. Currently Monitored Topics 75
Table 4. Mental and Behavioral Health: 13 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adolescent females aged 15 Brexanolone (Zulresso) purportedly produces a rapid and Antidepressants Depression symptoms Approval date: March 19, years or older and adult up to sustained reduction in depression symptoms and severity and severity 2019 45 years who have confirmed in women with PPD. Its mechanism of action is not fully Psychotherapy postpartum depression (PPD) understood but is thought to be related to its positive FDA designation(s): Priority allosteric modulation of both synaptic and extrasynaptic Review, Breakthrough Therapy GABAA receptors, which mimic progesterone. Falling levels of progesterone after childbirth are thought to Clinical trial(s): Phase III contribute to PPD. Brexanolone is intended to provide primary completion June relief from symptoms more rapidly than can be achieved 2020; phase III completed with conventional antidepressants used to treat PPD. October 2017 (moderate Because of the risk of serious harm resulting from PPD); phase III completed excessive sedation or sudden loss of consciousness, October 2017 (severe brexanolone can be prescribed only by physicians PPD); pivotal integrated enrolled in a Risk Evaluation and Mitigation Strategy data published September program for the drug. Brexanolone is the only treatment 2018, additional data FDA approved to treat PPD. It is a one-time treatment, presented October 2018 given by continuous intravenous infusion for a total of 60 hours (2.5 days) in a certified health facility. The instructions for use state that a “healthcare provider must be available on site to continuously monitor the patient, and intervene as necessary, for the duration of the infusion.” Developer(s) Sage Therapeutics Inc (Cambridge, Massachusetts)
Section 1. Currently Monitored Topics 76
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Patients of any age who have Cranial electrotherapy stimulator (Cervella) is a Pharmacotherapy (eg, Anxiety symptoms and Clearance date: FDA generalized anxiety disorder neurostimulation device intended to treat GAD. The benzodiazepines, severity 510(k) March 15, 2019 (GAD) device transmits a low-level, constant electrical current to selective serotonin the brain through the patient’s skin via a pair of reuptake inhibitors Quality of life conductive electrodes placed bilaterally on the mastoid [SSRIs], serotonin and processes. The portable device can be used discreetly norepinephrine reuptake and is intended to facilitate adherence to therapy. Unlike inhibitors [SNRIs]) previously cleared cranial electrotherapy stimulation (CES) devices, Cervella incorporates conductive Psychotherapy (eg, electrodes into ear cushions of Bluetooth-enabled, noise- cognitive behavioral canceling stereo headphones controlled by a smartphone therapy [CBT]) app. The app allows patients to adjust treatment intensity level, frequency, and duration, and the device records data, sends reminders, and provides analytics intended to improve treatment outcomes. The headphones allow patients to engage in everyday activities while undergoing therapy. CES devices have been in use for several decades and are cleared by FDA to treat insomnia, depression, and anxiety. Use of the device for reducing GAD symptoms is purported to work by modulating the default mode network, altering endogenous brain oscillations, and regulating levels of the neurotransmitter serotonin. The exact mechanism of action is unknown. The device is intended to be used for 30 minutes at a time. Developer(s): Innovative Neurological Devices LLC (Carmel, Indiana)
Section 1. Currently Monitored Topics 77
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 55 years Dasotraline is a serotonin, dopamine, and norepinephrine Lisdexamfetamine Anxiety symptoms and PDUFA date: May 14, who have moderate to severe reuptake inhibitor that is intended to treat BED by severity 2020 binge eating disorder (BED) reducing the frequency of binge eating episodes. BED is Off-label a mental health disorder characterized by recurring pharmacotherapies (eg, Binge eating frequency Clinical trial(s): Phase II/III episodes in which a person consumes large amounts of antiepileptics, completed October 2016; norepinephrine reuptake Depression symptoms phase III completed May food in a short time and feels loss of control; physical and severity discomfort from overeating; and shame, guilt, or inhibitors, serotonin- 2018, pivotal phase III data depression. It is thought to be caused by underlying norepinephrine reuptake reported July 2018; phase anxiety, depression, or other psychological factors. inhibitors [SNRIs]) III extension primary Dasotraline purportedly increases the amount of completion June 2019 serotonin, dopamine, and norepinephrine in the brain, which helps to increase positive mood states and decrease anxiety and other negative mood states, thereby preventing binge eating behavior. Dasotraline was given to participants in a randomized controlled trial twice daily (4 or 6 mg/day) for 12 weeks. Developer(s): Sunovion (Marlborough, Massachusetts), a subsidiary of Sumitomo Dainippon Pharma (Osaka, Japan)
Adults aged 22 to 68 years Deep transcranial magnetic stimulation (TMS) is a Off-label use of repetitive Change in cognitive Clinical trial(s): Phase I/II who have moderate to severe noninvasive outpatient treatment that uses directed TMS function completed July 2011, data posttraumatic stress disorder electromagnetic fields to target and stimulate the published May 2013; (PTSD) prefrontal cortex region of the brain to treat PTSD. A new Psychotherapy (eg, PTSD symptoms and unphased primary coil design purportedly allows for deeper stimulation at cognitive behavioral severity completed June 2019 safe levels to try to reduce PTSD symptoms and severity. therapy [CBT], eye movement Quality of life Note(s): FDA approved The manufacturer asserts that the H1 coil used in the device stimulates deeper regions of the prefrontal cortex desensitization and deep TMS for treatment- than the figure-8 coil used in repetitive TMS. The reprocessing [EMDR] resistant depression in treatment is intended as an adjunct to pharmacologic therapy, and prolonged 2013, and for obsessive and/or psychologic treatment. In an ongoing trial, deep exposure therapy [PET]) compulsive disorder in 2018 TMS is given in 20-minute sessions, 3 times a week, for Selective serotonin 4 weeks, with a booster treatment at week 5 and another reuptake inhibitors (eg, at week 9, totaling 14 treatment sessions. At least paroxetine, sertraline) 8 sessions are required for treatment. Developer(s): BrainsWay Ltd (Hackensack, New Jersey)
Section 1. Currently Monitored Topics 78
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Esketamine HCL nasal spray (Spravato) is the (S+)– Antidepressants (eg, Anxiety symptoms and Approval date: March 6, who have treatment-resistant enantiomer of ketamine, delivered through a single-use monoamine oxidase severity 2019 major depressive disorder intranasal device. The drug is indicated for use in inhibitors, selective (MDD) that has not abated combination with an oral antidepressant for treatment- serotonin reuptake Depression symptoms FDA designation(s): after 2 or more courses of resistant depression in adults. Esketamine is absorbed by inhibitors [SSRIs], and severity Breakthrough Therapy antidepressants at adequate the lining of the nasal passages and into the bloodstream, serotonin-norepinephrine Quality of life Clinical trial(s): Phase III dose and duration during the purportedly leading to rapid (within hours) improvement in reuptake inhibitors TRANSFORM-1 completed current moderate to severe depression symptom severity in patients with MDD. [SNRIs], tricyclic Suicide attempts February 2018, data episode of depression Esketamine works through noncompetitive antagonism of antidepressants) Suicidal thoughts published July 2019; phase the N-methyl-D-aspartate (NMDA) receptor. Blocking Brain stimulation (eg, III TRANSFORM-2 activation of the NMDA receptor facilitates sensory input; completed November moderates emotional responses; and might increase deep brain stimulation, electroconvulsive 2017; phase III SUSTAIN-1 dopamine, norepinephrine, and serotonin levels in the completed February 2018, brain. The single-use nasal spray device contains 28 mg therapy, TMS, vagal nerve stimulation) data published June 2019; of esketamine and delivers two 14-mg sprays per device. phase III SUSTAIN-2 Treatment is initiated in the induction phase at weeks 1 to Ketamine (intravenous; completed October 2017; 4 at a dose of 56 mg on day 1 and at a dose of 56 or off-label) phase III SUSTAIN-3 84 mg subsequently, twice weekly. During the primary completion August maintenance phase, from weeks 5 to 8, esketamine is Psychotherapy (eg, 2021 given once weekly at a dose of 56 or 84 mg, and from cognitive behavioral week 9 and after it is given every 1 or 2 weeks at a dose therapy [CBT]) of 56 or 84 mg. Developer(s): Janssen Research & Development LLC, a unit of Johnson & Johnson (New Brunswick, New Jersey)
Section 1. Currently Monitored Topics 79
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 75 years External trigeminal nerve stimulation (eTNS) sends Psychotherapy (eg, Depression severity and Clinical trial(s): Phase I who have posttraumatic electrical stimulation to the trigeminal nerve through a cognitive behavioral symptoms completed January 2012, stress disorder (PTSD) patch placed on the patient’s forehead to treat PTSD, therapy [CBT], eye data published April 2016; which has limited, effective treatment options. This small movement Functional capacity unphased primary portable device is intended to improve symptom severity desensitization and PTSD severity and completion September and quality of life. The eTNS system is a cell phone–sized reprocessing [EMDR] symptoms 2019 electrical pulse generator that delivers mild electrical therapy, and prolonged signals via 2 wires connected to a small single-use exposure therapy [PET]) Quality of life Note(s): FDA approved in electric patch that adheres to the forehead. The therapy April 2019 for pediatric is intended to be used by the patient at home nightly for Selective serotonin attention 8 hours while sleeping. The eTNS therapy purportedly reuptake inhibitors deficit/hyperactivity changes the neuronal activity in key regions of the (paroxetine, sertraline) disorder brainstem, thalamus, and cortex, increasing activity in underactive regions. It is used in conjunction with pharmacotherapy. Developer(s): Neurosigma (Los Angeles, California), in collaboration with University of California (Los Angeles, California)
Children aged 7 to 12 years External trigeminal nerve stimulation (eTNS; Monarch) is Behavior therapy (eg, ADHD symptoms and Clearance date: FDA who have attention a noninvasive medical device that externally delivers applied behavior severity 510(k) April 19, 2019 deficit/hyperactivity disorder nerve stimulation to treat ADHD. The eTNS system is analysis, cognitive (ADHD) and are not taking intended as a nonpharmacologic approach to improve behavioral therapy Anxiety symptoms Clinical trial(s): Unphased open extension completed prescription ADHD ADHD symptoms and cognition in the affected child. The [CBT]) Depression symptoms medications eTNS system delivers pulses of low-level electrical May 2018, data reported current to the trigeminal nerve, the largest cranial nerve. Nonstimulant Executive function April 2019; unphased medications (eg, completed May 2018; The external electrical nerve stimulation purportedly Global functioning changes the neuronal activity in regions of the brain atomoxetine, clonidine, unphased open extension associated with ADHD—the brainstem, thalamus, and guanfacine) Quality of life for patients completed May 2018 cortex—increasing activity in regions that are underactive Stimulant medications and caregivers by triggering nerve fibers. The eTNS therapy is delivered (eg, dexmethylphenidate, using a handheld system and lead wires that connect to a lisdexamfetamine, patch adhered to the patient’s forehead while the patient methylphenidate) sleeps at night. The system is intended for use at home under supervision of a caregiver and is typically used nightly for 8 hours at a time. Developer(s): Neurosigma (Los Angeles, California)
Section 1. Currently Monitored Topics 80
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 65 years Ketamine is an N-methyl-d-aspartate (NMDA) receptor Psychotherapy (eg, Depression symptoms Clinical trial(s): Phase II/III who fulfill DSM-5 criteria for antagonist intended to treat PTSD symptoms in adults. cognitive behavioral and severity primary completion current civilian or combat- Glutamate, an excitatory neurotransmitter that binds to therapy [CBT], eye January 2020 (repeated related posttraumatic stress NMDA receptors, is purported to be highly involved in the movement PTSD symptoms and dose); phase II completed disorder (PTSD) stress response and formation of traumatic memories in desensitization and severity September 2013 (single PTSD. By decreasing glutamate's excitatory activity and reprocessing [EMDR] Quality of life dose), data published June thus reducing stress-related synaptic activity that therapy, prolonged 2014 contributes to PTSD symptoms, ketamine is intended to exposure therapy [PET]) improve PTSD symptoms and patient quality of life quicker than currently approved PTSD therapies, Selective serotonin including psychotherapy and selective serotonin reuptake reuptake inhibitors inhibitors. Ketamine purportedly provides rapid and (SSRIs), (eg, paroxetine, sustained therapeutic effects for patients with PTSD. Its sertraline) use for this purpose is off-label. In clinical trials, Off-label use of repetitive participants are given 0.2- or 0.5-mg/kg doses of transcranial magnetic ketamine intravenously for 6 to 8 infusions over 2 to 4 stimulation weeks. After treatment, patients must be monitored for at least 4 hours before discharge. Developer(s): Icahn School of Medicine at Mount Sinai (New York, New York), in collaboration with VA Office of Research and Development (Washington, DC)
Children and adolescents Molindone HCl extended release (SPN-810) is an Off-label antipsychotics Impulsive aggression Submission date: New aged 6 to 17 years who have antipsychotic that blocks the D2 dopamine receptor in the (eg, risperidone) behaviors (self-reported) Drug Application planned attention deficit/hyperactivity brain and purportedly reduces impulsive aggression in for fourth-quarter 2020 disorder (ADHD) and children and adolescents with ADHD. Impulsive Selective norepinephrine Quality of life impulsive aggression aggression is a clinically distinct feature of ADHD and reuptake inhibitors (eg, FDA designation(s): Fast involves explosive or violent overreactions in social atomoxetine) Track settings. Impulsive aggression often does not respond to Selective serotonin Clinical trial(s): Phase II standard ADHD medications and has been shown to reuptake inhibitors (eg, completed October 2012, increase negative outcomes. No FDA-approved bupropion, fluoxetine, data published April 2016; medications exist for managing impulsive aggression. In venlafaxine) phase III CHIME 2 primary ongoing trials, SPN-810 is given orally at 36 to 54 mg for completion May 2018; 7 weeks, combined with standard ADHD treatment. Stimulants (eg, phase III primary methylphenidate) Developer(s): completion July 2019; phase III CHIME 1 primary Supernus Pharmaceuticals, Inc (Rockville, Maryland) completion October 2019
Section 1. Currently Monitored Topics 81
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 65 years Oxytocin is a naturally occurring hormone in the brain that Antidepressants (eg, Negative schizophrenia Clinical trial(s): Unphased who have schizophrenia is known for its association with social bonding and, when selective serotonin symptoms completed August 2012, given intranasally, purportedly improves social cognition reuptake inhibitors data published July 2013; in patients with schizophrenia. Studies have shown that [SSRIs] and serotonin- Quality of life phase II CIDAR-3 patients with schizophrenia have lower oxytocin levels, norepinephrine reuptake Social cognition completed July 2014; which has been associated with impaired trust, empathy, inhibitors [SNRIs]) phase II completed and ability to interpret mental states. Current November 2015, data antipsychotic drugs have been used successfully to treat Antipsychotics (oral and published April 2016; the positive symptoms of patients with schizophrenia but injectable) unphased primary have minimal effects on negative symptoms and cognitive Combination therapy completion December deficits. Increasing oxytocin levels might reduce negative 2019 symptoms and normalize social dysfunction associated Electroconvulsive with schizophrenia. Oxytocin is being studied as both a therapy standalone and adjunct treatment. In the most recent Mood stabilizers clinical trial, oxytocin was used in combination with risperidone. In this study, oxytocin is given intranasally at Psychotherapy (ie, a dose of three 4-IU puffs per nostril for a total dose of cognitive behavioral 24 IU. Other trials used doses of 24 to 80 IU per day, for therapy [CBT]) 1 to 6 weeks, and a dose-range study evaluated doses of 6 to 84 IU. Trials have studied single-dose treatments as well as daily treatment for up to 4 weeks. Developer(s): Emory University (Atlanta, Georgia), in collaboration with Atlanta VA Medical Center (Atlanta, Georgia)
Section 1. Currently Monitored Topics 82
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children and adolescents Sodium benzoate (NaBen) is a prescription-strength Antidepressants (eg, Efficacy of antipsychotics FDA designation(s): aged 12 years or older and formulation of the sodium salt used as a common food selective serotonin Orphan Drug, adults aged 18 to 55 years preservative and is intended to treat both the positive and reuptake inhibitors Quality of life Breakthrough Therapy who have a confirmed DSM- negative symptoms of schizophrenia. Existing drugs for [SSRIs] and serotonin- Schizophrenia symptoms Clinical trial(s): Phase IIb/III IV or DSM-5 diagnosis of treating schizophrenia have limited efficacy in reducing norepinephrine reuptake (positive and negative) schizophrenia and are both positive and negative symptoms, and many are inhibitors [SNRIs]) primary completion clinically stable with residual associated with serious side effects. A key dysfunction December 2018; phase symptoms; adults aged 18-55 related to schizophrenia is the reduced function of the Antipsychotics (oral and IIb/III primary completion years who have treatment- N-methyl-D-aspartate (NMDA) receptor in the brain. injectable) December 2018; phase IIb/III primary completion refractory schizophrenia NaBen addresses this by inhibiting D-amino acid oxidase Combination therapy (DAAO) metabolism to increase DAAO activity, leading to June 2019 production of more D-serine, which increases NMDA Mood stabilizers activity in the hypothalamus. In ongoing phase IIb trials Psychotherapy (ie, for patients with clinically stable schizophrenia, 500-mg cognitive behavioral NaBen oral tablets are given twice daily at a total dose of therapy [CBT]) 1000 mg/day for 6 to 8 weeks. Participants’ current antipsychotic medication regimens remained unchanged for at least 8 weeks before study screening and during the study. In an ongoing phase IIb trial for patients with treatment-refractory schizophrenia, two 500-mg NaBen oral tablets are given twice daily, for a total dose of 2000 mg/day, or one 500-mg NaBen oral tablet is given twice daily, for a total dose of 1000 mg/day, for 8 weeks, with participants’ current dose of clozapine. Participants’ clozapine regimens remained unchanged for at least 3 months before study screening and during the study. After the 6 to 8 weeks of treatment, phase III open-label extension studies will continue for a randomized sample of these participants. Developer(s): SyneuRx International (Taiwan) Corp (New Taipei City, Taiwan)
Section 1. Currently Monitored Topics 83
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children and adolescents Viloxazine HCl (SPN-812) is a nonstimulant, selective Atomoxetine ADHD symptoms (eg, Submission date: New aged 6 to 17 years and adults norepinephrine reuptake inhibitor (SNRI) that also acts on hyperactivity, impulsivity, Drug Application planned aged up to 55 years who the serotonin receptor. It is intended to treat children and Behavior therapy inattentiveness) for fourth-quarter 2019 have attention- adolescents with ADHD. As a nonstimulant medication, Extended-release deficit/hyperactivity disorder viloxazine has a novel mechanism of action and Functional impairment Clinical trial(s): Phase III clonidine completed September (ADHD) purportedly produces a stimulant effect similar to that Suicidality of amphetamines, without the risk of dependence. Extended-release 2018; phase III completed Viloxazine has an extensive safety record in Europe, guanfacine October 2018; phase III completed October 2018; where it was marketed for many years as an Stimulants (eg, antidepressant. In clinical trials, viloxazine is given orally phase III completed dextroamphetamine, February 2019; phase III at a dose of 100, 200, 400, or 600 mg, once a day, for mixed amphetamine 5 to 7 weeks. primary completion August salts) 2020; phase III primary Developer(s): completion September 2020 Supernus Pharmaceuticals Inc (Rockville, Maryland) Note(s): Combined topline study results reported March 2019.
Adults aged 18 to 70 years Zonisamide (Zonegran) is a sulfonamide anticonvulsant Pharmacotherapy (eg, Alcohol consumption Clinical trial(s): Pilot who have alcohol use demonstrated to modulate GABAergic and glutamatergic acamprosate, disulfiram, unphased completed disorder (AUD) neurotransmission. Approved medications to treat AUD naltrexone) Alcohol cravings October 2007; pilot phase have shown limited effectiveness; only one-third of IV completed May 2009; Psychotherapy (eg, CBT) Alcohol withdrawal patients achieve full remission with available therapies. symptoms phase III primary Zonisamide is intended to reduce alcohol consumption in completion October 2018; patients with heavy drinking behaviors or AUD; treatment Health outcomes phase III primary with zonisamide might also ameliorate the symptoms of associated with completion February 2021 alcohol withdrawal syndrome. Its exact mechanism of abstinence action is unknown, but zonisamide purportedly reduces Quality of life GABAergic and glutamatergic neurotransmission in the brain, which is signaling involved with alcohol’s effect on Relapse the brain. In clinical trials, zonisamide is given orally at
doses up to 500 mg daily. Developer(s): VA Office of Research and Development (Washington, DC)
Section 1. Currently Monitored Topics 84
Table 5. Rare Diseases: 49 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 6 months or ABO-101 is a recombinant adeno-associated viral vector Supportive care Cognitive and motor FDA designation(s): older and adults who have carrying a wild-type copy of the N-acetyl-alpha-D- function, as measured by Orphan Drug, Rare Sanfilippo syndrome type B glucosaminidase gene, NAGLU. The therapy is intended validated clinical ratings Pediatric Disease, Fast (mucopolysaccharidosis type to treat MPSIIIB, a childhood-onset, progressive, inherited and scales Track 3B [MPSIIIB]) metabolic disorder caused by a mutation in NAGLU. Sanfilippo syndrome type B (about 30% of all Sanfilippo Heparan sulfate levels Clinical trial(s): Phase I/II primary completion syndrome cases) has no cure, and patients typically do NAGLU enzyme activity not survive beyond their 20s. Patients with the disorder October 2020 cannot break down the polysaccharide heparan sulfate, a process normally mediated by the NAGLU enzyme. Buildup of heparan sulfate in cells of the central nervous system causes degeneration that manifests as behavioral problems, sleeplessness, loss of speech and cognitive skills, mental retardation, heart problems, seizures, and loss of mobility. In patients with this syndrome, ABO-101 purportedly restores NAGLU function, blocks central nervous system degeneration, and reduces disease- related symptoms. In clinical trials, ABO-101 is given in viral genomes (vg) at a low dose (2 × 1013 vg/kg) or high dose (5 × 1013 vg/kg), intravenously via a peripheral-limb vein, once. Developer(s): Abeona Therapeutics Inc (Dallas, Texas)
Section 1. Currently Monitored Topics 85
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 6 months or ABO-102 is a recombinant adeno-associated viral vector Bone marrow transplant Cognitive and motor FDA designation(s): older who have Sanfilippo carrying a wild-type copy of the N-sulfoglucosamine function, as measured by Orphan Drug, Fast Track, syndrome type A sulfohydrolase gene, SGSH. It is intended to treat Supportive care accepted clinical ratings Rare Pediatric Disease, (mucopolysaccharidosis type Sanfilippo syndrome type A (MPSIIIA), a childhood-onset, and scales Regenerative Medicine 3A [MPSIIIA]) and a minimum progressive, inherited metabolic disorder caused by a Advanced Therapy cognitive developmental mutation in SGSH. Patients with the disorder cannot Heparan sulfate levels quotient of 60 or above break down the polysaccharide heparan sulfate, a Clinical trial(s): Phase I/II Sulfamidase enzyme primary completion process normally mediated by the SGSH-encoded activity enzyme heparan-N-sulfamidase. Buildup of heparan December 2019, interim sulfate in cells of the central nervous system causes data reported July 2019 degeneration that manifests as behavioral problems, sleeplessness, loss of speech and cognitive skills, mental retardation, heart problems, seizures, and loss of mobility. No cure exists for Sanfilippo syndrome type A (about 60% of all Sanfilippo syndrome cases), and patients typically do not survive past their 20s. Treatment consists of supportive care. In patients with Sanfilippo syndrome type A, ABO-102 purportedly restores sulfamidase enzyme function, blocks central nervous system degeneration, and reduces disease-related symptoms. In clinical trials, ABO-102 is given in vg at a low dose (0.5 × 1013 vg/kg), mid dose (1 × 1013 vg/kg), or high dose (3 × 1013 vg/kg), intravenously via a peripheral-limb vein, once. Developer(s): Abeona Therapeutics Inc (Dallas, Texas)
Section 1. Currently Monitored Topics 86
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Neonates aged up to 28 days ALXN1101 is a synthetic version of cyclic pyranopterin Anticonvulsants Ability to sit upright FDA designation(s): who have molybdenum monophosphate (cPMP) intended to restore molybdenum independently for at least Breakthrough Therapy cofactor deficiency (MoCD) cofactor (MoCo) levels and sulfite oxidase activity to Supportive care 30 seconds at 12 months Clinical trial(s): Phase II/III type A enable clearance of sulfite from patients with MoCD type Ventilator A. An ultra-rare, genetic metabolic disorder, MoCD type A Bayley Scales of Infant primary completion causes catastrophic and irreversible neurologic damage Development at September 2019 within the first weeks of life. MoCD type A has no effective 12 months
treatments and is caused by a mutation in the Pediatric Evaluation of molybdenum cofactor synthesis 1 gene, MOCS1, which Disability Inventory at turns guanosine triphosphate to cPMP, an intermediate in 12 months the body’s production of MoCo. MoCo is a key component of the sulfite oxidase enzyme, which clears the neurotoxic Survival at 12 months metabolic byproduct sulfite from the body. In a clinical trial, ALXN1101 is given daily, intravenously, at a dose of 80 to 320 μg/kg. Developer(s): Origin Biosciences (Palo Alto, California), a subsidiary of BridgeBio Pharma (Palo Alto, California)
Adults aged 18 years or older Apremilast (Otezla) is a small-molecule anti-inflammatory Corticosteroids Disease progression Approval date: July 19, who have active Behçet’s drug that inhibits phosphodiesterase type 4 (PDE-4). 2019 disease Behçet’s disease is a rare disease caused by blood Immunosuppressants Pain, frequency, or vessel inflammation that can cause skin symptoms, (eg, azathioprine, duration of oral ulcers FDA designation(s): including oral and genital ulcers, as well as eye cyclosporine) from baseline Orphan Drug inflammation that can eventually lead to blindness. Few Nonsteroidal anti- Quality of life Clinical trial(s): Phase III effective treatment options (ie, immunosuppressant inflammatory drugs primary completed therapy) exist for affected patients. Investigators have (NSAIDs) September 2017, pivotal linked Behçet’s disease to overactive T helper 17 cells data reported February (Th17 cells) and increased interleukin 17 (IL-17) 2018, data from meeting production. Apremilast’s PDE-4 inhibitory activity abstract reported March purportedly increases cyclic adenosine monophosphate in 2019 immune cells to decrease production of proinflammatory mediators, such as tumor necrosis factor (TNF)-alpha, Note(s): FDA approved IL-17, and IL-23, which purportedly might alleviate blood apremilast in March 2014 vessel inflammation and symptoms. In clinical trials, the to treat psoriatic arthritis, drug is given orally at a dose of 30 mg, twice daily. and in September 2014 to treat plaque psoriasis. Developer(s): Celgene Corp (Summit, New Jersey)
Section 1. Currently Monitored Topics 87
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Arimoclomol (BRX-345) is a small-molecule amine Edaravone Disability Submission date: New who have amyotrophic lateral intended to treat ALS by helping to regulate proteins Drug Application planned sclerosis (ALS) involved with the disease. ALS is a disease in which the Riluzole Disease progression for the second half of 2021 death of neural cells in the brain and spinal cord leads to (ALS) Supportive care FDA designation(s): progressive weakness and muscle wasting. It is thought Functional capacity to be caused by accumulations of abnormal proteins in Orphan Drug neural cells. Arimoclomol might reduce abnormal protein Survival Clinical trial(s): Phase II/III accumulation and help deconstruct abnormal proteins, (patients with SOD1 thereby slowing disease progression and improving mutation) completed patient quality of life by prolonging motor function. The November 2016, data exact cause of abnormal protein collection in ALS is published February 2018; unknown, although patients with inherited forms of ALS phase III ORARIALS-01 might have mutations in other genes that might primary completion contribute, such as the copper-zinc superoxide dismutase December 2020; planned 1 gene, SOD1. FDA-approved drugs to treat the disease phase III open-label (eg, edaravone, riluzole) might decrease symptom extension primary severity but do not prevent disease progression. completion August 2022 Arimoclomol purportedly increases the activity of heat shock factor 1, a transcription factor that promotes Note(s): Headline results expression of heat shock proteins. These proteins are are expected in the first thought to regulate normal protein folding and deconstruct half of 2021. abnormal proteins. In clinical trials, patients take arimoclomol orally. One recent trial reported giving a dose of 200 mg, 3 times daily, for up to 12 months. The dose in the ongoing phase III trial is unspecified. Developer(s): Orphazyme US Inc (Newton, Massachusetts)
Section 1. Currently Monitored Topics 88
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Males aged younger than AT132 is an adeno-associated virus vector that delivers a Supportive care Children’s Hospital of FDA designation(s): 5 years who have functional copy of the myotubularin gene, MTM1, to treat Philadelphia Infant Test Orphan drug, Rare chromosome X–linked X-linked myotubular myopathy. An ultra-rare, severe, of Neuromuscular Pediatric Disease, Fast myotubular myopathy debilitating condition, X-linked myotubular myopathy is Disorders Track, Regenerative caused by an MTM1 mutation that leads to muscle Medicine Advanced weakness and affects children as early as birth. The gene Motor function Therapy makes a phosphatase enzyme thought to be involved in Quality of life the development and maintenance of muscle cells Clinical trial(s): Phase I/II throughout the body. No cure exists for the disease; Respiratory function (ASPIRO) primary completion March 2024, AT132 is intended to increase levels of functional Survival myotubularin and thereby reduce symptoms. In clinical interim data presented May trials, AT132 is given in vg at a dose of 1.0 × 1014, 3.0 × Ventilator use 2019 1014, or 5.0 × 1014 vg/kg, once intravenously.
Developer(s): Audentes Therapeutic Inc (San Francisco, California)
Adults aged 18 years or older Budesonide (Nefecon) is a synthetic corticosteroid Corticosteroids Change in eGFR from FDA designation(s): who have biopsy-proven intended to treat IgA nephropathy, which occurs when baseline Orphan Drug immunoglobulin A (IgA) IgA antibody complexes accumulate in the kidneys. IgA Immunosuppressants nephropathy (Berger nephropathy causes local inflammation and reduced (eg, azathioprine, Change in quality of life Clinical trial(s): Phase III disease) and an estimated glomerular filtration and leads to chronic kidney disease cyclophosphamide, from baseline Nefigard primary mycophenolate) completion October 2020 glomerular filtration rate within 10 to 20 years in 20% to 40% of affected patients. Occurrence of end-stage (eGFR) between 45 and 90 Standard of care (high-dose systemic corticosteroids) is renal disease mL/min/1.73 m2 (stage II to controversial because of the increased risks of adverse IIIA chronic kidney disease) events and serious infections, high blood pressure, weight Proteinuria change from and medically controlled gain, diabetes mellitus, and osteoporosis. Budesonide is baseline blood pressure intended to avert these systemic side effects. Treatment is targeted to the Peyer patches of the small intestine, where IgA complexes are thought to originate, via the manufacturer’s proprietary TARGIT technology. Drug tolerability is purportedly optimized by the drug’s low bioavailability (about 90% is inactivated in the liver before reaching the circulation) compared with corticosteroids. In clinical trials, 16 mg of budesonide is given orally, once daily, for 9 months. Developer(s): Calliditas Therapeutics AB (Stockholm, Sweden)
Section 1. Currently Monitored Topics 89
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 10 years or CAP-1002 is a cell-based therapy intended for DMD, an Corticosteroids (eg, Muscle strength, as FDA designation(s): older and adults who have inherited, X chromosome–linked genetic disorder caused deflazacort, prednisone) measured by accepted Orphan Drug, Rare genetically confirmed by mutations or deletions in the dystrophin gene, DMD. DMD-specific ratings and Pediatric Disease, Duchenne muscular DMD encodes dystrophin, a protein that helps keep Supportive care scales Regenerative Medicine dystrophy (DMD) and are muscle cells intact. The absence of wild-type dystrophin Advanced Therapy ambulatory or nonambulatory protein causes progressive muscle fiber necrosis and Quality of life Clinical trial(s): Phase II and receiving stable doses of eventual widespread muscle weakness. No cure for DMD 6-minute walk test systemic glucocorticoids exists, and first-line corticosteroid treatment addresses HOPE-2 primary symptoms but does not prevent disease progression and Upper limb function, as completion December has significant side effects. FDA approved a gene therapy measured by accepted 2019, interim data reported for patients who have a specific mutation in DMD (ie, in DMD-specific ratings and July 2019 exon 51); however, patients who have other DMD scales mutations do not qualify. CAP-1002 might help fill this gap and improve patient health outcomes. CAP-1002 contains cardiosphere-derived cells (CDCs) derived from donor heart tissue. The CDCs in CAP-1002 purportedly secrete growth factors and exosomes that promote cellular regeneration and improve muscle function in patients with DMD. In clinical trials, a solution of CAP-1002 containing 150 million CDCs is given intravenously once every 3 months, 4 times. Developer(s): Capricor Therapeutics Inc (Beverly Hills, California)
Section 1. Currently Monitored Topics 90
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Caplacizumab-yhdp (Cablivi) is a highly potent and Antiplatelet therapy Disease recurrence Approval date: February 6, who have acquired selective bivalent antibody fragment targeting von 2019 thrombotic thrombocytopenic Willebrand factor and designed to treat aTTP. This Corticosteroids Major thromboembolic purpura (aTTP) condition develops when the spleen produces antibodies events FDA designation(s): Cyclosporine A Orphan Drug, Priority against ADAMTS13 (ie, von Willebrand factor–cleaving Quality of life protease), an enzyme involved in blood clotting. The Daily plasmapheresis (ie, Review current standard treatment is plasma exchange. plasma exchange) Survival Clinical trial(s): Phase III Caplacizumab purportedly inhibits the interaction between Rituximab HERCULES completed von Willebrand factor and platelets by targeting von August 2017, pivotal data Willebrand factor A1 domain, potentially blocking platelet Splenectomy (to published January 2019; interactions mediated by ultra-large von Willebrand factor eliminate production of phase III Post-HERCULES and the formation of string-like blood clots. It is intended antibodies to primary completion to reduce aTTP recurrence and its serious and life- ADAMTS13) October 2020 threatening effects. The recommended first dose is an Vincristine 11-mg bolus intravenous injection at least 15 minutes before plasma exchange, with an 11-mg subcutaneous injection after completing plasma exchange, continuing daily for 30 days after the last plasma exchange. If signs of aTTP persist after the initial treatment course (eg, suppressed ADAMTS13 activity), caplacizumab treatment might be extended another 28 days. Developer(s): Ablynx NV (Ghent, Belgium), a Sanofi (Paris, France) company
Section 1. Currently Monitored Topics 91
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or Crizanlizumab (SEG101) is a humanized immunoglobulin Analgesia (eg, Amount and length of Submission date: Biologics older and adults who have G2 antibody against P-selectin, which promotes the acetaminophen, intravenous opioid use License Application July sickle cell disease (SCD) and inflammation and adhesion involved in VOC. morphine, nonsteroidal 16, 2019 have experienced a vaso- Crizanlizumab is intended to improve treatment efficacy anti-inflammatory drugs) Frequency of VOCs FDA designation(s): occlusive crisis (VOC) by blocking P-selectin to prevent red blood cell occlusion Hospital length of stay in small blood vessels and maintain blood flow. In SCD, Hydration Orphan Drug, sickled red blood cells are more susceptible to oxidative Quality of life Breakthrough Therapy, Hydroxyurea Priority Review damage, inappropriate adhesion, and vascular Rehospitalizations within obstruction, leading to VOCs that cause severe pain, 3 days of discharge Clinical trial(s): Phase III requiring hospitalization. VOC complications can include STAND primary completion circulating blood clots, stroke, organ failure, or early May 2022; key phase II death, and available treatments are often ineffective. The SUSTAIN data reported only FDA-approved treatment for SCD, hydroxyurea, can December 2018 reduce VOC incidence but is ineffective in about one-third of adult patients. In clinical trials, crizanlizumab is given by intravenous infusion at a dose of 5.0 or 7.5 mg/kg, once every 4 weeks. Developer(s): Novartis AG (Basel, Switzerland)
Section 1. Currently Monitored Topics 92
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 behavioral Aggression and FDA designation(s): older and adults who have investigational proprietary crystalline salt formulation of therapy behavioral problems Orphan Drug, Fast Track hyperphagic Prader-Willi diazoxide, a potassium channel activator that inhibits syndrome (PWS) insulin secretion and is intended to treat PWS. PWS is a Dietary intervention and Rate of comorbidities Clinical trial(s): Phase III rare genetic disease (about 8000-11 000 estimated US close supervision of food (eg, cardiovascular primary completion patients) caused by lack of expression of several genes intake disease, diabetes December 2019; phase III on chromosome 15. It is often managed with off-label mellitus, obesity) open-label extension Exercise programs primary completion diazoxide (Proglycem), which is approved to treat low blood sugar. However, patients with PWS require a lower Off-label diazoxide December 2019 dose of diazoxide than the current formulation, which often causes high blood sugar as a side effect. DCCR purportedly blocks the production and release of the appetite stimulatory neuropeptides Y and agouti-related protein and blocks fatty acid production. DCCR might also augment the action of gamma-aminobutyric acid (GABA) receptors, which are thought to be disrupted in patients with PWS, who experience behavioral problems, such as aggression. Thus, DCCR might address overeating and behavioral PWS symptoms and decrease body fat and circulating fat levels. In clinical trials, DCCR is given as an oral tablet at a dose of 75 to 450 mg (depending on body weight), once daily. Developer(s): Soleno Therapeutics Inc (Redwood City, California)
Section 1. Currently Monitored Topics 93
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Eculizumab (Soliris) is a recombinant humanized Azathioprine Functional impairments Approval date: June 27, who have neuromyelitis monoclonal antibody that binds with high affinity to the (eg, vision, mobility, and 2019 optica or neuromyelitis optica complement protein C5 (a soluble component of the Intravenous bowel or bladder spectrum disorder and innate immune system). Eculizumab is the first FDA- corticosteroids incontinence) change FDA designation(s): Orphan Drug 2 relapses in the past approved therapy for neuromyelitis optica. Eculizumab Mycophenolate mofetil from baseline 12 months or 3 relapses in is intended to relieve the autoimmune and Clinical trial(s): Phase III the past 24 months despite neurodegenerative symptoms and pathology of Plasmapheresis Incidence of relapse from baseline PREVENT completed July stable immunosuppressive neuromyelitis optica by binding C5 and inhibiting its Rituximab 2018, data published May therapy cleavage to C5a and C5b. This action prevents the Quality of life change 2019; phase III open-label downstream formation and activation of the cell lysing from baseline extension primary terminal complement complex C5b-9, which damages cell completion June 2020 membranes targeted with the complexes. C5b-9 complex production is thought to directly drive the uncontrolled complement activation that promotes some autoimmune reactions. In clinical trials, patients received eculizumab intravenously, 900 mg, weekly for 4 weeks, followed by 1200 mg, every 2 weeks, for up to 4 years. Developer(s): Alexion Pharmaceuticals Inc (Boston, Massachusetts)
Section 1. Currently Monitored Topics 94
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 7 years or FCX-007 is a cell-based gene therapy consisting of Supportive care for pain Change in wound size FDA designation(s): older and adults who have patient-derived dermal fibroblasts (skin cells) treated to and infection risk from baseline Orphan Drug, Fast Track, recessive dystrophic produce a functional copy of the collagen VIIA1 gene. The Rare Pediatric Disease, epidermolysis bullosa cell therapy is delivered by injection into the patient’s skin Time to wound closure Regenerative Medicine (RDEB) lesions to promote wound healing. RDEB is a rare genetic from baseline Advanced Therapy disease caused by mutations in the collagen COL7A1 protein, which is needed to maintain proper skin integrity. Clinical trial(s): Phase I/II Loss of COL7A1 expression in RDEB leads to FI-EB-001 primary widespread blistering, resulting in severe scarring, vision completion June 2020, loss, disfigurement, and other serious medical problems. interim data reported May FCX-007 is intended to prevent blistering and promote 2018; phase III DEFI- wound healing without heavy scarring by delivering RDEB planned transduced COL7A1-expressing fibroblasts into poorly healing lesions. The therapy is thought to form anchoring fibrils that hold the layers of skin together to prevent RDEB-caused wounds. In clinical trials, FCX-007 was injected directly at an unspecified dose into the papillary dermis of blisters and wounds. Developer(s): Fibrocell Technologies Inc (Exton, Pennsylvania), in collaboration with Castle Creek Pharmaceuticals LLC (Parsippany-Troy Hills, New Jersey)
Section 1. Currently Monitored Topics 95
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 2 years or Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, Convulsive seizure Submission date: New older and adults aged up to amphetamine derivative intended as an adjunctive clobazam, stiripentol, duration Drug Application 35 years who have Dravet therapy for Dravet syndrome. A rare, severe, infantile- topiramate, valproate) resubmission planned for syndrome and are taking one onset form of epilepsy, Dravet syndrome is usually Functional capacity third-quarter 2019 or more antiepileptic drugs caused by a mutation in the sodium voltage-gated Ketogenic diet Monthly convulsive FDA designation(s): channel alpha subunit 1 gene, SCN1A. Fintepla is Plant-derived CBD seizure frequency intended as an option for patients who have prolonged Orphan Drug, Fast Track seizures that are difficult to control with currently available Quality of life Clinical trial(s): Phase III antiepileptic drugs. In addition, patients typically Seizure-free interval completed June 2018, data experience cognitive impairment, behavioral problems, presented December 2018; muscle weakness, and sleep disorders. FDA has phase III primary approved cannabidiol (CBD) to treat the disease, but it completed June 2019, data may cause hepatic impairment, especially when used in presented December 2017; conjunction with certain antiepileptics; the drug also can phase III open-label cause sleepiness, sedation, and suicidal behavior. In extension primary patients with Dravet syndrome, Fintepla purportedly completion December promotes serotonin release and stabilizes nerve activity in 2019, data presented the brain, which might decrease seizure frequency and December 2018; phase III duration. In clinical trials, patients or caregivers orally primary completion administer Fintepla at a dose of 0.2, 0.4, or 0.8 mg/kg/day January 2020, data (up to 20 mg/day), for up to 156 weeks. presented December 2017; Developer(s): phase III long-term follow- up primary completion April Zogenix Inc (Emeryville, California) 2023 Note(s): FDA issued a Refusal to File letter on April 8, 2019, citing missing and incorrect data.
Section 1. Currently Monitored Topics 96
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 2 years or Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, Duration of seizures that FDA designation(s): older and adults aged up to amphetamine derivative intended as an adjunctive clobazam, stiripentol, result in drops Orphan Drug 35 years who have Lennox- therapy for Lennox-Gastaut syndrome, a rare, severe, topiramate, valproate) Gastaut syndrome that is infantile- or childhood-onset form of epilepsy. Fintepla Frequency of seizures Clinical trial(s): Phase III being treated with 1 to might improve health outcomes in patients with Lennox- Ketogenic diet that result in drops primary completion 4 antiepileptic drugs Gastaut syndrome, who often experience multiple types December 2019; phase III Plant-derived cannabidiol Functional capacity long-term follow-up primary of seizures (eg, atonic, tonic, atypical absence, drop (CBD) attacks) difficult to control with FDA-approved antiepileptic Quality of life completion April 2023 drugs. In addition, patients typically experience cognitive Seizure-free interval impairment, intellectual disability, behavioral problems, delayed development, and muscle weakness. FDA has approved CBD to treat the disease, but it might cause hepatic impairment, especially when used in conjunction with certain antiepileptics; the drug can also cause sleepiness, sedation, and suicidal behavior. In patients with Lennox-Gastaut syndrome, Fintepla purportedly promotes serotonin release and stabilizes nerve activity in the brain, which might decrease seizure frequency and duration. In clinical trials, patients take Fintepla by mouth at a dose of 0.2 or 0.8 mg/kg/day (up to 20 mg/day), for up to 52 weeks. Developer(s): Zogenix Inc (Emeryville, California)
Section 1. Currently Monitored Topics 97
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adolescents aged 13 years Gaboxadol, also known as OV101 or THIP, is a small- Supportive care (eg, Behavioral disturbances, FDA designation(s): or older and adults aged up molecule derivative of muscimol, a compound found in physical therapy, as measured by Orphan Drug, Fast Track to 49 years who have the mushroom Amanita muscaria. It is intended to occupational therapy, accepted clinical ratings genetically confirmed treat Angelman syndrome, a rare, noninherited, speech/language and scales Clinical trial(s): Phase II Angelman syndrome X chromosome–linked neurodevelopmental disorder therapy, assistive completed June 2018 caused by a mutation in the ubiquitin protein ligase E3a devices, anticonvulsants, Motor function, as (children and adults), data gene, UBE3A. UBE3A encodes the UBE3A protein, which benzodiazepines for measured by accepted presented October 2018, mediates cellular protein degradation and is expressed in sleep disturbances) clinical ratings and data reported May 2019; both excitatory and inhibitory neurons in the brain. scales phase II ELARA open-label extension primary Normally, the brain can differentiate between excitatory Time to sleep onset and inhibitory signals, a process called tonic inhibition, completion July 2020 that is partially mediated by gamma-aminobutyric acid Total sleep time (children and adults); phase III NEPTUNE (GABA) receptors. In a mouse model of Angelman syndrome in which the animals lacked UBE3A and planned for third-quarter UBE3A expression, loss of tonic inhibition disrupted nerve 2019 (children only) cell function and normal brain activity, resulting in motor Note(s): Gaboxadol is also dysfunction. Patients with Angelman syndrome in phase II clinical experience severe developmental delays, intellectual development to treat fragile disability, impaired speech and motor function, behavioral X syndrome. and sleep disturbances, and seizures. No cure exists, and treatment consists of supportive care. If effective, gaboxadol could decrease symptom severity in patients with the disease. Because the drug is a delta-selective, GABAA receptor agonist that selectively activates GABAA receptors, it purportedly restores the process of tonic inhibition and normalizes brain activity in patients with Angelman syndrome. In clinical trials, patients receive 10 to 25 mg of gaboxadol, once or twice daily, for up to 52 weeks. Developer(s): Ovid Therapeutics Inc (New York, New York)
Section 1. Currently Monitored Topics 98
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Galcanezumab-gnlm (Emgality) is a humanized Corticosteroids Cluster headache Approval date: June 4, who have episodic cluster monoclonal antibody against calcitonin gene–related severity, as measured by 2019 headache peptide (CGRP) intended to prevent chronic or episodic Off-label topiramate accepted clinical ratings FDA designation(s): cluster headache. However, FDA’s approved indication Off-label verapamil and scales from June 2019 pertains to “treating episodic cluster Breakthrough Therapy headache in adults.” Galcanezumab-gnlm is the first Weekly cluster headache (episodic cluster biologic approved to treat these headaches. CGRP is a frequency headache) neuropeptide thought to contribute to pain signaling of the Clinical trial(s): Phase III trigeminal sensory nerve, leading to headache completed February 2018, development. Galcanezumab purportedly prevents CGRP data published July 2019; from binding to its receptor, which might reduce cluster phase III open-label headache frequency. For episodic cluster headache, extension primary the recommended dosage of galcanezumab-gnlm is completion July 2020 300 mg, which patients self-administer subcutaneously (episodic, chronic cluster as 3 consecutive injections of 100 mg each, at the onset headache) of the cluster period and then monthly until the end of the same cluster period. Note(s): FDA approved galcanezumab-gnlm to Developer(s): treat migraine headache in Eli Lilly and Co (Indianapolis, Indiana) September 2018.
Section 1. Currently Monitored Topics 99
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or Givosiran (ALN-AS1) is an RNA interference therapeutic Carbohydrate perfusion Fatigue score change PDUFA date: February 4, older and adults who have that reduces the expression of aminolevulinic acid (acute) from baseline 2020 Priority Review acute hepatic porphyrias synthase 1 (ALAS1) to treat AHP. A group of rare (AHP), including acute metabolic disorders, AHPs are caused by genetic Hemin injection (acute) Nausea score change FDA designation(s): intermittent porphyria, mutations (usually autosomal dominant) in enzymes that from baseline Orphan Drug, Supportive therapy Breakthrough Therapy variegate porphyria, and are involved in heme production in the liver and converge (acute) Pain score change from hereditary coproporphyria in their respective metabolic pathways on the ALAS1 baseline Clinical trial(s): Phase III enzyme. This is thought to increase the production heme Trigger avoidance ENVISION primary intermediates in the liver that are toxic to nerves and (acute) Rate of attacks completed January 2019, contribute to developing AHP. The manifestations include Rate of hemin data reported April 2019 intermittent porphyria, aminolevulinic acid dehydratase- administration deficiency porphyria, hereditary coproporphyria, and variegate porphyria. Common symptoms from these manifestations can include confusion; fatigue; nausea; weakness; blisters on sun-exposed skin; and severe, diffuse abdominal pain. The disorders are chronic and are associated with serious morbidity. Acute flares can be life- threatening. No treatments are FDA approved to prevent attacks or treat chronic manifestations of these disorders. Givosiran is designed to reduce the expression of ALAS1 enzyme in the liver, reduce buildup of neurotoxic heme intermediates, and prevent or reduce recurrent AHP attacks. It is given as a subcutaneous injection. Developer(s): Alnylam Pharmaceuticals Inc (Cambridge, Massachusetts)
Section 1. Currently Monitored Topics 100
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 7 to 13 years Golodirsen (Vyondys 53) is a phosphorodiamidate Corticosteroids (eg, Ambulatory capacity, as FDA designation(s): who have Duchenne morpholino oligomer (DNA analogue) intended to treat deflazacort, prednisone) measured by accepted Orphan Drug muscular dystrophy (DMD) DMD, an inherited, X chromosome–linked genetic clinical ratings and with a deletion in the DMD disorder caused by mutations or deletions in the Supportive care scales Clinical trial(s): Phase III gene that involves exon 53 dystrophin gene, DMD. DMD encodes the dystrophin ESSENCE primary that is being treated with a protein, which helps keep muscle cells intact. The Quality of life completion May 2022; stable dose of corticosteroids absence of wild-type dystrophin protein causes phase III open-label 6-minute walk test extension primary progressive muscle fiber necrosis and eventual distance widespread muscle weakness. No cure exists for DMD, completion June 2026 and first-line corticosteroid treatment manages symptoms Note(s): The manufacturer but does not prevent disease progression and has submitted a New Drug significant side effects. FDA approved a gene therapy for Application (NDA) in 2018, patients with a specific mutation in DMD (ie, in exon 51), and FDA scheduled a but patients who have other DMD mutations do not qualify PDUFA date of August 19, for these therapies. Additional therapies are needed. 2019, with Priority Review. Golodirsen purportedly binds exon 53 of dystrophin pre- On that date, FDA issued a mRNA (precursor RNA composed of introns and exons) Complete Response Letter and promotes skipping of exon 53 during mRNA rejecting the NDA, citing processing, which allows for synthesis of an internally concerns about infection truncated but functional dystrophin protein. Therefore, risk and renal toxicity golodirsen treatment might promote skeletal muscle related to drug function and prevent or delay disease progression in administration. patients who have mutations in DMD exon 53. In clinical trials, 30 mg/kg of golodirsen is given intravenously, once weekly, for up to 96 weeks. Developer(s): Sarepta Therapeutics Inc (Cambridge, Massachusetts)
Section 1. Currently Monitored Topics 101
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 2 to 6 years GT-AADC (formerly known as AGIL-AADC and AAV2- Dopamine agonists (eg, Developmental delays Submission date: Biologics who have genetically hAADC) is an adeno-associated viral vector containing a bromocriptine, License Application confirmed, symptomatic functional copy of the human dopa decarboxylase gene, pramipexole, ropinirole, Dyskinesia planned for fourth-quarter aromatic l-amino acid DDC. It is intended to treat patients with AADCD, a rotigotine) Motor function, as 2019 decarboxylase deficiency childhood-onset, progressive, inherited neurometabolic measured by accepted (AADCD) disorder. AADCD is caused by a mutation in DDC that Monoamine oxidase FDA designation(s): inhibitors (eg, selegiline, clinical ratings and Orphan Drug, Rare results in the loss of the gene’s encoded enzyme, scales aromatic l-amino acid decarboxylase (AADC), which is tranylcypromine) Pediatric Disease Quality of life critical for converting neurotransmitter precursors into Vitamin B6 Clinical trial(s): Phase I/II dopamine, epinephrine, norepinephrine, or serotonin. primary completion Patients with AADCD experience symptoms including December 2020, data severe developmental delays, weak muscle tone, published December 2017; involuntary movements of the arms and legs, and painful phase II MIND primary seizures. Existing treatments only manage symptoms and completion December do not prevent disease progression. Delivery of a 2018; pooled data functional copy of DDC by GT-AADC treatment might published May 2018 enhance neurotransmitter production, restore motor function, and delay or prevent other disease symptoms. In clinical trials, 1.8 × 1011 or 2.4 × 1011 vg of GT-AADC is given intracerebrally into the bilateral putamen via stereotactic surgery, once. Developer(s): PTC Therapeutics Inc (South Plainfield, New Jersey)
Section 1. Currently Monitored Topics 102
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children (mostly males) aged Idebenone is a small-molecule drug intended to treat Corticosteroids (eg, Forced vital capacity FDA designation(s): 8 years or older and adults DMD, an inherited, X chromosome–linked genetic deflazacort, prednisone) (total, percentage Orphan Drug, Rare who have Duchenne disorder caused by mutations or deletions in the predicted) Pediatric Disease, Fast muscular dystrophy (DMD) dystrophin gene, DMD. DMD encodes the dystrophin Track protein, which helps keep muscle cells intact. The Muscle strength Clinical trial(s): Phase III absence of wild-type dystrophin protein causes Percentage predicted progressive muscle fiber necrosis and eventual SIDEROS primary forced expiratory volume completion August 2021; widespread muscle weakness. No cure exists for DMD, in 1 second and first-line corticosteroid treatment manages symptoms phase III SIDEROS-E but does not prevent disease progression and has Percentage predicted primary completion significant side effects. FDA approved a gene therapy for peak expiratory flow December 2023; phase III DELOS study completed patients who have a specific mutation in DMD (ie, in exon Quality of life 51), but patients who have other DMD mutations do not April 2014, data published qualify. Therefore, additional therapies are needed. April 2015, additional data Idebenone is similar to coenzyme Q10 and purportedly published December 2017 facilitates electron transport within mitochondria. According to the manufacturer, maintaining correct electron balance is essential for normal energy metabolism, particularly in nerve and muscle cells, which demand more energy, making them more prone to rapid cell damage or death from mitochondrial dysfunction. In patients with DMD, preserving mitochondrial function and protecting cells from oxidative stress through idebenone treatment might prevent cell damage and increase energy production within impaired respiratory nerve and muscle tissue, potentially improving symptoms. In clinical trials, patients or caregivers orally administer 900 mg of idebenone daily, divided into 3 equal doses of two 150- mg tablets each, taken with meals. Developer(s): Santhera Pharmaceuticals (Pratteln, Switzerland)
Section 1. Currently Monitored Topics 103
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older jCell is an allogeneic (unrelated donor) stem cell therapy Supportive care Best corrected visual FDA designation(s): who have genetically that uses human retinal progenitor cells that have been acuity Orphan Drug, confirmed retinitis cultured and expanded. No effective treatments are Vitamin and nutritional Regenerative Medicine pigmentosa (RP) available for RP, so jCell could be the first nonsurgical supplementation Contrast sensitivity Advanced Therapy therapy for RP. It is intended to delay RP progression or Functional vision reverse vision loss through the release of neurotrophic Clinical trial(s): Phase II (assessed by visual JC-02 primary completion factors that might rescue diseased retinal cells and quality of life evaluation) possibly differentiate into new rod cells in the retina. In August 2019 clinical trials, jCell has been given as 3.0 × 106 or 6.0 × Microperimetry change 106 human retinal progenitor cells suspended in medium. from baseline It is injected intravitreally under local anesthesia into the Mobility (eg, maze eye with the poorest visual acuity or, if vision is testing) comparable in both eyes, the nondominant eye. Spectral domain optical Developer(s): coherence tomography jCyte Inc (Newport Beach, California), in collaboration Visual fields with California Institute of Regenerative Medicine (Oakland, California)
Section 1. Currently Monitored Topics 104
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Lenabasum is a novel synthetic anti-inflammatory and Combined autologous Disease progression Submission date: Biologics who have diffuse cutaneous antifibrotic (anti-scarring) medication under investigation hematopoietic stem cell License Application systemic sclerosis for treating the rare, incurable, autoimmune, connective transplant and high-dose Mortality planned for 2021 tissue disease systemic sclerosis. Conventional immunosuppressive Quality of life immunosuppressive therapy has limited efficacy in therapy FDA designation(s): preventing disease progression or reducing mortality Skin fibrosis and Orphan Drug, Fast Track Low-dose rates. The disease is marked by vasculopathy, skin inflammation Clinical trial(s): Phase III thickening due to collagen accumulation, autoantibody immunosuppressive therapy primary completion March formation, and inflammation, which leads to fibrosis in 2020 skin and internal organs. Patients with limited cutaneous Symptom-based systemic sclerosis have fairly high survival rates but are palliative at increased risk of pulmonary arterial hypertension. pharmacotherapy Patients with diffuse cutaneous systemic sclerosis have (angiotensin-converting worse survival rates. Preclinical studies suggest that enzyme [ACE] inhibitors, lenabasum preferential activates immune cell cannabinoid nonsteroidal anti- receptors (CB2). Lenabasum purportedly binds CB2 inflammatory drugs receptors and triggers inflammation resolution, a [NSAIDs]) multifaceted process that reduces immune-mediated inflammation and tissue injury to improve systemic sclerosis symptoms. In clinical trials, lenabasum is given orally, at 5- or 20-mg doses, twice daily. Developer(s): Corbus Pharmaceuticals Holdings Inc (Norwood, Massachusetts)
Section 1. Currently Monitored Topics 105
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or LentiGlobin (BB305) consists of patient-derived Blood transfusion Frequency of vaso- FDA designation(s): older and adults aged up to hematopoietic stem cells transduced with a functional occlusive crises and Orphan Drug, 50 years who have severe copy of the human β-globin gene, which are then Hematopoietic stem cell hospitalizations Regenerative Medicine sickle cell disease (SCD) reintroduced to the patient. In SCD, sickled red blood transplantation Advanced Therapy Number of blood cells are more susceptible to oxidative damage, Hydroxyurea inappropriate adhesion, and vascular obstruction. transfusions required Clinical trial(s): Phase I/II primary completion LentiGlobin has a unique amino acid substitution in the β- Pharmaceutical-grade L- Quality of life globin gene that promotes antisickling of red blood cells. glutamine February 2022; interim data reported June 2019 By replacing dysfunctional human β-globin genes, LentiGlobin might address SCD’s underlying cause rather than just reduce symptoms. LentiGlobin is given by intravenous infusion as a single dose after myeloablative conditioning with busulfan. Developer(s): bluebird bio Inc (Cambridge, Massachusetts)
Children, adolescents, and LentiGlobin (BB305) is a gene therapy intended for β- Allogeneic stem cell Level of iron overload FDA designation(s): adults aged up to 50 years thalassemia, an inherited blood disorder caused by a transplant Orphan Drug, who have transfusion- mutation in the hemoglobin subunit β gene HBB. This Organ function Breakthrough Therapy Repeated blood dependent β-thalassemia, mutation causes ineffective red blood cell production, Quality of life also known as β-thalassemia leading to severe anemia. Standard of care involves the transfusions Clinical trial(s): Phase III major, with a β0/β0 genotype use of frequent blood transfusions and supportive care. Transfusion need status NORTHSTAR-2 primary completion January 2020, (no β-globin expression) or a LentiGlobin might provide a one-time functional cure for β+/β0 genotype (little β-globin β-thalassemia. LentiGlobin consists of patient bone interim data reported June expression) marrow–derived CD34+ hematopoietic stem cells (HSCs) 2019; phase III harvested from the patient and treated with a lentivirus NORTHSTAR-3 primary vector that stably inserts a functional copy of the HBB completion April 2021, gene into the cells. The cells are then multiplied in culture preliminary data reported to facilitate uptake. This autologous HSC therapy does June 2019 not require immunosuppressive therapy. In clinical trials, LentiGlobin is given as a single intravenous infusion, at an unspecified dose, after patients are treated with busulfan to destroy β-thalassemia–causing blood cells. Developer(s): bluebird bio Inc (Cambridge, Massachusetts)
Section 1. Currently Monitored Topics 106
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 8 years or Livoletide (AZP-531) is a first-in-class analogue of Cognitive and behavioral Caregiver burden FDA designation(s): older and adults aged up to unacylated ghrelin, a naturally occurring hormone. therapy Orphan Drug 65 years who have Prader- Unacylated ghrelin is thought to counteract the effects of Hyperphagia (abnormal Willi syndrome (PWS) with acylated ghrelin, commonly called the “hunger hormone,” Controlled diet appetite) Clinical trial(s): Phase IIb/III ZEPHYR pivotal primary abnormally increased which stimulates food-seeking behavior. No effective Exercise programs Mortality appetite (hyperphagia) treatments are approved to treat PWS-associated completion June 2020, abnormal eating behaviors. If livoletide is effective for Glucagon-like peptide 1 Quality of life topline results expected in receptor agonist (ie, the first half of 2020 treating abnormal eating in PWS, it might reduce obesity- Rate of comorbidities related complications and improve quality of life for exenatide or liraglutide; off-label) (eg, cardiovascular patients. Livoletide is under development to treat disease, diabetes hyperphagia associated with PWS, a rare genetic disease Hormone therapy (ie, mellitus, obesity) (about 8000-11 000 estimated US patients) caused by human growth hormone) lack of expression of several genes on chromosome 15. In addition to having intellectual disability and short stature, patients with PWS often die by about 40 years of age, mainly from obesity-related comorbidities, including cardiovascular and respiratory (eg, sleep apnea) complications and type 2 diabetes mellitus. In clinical trials, patients receive daily subcutaneous injections at dosages between about 60 and 120 mcg/kg. Developer(s): Millendo Therapeutics (Ann Arbor, Michigan)
Section 1. Currently Monitored Topics 107
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Nintedanib (Ofev) is a kinase inhibitor and antifibrotic drug Azathioprine Breathing function Approval date: September who have systemic sclerosis– approved by FDA to treat idiopathic pulmonary fibrosis 6, 2019 associated interstitial lung (IPF) and being developed to treat SSc-ILD. Patients with Cyclophosphamide Disease progression disease (SSc-ILD) SSc, also known as scleroderma, have thickening and (SSc-ILD) FDA designation(s): Mycophenolate mofetil Orphan Drug, Fast Track scarring of connective tissue in multiple organs. Most will Survival develop ILD, which is the leading cause of death in these Rituximab Clinical trial(s): Phase III Quality of life patients. No cure exists for SSc-ILD, and existing Supportive care SENSCIS completed treatments manage symptoms but do not prevent disease October 2018, data progression and have significant side effects. Nintedanib published May 2019; purportedly binds to and blocks intracellular signaling of phase III open-label the receptor tyrosine kinases platelet-derived growth extension primary factor receptor α and β, fibroblast growth factor receptor completion July 2021 1-3, and vascular endothelial growth factor receptor 1-3, which are thought to contribute to lung tissue fibrosis in both IPF and ILD. Therefore, nintedanib might be effective in preventing SSc-ILD disease progression. In clinical trials, patients orally self-administer nintedanib 150 mg, twice daily, for up to 100 weeks. Developer(s): Boehringer Ingelheim Pharmaceuticals, Inc (Ridgefield, Connecticut)
Section 1. Currently Monitored Topics 108
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Men aged 18 years or older NSR-REP1 (AAV2-REP1) is an adeno-associated virus Low vision aids (eg, Best corrected visual FDA designation(s): who have genetically serotype 2 (AAV2) vector that delivers a recombinant telescopic and acuity (BCVA) Orphan Drug, confirmed choroideremia human CHM-associated gene. The gene encodes Rab magnifying lenses) Regenerative Medicine (CHM) escort protein 1 (REP1) inside the eye to treat Color vision Advanced Therapy Supportive care choroideremia, a rare, degenerative, chromosome Contrast sensitivity X–linked genetic retinal disorder primarily affecting men, Clinical trial(s): Phase III and for which no treatment is available. NSR-REP1 is Microperimetry STAR primary completion intended to introduce a functional choroideremia gene, March 2020 CHM, designed to enhance expression of REP1. This is thought to reduce accumulation of waste products in retinal cells and slow or stop vision decline. REP1’s enhanced expression might also slow or reverse early stages of cell death in damaged retinal cells, possibly improving visual acuity in some patients. In clinical trials, NSR-REP1 was given by injection into the subretinal space, which is between the retina’s outer layers, at a low (1 × 1010) or high (1 × 1011) vector dose. Developer(s): Biogen (Cambridge, Massachusetts), in collaboration with Nightstar Therapeutics plc (London, United Kingdom), which was acquired by Biogen in June 2019
Section 1. Currently Monitored Topics 109
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Men aged 18 years or older NSR-RPGR is a recombinant adeno-associated viral Supportive care BCVA Clinical trial(s): Phase II/III who have retina specialist– vector that delivers a codon-optimized form of the retinitis XIRIUS primary completion confirmed chromosome X– pigmentosa GTPase regulator-open reading frame 15 Vitamin and nutritional Microperimetry change August 2020, preliminary linked retinitis pigmentosa gene, RPGR-ORF 15, which encodes a full-length supplementation from baseline safety and efficacy data (XLRP) and RPGR-ORF 15 functional protein intended to treat XLRP. No effective Spectral domain optical reported September 2018 gene mutations treatments are approved for this rare condition, and NSR- coherence tomography RPGR could become the first retinal gene therapy to delay XLRP or reverse vision loss. XLRP is the most Visual fields common form of RP caused by mutations in the eye- specific form of the RPGR gene, called RPGR-ORF 15. NSR-RPGR is intended to express a full-length RPGR- ORF 15 protein in retinal cells that will restore the function of cones and rods. In clinical trials, a single dose is given via subretinal injection into the eye. Developer(s): Biogen (Cambridge, Massachusetts), in collaboration with Nightstar Therapeutics plc (London, United Kingdom), which was acquired by Biogen in June 2019
Adults aged 21 to 80 years NT-501 (Renexus) is an eye implant containing Vascular endothelial Macular thickness FDA designation(s): who have macular genetically modified human cells that secrete growth factor inhibitors Orphan Drug, Fast Track telangiectasia type 2 neuropeptide ciliary neurotrophic factor (CNTF). No Neurodegeneration, as implants are approved to carry biologics for macular measured by changes in Clinical trial(s): Phase III telangiectasia type 2, a neurodegenerative disorder that macular ellipsoid zone primary completion March 2021; phase III primary causes gradual central vision loss over a period of 10 to Reading speed 20 years. Therefore, NT-501 might represent a novel completion March 2021; treatment option for these patients. NT-501 allows Retinal sensitivity phase II completed April 2017, data published April controlled release of biologic drugs and is intended to Visual acuity slow retinal degeneration. CNTF purportedly diffuses into 2019 the retina from the cells contained within the Renexus device to stimulate retinal cell growth and protect the cells from damage. In clinical trials, Renexus is surgically implanted into the vitreous humor and contains an unspecified dose of CNTF. The implant purportedly secretes CNTF for up to 2 years after placement. Developer(s): Neurotech Pharmaceuticals (Cumberland, Rhode Island), in collaboration with Lowy Medical Research Institute (La Jolla, California)
Section 1. Currently Monitored Topics 110
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 60 years NurOwn is an autologous, bone marrow–derived, Edaravone Disability FDA designation(s): who have rapidly progressing mesenchymal stromal cell therapy intended for ALS. In Orphan Drug, Fast Track amyotrophic lateral sclerosis patients with ALS, the presence of abnormal proteins in Riluzole Disease progression (ALS) the brain and spinal cord causes neuronal death and (ALS) Clinical trial(s): Phase II Supportive care completed March 2016, contributes to disease progression. The exact cause of Quality of life these aggregates is unknown. FDA-approved drugs to data presented October treat the disease (eg, riluzole, edaravone) decrease 2018, data presented May symptom severity in some patients but do not prevent 2019; phase III BCT-002 neuronal injury and ALS progression. NurOwn grows the completed July 2019 patient’s bone marrow cells in a proprietary culture media to differentiate mesenchymal stromal cells into astrocyte- like cells. The cultured cells purportedly secrete neurotrophic and growth factors, including glial-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor, and hepatocyte growth factor, which have immunomodulatory characteristics intended to protect neurons and glial cells from toxins and facilitate tissue repair. Thus, NurOwn could delay or prevent neuronal injury in patients with rapidly progressing ALS. In clinical trials, an unspecified dose of NurOwn is given intrathecally (into the spinal cord), every other month, 3 times. Developer(s): BrainStorm Cell Therapeutics (New York, New York)
Section 1. Currently Monitored Topics 111
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 2 years or Onasemnogene abeparvovec-xioi (Zolgensma) is an Manual chest Developmental milestone Approval date: May 24, younger who have spinal adeno-associated viral vector (AAV9) containing a physiotherapy for achievement 2019 muscle atrophy (SMA) type 1 functional copy of the SMN1 gene intended to restore ineffective cough (eg, (infantile-onset SMA or SMN1 expression in patients with SMA type 1. SMA, a Cough Assist or Hospitalization rates FDA designation(s): Orphan Drug (all types of Werdnig-Hoffmann disease) severe neuromuscular disorder caused by a genetic VitalCough) Mortality with bi-allelic mutations in the defect in SMN1, results in loss of the gene’s encoded SMA), Breakthrough survival motor neuron 1 SMN protein. The protein is critical for motor neuron Noninvasive positive Motor function, as Therapy (SMA type 1), gene, SMN1 function and transmission of signals from the brain to pressure ventilation measured by accepted Fast Track (SMA type 1) skeletal muscles. Patients with SMA experience motor Nusinersen clinical ratings and Clinical trial(s): Phase I neuron loss, resulting in progressive muscle weakness scales START completed and eventual paralysis. Restoring functional SMN1 Muscle strength, as December 2017, long-term expression through Zolgensma could delay or halt measured by accepted follow-up data reported disease progression in patients with SMA type 1. In clinical ratings and February 2019; phase III 13 clinical trials, patients received either 6.7 x 10 vg/kg scales STR1VE primary of body weight or 2.0 x 1014 vg/kg of body weight of completion November Zolgensma, intravenously via a peripheral vein, once. Nutritional support use 2019, interim data reported Developer(s): Ventilator support use May 2019 AveXis Inc (Bannockburn, Illinois), a wholly owned Note(s): In August 2019, subsidiary of Novartis AG (Basel, Switzerland) FDA released a statement regarding manipulation of data that were included in the manufacturer’s Biologics License Application.
Section 1. Currently Monitored Topics 112
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Infants, children, and OTL-101 is a bone marrow–derived gene therapy product Bone marrow transplant Event-free survival Submission date: Biologics adolescents aged 30 days to intended for ADA-SCID (“bubble boy disease”), a rare and License Application 17 years who have life-threatening inherited disease of the immune system Enzyme replacement Overall survival planned for 2020 adenosine deaminase/ due to a faulty ADA gene. ADA is essential for T-cell and Quality of life severe combined B-cell production (lymphocytes); patients with ADA-SCID FDA designation(s): immunodeficiency (ADA- produce no functional lymphocytes, leading to Orphan Drug, SCID) and are ineligible for susceptibility to serious and life-threatening infections. Breakthrough Therapy, allogeneic bone marrow Without enzyme replacement therapy, patient life Rare Pediatric Disease transplantation from a expectancy is short. OTL-101 was designed to restore Clinical trial(s): Phase I/II matched family donor lymphocyte development and immunity in patients with primary completed October ADA/SCID. OTL-101 consists of patient-derived CD34+ 2018, initial data reported stem cells that are harvested from the patient and treated February 2019; phase I/II with a lentivirus vector that stably inserts a functional copy primary completion of the ADA gene into the cells. The cells are then December 2020 multiplied in culture to facilitate uptake. OTL-101 is given as a single intravenous infusion of an unspecified dose. Developer(s): Orchard Therapeutics Ltd (London, United Kingdom)
Section 1. Currently Monitored Topics 113
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children, adolescents, and OTL-103 is a bone marrow–derived gene therapy product Hematopoietic stem cell Frequency of FDA designation(s): adults aged up to 65 years intended for WAS, a rare X chromosome–linked inherited transplant immunoglobulin or Orphan Drug, Rare who have Wiskott-Aldrich primary immunodeficiency disorder caused by mutations platelet infusions Pediatric Disease, syndrome (WAS) in the WAS gene. The WAS gene is a cytoskeleton Immunoglobulin infusion Regenerative Medicine Rate of hospitalizations regulator expressed only in hematopoietic (blood-forming) Platelet infusion Advanced Therapy cells. WAS deficiency leads to eczema, petechiae, for infection or bleeding thrombocytopenia, reduced blood clotting, and episodes Clinical trial(s): Phase I/II susceptibility to infections. A bone marrow transplant from TIGET-WAS completed an allogeneic (unmatched) donor can potentially cure October 2018, data WAS. OTL-103 is intended to relieve WAS symptoms by published May 2019; repopulating the bone marrow with WAS-expressing phase II primary hematopoietic stem cells to restore growth, replication, completion February 2022 and functional capacities that enable immune responses to infectious agents and injury. OTL-103 consists of patient-derived CD34+ hematopoietic stem cells that are harvested from the patient and treated with a lentivirus vector that stably inserts a functional copy of the WAS gene into the cells. The cells are then multiplied in culture to facilitate uptake and frozen until needed for use. In clinical trials, the transduced OTL-103 cell product is regiven as a single intravenous infusion of an unspecified number of cells, after patients have received a myeloablative (bone marrow–destroying) conditioning regimen with busulfan, fludarabine, and anti-CD20 antibody. Developer(s): Orchard Therapeutics Ltd (London, United Kingdom)
Section 1. Currently Monitored Topics 114
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 4 years or Palovarotene is a selective retinoic acid receptor gamma Supportive care (eg, Flare rate Submission date: New older and adults who have (RARγ) agonist being developed to treat FOP. A rare assistive devices, Drug Application planned fibrodysplasia ossificans connective tissue disorder, FOP leads to the abnormal corticosteroids, New HO formation for the second half of 2019 progressiva (FOP) growth of bone in muscles, tendons, and ligaments, nonsteroidal anti- Number of body regions (flare treatment indication known as heterotopic ossification (HO). Palovarotene inflammatory drugs with HO only) treatment might prevent HO in patients with FOP. HO [NSAIDs], occupational flares can occur spontaneously or after physical trauma therapy) Physical function, as FDA designation(s): (eg, injury, infection). Once formed, the heterotopic bone measured by accepted Orphan Drug, cannot be removed because tissue disruption causes clinical ratings and Breakthrough Therapy, additional HO episodes. HO progressively interferes with scales Fast Track, Rare Pediatric Disease normal body functions, including walking, bending, Range of motion, as breathing, chewing, and swallowing. FOP is caused by a measured by accepted Clinical trial(s): Phase III mutation in the activin A receptor type 1 gene, ACVR1, clinical ratings and MOVE primary completion which encodes for the ACVR1/ALK2 receptor. ALK2 scales September 2020; phase II normally regulates the bone morphogenetic protein (BMP) completed May 2016, data pathway, which is responsible for cartilage regulation and presented September bone development and growth. In patients with FOP, 2017; phase II long-term mutant ALK2 overactivates Smad 1/5/8 transcription extension primary factors in the BMP2 pathway. Palovarotene purportedly completion March 2021 binds to and activates RARγ, which promotes Smad destruction. In clinical trials, for preventive treatment, Note(s): Palovarotene is patients receive 5 mg of oral palovarotene, once daily, for also in phase II 24 months. For disease flares, patients receive 20 mg of development to treat oral palovarotene, once daily, for 4 weeks, followed by 10 multiple osteochondromas. mg of palovarotene, once daily, for 8 weeks. Developer(s): Clementia, an Ipsen company (Montreal, Québec, Canada)
Section 1. Currently Monitored Topics 115
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adolescents aged 16 years PBI-4050 (3-pentylbenzeneacetic acid sodium salt) is a Organ transplant Change from baseline in FDA designation(s): or older and adults who have novel, synthetic, medium-chain fatty acid derivative, oral blood glucose, as Orphan Drug, Rare Alström syndrome antifibrotic (reduces scar tissue formation) intended to Supportive care measured by weekly 4- Pediatric Disease treat Alström syndrome, a rare genetic syndrome. The point profile syndrome is characterized by obesity in childhood or Clinical trial(s): Phase II/III adolescence and type 2 diabetes mellitus, often with Change from baseline in primary completion July severe insulin resistance, dyslipidemia, hypertension, and fasting plasma glucose 2020, preliminary data severe life-threatening multiorgan fibrosis involving the over time reported April 2018; pivotal phase III planned bladder, kidney, liver, and heart. Progressive loss of Change from baseline in vision and hearing, dilated cardiomyopathy, and short glycated hemoglobin stature might also occur. PBI-4050 is intended to alleviate (HbA1c) over time the development of insulin resistance, dyslipidemia, and hypertension and severe multiorgan fibrosis. PBI-4050 Change from baseline in purportedly has stimulating and inhibiting activity toward liver stiffness the G-protein coupled receptors GPR40 and GPR84, Change from baseline in respectively, which reduce fibrotic activity in plasma insulin over time macrophages, fibroblasts/myofibroblasts, and epithelial cells. In clinical trials, PBI-4050 was given as four 200-mg Change from baseline in capsules (800 mg total), once daily. skin pathology Developer(s): Prometic Life Sciences Inc (Laval, Québec, Canada)
Section 1. Currently Monitored Topics 116
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 10 years or Plerixafor (Mozobil) is a CXC chemokine receptor 4 Granulocyte colony- Hematologic and FDA designation(s): older and adults aged up to (CXCR4) inhibitor, which purportedly prevents most stimulating factor (G- immunologic parameters Orphan Drug 75 years who have a clinical leukocyte subsets from homing in and localizing in the CSF; infection diagnosis of WHIM syndrome bone marrow. This is a characteristic of WHIM syndrome, prevention) Infection rate Clinical trial(s): Phase III primary completion (warts, a rare primary immunodeficiency caused by several Quality of life hypogammaglobulinemia, different mutations in the C-X-C motif chemokine receptor Imiquimod (warts) November 2020 infections, and 4 gene, CXCR4. The mutations associated with the Intravenous Severity of infections Note(s): In December myelokathexis) with a syndrome cause dysfunction of the immune system, immunoglobulin Wart control 2008, FDA approved heterozygous mutation in the which increases infection risk and other complications, (infection prevention) plerixafor to treat ovarian C-tail of CXCR4, documented resulting in many types of bacterial infection that can be cancer and for use in neutropenia, and history of mild to severe with serious sequelae. No cure exists. combination with G-CSF to severe or recurrent infections Standard treatment involves antibiotic prophylaxis, mobilize HSCs to the immune stimulation, and treatment of infections and their peripheral blood for consequences. Plerixafor is intended to reduce infection collection and subsequent risk. In a clinical trial, plerixafor is given by injection, 0.02 autologous transplantation to 0.04 mg/kg/day, for 6 months. in patients with non- Developer(s): Hodgkin lymphoma and multiple myeloma. Sanofi Genzyme (Cambridge, Massachusetts)
Adults aged 40 to 80 years PRM-151 (rhPTX-2) is a recombinant form of the innate Nintedanib Exercise capacity FDA designation(s): who have idiopathic immunity protein pentraxin-2, which is active at sites of Orphan Drug, pulmonary fibrosis (IPF) tissue damage and has demonstrated broad antifibrotic Pirfenidone Mortality Breakthrough Therapy activity in preclinical models. Unlike available therapies Quality of life for IPF that only slow the rate of disease progression, Clinical trial(s): Phase III PRM-151 is an agonist that purportedly reverses IPF Respiratory function planned; phase II primary completed May 2018, data pathology. PRM-151 purportedly turns off the proliferation pathway mediated by proinflammatory and profibrotic published June 2018, data macrophages that leads to fibrosis and helps activate the published August 2019 healing resolution pathway by directing the differentiation of monocytes into proresolution macrophages. In clinical trials, PRM-151 was given as an intravenous infusion, 10 mg/kg over 60 minutes, on days 1, 3, and 5, then once every 4 weeks. Developer(s): Promedior Inc (Lexington, Massachusetts)
Section 1. Currently Monitored Topics 117
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adolescents aged 16 years PXT3003 is a proprietary combination of 3 FDA-approved Analgesics Functional mobility FDA designation(s): or older and adults aged up pharmaceuticals ([RS]-baclofen, naltrexone Orphan Drug, Fast Track to 67 years who have hydrochloride, and D-sorbitol) intended to treat CMT1A. Foot surgery Pain Clinical trial(s): Phase II genetically confirmed Patients with CMT1A overexpress PMP22 protein due to Mobility aids Quality of life Charcot-Marie-Tooth disease an extra copy of the peripheral myelin protein 22 gene, completed December type 1A (CMT1A) PMP22. PMP22 overexpression degrades the protective Occupational and 2012, data available myelin sheath on nerve fibers, leading to peripheral nerve physical therapy December 2014; phase III PLEO-CMT completed dysfunction and eventual nerve conduction loss. No Orthotic devices curative or disease-modifying treatments exist, and September 2018, topline patients typically receive supportive care to address data reported October functional disability and neuropathic pain. Therefore, 2018, additional data
additional therapies for CMT1A are needed. The 3 drugs reported May 2019; phase
in PXT3003 are all involved in modulation of cellular III PLEO-CMT-FU follow-up activity in the central nervous system: (RS)-baclofen is a extension primary gamma-aminobutyric acid receptor agonist that blocks completion September excitatory neurotransmitter release, naltrexone 2019 hydrochloride is an opioid receptor antagonist, and D- sorbitol purportedly is a muscarinic acetylcholine receptor activator that might promote expression of genes involved in myelin production. Thus, PXT3003 might improve myelination, protect nerve and muscle cell function, and prevent disease progression in patients with CMT1A. In clinical trials, patients drink a solution of PXT3003, twice daily with food, for 15 months. Developer(s): Pharnext SA (Paris, France)
Section 1. Currently Monitored Topics 118
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 70 years Reboxetine (AXS-12) is a selective norepinephrine Amphetamines Cataplexy attack FDA designation(s): who have narcolepsy with reuptake inhibitor intended to treat patients with EDS and frequency Orphan Drug excessive daytime sleepiness cataplexy from narcolepsy, a chronic neurologic sleep Antidepressants (eg, (EDS) and cataplexy disorder. Treatments for narcolepsy typically address only selective serotonin EDS symptoms and Clinical trial(s): Phase II EDS or cataplexy, whereas reboxetine is purportedly for reuptake inhibitors severity CONCERT completed both. Narcolepsy is caused by impaired production of [SSRIs], tricyclic June 2019 antidepressants) Quality of life hypocretin, an excitatory neuropeptide that regulates the Note(s): A number of sleep–wake cycle. About 60% to 70% patients with Nonamphetamine Wakefulness countries outside the narcolepsy also experience cataplexy, a disorder stimulants (eg, United States have characterized by sudden, uncontrollable muscle armodafinil, modafinil) approved reboxetine to weakness or paralysis that occurs during the daytime and treat major depressive is often triggered by a strong emotion, such as crying, Sodium oxybate disorder. excitement, or laughter. Reboxetine purportedly promotes Solriamfetol wakefulness and increases the activity of the excitatory neurotransmitter norepinephrine. In clinical trials, patients receive an unspecified dose of reboxetine orally, twice daily, for 3 weeks. Developer(s): Axsome Therapeutics Inc (New York, New York)
Section 1. Currently Monitored Topics 119
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 4 months to RGX-121 is a recombinant, adeno-associated viral vector Supportive care Cognitive, behavioral, FDA designation(s): 5 years who have Hunter (AAV9) carrying the human iduronate 2-sulfatase gene, and adaptive function, as Orphan Drug, Fast Track, syndrome IDS, and intended to treat Hunter syndrome (MPSII). This measured by accepted Rare Pediatric Disease (mucopolysaccharidosis type childhood-onset, progressive, inherited metabolic disorder MPSII-specific clinical 2; MPSII) is caused by a mutation in IDS. Patients with the disorder ratings and scales Clinical trial(s): Phase I/II cannot break down the polysaccharides dermatan sulfate RGX-121-101 primary and heparan sulfate, the process of which is normally Quality of life completion August 2019 mediated by the IDS-encoded enzyme iduronate 2-sulfatase. Buildup of dermatan sulfate and heparan sulfate in cells of the central nervous system causes degeneration that manifests as behavioral problems, sleeplessness, loss of speech and cognitive skills, mental retardation, heart problems, seizures, and loss of mobility. No cure exists for Hunter syndrome, and standard-of-care treatment consists of weekly enzyme replacement infusions. RGX-121 is a gene therapy intended to deliver a functional copy of the IDS gene to the central nervous system. It purportedly restores iduronate 2-sulfatase function, blocks central nervous system degeneration, and reduces disease-related symptoms with a single injection, thereby eliminating the need for weekly enzyme replacement therapy. In clinical trials, RGX 1.3 × 1010 genome copies per gram (GC/g) of brain mass or 6.5 x 1010 GC/g brain mass is injected intracisternally (into the cerebrospinal fluid), once. Developer(s): Regenxbio Inc (Rockville, Maryland)
Section 1. Currently Monitored Topics 120
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 6 years or Rivipansel is a synthetic glycomimetic (ie, similar Analgesia (eg, Frequency of VOCs FDA designation(s): older and adults who have structure to a carbohydrate), panselectin inhibitor that acetaminophen, Orphan Drug, Fast Track sickle cell disease (SCD) and targets inflammatory and adhesion processes that might morphine, nonsteroidal Hospital stay Clinical trial(s): Phase III are experiencing a vaso- contribute to VOC. It is intended to reduce the duration of anti-inflammatory drugs Opioid use occlusive crisis (VOC) VOC and hospital stays. In SCD, sickled red blood cells [NSAIDs]) primary completed June are more susceptible to oxidative damage, inappropriate Quality of life 2019, designed under adhesion, and vascular obstruction, leading to VOCs that Hydration Special Protocol Rehospitalizations within Assessment, pivotal data cause severe pain, requiring hospitalization. VOC Hydroxyurea 3 days of discharge complications can include circulating blood clots, stroke, reported August 2019; organ failure, or early death. In clinical trials, rivipansel is phase III primary given by intravenous infusion every 12 hours for up to completion June 2021 15 doses. For patients older than 12 years and heavier Note(s): Phase III trial than 40 kg, the first dose is 1680 mg and subsequent failed to meet primary and doses are 840 mg. For patients aged 6-12 or weighing key secondary endpoints. less than 40 kg, the first dose is 40 mg/kg up to 1680 mg and subsequent doses are 20 mg/kg up to 840 mg, every 12 hours. Developer(s): GlycoMimetics Inc (Rockville, Maryland), in partnership with Pfizer Inc (New York, New York)
Section 1. Currently Monitored Topics 121
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Infants and children who RVT-802 is an allogeneic (unmatched) donor thymus- Hematopoietic stem cell Survival Submission date: Rolling have primary immune derived, cell-based therapy intended to restore immune transplant Biologics License deficiency from congenital function in patients with primary immune deficiencies from T-cell proliferation Application began June Supportive care athymia (lack of a thymus), congenital athymia, which includes complete DiGeorge 2019 which includes complete genetic anomaly, CHARGE syndrome, and FOXN1 DiGeorge genetic anomaly; deficiency. Patients with congenital athymia have a high FDA designation(s): coloboma, heart defects, risk of death (often by 24 months of age) due to Orphan Drug, Rare atresia choanae (CHARGE) chromosomal mutations that disrupt T-cell production. Pediatric Disease, syndrome; and Forkhead Box The absence of functional mature T cells or B cells Breakthrough Therapy, N1 (FOXN1) deficiency severely compromises immunity. RVT-802 is intended to Regenerative Medicine restore the patient’s ability to produce naïve T cells with a Advanced Therapy broad T-cell receptor repertoire, conferring effective Clinical trial(s): Phase II immune responses. Isolated thymocytes are cultured in a primary completed March manufacturing facility for 14 to 21 days. In clinical trials, 2008; phase II primary RVT-802 is given by placing a cultured thymus slice into a completed August 2010 small hole in the quadriceps muscle that is then pulled over the slice using an insoluble stitch. The dose is 4 to 18 g/m2 of thymus tissue per patient body weight in kilograms. Developer(s): Enzyvant Therapeutics GmbH (Basel, Switzerland), a subsidiary of Roivant Sciences GmbH (Basel, Switzerland)
Section 1. Currently Monitored Topics 122
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 5 years or SB-913 is a gene-editing technology that uses an Idursulfase Frequency of idursulfase FDA designation(s): older and adults who adenovirus vector to modify liver cells with zinc-finger administration change Orphan Drug, Rare have Hunter syndrome endonucleases that insert a functional copy of the from baseline Pediatric Disease, Fast (mucopolysaccharidosis type iduronate-2-sulfatase gene, IDS, into a precise location in Track 2; MPSII) the patient’s DNA to treat Hunter syndrome (MPSII). IDS activity (clinical Hunter syndrome is a childhood-onset, progressive, laboratory measurement) Clinical trial(s): Phase I/II inherited metabolic disorder caused by a mutation in IDS. change from baseline primary completion February 2021, interim IDS encodes a lysosomal enzyme of the same name that Urine glycosaminoglycan metabolizes glycosaminoglycans and prevents their data reported February (GAG) levels (in ratio to 2019 accumulation, toxicity, and widespread tissue and organ creatinine) change from damage. No cure exists for Hunter syndrome, and the baseline current standard of care is weekly infusions of replacement enzyme. SB-913 is intended to enable the liver to sustainably produce sufficient functional IDS to relieve disease symptoms after a single treatment, thereby eliminating the need for weekly infusions. In a clinical trial, SB-913 was given as a single intravenous infusion of vg containing 5 × 1013 vg/kg, containing each of the 3 components of SB-913: ZFN1, ZFN2, and hIDS donor gene. Developer(s): Sangamo Therapeutics (Richmond, California)
Section 1. Currently Monitored Topics 123
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 75 years Solriamfetol (Sunosi) is a selective norepinephrine and Amphetamines EDS symptoms and Approval date: March 20, who have narcolepsy and dopamine reuptake inhibitor approved by FDA to treat severity 2019 excessive daytime sleepiness EDS in patients with narcolepsy, a chronic neurologic Antidepressants (eg, (EDS) sleep disorder. Narcolepsy is caused by impaired tricyclic antidepressants, FDA designation(s): production of hypocretin, an excitatory neuropeptide that selective serotonin Orphan Drug reuptake inhibitors) regulates the sleep–wake cycle. Sodium oxybate is a Clinical trial(s): Phase III gamma hydroxybutyrate derivative approved by FDA to Nonamphetamine completed February 2017, treat EDS in patients with narcolepsy, but the drug causes stimulants (eg, results published March central nervous system depression and has the potential armodafinil, modafinil) 2019; phase III open-label for abuse and misuse. Other treatments also have the extension study completed potential to cause significant side effects (eg, Sodium oxybate December 2017 amphetamines, antidepressants, nonamphetamine stimulants). Solriamfetol purportedly promotes Note(s): FDA has approved wakefulness and reduces EDS by increasing the activity solriamfetol to treat of the excitatory neurotransmitters norepinephrine and obstructive sleep apnea. dopamine. Patients receive solriamfetol orally, once daily, at a dose of 75 or 150 mg. Developer(s): Jazz Pharmaceuticals plc (Dublin, Ireland)
Section 1. Currently Monitored Topics 124
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children and adults aged 16 Tasimelteon (Hetlioz) is a melatonin receptor agonist Beta blockers (eg, Quality of life Submission date: to 65 years who have Smith- approved by FDA to treat non–24 hour sleep–wake acebutolol) Supplemental New Drug Magenis syndrome (SMS) disorder and is being developed to treat sleep Sleep quality and Application planned for and a history of sleep disturbances in patients with SMS. A developmental Daytime light therapy duration third-quarter 2019 disturbances disorder, SMS is caused by a mutation in the retinoic acid Nighttime melatonin Clinical trial(s): Phase II/III induced 1 gene, RAI1. Patients with SMS typically have supplementation intellectual disabilities and behavioral problems and primary completion July experience sleep disturbances due to disrupted melatonin 2017, data reported production. Sleep disturbances decrease quality of life in December 2018 patients with SMS. No established guidelines exist for Note(s): FDA previously melatonin use in patients with SMS, so dosage might be approved Hetlioz for non– difficult to optimize, and daytime sleepiness might 24 hour sleep-wake increase as because of excess melatonin levels. disorder. On August 20, Therefore, additional therapies to help regulate sleep are 2019, FDA rejected needed for patients with SMS. Hetlioz is intended to Vanda’s supplemental improve sleep quality and overall quality of life by NDA for Hetlioz for jet lag increasing natural melatonin levels at night. In clinical disorder. trials, patients receive an unspecified dose of Hetlioz orally once daily at bedtime for 21 weeks. Developer(s): Vanda Pharmaceuticals Inc (Washington, DC)
Section 1. Currently Monitored Topics 125
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 6 months or Triheptanoin (UX007) is a purified synthetic triglyceride High-carbohydrate, fat- Energy production Submission date: New older and adults who have a that purportedly treats FAOD by providing supplemental, restricted diet to maintain Drug Application August 1, confirmed diagnosis of long- medium-length, odd-chain fatty acids that can be constant energy supply Incidence of disease- 2019 chain fatty acid oxidation metabolized into ketones to increase intermediates used related hospitalization, disorder (FAOD), including in Krebs cycle energy generation and improve energy Intravenous glucose emergency department FDA designation(s): carnitine palmitoyltransferase production. Triheptanoin purportedly can also be administration (if oral visits, acute care visits, Orphan Drug, Fast Track, (CPT) deficiency (CPT1 or converted into glucose when patients’ glucose levels are feeding not tolerated) or other unscheduled Rare Pediatric Disease emergency interventions CPT2), very-long-chain acyl- low. No pharmacologic therapies exist for FAODs, so Clinical trial(s): Phase II CoA dehydrogenase triheptanoin could provide an option besides traditional Incidence of symptoms primary completion deficiency, long-chain 3- dietary supplementation for these patients. Traditional September 2021; hydroxy-acyl-CoA dietary supplementation with medium-chain triglycerides Quality of life unphased retrospective dehydrogenase deficiency, provides only even-chain fatty acids, potentially depleting observational chart review trifunctional protein odd-chain carbon intermediates during tricarboxylic acid primary completion deficiency, or carnitine- cycle energy generation. This depletion compromises September 2019 acylcarnitine translocase optimal energy production and gluconeogenesis during deficiency hypoglycemia. In clinical trials for treating FAOD, triheptanoin is given as an orally ingested oil with food or by gastronomy tube, at dosages equivalent to 25% to 35% of individual patients’ caloric requirements. Developer(s): Ultragenyx Pharmaceutical Inc (Novato, California); licensed rights to UX007 from Baylor Scott & White Research Institute (Dallas, Texas)
Section 1. Currently Monitored Topics 126
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 5 years or Trofinetide (NNZ-2566) is a novel synthetic analogue of Supportive care (eg, Motor function, as FDA designation(s): older and adults aged up to the amino‐terminal tripeptide of insulin-like growth factor 1 anticonvulsants, measured by accepted Orphan Drug, Fast Track 45 years who have (IGF-1) intended to treat Rett syndrome, a rare, postnatal, assistive devices, clinical ratings and Clinical trial(s): Phase II genetically confirmed Rett progressive neurologic disorder. Rett syndrome is caused noninvasive ventilation, scales Rett-001 (enrolling syndrome by a mutation in the methyl CpG binding protein 2 gene, nutritional support, Symptom frequency and adolescents aged 16-17 MECP2. Located on the X chromosome, MECP2 encodes oxygen treatment, severity, as measured by and adults aged 18-45) the MeCP2 protein that normally mediates gene physical and accepted clinical ratings completed September expression in neuronal and glial cells. Loss of MeCP2 occupational therapy, and scales 2014, data published function results in nerve cell dysfunction, which is thought speech/language November 2017; phase II to be reversible. Patients with Rett syndrome develop therapy) Rett-002 (enrolling children normally until 6-18 months of age and subsequently aged 5-15) completed experience developmental delays and regression of previously learned motor and verbal skills. The disease January 2017, data published April 2019; eventually causes additional symptoms, such as repeated phase III (enrolling children hand movements, impaired gait, slowed head growth, aged 5-17 and adults aged disordered breathing, and seizures. Symptom severity varies by patient and depends on the individual’s specific 18-20) planned for fourth- quarter 2019 MECP2 mutation and the amount of mutant MeCP2 protein expression. No cure exists, and treatment generally consists of supportive care for managing symptoms. Trofinetide, because of its homology with the amino-terminal peptide tripeptide of IGF-1, which promotes neuronal and glial function, is intended to decrease symptom severity and disease progression in patients who have Rett syndrome. In clinical trials, patients receive trofinetide at a dose of 35, 50, 70, 100, or 200 mg/kg, either orally or via a gastrostomy tube, twice daily, for 40 to 56 days. Developer(s): Acadia Pharmaceuticals Inc (San Diego, California), in collaboration with Neuren Pharmaceuticals Ltd (Camberwell, Australia) and Rettsyndrome.org (Cincinnati, Ohio)
Section 1. Currently Monitored Topics 127
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or Voxelotor (GBT440) is intended as a disease-modifying Analgesia (eg, Frequency of vaso- Submission date: New older and adults who have agent to treat SCD, which currently has no cure. In SCD, acetaminophen, occlusive crises Drug Application planned sickle cell disease (SCD) sickled red blood cells are more susceptible to oxidative morphine, nonsteroidal for the second half of 2019 damage, inappropriate adhesion, and vascular anti-inflammatory drugs Hemolysis markers FDA designation(s): obstruction. Voxelotor purportedly binds mutated [NSAIDs]) Hospitalized days hemoglobin and prevents it from sickling and aggregating, Orphan Drug, Rare increasing native hemoglobin’s affinity for oxygen. Hydration Opioid use Pediatric Disease, Breakthrough Therapy, Because oxygenated sickle hemoglobin does not Hydroxyurea Quality of life polymerize, voxelotor purportedly blocks polymerization Fast Track and the resultant sickling and destruction of red blood Rehospitalizations Clinical trial(s): Phase III cells. With the potential to improve hemolytic anemia and GBT HOPE primary oxygen delivery, voxelotor might modify the underlying completion October 2019, SCD disease process rather than merely decrease pivotal data published disease symptoms. In a clinical trial, the drug is given August 2019; phase III orally, 900 or 1500 mg, once daily. primary completion Developer(s): December 2019 Global Blood Therapeutics Inc (South San Francisco, California)
Section 1. Currently Monitored Topics 128
Section 2. Topics Added Since Last Status Report: 66 Topics
Table 6. Alzheimer’s Disease and Other Dementias: 2 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 55 to 85 years AGB101 is a proprietary, low-dose, extended-release Supportive care AD progression Clinical trial(s): Phase III who have mild Alzheimer’s formulation of the antiepileptic drug levetiracetam, HOPE4MCI primary disease (AD) intended to treat mild cognitive impairment (MCI) due to Cognitive performance, completion November AD. AGB101 could be the first disease-modifying as measured by AD- 2021 treatment that slows the progression and delays the onset specific clinical ratings of Alzheimer’s dementia, leading to improved cognitive and scales ability and reduced long-term care costs. AGB101 Quality of life purportedly blocks hippocampal overactivity that is associated with neurodegeneration and memory loss symptoms in patients with MCI due to AD. In clinical trials, AGB101 220 mg is given orally, once daily, for 78 weeks. Developer(s): AgeneBio Inc (Baltimore, Maryland)
Section 2. Topics Added Since Last Status Report 129
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 55 to 85 years Human albumin (Albutein) infusion combined with Cholinesterase inhibitors Cognitive function Clinical Trial(s): Phase II/III who have mild to moderate intravenous immunoglobulin is intended to treat AD by (eg, donepezil, (AMBAR) completed March Alzheimer’s disease (AD) periodically extracting plasma and exchanging the galantamine, Disease progression 2018, topline data reported patient’s albumin with Albutein solution. Investigators rivastigmine) October 2018, updated theorize that since most amyloid-beta protein is bound to Quality of life data reported July 2019 albumin and circulating in plasma, plasma exchange Memantine (off-label) might “flush” amyloid-beta from the brain into the Symptom severity Note(s): FDA granted circulation, mitigating cognitive decline. This treatment is Biologics License also called Alzheimer Management by Albumin Application approval for Replacement (AMBAR). In clinical trials, the treatment Albutein in 1978 as adjunct groups were assigned to receive either a high dose (total therapy for patients with plasma exchange once weekly, 2.5 to 3 L plasma removal hypovolemia, with albumin replacement for 6 weeks) or a low dose cardiopulmonary bypass (low-volume plasma exchange monthly, 650-880 mL procedures, plasma removal with a low dose of albumin or hypoalbuminemia, and immunoglobulin for 12 months). plasma exchange. Developer(s):
Grifols, SA (Barcelona, Spain)
Section 2. Topics Added Since Last Status Report 130
Table 7. Cancer: 19 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Men aged 18 years or older 177Lu-PSMA-617 is a novel small-molecule radioligand Supportive care Overall survival Clinical trial(s): VISION who have progressive therapy comprising a high-affinity targeting ligand phase III primary prostate specific membrane specific for the PSMA that is chemically linked with a Progression-free survival completion August 2020; antigen (PSMA)-positive, radionucleotide called lutetium-177 (177Lu). 177Lu- Quality of life phase II primary metastatic, castration- PSMA-617 is intended to deliver systemic and targeted completion April 2020 resistant prostate cancer radiation, causing cell death to prostate cancer cells. The Time to a first PSMA protein is highly expressed on the surface of most symptomatic skeletal prostate cancer cells but absent on most normal cells. event After 177Lu-PSMA-617 purportedly attaches to prostate cancer cells via binding to PSMA, the 177Lu component emits beta-particle radiation intended to induce cytotoxic DNA damage to the tumor cells. In clinical trials, 177Lu- PSMA-617 is given intravenously at a dose of 7.4 GBq (±10%) every 6 weeks for up to 6 cycles. Developer(s): Endocyte (West Lafayette, Indiana), a subsidiary of Novartis (Basel, Switzerland)
Section 2. Topics Added Since Last Status Report 131
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older ABI-009 (Tarzifix) is an mTOR inhibitor associated with One or more of the Overall survival FDA designation(s): who have locally advanced or human albumin nanoparticles (nab-sirolimus) through following: Orphan Drug, Fast Track, metastatic perivascular noncovalent hydrophobic interactions. ABI-009 has been Progression-free survival Breakthrough Therapy Alkylating agents (eg, epithelioid cell tumor developed to block the mTOR pathway, a pathway Quality of life (PEComa) involved in cell proliferation frequently activated in dacarbazine, Clinical trial(s): Phase II PEComas by TSC1 and/or TSC2 gene mutations. temozolomide, AMPECT primary PEComa is a rare type of sarcoma originating from the trabectedin) completion September soft tissues lining organs such as the intestines, lungs, 2019, preliminary results Anthracyclines (eg, reported June 2019 and stomach. PEComas are malignant in rare cases and doxorubicin, epirubicin, have the potential to spread to other parts of the body. No liposomal doxorubicin) approved treatments exist for PEComas and standard sarcoma cytotoxic chemotherapies have minimal survival Antimetabolites (eg, benefit. ABI-009 purportedly enters proliferating tumor gemcitabine, ifosfamide) cells via endocytosis and macropinocytosis to have higher Microtubule inhibitors accumulation and improved efficacy compared with other (eg, eribulin, vinorelbine) mTOR inhibitors. Testing for TSC1/2 mutation status will require use of a companion diagnostic. In clinical trials, mTOR inhibitors (eg, ABI-009 is given by intravenous infusion at a weekly dose everolimus, sirolimus, of 100 mg/m2 in a 2-week-on, 1-week-off schedule until temsirolimus) disease progression or intolerable toxicity. Multikinase inhibitors Developer(s): (eg, imatinib, pazopanib, regorafenib, sorafenib, Aadi Bioscience Inc (Pacific Palisades, California) sunitinib)
Section 2. Topics Added Since Last Status Report 132
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older ALT-803 is a novel interleukin-15 (IL-15) superagonist Intravesical Overall survival FDA designation(s): Fast who have bacillus Calmette- complex. NMIBC is unresponsive to standard BCG chemotherapy with one Track Guérin (BCG)-unresponsive, treatment in about half of affected patients, whose or more of the following: Progression-free survival Clinical trial(s): Phase II high-grade, non–muscle disease then progresses. ALT-803 is intended to provide Quality of life invasive bladder cancer an option after BCG treatment has failed. The ALT-803 Anthracyclines (eg, QUILT-3.032 primary (NMIBC) complex consists of a mutant form of IL-15 (IL-15N72D) epirubicin, valrubicin) completion December bound to a fusion protein composed of the soluble form of 2019, preliminary data Antimetabolites (eg, presented May 2019 IL-15 receptor α linked to the fragment crystallizable (Fc) gemcitabine) region of immunoglobulin G1 (IL-15Rα/IgG1 Fc). ALT-803 purportedly generates rapid and durable immune DNA synthesis inhibitors responses against NMIBC by simultaneously mobilizing (eg, mitomycin-C) both innate and adaptive immune cells to infiltrate the Taxanes (eg, docetaxel) tumor. While IL-15 and IL-15α enhance cytotoxic T-cell proliferation, IgG1 Fc activates NK (natural killer) cell- specific, antibody-dependent, cell-mediated cytotoxicity. In clinical trials, ALT-803 is mixed with BCG and given as an intravesical instillation at an unspecified dose weekly for 6 consecutive weeks. At month 3, patients receive either a 3-week maintenance course or a 6-week reinduction course. Subsequently, patients receive 3- week maintenance treatment at 6, 9, 12, and 18 months. Developer(s): Altor BioScience Corp (Miramar, Florida), in collaboration with AGC Biologics Inc (Bothell, Washington)
Section 2. Topics Added Since Last Status Report 133
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years APR-246 is a small-molecule anticancer drug that Azacitidine Complete response rate FDA designation(s): or older who have purportedly restores and reactivates wild-type p53 Orphan Drug, Fast Track myelodysplastic syndrome conformation and function in myelodysplastic cells, Decitabine Overall response rate Clinical trial(s): Phase III (MDS) with at least one causing initiation of programmed cell death (apoptosis) in Growth factors (eg, Overall survival mutation in the tumor protein cancer cells. Triggering programmed cell death of primary completion darbepoetin alfa, epoetin December 2020 p53 gene, TP53 myelodysplastic cells might restore proper bone marrow alfa, filgrastim) Quality of life function, including blood cell production and function. MDSs represent a spectrum of blood stem cell malignancies in which the bone marrow fails to produce sufficient quantities of healthy blood cells. About 30% to 40% of patients with MDS progress to acute myeloid leukemia (AML). Mutations in p53 occur in about 20% of patients with MDS and AML and are associated with treatment resistance and poor prognosis. The manufacturer asserts that APR-246 has synergistic effects in combination with chemotherapy, small-molecule inhibitors, and immuno-oncology checkpoint inhibitors. In clinical trials, APR-246 is given as an intravenous infusion at an unspecified dose in combination with azacitidine. Developer(s): Aprea Therapeutics AB (Boston, Massachusetts)
Section 2. Topics Added Since Last Status Report 134
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Atezolizumab (Tecentriq) is a monoclonal antibody that One or more of the Overall survival FDA designation(s): who have locally advanced or targets the programmed death-ligand 1 (PD-L1), an following: Breakthrough Therapy metastatic hepatocellular inhibitory surface molecule expressed by cells to Progression-free survival Anthracyclines (eg, Clinical trial(s): Phase III carcinoma (HCC) and have modulate immune responses. HCC, an aggressive Quality of life had no previous systemic cancer, has limited treatment options and is a major doxorubicin) COSMIC-312 primary therapy cause of cancer deaths, so more effective treatment completion August 2020; Antimetabolites (eg, 5- phase III IMbrave150 options are needed. A hallmark of cancer is its ability to fluorouracil, gemcitabine) evade an immune response. Several types of cancer primary completion cells, including HCC, activate an immune checkpoint Multikinase inhibitors November 2020 pathway in T cells by overexpressing PD-L1, which binds (eg, cabozantinib, Note(s): FDA approved to the programmed death-1 (PD-1) co-inhibitory receptor lenvatinib, regorafenib, atezolizumab to treat and limits the activation of cancer-specific T cells. sorafenib) urothelial carcinoma in May Atezolizumab purportedly prevents the interaction Platinum agents (eg, 2016, for non–small cell between PD-1 and PD-L1 to inhibit the immune cisplatin, oxaliplatin) lung cancer in October checkpoint pathway. Atezolizumab treatment in 2016, for triple-negative combination with bevacizumab or cabozantinib is breast cancer in March intended to restore anticancer immunity by inhibiting 2019, and for small cell VEGF-related immunosuppression. In clinical trials, lung cancer in March 2019. atezolizumab is given as an intravenous infusion at a dose of 1200 mg on day 1 of each 21-day cycle until disease progression or unacceptable toxicity, in combination with intravenous bevacizumab (15 mg/kg on day 1 of each 21-day cycle) or oral cabozantinib (40 mg daily). Developer(s): Genentech Inc (South San Francisco, California), a subsidiary of F Hoffman-La Roche AG (Basel, Switzerland)
Section 2. Topics Added Since Last Status Report 135
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 78 years BL-8040 is a high-affinity antagonist for the CXC- Stem cell transplantation Overall survival Clinical trial(s): Phase III who have newly diagnosed chemokine receptor-4 (CXCR4), a receptor after high-dose GENESIS primary multiple myeloma and are overexpressed in about 70% of cancers, including chemotherapy with one Progression-free survival completed April 2019, data eligible for autologous stem multiple myeloma, and associated with disease severity. or more of the following: Quality of life reported March 2019 cell transplantation BL-8040 is intended to mobilize hematopoietic stem cells (HSCs) for autologous transplantation and delay multiple Alkylating agents (eg, myeloma progression after high-dose primary therapy. bendamustine, BL-8040 is a bio-stable, synthetic, cyclic peptide with cyclophosphamide) 14 amino acid residues that binds CXCR4 with high Anthracyclines (eg, affinity. Expression of CXCR4 in CD34+ HSCs is directly doxorubicin) involved in their retention in the bone marrow via binding to the CXCL12 chemokine protein, but in multiple Glucocorticoids (eg, myeloma, CXCR4 expression is also involved in tumor dexamethasone) progression, angiogenesis, metastasis, and cell survival. Immunomodulatory As a CXCR4 antagonist, BL-8040 purportedly leads to the agents (eg, lenalidomide, mobilization of CD34+ HSCs, multiple myeloma cells, and pomalidomide, immune cells into peripheral blood. While mobilized thalidomide) CD34+ HSCs can be collected through apheresis for autologous transplantation, mobilized multiple myeloma Proteasome inhibitors cells are no longer protected in the bone marrow and are (eg, bortezomib, sensitive to maintenance therapy after transplantation. In carfilzomib, ixazomib) clinical trials, BL-8040 is given as a single subcutaneous Topoisomerase inhibitors injection at a dose of 1.25 mg/kg on day 1 in combination (eg, etoposide) with granulocyte colony-stimulating factor (G-CSF) injected at a dose of 10 µg/kg/day for 5 days. If initial treatment does not result in enough mobilized CD34+ HSCs needed for autologous transplantation (≥6 x 106 cells/kg), treatment can be extended up to 2 days for BL- 8040 and up to 8 days for G-CSF. Developer(s): BioLineRx Ltd (Tel Aviv, Israel), in collaboration with Biokine Therapeutics Ltd (Rehovot, Israel)
Section 2. Topics Added Since Last Status Report 136
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Infigratinib (BGJ398) is a novel, highly selective, small- One or more of the Overall survival Clinical trial(s): Phase III who have surgically molecule inhibitor of 3 members of the FGFR family (1, 2, following: PROOF primary unresectable, recurrent, and 3). Because about 20% of cholangiocarcinoma cases Progression-free survival completion October 2021 Antimetabolites (eg, or metastatic contain FGFR2 genetic alterations, using infigratinib for Quality of life cholangiocarcinoma that targeting only FGFRs has potential to improve outcomes gemcitabine) harbors fusions or of patients with limited treatment options who usually Platinum agents (eg, translocations in the have poor health outcomes. Infigratinib is designed to cisplatin, oxaliplatin) fibroblast growth factor specifically target FGFRs (with limited activity against receptor gene, FGFR2 FGFR4) and not bind to similar signaling domains in the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor. Infigratinib purportedly blocks angiogenesis, proliferation, and survival pathways in biliary tract cancer cells by inhibiting constitutive ligand-independent FGFR2 signaling. In some cholangiocarcinoma cases, the presence of activating FGFR alterations, including gene fusions and chromosome translocations, leads to uncontrolled cell proliferation. Eligibility for the therapy requires testing for FGFR2 gene rearrangements. In clinical trials, infigratinib is given daily orally at a dose of 125 mg in a schedule of 3 weeks on, 1 week off until disease progression or intolerable toxicity. Developer(s): QED Therapeutics Inc (San Francisco, California), a subsidiary of BridgeBio Pharma Inc (Palo Alto, California)
Section 2. Topics Added Since Last Status Report 137
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Ivosidenib (Tibsovo) is a small-molecule inhibitor of a One or more of the Overall survival Submission date: who have locally advanced or mutated form of the enzyme IDH1 that occurs in about following: Supplemental New Drug metastatic 25% of intrahepatic cholangiocarcinomas. IDH1’s Progression-free survival Application planned for Fluoropyrimidine-based cholangiocarcinoma that mutant form causes a tumor-inducing metabolite (D-2- Quality of life fourth-quarter 2019 harbors a mutation in the hydroxyglutarate) to accumulate while decreasing levels chemotherapy isocitrate dehydrogenase 1 of IDH1’s normal metabolite (α-ketoglutarate). This Clinical trial(s): Phase III Pembrolizumab (for ClarIDHy trial primary gene, IDH1, and has been metabolite imbalance causes histone modification and patients with treated with at least one DNA methylation that dedifferentiates cells (ie, makes completion May 2019, data microsatellite instability- reported May 2019 previous line of systemic them lose specialized characteristics) and might lead to a high or mismatch repair therapy neoplastic state (ie, cells that divide more than normal). deficient tumors) Note(s): FDA approved By inhibiting the mutated form of IDH1, ivosidenib ivosidenib to treat relapsed purportedly prevents uncontrolled cell division by leading or refractory IDH1-mutated cholangiocarcinoma cells to differentiate. Ivosidenib is AML in July 2018 and for given orally, at a dose of 500 mg, daily until disease newly diagnosed IDH1- progression or intolerable toxicity. mutated AML in May 2019. Developer(s): Agios Pharmaceuticals Inc (Cambridge, Massachusetts)
Women aged 18 years or LN-145 is an autologous T-cell therapy that uses cells One or more of the Disease-free survival Submission date: Biologics older who have recurrent, isolated from the patient’s cervical cancer. LN-145 relies following: License Application metastatic, or persistent on naturally occurring T cells called tumor infiltrating Overall survival planned for the second half Alkylating agents (eg, cervical cancer that is lymphocytes (TILs) that can penetrate cancerous tumors. Quality of life of 2020 unsuited to surgical resection TILs isolated from a patient’s tumor are expanded in ifosfamide) and/or radiation therapy, and culture until reaching a count of billions of cells. LN-145 is FDA designation(s): Angiogenesis inhibitors Breakthrough Therapy, have received at least 1 and intended as a tumor-specific therapy that can overcome (eg, bevacizumab) no more than 3 prior systemic the tumor’s immune-suppressive environment and Fast Track therapy regimens promote its elimination. In clinical trials, LN-145 is given Antimetabolites (eg, 5- Clinical trial(s): Phase II as an intravenous infusion followed by up to 6 doses of fluorouracil, gemcitabine, innovaTIL-04 primary interleukin 2 to support growth and activation of TILs. pemetrexed) completion March 2020, Developer(s): DNA synthesis inhibitors data presented May 2019 (eg, mitomycin-C) Iovance Biotherapeutics Inc (San Carlos, California) Immunotherapy (eg, pembrolizumab) Taxanes (eg, albumin- bound paclitaxel, docetaxel) Topoisomerase inhibitors (eg, irinotecan)
Section 2. Topics Added Since Last Status Report 138
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Melflufen (Ygalo) is a lipophilic peptide-conjugated One or more of the Overall survival Submission Date: New who have relapsed and alkylator that is proposed to rapidly deliver a highly following: Drug Application planned refractory multiple myeloma cytotoxic payload into multiple myeloma cells. Melflufen Progression-free survival for first-quarter 2020 Alkylating agents (eg, that has been treated with 2 is a novel peptidase enhanced cytotoxic molecule Quality of life or more lines of therapy, composed of a lipophilic peptide entrapping a hydrophilic bendamustine, FDA designation(s): including a protease inhibitor, alkylator payload. Melflufen’s high lipophilicity allows it to cyclophosphamide) Orphan Drug an immunomodulatory agent, be taken up rapidly by multiple myeloma cells and Anthracyclines (eg, Clinical trial(s): Phase III and an anti-CD38 antibody immediately cleaved by peptidases to deliver its doxorubicin) OCEAN primary hydrophilic alkylator payload. Peptidases play a key role completion December in protein homeostasis and in cellular processes, such as Glucocorticoids (eg, 2019; phase II HORIZON cell-cycle progression and programmed cell death. But dexamethasone) primary completion March because multiple myeloma cells overexpress peptidases, Immunomodulatory 2020, interim data reported melflufen purportedly displays selective cytotoxic activity agents (eg, lenalidomide, June 2019 against myeloma cells and overcomes resistance to other pomalidomide, treatments, including alkylators. Once delivered to cells, thalidomide) the hydrophilic alkylator payload purportedly induces irreversible DNA damage, inhibits DNA repair, prevents Monoclonal antibodies angiogenesis, and promotes apoptosis. In clinical trials, (eg, daratumumab, melflufen is given intravenously at a dose of 40 mg on elotuzumab) day 1 of each 28-day cycle until disease progression or Proteasome inhibitors intolerable toxicity. Melflufen is combined with (eg, bortezomib, dexamethasone given intravenously at a dose of 40 mg carfilzomib, ixazomib) on days 1, 8, 15, and 22 of each 28-day cycle. Topoisomerase inhibitors Developer(s): (eg, etoposide) Oncopeptides AB (Stockholm, Sweden)
Section 2. Topics Added Since Last Status Report 139
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older NovoTTF-100L is a device intended to treat solid tumors One or more of the Overall survival Approval date: May 24, who have locally advanced or by exposing the tumors to low-intensity, intermediate- following: 2019 metastatic malignant pleural frequency, alternating electric fields (ie, tumor treating Progression-free survival Antimetabolites (eg, FDA designation(s): mesothelioma (MPM) and fields [TTFs]). Front-line therapy for MPM relies on Quality of life have had no previous platinum-based chemotherapy, but response rates are pemetrexed) Humanitarian Use Device systemic therapies for low, so effective options are needed. TTFs purportedly Platinum agents (eg, Clinical trial(s): Phase II mesothelioma disrupt cell division through effects on charged cisplatin) STELLAR completed April macromolecules and organelles within cancer cells, 2018, pivotal results potentially limiting tumor growth. The NovoTTF-100L reported September 2018 device is a battery-powered field generator coupled with an electrode array that is attached to the skin of the patient’s torso. In clinical trials, TTFs therapy is given in the home setting 24 hours a day, 7 days a week and is intended for use in combination with intravenous pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC 5) on day 1 of each 21-day cycle until disease progression or intolerable toxicity. Developer(s): NovoCure Ltd (St. Helier, Jersey)
Section 2. Topics Added Since Last Status Report 140
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older NovoTTF-100M is a device intended to treat solid tumors Radiation therapy (eg, Overall survival Clinical trial(s): Phase III who have metastatic non– by exposing the tumors to low-intensity, intermediate- stereotactic radiosurgery, METIS primary completion small cell lung cancer frequency, alternating electric fields (ie, tumor treating whole-brain Progression-free survival July 2019 (NSCLC) and newly fields [TTFs]). TTFs purportedly disrupt cell division radiotherapy) Quality of life diagnosed brain metastases through effects on charged macromolecules and that have been treated with organelles within cancer cells, potentially limiting tumor In lieu of upfront stereotactic radiosurgery growth. The NovoTTF-100M device consists of a battery- radiation therapy, powered field generator coupled to 4 electrically insulated systemic therapy with electrode arrays attached to the skin of the patient’s head. one of the following: In clinical trials, TTFs therapy is given in the home setting ALK inhibitors (eg, 24 hours a day, 7 days a week and is intended for use in alectinib, brigatinib, combination with the best supportive treatment available ceritinib) if ALK until disease progression or intolerable toxicity. rearrangement positive Developer(s): EGFR inhibitors (eg, NovoCure Ltd (St. Helier, Jersey) osimertinib) if EGFR mutation positive Immune checkpoint inhibitors (eg, nivolumab, pembrolizumab) if programmed death- ligand 1 (PD-L1) positive
Section 2. Topics Added Since Last Status Report 141
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Women aged 18 years or Ofranergene obadenovec (VB-111) is an adeno virus One or more of the Overall survival Clinical trial(s): Phase III older who have recurrent vector therapy intended for recurrent platinum-resistant following: OVAL primary completion platinum-resistant ovarian ovarian cancer. It is intended to induce programmed cell Progression-free survival December 2022 Angiogenesis inhibitors cancer death in angiogenic endothelial cells in the tumor Quality of life microenvironment as well as induce cellular immune (eg, bevacizumab) Note(s): European responses against the tumor. Patients with recurrent Commission has granted Anthracyclines (eg, Orphan Drug designation. platinum-resistant ovarian cancer have a poor prognosis doxorubicin, pegylated and need more effective treatment options. VB-111 liposomal doxorubicin) purportedly penetrates and introduces a propriety angiogenesis-specific promoter that specifically induces Taxanes (eg, docetaxel, cell death in angiogenic endothelial cells in the tumor paclitaxel) milieu. VB-111 also purportedly recruits CD8+ T cells capable of inducing tumor-specific cellular immune responses. In clinical trials, VB-111 is given intravenously at a dose of 1 x 1013 viral particles every 2 months in combination with paclitaxel, which is given intravenously at a dose of 80 mg/m2 weekly. Developer(s): VBL Therapeutics Ltd (Tel Aviv, Israel), in collaboration with Gynecologic Oncology Group Foundation Inc (Philadelphia, Pennsylvania)
Section 2. Topics Added Since Last Status Report 142
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 99 years Pamiparib (BGB-290) is a small-molecule inhibitor of One or more of the Overall survival Clinical trial(s): Phase III who have inoperable, locally 2 enzymes involved in DNA repair, the poly adenosine following: PARALLEL 303 primary advanced or metastatic diphosphate-ribose polymerases 1 and 2 (PARP1/2). Progression-free survival completion June 2020 Antimetabolites (eg, 5- gastric cancer or Pamiparib’s inhibition of PARP1/2 causes various mitotic Quality of life gastroesophageal junction defects, such as centrosome amplification, multipolar fluorouracil, cancer that has responded to spindles, chromosome misalignment, premature loss of capecitabine) a previous line of platinum- cohesion, metaphase arrest, anaphase DNA bridges, Anthracyclines (eg, based chemotherapy lagging chromosomes, and micronuclei. Patients with epirubicin) advanced gastric cancer usually experience recurrence and need effective options to delay progression. Human epidermal growth Maintenance therapy with pamiparib purportedly mediates factor receptor 2 (HER2) death of gastric cancer cells that survived platinum-based antibodies (eg, chemotherapy regimens by inhibiting PARP1/2’s DNA trastuzumab) repair. In clinical trials, 60 mg of pamiparib is given orally, Platinum-based agents twice daily, until disease progression or intolerable (eg, carboplatin, toxicity. cisplatin, oxaliplatin) Developer(s): Taxanes (eg, docetaxel, BeiGene Ltd (Shanghai, China) paclitaxel)
Section 2. Topics Added Since Last Status Report 143
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Plinabulin is a marine fungus–derived microtubule Myelosuppressive Infection incidence Clinical trial(s): Phase II/III who have advanced inhibitor intended to prevent chemotherapy-induced chemotherapy with Protective-1 primary or metastatic cancer (eg, neutropenia (loss of neutrophils) in patients with cancer adjunctive long-lasting Neutropenia completed April 2019, breast cancer, non–small cell receiving myelosuppressive chemotherapy. Most patients granulocyte colony- Quality of life interim data reported lung cancer, prostate cancer) with cancer are at risk of developing chemotherapy- stimulating factor (eg, December 2018; phase that has progressed after at induced neutropenia. This condition renders them pegfilgrastim) Thrombocytopenia II/III Protective-2 primary least one previous line of susceptible to complications including infection, because completion January 2020, treatment they generally receive cytotoxic regimens that also data presented May 2019 deplete blood-forming cells in the bone marrow. Unlike granulocyte colony-stimulating factor that promotes growth of white blood progenitor cells to restore neutrophils, plinabulin’s novel mechanism of action (ie, targets microtubules differently from taxanes and vinca alkaloids) purportedly facilitates the release of cytokines that protect neutrophils from programmed cell death (apoptosis). In clinical trials, plinabulin is given as an intravenous infusion at a dose from 5 to 40 mg/m2. Treatment with plinabulin continues until completion of systemic chemotherapy. Developer(s): BeyondSpring Pharmaceuticals Inc (New York, New York)
Section 2. Topics Added Since Last Status Report 144
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pracinostat is an oral histone deacetylase (HDAC) Antibody–drug conjugate Complete remission rate FDA designation(s): who have newly diagnosed inhibitor. HDACs act as epigenetic regulators (functioning (eg, gemtuzumab Orphan Drug, acute myeloid leukemia peripherally to the genetic code) that chemically modify ozogamicin) Overall survival Breakthrough Therapy (AML) and cannot tolerate the DNA structure or its associated chromosomal proteins Quality of life intensive remission induction (eg, histones). Abnormal activity of epigenetic regulators Glasdegib in Clinical trial(s): Phase III chemotherapy and have is thought to contribute to upregulating the accessibility combination with low- primary completion May Eastern Cooperative and expression of tumor-promoting genes, contributing to dose cytarabine 2021 Oncology Group (ECOG) the pathogenesis of AML, the most common type of acute Low-dose cytarabine performance status of 2 with leukemia. AML has a poor prognosis, and patients who significant cardiovascular cannot tolerate high doses of chemotherapy need other Low-intensity therapy disease or are older than age options. Pracinostat might improve patient health (eg, azacitidine and 75 years outcomes in the first-line setting for AML by restoring decitabine) normal chromosomal structure and gene expression Venetoclax alone or in patterns in AML cells. Pracinostat purportedly inhibits combination with class I, II, and IV HDACs and works synergistically in azacitidine or low-dose combination with a hypomethylating agent such as cytarabine azacitidine. In a clinical trial, pracinostat was given orally as a 60-mg capsule, once daily, 3 times weekly for 3 weeks, followed by 1 week of rest for each 28-day cycle
in combination with azacitidine given as a subcutaneous or intravenous injection daily at a dose of 75 mg/m2 for 7 days of each 28-day cycle. Developer(s): MEI Pharma Inc (San Diego, California), in collaboration with Helsinn Group (Lugano, Switzerland)
Section 2. Topics Added Since Last Status Report 145
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or Ruxolitinib phosphate (Jakafi) inhibits the Janus Alemtuzumab Mortality Approval date: May 24, older and adults with steroid- associated kinases (JAK) JAK1 and JAK2, which mediate 2019 refractory acute graft-versus- signaling for several cytokines and growth factors Alpha-1 antitrypsin Quality of life FDA designation(s): host disease (GVHD) after involved in white blood cell formation and immune Antithymocyte globulin Treatment-response rate allogeneic stem cell function. JAK1 and JAK2 are implicated in GVHD, a life- Orphan Drug, transplantation (ASCT) to threatening complication of ASCT for cancer. Patients Calcineurin inhibitors Breakthrough Therapy, treat cancer receiving ASCT are at high risk of GVHD, and steroids (eg, cyclosporine, Priority Review are first-line therapy but do not work in some patients. tacrolimus) Clinical trial(s): Phase III Effective options are needed. Ruxolitinib could provide a Cyclophosphamide REACH2 primary new option by inhibiting JAK1 and JAK2 and purportedly completed July 2019; decreasing production of inflammatory cytokines and Etanercept phase III REACH3 primary reducing immune cell migration to the gastrointestinal Extracorporeal completed July 2019 tract, which is frequently involved in GVHD. For GVHD, photopheresis the recommended starting dose is 5 mg (tablet) orally, twice daily. Methotrexate Developer(s): Mycophenolate mofetil Incyte Corp (Wilmington, Delaware) Pentostatin Sirolimus
Section 2. Topics Added Since Last Status Report 146
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Sacituzumab govitecan-hziy is an antibody–drug One or more of the Overall survival Submission date: Biologic who have locally advanced or conjugate consisting of a monoclonal antibody coupled following: License Application metastatic triple-negative via a cleavable linker to an active metabolite of the Progression-free survival resubmission planned for Alkylating agents (eg, breast cancer and have chemotherapy drug irinotecan. The monoclonal antibody Quality of life fourth-quarter 2019 received is specific for trophoblast cell surface antigen 2 (Trop-2), cyclophosphamide) at least 2 prior systemic and the irinotecan metabolite is called SN-38. Trop-2 is a FDA designation(s): Anthracyclines (eg, Breakthrough Therapy therapy regimens for locally cell surface protein overexpressed by several epithelial doxorubicin) advanced/metastatic disease cancers, including triple-negative breast cancers. Upon Clinical Trial(s): Phase III binding to Trop-2, sacituzumab govitecan-hziy is Antimetabolites (eg, ASCENT primary internalized and the linker is cleaved, releasing the fluorouracil, gemcitabine) completion December chemotherapy drug. By targeting delivery of SN-38 to Microtubule 2019 Trop-2-expressing cells, sacituzumab govitecan-hziy polymerization inhibitors Note(s): FDA response purportedly delivers therapeutic doses of the drug to (eg, eribulin) cancer cells while limiting exposure of noncancer cells. In letter received January clinical trials, sacituzumab govitecan-hziy is given as an poly adenosine 2019 citing issues related intravenous infusion at a dose of 10 mg/kg on days 1 diphosphate-ribose to “chemistry, and 8 of each 21-day treatment cycle until disease polymerase (PARP) manufacturing and control progression or intolerable toxicity. inhibitors (eg, olaparib) matters.” Developer(s): Taxanes (eg, docetaxel, paclitaxel) Immunomedics (Morris Plains, New Jersey) Vinca alkaloid (eg, vinorelbine)
Section 2. Topics Added Since Last Status Report 147
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older UGN-101 (MitoGel) is a proprietary form of the small- Endoscopic Overall survival Submission date: Rolling with low-grade, noninvasive, molecule drug mitomycin C (MMC) intended to treat low- management New Drug Application upper tract urothelial cancer grade upper tract urothelial cancer. No treatments are Progression-free survival began December 2018, Surgery currently approved for this cancer type, and patients need Quality of life expected completion mid- effective options. This hydrogel-based formulation is (nephroureterectomy; 2019 intended to enable longer exposure of MMC to urinary might require ongoing tract tissue to enable nonsurgical treatment of tumors. dialysis or organ FDA designation(s): UGN-101 purportedly kills bladder cell tumors by transplantation) Orphan Drug, Breakthrough Therapy inhibiting DNA synthesis, which is required for the cells to One or more of the divide and tumors to grow. UGN-101 is given as a once- following: Clinical trial(s): Phase III weekly instillation, a total of 6 times, using standard OLYMPUS primary intravesical catheters. Alkylating agents (eg, completed April 2019, ifosfamide) Developer(s): pivotal data reported May Antimetabolites (eg, 2019 UroGen Pharma Ltd (New York, New York) gemcitabine, methotrexate) Immune checkpoint inhibitors (eg, atezolizumab, avelumab) Platinum agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, paclitaxel)
Section 2. Topics Added Since Last Status Report 148
Table 8. Cardiovascular: 7 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 21 years or older Baroreflex activation therapy (BAT; Barostim neo) is Cardiac contractility Exercise tolerance Approval date: August 16, who have New York Heart intended for heart failure and electrically stimulates the modulation 2019 Association (NYHA) carotid baroreceptors using the Barostim neo implantable Heart failure–related functional class III heart device. The human baroreflex system is a network of Guideline-directed hospitalization FDA designation(s): failure and left ventricular blood pressure sensors (baroreceptors) located optimal drug therapy (eg, Expedited Access Pathway angiotensin-converting NYHA functional class ejection fraction of 35% or throughout the arteries and veins that help control blood Clinical trial(s): Phase III less despite optimal pressure and heart rate. BAT purportedly augments enzyme [ACE] inhibitors, Quality of life diuretics, hydralazine, BeAT-HF pivotal primary guideline-directed medical impaired natural baroreflex activity to reduce heart rate, Survival completion December therapy and who are cardiac output, and blood pressure. A physician places ivabradine, sacubitril/valsartan) 2021, interim data ineligible for cardiac the pacemaker-like implantable pulse generator (IPG) presented May 2019; resynchronization therapy under the skin near the collarbone. The IPG’s single unphased HOPE4HF electrode lead is tunneled to the carotid sinus in the neck. completed May 2015, data Physicians noninvasively program the system and published September regulate stimulation intensity using an external 2018; European programmer. Implementing a BAT program for heart observational registry failure would shift care from office-based medical primary completion July management to surgical management plus periodic 2024 device monitoring. Barostim neo implantation requires about 1.5 to 2 hours with the patient under general Note(s): The developer anesthesia or conscious sedation. Patients might require originally assessed the an overnight stay. In clinical trials, physicians test the technology to treat device during implantation and gradually increase refractory hypertension but stimulation over 3 months to achieve optimal tolerated has halted further stimulation levels. The IPG might require replacement development for that due to battery depletion after about 3 to 5 years, indication in the United depending on programmed stimulation level. States. Developer(s): CVRx Inc (Minneapolis, Minnesota)
Section 2. Topics Added Since Last Status Report 149
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 85 years Ischemic Stroke System (ISS) uses a process known as Supportive care (eg, Quality of life Clinical trial(s): Unphased who have clinical and sphenopalatine ganglion stimulation to treat acute blood pressure control, ImpACT-P primary radiologic evidence of acute ischemic stroke by increasing circulation through cardiac monitoring, fluid Stroke-induced disability completion January 2021; ischemic stroke in the collateral vessels to blood-starved brain tissue. About management, ventilatory Survival unphased ImpACT-24B anterior cerebral circulation 85% of strokes are ischemic, and many patients do not [ie, breathing] pivotal primary completed with symptom onset within reach treatment facilities in time to be safely given assistance) June 2018, data published the preceding 8 to 24 hours conventional thrombolysis (with clot-dissolving drugs) or May 2019 and National Institutes of mechanical thrombectomy (clot removal). Also, some Health Stroke Scale scores patients are ineligible to receive these therapies for other between 7 and 18 and who reasons. Thus, options are needed for these patients. ISS are ineligible for thrombolytic delivers electrical stimulation to 1 of the 2 sphenopalatine therapy or mechanical ganglia, parasympathetic nerve bundles located behind thrombectomy the nasal cavity that help regulate cerebral circulation. A physician temporarily implants the 1-inch-long, needle-like neurostimulator through the mouth into the extracranial sphenopalatine fossa, a hollow space behind the upper palate near the third molar, using a small hand tool and local anesthesia. A physician uses a wireless controller to deliver stimulation and monitor treatment to the sphenopalatine ganglion through the neurostimulator via a radiofrequency transmitter coil placed on the patient’s cheek. ISS delivers a steady stream of electrical stimulation intermittently over several days during the index hospitalization, after which the physician removes the neurostimulator in a minor procedure analogous to removing sutures. Developer(s): BrainsGate Ltd (Caesarea, Israel)
Section 2. Topics Added Since Last Status Report 150
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Neovasc Reducer is a stent-like implant intended to treat Enhanced external Angina incidence FDA designation(s): who have Canadian refractory chronic angina by improving blood flow to counterpulsation Breakthrough Device Cardiovascular Society class ischemic heart tissue. For patients whose angina persists Device-related adverse III or IV chronic angina from despite optimal medical therapy and who are unable to Guideline-directed events Clinical trial(s): REDUCER- medical therapy for 1 (phase not stated) obstructive coronary artery undergo conventional bypass surgery, other options are Exercise tolerance disease that is refractory to needed. This implanted device could provide such an ischemic heart disease prospective-retrospective optimal medical therapy and option. Physicians implant the Reducer in the coronary (eg, aspirin, beta Quality of life observational primary blockers, calcium completion December who are unsuited for sinus, the large vein that drains blood from heart muscle, Survival conventional to create a pressure backflow that purportedly modulates channel blockers, 2022; single-arm revascularization blood flow through the coronary sinus and redistributes nitrates, ranolazine) interventional (phase not stated) primary completion blood to areas of heart muscle with poor circulation. To implant the balloon-expandable, hourglass-shaped December 2021 device, a physician inserts the delivery catheter at the jugular vein in the neck and advances it to the coronary sinus, located on the external heart wall between the left atrium and left ventricle. Implantation purportedly takes about 20 minutes with patients under local anesthesia. Developer(s): Neovasc Inc (Richmond, British Columbia, Canada)
Section 2. Topics Added Since Last Status Report 151
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Organ Care System (OCS) is intended to maintain a Conventional cold Graft organ survival Submission date: April 14, who are candidates for heart donor organ in a warm, functioning state outside the body storage 2014 transplantation for an extended period to optimize donor organ health Overall survival Clinical trial(s): Unphased and allow for continuous clinical evaluation. The OCS Quality of life Heart is optimized for preserving donor hearts. Many EXPAND Heart completed donor hearts are never transplanted because their June 2019, preliminary condition degrades quickly after harvesting, and thus data published April 2019; fewer patients receive the heart transplant they need. unphased HEART OCS Heart would represent a substantial change to EXPAND continued access pretransplant procedures for potential donor organ protocol primary assessment, procurement, and transport compared with completion January 2020; static cold storage, which is the current standard. OCS unphased Donors After Heart purportedly could increase the volume of heart Circulatory Death primary transplantations, enabling longer-distance transport and completion August 2021; giving clinicians more clinical data to better assess donor unphased observational organ suitability. The manufacturer has developed similar clinical use cohort primary technology to preserve lung and liver grafts. The OCS completion December device comprises 2 principal components: a portable 2021 battery-powered console and an organ-specific perfusion Note(s): FDA approved kit that function together as an integrated system. The OCS Lung for standard- system perfuses donor organs with a proprietary blood- criteria lung preservation in based solution to replenish oxygen and essential March 2018 and for nutrients. When physicians harvest the donor heart, they expanded-criteria lung place it in the perfusion module and revive it to a beating preservation in June 2019; state. The self-contained perfusion module maintains the OCS Liver is under proper temperature and humidity, protects the organ from investigation. external contaminants, and allows sterile ultrasound assessment of heart function and sterile blood sampling for laboratory analysis. A wireless monitor allows clinicians to assess the organ’s status and control system functions. Developer(s): TransMedics Inc (Andover, Massachusetts)
Section 2. Topics Added Since Last Status Report 152
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 75 years Paradise Renal Denervation System is a catheter-based Guideline-directed Blood pressure Clinical trial(s): who have essential device intended to ablate the sympathetic nerves that line optimal antihypertensive RADIANCE-HTN primary hypertension controlled on the main renal arteries connecting the kidneys to the drug therapy with one or Cardiovascular adverse completion March 2020, 1 or 2 medications or aorta. Deactivating the renal sympathetic nerves can more agents (eg, ACE events interim pivotal trial data uncontrolled hypertension on purportedly help reduce difficult-to-manage, treatment- inhibitors, angiotensin- Quality of life published March 2019; 0 to 2 medications (average resistant hypertension. An interventional procedure would receptor blockers, RADIANCE-II pivotal office blood pressure shift care away from standard office-based medical calcium channel Survival primary completion between 140/90 and 180/110 management for most patients with uncontrolled blockers, thiazide December 2020 mm Hg) hypertension. A physician inserts the proprietary balloon diuretics) catheter into the femoral artery in the groin and advances it into the left and right renal arteries, alternately, to deliver 2 to 4 applications of circumferentially delivered ultrasound energy, about 7 seconds each, to each artery. The liquid-cooled balloon purportedly protects the artery walls from thermal damage while the sympathetic nerves are ablated. The physician removes the catheter using standard interventional techniques after treating both renal arteries. Developer(s): ReCor Medical Inc (Palo Alto, California)
Section 2. Topics Added Since Last Status Report 153
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Rexlemestrocel-L (Revascor) is a regenerative cellular LVAD implantation alone Functional capacity FDA designation(s): who have New York Heart therapy made from human bone marrow–derived, Orphan Drug, Association (NYHA) allogeneic adult mesenchymal stem cells. Patients who Mucosal/gastrointestinal Regenerative Medicine functional class IIIB or IV have end-stage heart failure and require LVAD bleeding Advanced Therapy heart failure that is implantation face a high risk of serious gastrointestinal Quality of life unresponsive to optimal bleeding and repeated hospitalizations. Rexlemestrocel-L Clinical trial(s): Phase II medical management and given immediately after LVAD implantation is intended to Survival randomized primary who are candidates for left reduce the risk of gastrointestinal bleeding and related completed August 2018, Treatment-related data published March 2019 ventricular assist device hospitalization. Rexlemestrocel-L purportedly releases a adverse events (LVAD) implantation as a range of factors that induce functional recovery of bridge-to-transplant or damaged heart tissue by activating multiple pathways to destination therapy induce new blood vessel growth, reduce inflammation, reduce fibrosis and scar tissue formation, and regenerate heart muscle. Rexlemestrocel-L is isolated from bone mononuclear cells that are expanded in a laboratory and cryopreserved until being given to the patient. The product is intended as an off-the-shelf therapy given as a single injection of 25 million to 150 million cells into the endocardium using standard cardiac catheterization techniques. Developer(s): Mesoblast Ltd (Melbourne, Australia)
Section 2. Topics Added Since Last Status Report 154
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Tafamidis (Vyndaqel, Vyndamax) is a first-in-class Loop diuretics Cardiovascular-related Approval date: May 6, who have hereditary or wild- transthyretin stabilizer designed to selectively bind to hospitalizations 2019 type amyloid transthyretin- transthyretin, purportedly stabilizing the tetramer of the Supportive care for heart mediated cardiomyopathy transthyretin transport protein and slowing amyloidosis failure Quality of life FDA designation(s): Orphan Drug, Fast Track, (ATTR-CM) (amyloid accumulation) in organs and tissues. In ATTR- Survival CM, amyloidosis gradually stiffens heart muscles, leading Priority Review, to heart failure. A treatment that targets the underlying Breakthrough Therapy disease process could provide a disease-modifying option Clinical trial(s): Phase III and slow progression to advanced heart failure. Tafamidis primary completion is available in 2 nonsubstitutable oral formulations with December 2021; phase III the following recommended dosages: 80 mg of tafamidis long-term safety primary meglumine once daily, taken as four 20-mg capsules; and completion December 61 mg of tafamidis once daily, taken as a single capsule 2024 (purportedly for patient convenience). Developer(s): Pfizer Inc (New York, New York)
Section 2. Topics Added Since Last Status Report 155
Table 9. Mental and Behavioral Health: 6 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults who have severe 3,4-Methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy (eg, Depression symptoms FDA designation(s): posttraumatic stress disorder psychotherapy involves treatment with MDMA during an cognitive behavioral and severity Breakthrough Therapy (PTSD) 8-hour standardized nondirective psychotherapy session therapy [CBT], eye performed by a therapist team. In the context of therapy, movement PTSD symptoms and Clinical trial(s): Phase III MDMA administration is intended to reduce avoidance desensitization and severity primary completion June 2020, designed under and hyperarousal, purportedly leading to a desirable reprocessing therapy, psychological state that enhances the therapeutic process prolonged exposure Special Protocol for patients with severe PTSD, which has limited effective therapy) Assessment treatment options. MDMA, known by the street names Ecstasy and Molly, is a psychedelic compound that is Selective serotonin known to release serotonin, norepinephrine, and reuptake inhibitors (eg, dopamine in the brain and to indirectly increase oxytocin paroxetine, sertraline) and cortisol levels. MDMA is intended to reduce anxiety and emotional distress and increase prosocial behaviors, including communication, compassion, and introspection. According to the DMS-5, PTSD’s 4 main symptom categories are arousal and reactivity, avoidance of triggers, negative thoughts and feelings, and intrusive thoughts and nightmares. In trials, a flexible dose of MDMA is given orally once a month for 3 months, during an 8-hour psychotherapy session. An initial dose (80-120 mg) is given, followed by a supplemental half- dose (40 or 60 mg) 1.5 to 2.0 hours after the initial dose during each session. The sessions are preceded by preparatory sessions and interspersed with 12 weeks of integrative psychotherapy sessions. A Risk Evaluation and Mitigation Strategy is planned. Developer(s): Multidisciplinary Association for Psychedelic Studies (Santa Cruz, California)
Section 2. Topics Added Since Last Status Report 156
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children and adolescents Balovaptan (RO5285119) is a small-molecule antagonist Atypical antipsychotics Adverse events FDA designation(s): aged 5 to 17 years and adults of the vasopressin 1a receptor intended to improve (eg, aripiprazole, Breakthrough Therapy who have high-functioning emotional processing and reduce social deficits in risperidone) Change in adaptive (IQ ≥ 70) autism spectrum patients with ASD. Impairments of social interaction and behavior (eg, Clinical trial(s): Phase III disorder (ASD) communication are core symptoms of ASD that cause Behavioral therapy (eg, communication and primary completion multiple challenges and affect quality of life. The applied behavior socialization) December 2020; phase II analysis) primary completion July neuropeptide vasopressin is an endocrine hormone that is Quality of life implicated in the regulation of both aggression and 2021; phase II completed September 2016, data affiliation. Blocking vasopressin might reduce aggression and anxiety and promote social bonding in patients with presented May 2019 ASD. In trials, balovaptan is given orally at doses from 4 to 10 mg, once daily. Developer(s): F Hoffmann-La Roche (Basel, Switzerland)
Section 2. Topics Added Since Last Status Report 157
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 5 years or Full-spectrum microbiota (FSM) therapy, an oral route of Dietary modifications and Aberrant behavior FDA designation(s): Fast older and adults aged up to stool transplantation, introduces key strains of beneficial nutritional counseling Track 60 years who have autism bacteria to increase microbial biodiversity within the gut Autism symptoms and spectrum disorder (ASD) with using gut bacteria collected from healthy human donors. Fecal microbiota severity Clinical trial(s): Phase II transplantation by other SPROUT primary gastrointestinal (GI) About half of individuals with ASD have chronic GI GI symptoms symptoms symptoms, such as constipation, diarrhea, and abdominal means completion May 2020; pain. This treatment is intended to improve GI symptoms Social responsiveness phase II MTT-ASD primary completion October 2020 and core symptoms in individuals with ASD. Research has found that individuals with ASD are more likely to have an abnormal gut microbiome than are healthy controls, which might affect neurological health in addition to GI symptoms. Based on preliminary research, one course of FSM therapy has the potential to improve autism symptoms over the long term (2 years). The oral capsules are made by processing feces until only bacteria remain, then encapsulating the bacteria concentrate inside a 3-layer gelatin capsule. In trials, an oral capsule of gut bacteria from healthy human donors is given daily for 8 weeks. In one trial, patients also receive vancomycin and a bowel cleanse before FSM therapy. Developer(s): Finch Therapeutics (Somerville, Massachusetts), in collaboration with Arizona State University (Tempe, Arizona)
Section 2. Topics Added Since Last Status Report 158
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 65 years Ketamine (NRX-100)/cyclurad (NRX-101) is a sequential Electroconvulsive Attempted suicide FDA designation(s): who have severe bipolar drug plan that includes a single infusion of ketamine therapy Breakthrough Therapy depression with acute followed by an oral, fixed dose of 2 FDA-approved drugs. Completed suicide Lurasidone Clinical trial(s): NRX- suicidal ideation and behavior These 2 drugs, combined as NRX-101, are lurasidone (monotherapy or in Depression symptoms 100/NRX-101: Pivotal (Latuda), a serotonin (5-HT2a) receptor antagonist, and combination with lithium and severity phase II STABIL-B D-cycloserine, an N-methyl-D-aspartate (NMDA) receptor modulator. This combination therapy purportedly extends or valproate) Suicidal ideation completed November 2018, data reported May ketamine’s antidepressant and antisuicidal effects and is Off-label IV ketamine Time to relapse intended to provide both rapid-onset and sustained 2019; NRX-101: phase II/III treatment effects. The therapy can be given in the Olanzapine/fluoxetine primary completion March outpatient setting after a single dose of ketamine in a combination 2019; phase II/III primary completion September clinical setting. Lurasidone, alone or in combination with Quetiapine lithium or valproate, is an approved treatment for bipolar 2020; NRX-100: phase III depression. Increasing evidence shows D-cycloserine, Supportive care (eg, primary completion known from tuberculosis therapy, might be effective in hospitalization) September 2020 various psychiatric diseases since its central active Note(s): FDA has approved mechanism as a partial NMDA agonist has been found. In Latuda to treat depressive trials, one 40-minute intravenous (IV) infusion of ketamine episodes in bipolar (.5 mg/kg) is given followed by administration of NRX-101 depression. twice daily, adjusted to a combined dose of 950/66 mg per day for 6 weeks. Patient observation is required after ketamine infusion. Developer(s): NeuroRx Inc (Wilmington, Delaware)
Section 2. Topics Added Since Last Status Report 159
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 to 40 years SEP-363856 is a psychotropic medication intended to Antidepressants (eg, Adverse events FDA designation(s): who have schizophrenia treat schizophrenia through a different mechanism from selective serotonin Breakthrough Therapy currently approved antipsychotics by not binding to reuptake inhibitors Depression symptoms and severity Clinical trial(s): Phase II dopamine 2 (D2) or serotonin 2A (5-HT2A) receptors. [SSRIs], serotonin and completed July 2018, Although the exact way it works is unknown, SEP-363856 norepinephrine reuptake Quality of life is thought to activate trace amine-associated receptor 1 inhibitors [SNRIs]) pivotal data presented December 2018; phase II and the serotonin 1A (5-HT1A) receptor. Many options for Rate of relapse treating schizophrenia treat only the positive or negative Antipsychotics (oral and completed January 2019 injectable) Schizophrenia symptoms symptoms. This drug is intended to improve both positive (positive and negative) Note(s): SEP-363856 is in and negative symptoms without the serious side effects of Combination therapy phase II studies to treat currently available antipsychotics. In clinical trials, flexibly Parkinson’s disease dosed SEP-363856 was given orally at a dose of 25, 50, Electroconvulsive psychosis. or 75 mg, once daily, for up to 26 weeks. therapy Developer(s): Mood stabilizers Sunovion (Marlborough, Massachusetts), a subsidiary of Psychotherapy (eg, Sumitomo Dainippon Pharma (Osaka, Japan) cognitive behavioral therapy [CBT])
Adults aged 18 to 75 years Zuranolone (SAGE-217) is a positive allosteric modulator Pharmacotherapy (eg, Depression symptoms FDA designation(s): who have major depressive of the GABAA receptor intended to treat MDD and selective serotonin and severity Breakthrough Therapy disorder (MDD) yield benefits in about half the time of standard reuptake inhibitors pharmacotherapies (2 weeks or sooner vs 4-6 weeks). [SSRIs], serotonin and Quality of life Clinical trial(s): Phase II The manufacturer asserts that zuranolone might improve norepinephrine reuptake completed October 2017, symptoms within a few days. Reduced brain inhibitors [SNRIs]) data presented October concentrations of the inhibitory neurotransmitter GABA as 2018; phase III primary Psychotherapy (eg, completion November well as alterations in the subunit composition of GABAA (deficits in GABAergic transmission) are thought to cognitive behavioral 2019; phase III primary contribute to MDD. Zuranolone purportedly works by therapy [CBT]) completion April 2021; phase III (open label) amplifying GABAA receptor activity. Investigators postulate that standard care antidepressants might primary completion ultimately reduce GABAergic deficits due to downstream December 2021 effects. The manufacturer states that zuranolone is given orally once daily (dose unspecified) for a target treatment length of 2 weeks. Developer(s): Sage Therapeutics (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 160
Table 10. Rare Diseases: 32 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older ACE-083 is a locally acting, follistatin protein-based Shoulder stabilization Muscle function (eg, 4- FDA designation(s): who have genetically therapy intended for FSHD type 1 or 2, which is caused surgery stair climb, 6-minute walk Orphan Drug, Fast Track confirmed by shortening of the D4Z4 region of the long (q) arm of distance, performance of facioscapulohumeral chromosome 4. The DNA in the D4Z4 region is normally Supportive care (eg, upper limb) Clinical trial(s): Phase II muscular dystrophy (FSHD) hypermethylated, which silences genes. In patients with analgesics, mobility aids, primary completion March type 1 or 2 FSHD, shortening of D4Z4 causes hypomethylation, physical and Muscle strength 2020, topline results occupational therapy, expected in the second half leading to expression of genes that are normally silenced. Muscle volume While all the genes involved in FSHD have not yet been orthotic devices) of 2019; phase II open- identified, SMCHD1 and DUX4 have been implicated in Quality of life label extension primary disease pathogenesis. Patients with FSHD experience completion June 2022 muscle weakness and atrophy, first affecting the face, Note(s): ACE-083 is also in shoulders, upper arms, and lower legs, typically starting in phase II development to adolescence. The disease progressively worsens over treat Charcot-Marie-Tooth time. No curative or disease-modifying treatments are (CMT) disease types 1 or available for any type of FSHD, and patients typically X. receive supportive care to lessen functional disability. Therefore, additional therapies are needed. ACE-083 is a recombinant fusion protein consisting of a modified form of human follistatin linked to the human immunoglobulin G2 Fc domain that purportedly binds to and inhibits specific proteins in the TGF-beta protein superfamily that reduce muscle growth, such as activins and myostatin. Thus, ACE-083 is intended to increase muscle mass and strength in the areas where the drug is injected. In clinical trials, patients receive up to 250 mg of ACE-083, injected bilaterally into the tibialis anterior (lower leg) and/or the biceps brachii (upper arm) muscle, once every 3 to 4 weeks, up to 24 times. Developer(s): Acceleron Pharma Inc (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 161
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older ACE-083 is a locally acting, follistatin protein-based Foot surgery Balance and fall risk FDA designation(s): who have genetically therapy intended for CMT disease type 1 or X. The Orphan Drug, Fast Track confirmed CMT disease type majority of patients with CMT1 overexpress the PMP22 Supportive care (eg, Muscle function (eg, 1 or X protein due to an extra copy of the PMP22 gene, while analgesics, mobility aids, walk/run time, walk Clinical trial(s): Phase II the majority of patients with CMTX underexpress physical and distance) primary completion occupational therapy, February 2020, topline connexin-32 protein due to mutations in the GJB1 gene. Muscle strength Disruption of PMP22 or connexin-32 expression degrades orthotic devices) results expected in early the protective myelin sheath on nerve fibers, leading to Muscle volume 2020; phase II open-label extension primary peripheral nerve dysfunction, eventual nerve conduction Quality of life loss, and muscle weakness in the hands and lower limbs. completion June 2022 No curative or disease-modifying treatments are available Note(s): ACE-083 is also in for any type of CMT disease, and patients typically phase II development to receive supportive care to lessen functional disability and treat FSHD. neuropathic pain. Therefore, additional therapies are needed. ACE-083 is a recombinant fusion protein consisting of a modified form of human follistatin linked to the human immunoglobulin G2 Fc domain that purportedly binds to and inhibits specific proteins in the TGF-beta protein superfamily that reduce muscle growth, such as activins and myostatin. Thus, ACE-083 is intended to increase muscle mass and strength in the areas where the drug is given. In clinical trials, patients receive up to 250 mg of ACE-083, injected bilaterally into the tibialis anterior (lower leg) muscle, once every 3 to 4 weeks, up to 24 times. Developer(s): Acceleron Pharma Inc (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 162
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Men aged 18 years or older AMT-061 gene therapy consists of adeno-associated viral Factor IX replacement Bleeding episodes FDA designation(s): who have moderate to severe vector serotype 5 (AAV5) containing a codon-optimized therapy (human plasma– Orphan Drug, congenital (ie, inherited) human factor IX Padua gene (AAV5-hFIXco-Padua). The derived or recombinant) Quality of life Breakthrough Therapy hemophilia B and are adeno-associated viral vector delivers a copy of the Survival currently receiving factor IX Padua variant of the Factor IX gene, F9 or FIX. It Clinical trial(s): Phase III prophylaxis with more than purportedly has an 8-fold increase in activity compared Treatment-related HOPE-B primary 150 days’ exposure to factor with wild-type (ie, not caused by any known genetic complications completion March 2020 IX protein treatment variant) Factor IX to provide sustained coagulation. As a single-treatment gene therapy, AMT-061 could eliminate the need for repeated coagulation factor replacement. The manufacturer asserts that nearly all patients screened in clinical trials are eligible for therapy, potentially even patients with some preexisting antibodies to the AAV5 viral vector. In clinical trials, AMT-061 is given as a single intravenous infusion at a dose of 2 × 1013 genome copies (gc)/kg. Developer(s): uniQure NV (Amsterdam, The Netherlands)
Section 2. Topics Added Since Last Status Report 163
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 45 years or older Arimoclomol (BRX-345) is a small-molecule drug intended Immunosuppressants Disease progression Submission date: New who have sporadic inclusion to treat sIBM by increasing the production of reparative (eg, azathioprine, (sIBM) Drug Application planned body myositis (sIBM) heat shock proteins (HSPs) in damaged muscle cells. A methotrexate, for the second half of 2021 degenerative muscle disease of unknown cause, sIBM prednisone) Functional capacity FDA designation(s): presents most often after 50 years of age and causes Quality of life progressive loss of muscle strength and volume over 10 Supportive care Orphan Drug to 15 years. No cure or treatment is available. Patients Survival Clinical trial(s): Phase II/III progress to severe disability, requiring the use of a completed September wheelchair and help with daily activities. Complications 2012, data published including aspiration pneumonia can increase the risk of March 2016; phase II/III death. Investigators suspect that sIBM-induced muscle primary completion degeneration might be caused by the accumulation of December 2021; phase III abnormal and misfolded proteins in muscle cells. open-label extension Arimoclomol purportedly increases the activity of heat primary completion May shock factor 1, a transcription factor that promotes HSP 2022 expression in cells experiencing stress or toxicity. HSPs protect against the accumulation of misfolded proteins Note(s): Interim results are and other toxic waste products by restoring functional expected the first half of protein shapes and degrading abnormal protein 2020. aggregates. In clinical trials, arimoclomol is given orally 3 times daily at a dose of 400 mg (two 200-mg pills), for a daily dose of 1200 mg. Developer(s): Orphazyme US Inc (Newton, Massachusetts)
Section 2. Topics Added Since Last Status Report 164
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 2 to 18 years Arimoclomol (BRX-345) is a small-molecule drug intended Miglustat Disability Submission date: New who have Niemann-Pick to treat NPD-C by amplifying the production of reparative Drug Application planned disease type C (NPD-C) heat shock proteins (HSPs) that are purported to slow Supportive treatment Disease progression for the first half of 2020 disease progression. NPD is a neurovisceral disorder that (eg, bowel regimen, bronchoalveolar lavage, Disease symptoms and FDA designation(s): stems from a genetic mutation affecting lipid metabolism severity in the body. No cure or effective treatment is available. bronchodilation therapy, Orphan Drug, Fast Track NPD-C, a subtype of NPD, is characterized by mutations gastrostomy tube, Quality of life physical therapy) Clinical trial(s): Phase II/III in the NPC intracellular cholesterol transporter genes, Survival primary completion June NPC1 and NPC2, resulting in impaired cellular processing 2018, data reported and transport of low-density lipoprotein cholesterol. The January 2019 abnormal accumulation of lipids results in a range of symptoms and complications, including enlarged liver and spleen, liver disease, lung disease, ophthalmic disease, feeding difficulties, motor impairment, and cognitive deterioration. About one-third of patients develop seizures. Death commonly occurs in the second or third decade of life due to aspiration pneumonia. Arimoclomol purportedly amplifies the production of reparative HSPs, which are thought to rescue misfolded proteins, clear abnormal protein collections, and improve liposome function in NPD-C. The drug can purportedly cross the blood–brain barrier, thereby having a therapeutic effect in the brain as well as in the rest of the body. In clinical trials it is given orally 3 times daily at a dose of 150 to 600 mg (based on patient weight). Developer(s): Orphazyme US Inc (Newton, Massachusetts)
Section 2. Topics Added Since Last Status Report 165
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 5 to 17 years Ataluren (Translarna) is a small-molecule drug intended Corticosteroids (eg, Ambulatory function, as Submission date: New and adults aged 18 years to treat DMD, an inherited, X chromosome–linked genetic deflazacort, prednisone) measured by accepted Drug Application (NDA) who have Duchenne disorder caused by mutations or deletions in the clinical ratings or scales resubmission planned for muscular dystrophy (DMD) dystrophin gene, DMD. DMD encodes the dystrophin Supportive care 2020 and harbor a nonsense protein, which helps keep muscle cells intact. The 6-minute walk distance dystrophin mutation absence of wild-type dystrophin protein causes FDA designation(s): Time to climb or descend Orphan Drug progressive muscle fiber death and eventual widespread 4 stairs muscle weakness. No cure exists for DMD. First-line Clinical trial(s): Phase III corticosteroid treatment (eg, deflazacort) manages Time to loss of primary completion March symptoms but does not prevent disease progression and ambulation 2020 (patients not has significant side effects. FDA approved a gene therapy Time to run or walk 10 previously treated with for patients who have a specific mutation in DMD (ie, in meters ataluren); phase III primary exon 51), but patients who have other DMD mutations do completion December not qualify. Additional therapies are needed. In patients 2020 (patients previously with DMD who harbor DMD nonsense mutations, which treated with ataluren); cause premature stop signals in the messenger RNA phase III ACT DMD (mRNA) encoding dystrophin, ataluren purportedly completed August 2015, interacts with the ribosome and allows the cell’s data published July 2017; translational machinery to read through the stop signals phase III extension study and produce full-length dystrophin. Therefore, by completed June 2018 restoring dystrophin function, ataluren might prevent or delay disease progression. In clinical trials, patients Note(s): Ataluren has been receive an oral suspension of ataluren 3 times a day for approved to treat children up to 144 weeks. In the morning and afternoon, patients who have DMD in the receive a dose of 10 mg/kg, and in the evening, a dose of European Union, Iceland, 20 mg/kg, for a total of 40 mg/kg/day. Liechtenstein, Norway, and Brazil. The manufacturer Developer(s): submitted an NDA to FDA PTC Therapeutics Inc (South Plainfield, New Jersey) in March 2017; in October 2017, FDA issued a Complete Response Letter stating that data from additional trials were needed.
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adolescents aged 12 years Avacopan is a small-molecule anti-inflammatory drug that Prednisone with Estimated glomerular FDA designation(s): or older and adults who have purportedly inhibits the complement anaphylatoxin C5a cyclophosphamide filtration rate Orphan Drug newly diagnosed or relapsed from triggering inflammatory reactions through C5 followed by azathioprine antineutrophil cytoplasmic receptors, which are associated with AAV pathogenesis. Quality of life Clinical trial(s): Phase III Prednisone with ADVOCATE primary antibody-associated Avacopan might reduce inflammation, vascular tissue Remission vasculitis (AAV) requiring damage, and subsequent organ failure that occurs in rituximab followed by completion date treatment with many patients with poorly managed AAV. Patients with azathioprine Response time September 2019; topline data expected fourth- cyclophosphamide or AAV have limited treatment options and increased risk of Vasculitis Damage Index rituximab death from inflammatory vascular complications arising in quarter 2019 various organs (often the kidneys). AAV is caused by autoantibodies called anti-neutrophil cytoplasmic antibodies that increase vascular adhesion molecules and contribute to alternative complement pathway (including C5) activation and formation of immune complexes in blood vessels. These inflammatory effects trigger the homing and inflammatory processes of granulocytes (particularly neutrophils), causing tissue damage in areas of high cell and complex accumulation. Avacopan is intended to inhibit the activity of C5 and its role in downstream inflammatory effects. In clinical trials, avacopan is given orally at an unspecified dose in combination with rituximab or in combination with cyclophosphamide followed by azathioprine. Developer(s): ChemoCentryx Inc (Mountain View, California)
Section 2. Topics Added Since Last Status Report 167
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 12 years or BCX7353 is a plasma kallikrein inhibitor intended to treat C1 esterase inhibitors Number of angioedema Submission date: New older and adults who have type 1 or 2 HAE, a rare inherited genetic disorder caused (eg, Cinryze, Haegarda) attacks Drug Application planned type 1 or type 2 hereditary by a mutation in the gene encoding the C1 esterase for fourth-quarter 2019 angioedema (HAE) inhibitor protein (C1-INH). BCX7353 is intended to Plasma kallikrein Quality of life, as prevent the onset of HAE attacks by providing an oral inhibitors (eg, measured by accepted FDA designation(s): alternative to injectable HAE treatments, which may lanadelumab-flyo) clinical ratings and Orphan Drug, Fast Track scales improve treatment adherence. C1-INH normally regulates Clinical trial(s): Phase III the production and activity of the plasma serine protease APeX-2 primary completion kallikrein, which in turn regulates the production and October 2020, data activity of the inflammatory mediator bradykinin. reported May 2019 Unregulated kallikrein and bradykinin activity due to the absence of C1-INH causes fluid leakage from blood vessels and swelling of surrounding tissues. Patients with type 1 or 2 HAE, also known as C1 inhibitor deficiency, typically experience severe swelling (edema) of the hands, abdomen and gastrointestinal tract, upper and lower extremities, and throat that is triggered by stress, injury, illness, or hormone fluctuations. Swelling of the abdomen and intestines causes severe abdominal pain and gastrointestinal upset, and swelling of the throat may lead to asphyxiation. In clinical trials, patients receive BCX7353 110 or 150 mg orally, once daily, for up to 48 weeks. Developer(s): BioCryst Pharmaceuticals Inc (Durham, North Carolina)
Section 2. Topics Added Since Last Status Report 168
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 7 years or Casimersen (SRP-4045) is a phosphorodiamidate Corticosteroids (eg, Ambulatory function, as Submission date: New older and adults aged up to morpholino oligomer intended to treat DMD, an inherited, deflazacort, prednisone) measured by accepted Drug Application planned 23 years who have X chromosome–linked genetic disorder caused by clinical ratings and for the second half of 2019 Duchenne muscular mutations or deletions in the DMD gene. DMD encodes Supportive care scales dystrophy (DMD) with a for the dystrophin protein, which is involved in muscle FDA designation(s): mutation in the dystrophin function, and the absence of wild-type dystrophin protein Quality of life Orphan Drug gene, DMD, that involves causes progressive muscle fiber necrosis and eventual 6-minute walk test Clinical trial(s): Phase III exon 45 and who are on a widespread muscle weakness. Casimersen purportedly distance ESSENCE trial primary stable dose of corticosteroids binds exon 45 of dystrophin pre-mRNA (precursor RNA completion May 2022 composed of introns and exons) and promotes skipping of (children aged 7-13), exon 45 during mRNA processing. This allows for topline data reported synthesis of an internally truncated, but functional, March 2019; phase III dystrophin protein. Casimersen treatment is intended to open-label extension promote skeletal muscle function and prevent or delay primary completion June disease progression in patients with DMD who have DMD 2026 (children aged 7-17 exon 45 mutations. In clinical trials, casimersen 30 mg/kg and adults aged 18-23) is given intravenously, once weekly, for up to 144 weeks. Developer(s): Sarepta Therapeutics Inc (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 169
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 16 years or Elamipretide is a peptide compound designed to treat Supportive care, Exercise tolerance FDA designation(s): older and adults aged up to PMM by restoring cellular energy production. No curative especially to address Orphan Drug, Fast Track 80 years with a diagnosis of or disease-modifying treatments exist for PMM. In PMM, respiratory, Fatigue Clinical trial(s): Phase III primary mitochondrial DNA mutations impair the mitochondria’s ability to cardiovascular, or Quality of life myopathy (PMM) produce energy by metabolizing lipids, especially neurologic complications MMPOWER-3 primary cardiolipin. The impaired energy production causes completion December muscle degeneration. Tissues composed of cells with the 2019; phase II open-label highest energy requirements are most affected (eg, extension primary skeletal muscle, heart, brain). Prognosis worsens if completion December disease onset is early and depends on the number of 2021 organs affected. Elamipretide purportedly penetrates mitochondrial membranes to bond reversibly to cardiolipin, thereby normalizing the inner mitochondrial membrane structure and improving mitochondrial function. Elamipretide is thought to enhance energy generation through increased production of adenosine triphosphate, a critical component in energy transport, and potentially lower levels of reactive oxygen species that can damage cardiolipin. In clinical trials, patients receive 40 mg of elamipretide (0.5 mL) as once-daily subcutaneous (under the skin) injections for up to 168 weeks. Developer(s): Stealth Biotherapeutics Inc (Newton, Massachusetts)
Section 2. Topics Added Since Last Status Report 170
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Male children aged 12 years Elamipretide is a peptide compound designed to treat Supportive care directed Exercise tolerance FDA designation(s): or older and adults who have mitochondrial dysfunction disorders by restoring cellular at relieving individual Orphan Drug, Fast Track genetically confirmed Barth energy production. Barth syndrome is a chromosome symptoms (eg, bacterial Fatigue Clinical trial(s): Phase II/III syndrome and a baseline X–linked mitochondrial disorder characterized by infection, heart failure) Quality of life body weight of more than 30 degeneration of heart muscle (dilated cardiomyopathy) TAZPOWER primary kg and estimated glomerular and skeletal muscle (myopathy), recurrent infections due completed October 5, filtration rate (eGFR) greater to neutropenia (ie, low white cells), and short stature. 2018, preliminary results than 90 mL/min or a body Barth syndrome is managed primarily with supportive reported April 2019 weight of more than 40 kg care because no pharmacologic therapies have yet and eGFR greater than 60 demonstrated clinical benefits. In Barth syndrome, but less than 90 mL/min mutations in the TAZ gene result in the production of dysfunctional tafazzin protein. This protein ensures adequate levels of functional cardiolipin, a lipid required for normal mitochondrial structure, function, and energy production. Tissues with the highest energy demands (eg, heart and skeletal muscle) are most affected. Elamipretide purportedly penetrates mitochondrial membranes to bond reversibly to cardiolipin, thereby normalizing the inner mitochondrial membrane structure and improving mitochondrial function. Elamipretide is thought to enhance energy generation through increased production of adenosine triphosphate, a critical component in energy transport, and potentially lower levels of reactive oxygen species that can damage cardiolipin. In clinical trials for Barth syndrome, patients receive 40 mg of elamipretide as once-daily subcutaneous injections for 12 weeks. Developer(s): Stealth Biotherapeutics Inc (Newton, Massachusetts)
Section 2. Topics Added Since Last Status Report 171
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Males aged 12 years or older Fitusiran (ALN-AT3) is an RNA interference (RNAi) Emicizumab (hemophilia Bleeding episodes Clinical trial(s): Phase III with hemophilia A or B therapeutic under development to treat hemophilia A and A) ATLAS-INH primary B. Fitusiran purportedly reduces expression of Quality of life completion February 2020; Factor VIII replacement antithrombin, an enzyme that inactivates several other Survival phase III ATLAS-A/B enzymes in the blood-clotting cascade, thereby promoting (human plasma–derived primary completion April sufficient thrombin generation to restore hemostasis and or recombinant, porcine Treatment-related 2020; phase III ATLAS- prevent bleeding. Fitusiran therapy would replace regular recombinant; hemophilia complications PPX primary completion A) intravenous factor infusions with a monthly subcutaneous June 2021; phase II-III injection. In clinical trials, fitusiran is given as a once- Factor IX replacement ATLAS-PEDS primary monthly, 80-mg subcutaneous injection for up to 20 (human plasma–derived completion February 2023; months. or recombinant; phase III ATLAS-OLE hemophilia B) primary completion Developer(s): December 2024 Alnylam Pharmaceuticals (Cambridge, Massachusetts), in Note(s): FDA lifted a collaboration with Sanofi Genzyme (Cambridge, clinical hold on fitusiran Massachusetts) studies in December 2017.
Section 2. Topics Added Since Last Status Report 172
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 13 years or Gaboxadol, also known as OV101 or THIP, is a small- Supportive care (eg, Aberrant behavior FDA designation(s): older and adults aged up to molecule derivative of muscimol, a compound found in educational incidence and severity, Orphan Drug, Fast Track 22 years with fragile X the mushroom Amanita muscaria. It is intended to treat interventions, sensory as measured by syndrome fragile X syndrome, a rare, noninherited, X chromosome– integration techniques, accepted clinical ratings Clinical trial(s): Phase II linked neurodevelopmental disorder. This syndrome is behavior-stabilizing and scales ROCKET completion caused by mutations in the fragile X mental retardation 1 medications [eg, September 2019, results gene, FMR1. Expansion of the CGG trinucleotide repeats antidepressants, alpha2 expected in late 2019 or early 2020 in the 5′ untranslated region of FMR1 causes gene agonists, beta blockers], hypermethylation, which then silences expression of the anticonvulsants for Note(s): Gaboxadol is also encoded Fmr1 protein (Fmrp). Fmrp, which is expressed seizures and/or behavior in phase II clinical in neurons and glial cells, is thought to promote synapse stabilization) development to treat formation and adaptation (synaptic plasticity) in the brain Angelman syndrome. and is thought to be important for learning, memory, and regulating protein synthesis and transport of coding and noncoding RNA in the brain. Normally, the brain can differentiate between excitatory and inhibitory signals, a process called tonic inhibition that is partially mediated by gamma-aminobutyric acid (GABA) receptors. In patients with fragile X syndrome, loss of Fmrp function purportedly disrupts protein translation, synaptic plasticity, intracellular signaling, and GABA-mediated tonic inhibition, leading to the development of autism-like symptoms including anxiety, irritability, aggression, hyperactivity, and restricted and repetitive behaviors. Some patients also experience seizures. Symptom severity varies by patient and is determined by gender and the number of CGG trinucleotide repeats that the patient harbors (ie, males with high numbers of CGG trinucleotide repeats typically exhibit the most severe symptoms). Because gaboxadol is a delta-selective, GABA A (GABAA) receptor agonist that selectively activates GABAA receptors, it purportedly restores the process of tonic inhibition and normalizes brain activity in patients with fragile X syndrome. In clinical trials, patients receive an unspecified dose of gaboxadol, once, twice, or 3 times daily, for up to 12 weeks. Developer(s): Ovid Therapeutics Inc (New York, New York)
Section 2. Topics Added Since Last Status Report 173
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Galcanezumab-gnlm (Emgality) is a humanized Corticosteroids Cluster headache Clinical trial(s): Phase III with chronic cluster headache monoclonal antibody against calcitonin gene–related duration, as measured open-label extension peptide (CGRP) intended to prevent chronic or episodic Off-label topiramate by accepted clinical primary completion July cluster headache. Galcanezumab-gnlm is the first biologic Off-label verapamil ratings and scales 2020 (episodic, chronic approved to treat patients who experience episodic cluster headache); phase cluster headache. It is still being developed for preventing Cluster headache III completed July 2019 chronic cluster headache. CGRP is a neuropeptide severity, as measured by (chronic cluster headache) thought to contribute to pain signaling of the trigeminal accepted clinical ratings sensory nerve, leading to headache development. and scales Note(s): In June 2019, FDA Galcanezumab-gnlm purportedly prevents CGRP from approved Emgality to treat Suicidal ideation and episodic cluster headache binding to its receptor, which might reduce episodic behavior, as measured cluster headache frequency and/or length. In clinical in adults. In 2018, FDA by accepted clinical approved Emgality to trials, patients with chronic cluster headache receive an ratings and scales unspecified dose of galcanezumab-gnlm, subcutaneously, prevent migraine at a frequency of up to once monthly. headache. Developer(s): Eli Lilly and Co (Indianapolis, Indiana)
Section 2. Topics Added Since Last Status Report 174
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 6 to 17 years Givinostat is a small-molecule histone deacetylase Corticosteroids (eg, Ambulatory function (eg, Clinical trial(s): Phase III who have Duchenne (HDAC) inhibitor intended to treat DMD, an inherited deflazacort, prednisone) 6-minute walk test primary completion June muscular dystrophy (DMD), X chromosome–linked genetic disorder caused by distance, time to rise 2020; phase II/III long-term are ambulatory, and are mutations or deletions in the dystrophin gene, DMD. DMD Supportive care from floor, North Star follow-up primary receiving a stable dose of encodes the dystrophin protein, which helps keep muscle Ambulatory Assessment) completion December corticosteroids cells intact. The absence of wild-type dystrophin protein 2023 causes progressive muscle fiber necrosis and eventual Muscle strength widespread muscle weakness. Patients with DMD also have increased HDAC levels that might be caused by dystrophin loss. HDAC overactivity prevents gene expression, including that of genes responsible for muscle cell regeneration and normal function, and might trigger inflammation. No cure exists for DMD, and first-line corticosteroid treatment (eg, deflazacort) manages symptoms but does not prevent disease progression and has significant side effects. FDA approved a gene therapy for patients who have a specific mutation in DMD (ie, in exon 51), but patients who have other DMD mutations do not qualify. Therefore, additional therapies are needed. In patients with DMD, givinostat purportedly blocks HDAC overactivity and improves muscle regeneration and function. In clinical trials, patients receive an unspecified, weight-dependent dose of an oral suspension of givinostat, at a concentration of 10 mg/mL, twice daily with food, for up to 18 months. Developer(s): Italfarmaco SpA (Milan, Italy)
Section 2. Topics Added Since Last Status Report 175
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Inebilizumab (MEDI-551) is a humanized monoclonal Azathioprine Attack rate FDA Designation(s): who have a confirmed antibody intended to bind to clusters of differentiation Orphan Drug, diagnosis of neuromyelitis marker CD19+ that is expressed on a broad range of Eculizumab plus Functional impairments Breakthrough Therapy optica or neuromyelitis optica B cells. Inebilizumab is intended to bind to and deplete immunosuppressants (eg, vision, mobility, and spectrum disorder (NMOSD), autoreactive B cells involved in the neurodegenerative bowel or bladder Clinical trial(s): N- Intravenous incontinence) change MOmentum phase II/III including those with and disease course of NMOSD, for which no cure exists. corticosteroids without aquaporin-4 (AQP4)- NMOSD is a rare autoimmune disease that affects myelin from baseline completed October 2018; IgG antibodies, and one in the eyes, spinal cord, and other parts of the body. Mycophenolate mofetil topline data published April Hospitalizations 2019 relapse requiring rescue Patients with NMOSD can have pain, paralysis, vision Plasmapheresis therapy in the previous year loss, and bladder and bowel problems. Approved Quality of life change treatments are immunosuppressants and/or add-on Rituximab from baseline therapies for those with positive AQP4 antibodies. About 80% of patients test positive for antibodies to the water channel protein anti-AQP4, produced by B cells. In clinical trials, regardless of whether they tested positive or negative for AQP4-IgG antibodies, patients received inebilizumab intravenously and results were followed for 28 weeks. Developer(s): Viela Bio (Gaithersburg, Maryland)
Section 2. Topics Added Since Last Status Report 176
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Males aged 17 years or Lenti-D is a bone marrow–derived gene therapy product Histocompatible stem Delayed or halted CALD Submission date: Biologics younger with active cerebral intended for ALD, a rare chromosome X–linked inherited cell transplant progression License Application adrenoleukodystrophy (ALD) metabolic disorder caused by mutations in the ABCD1 planned for 2020 gene. The disorder leads to the accumulation of Lorenzo’s oil (4 parts Improved quality of life glyceryl trioleate to 1 part FDA designation(s): abnormally high levels of unbranched, saturated, very- Reduced functional long-chain fatty acids in patients’ brains and adrenal glyceryl trierucate) Orphan Drug, disability Breakthrough Therapy cortexes. Cerebral ALD (CALD) is the most severe form and involves neurodegeneration, including the breakdown Clinical trial(s): Phase II/III of the protective myelin sheath of nerve cells in the brain. Starbeam primary Symptoms occur in early childhood and progress rapidly, completion July 2020, causing severe loss of neurologic function and eventual interim results reported death. CALD can be treated with bone marrow or stem September 2018; phase III cell transplants. However, fewer than 30% of patients find primary completion matching donors, and allogenic donor transplants can February 2023 have potentially fatal side effects. Lenti-D is intended to restore expression of the adrenoleukodystrophy protein gene, ALDP, which metabolizes very-long-chain fatty acids that are thought to contribute to CALD neurodegeneration. Lenti-D consists of patient-derived CD34+ stem cells that are harvested and treated with a lentivirus vector that stably inserts a functional copy of ALDP into the cells. The cells are then multiplied in culture to facilitate uptake. In clinical trials, Lenti-D is given as a single intravenous infusion after myeloablative (bone marrow–destroying) conditioning with busulfan and cyclophosphamide. Developer(s): bluebird bio Inc (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 177
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Liposomal cyclosporine A (L-CsA) is an Immunosuppressants Disease progression FDA designation(s): with bronchiolitis obliterans immunosuppressive treatment intended to reduce BOS’s (eg, azithromycin, (BOS) Orphan Drug syndrome (BOS) after lung inflammatory disease burden, the most common cause of mycophenolate, transplantation chronic lung allograft dysfunction after transplantation. No tacrolimus) Lung retransplantation Clinical trial(s): Phase II/III completed December treatments are approved, and no standardized treatment Quality of life protocols are available for BOS. Cyclosporine A is a Supportive care (eg, 2014, data presented potent immunosuppressive drug for preventing transplant corticosteroids, oxygen) Survival March 2019, data presented April 2019, data rejection, but systemic administration has insufficient penetration into the lungs to treat BOS and carries a risk presented May 2019; of nephrotoxicity. L-CsA uses a proprietary inhaled phase III BOSTON-2 liposomal nanodelivery system to administer what primary completion researchers believe to be a sufficient concentration of September 2021; phase III cyclosporine A directly to the lung parenchyma, mediating BOSTON-1 primary immunosuppressive effects. L-CsA purportedly dampens completion December key inflammatory T-cell activity in the lungs thought to 2021; phase III open-label contribute to the chronic inflammation and irreversible extension (of BOSTON-3) scarring caused by BOS, slowing or preventing disease March 2023 progression. In clinical trials, the drug is inhaled using the PARI eFlow Nebulizer system at a dose of 5 mg twice daily for 48 weeks for participants with 1 lung transplantation or 10 mg twice daily for 48 weeks for participants with a double lung transplantation. Developer(s): Breath Therapeutics, a Zambon Group company (Menlo Park, California)
Section 2. Topics Added Since Last Status Report 178
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Infants, children, or adults Lumasiran (ALN-GO1) is an RNAi therapeutic intended to Diet management and Change in urinary FDA designation(s): with primary hyperoxaluria reduce glycolate oxidase (GO) expression in PH1, a rare fluid intake oxalate excretion Orphan Drug, type 1 (PH1) inherited disorder characterized by kidney and bladder Breakthrough Therapy stones from the buildup of excessive oxalate. Lumasiran Organ transplantation Hospitalizations (isolated or combined Clinical trial(s): is intended to improve health outcomes in patients with Quality of life in patients PH1 by reducing the morbidity from oxalate crystals liver and kidney) ILLUMINATE-A phase III and caregivers primary completion accumulating in the kidneys and urinary tract. No Renal dialysis pharmacologic treatment options are available for PH1. December 2019; Lumasiran purportedly lowers hepatic levels of GO, which Shock wave lithotripsy ILLUMINATE-B phase III produces the substrate necessary for the subsequent primary completion March 2020; phase I/II completed production of oxalate. Limiting the substrate necessary for oxalate production is intended to limit its buildup. In January 2019, data clinical trials, lumasiran is given subcutaneously by reported phase I/II injection at a dose of 3 mg/kg a month. February 2019 Developer(s): Alnylam Pharmaceuticals (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 179
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Luspatercept is an erythrocyte (red blood cell) maturation Allogeneic stem cell Blood transfusion PDUFA date: December 4, who have agent under development to treat β-thalassemia. transplant dependence 2019 β-thalassemia Luspatercept is intended to restore production of normal red blood cells, thus obviating the need for repeat Repeated blood Incidence of iron FDA designation(s): transfusions and the accompanying iron chelation transfusions overload Orphan Drug, Fast Track, Priority Review therapy. β-thalassemia is caused by a mutation in the Organ function β-globin gene that prevents normal erythrocyte Clinical trial(s): Phase III maturation, resulting in severe anemia requiring chronic Quality of life BELIEVE primary blood transfusions for survival plus nightly iron chelation completed November to prevent iron overload. Luspatercept is a first-in-class 2017; phase II single-arm biologic that purportedly stimulates maturation of primary completed erythrocyte precursor cells differently from erythropoietin, November 2015, data thereby correcting the maturation defect and restoring published March 2019 normal erythrocyte production. Luspatercept is a modified activin receptor type 2B fusion protein that acts as a ligand trap for members of the transforming growth factor β superfamily involved in late-stage erythrocyte production. In clinical trials for treating β-thalassemia, luspatercept is given as a subcutaneous injection at doses of 0.8 to 1.25 mg/kg once every 21 days. Developer(s): Acceleron Pharma Inc (Cambridge, Massachusetts), in collaboration with Celgene Corp (Summit, New Jersey)
Section 2. Topics Added Since Last Status Report 180
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 6 months to 17 LYS-SAF302 is a viral vector–based gene therapy Supportive care Developmental and FDA designation(s): years and adults aged 18 intended to treat Sanfilippo syndrome type A (also called cognitive delays, as Orphan Drug, Rare years or older who have MPS IIIA), a childhood-onset, progressive, inherited measured by MPS Pediatric Disease genotypically confirmed metabolic disorder caused by a mutation in the clinical ratings and Sanfilippo syndrome type A, N-sulfoglucosamine sulfohydrolase gene, SGSH. Patients scales Clinical trial(s): Phase II/III also called with the disorder cannot break down the polysaccharide AAVance primary mucopolysaccharidosis type heparan sulfate, a process normally mediated by the Independence, as completion January 2022 3A (MPS IIIA) SGSH-encoded enzyme heparan-N-sulfamidase. Buildup measured by MPS of heparan sulfate in central nervous system cells causes clinical ratings and degeneration that manifests as behavioral problems, scales sleeplessness, loss of speech and cognitive skills, mental Quality of life retardation, heart problems, seizures, and loss of mobility. No cure exists for Sanfilippo syndrome type A (about 60% Sleep duration of all Sanfilippo syndrome cases), and patients typically do not survive past their 20s. Treatment consists of supportive care. LYS-SAF302 is a recombinant adeno- associated viral vector carrying SGSH. LYS-SAF302 purportedly restores heparan-N-sulfamidase function, blocks central nervous system degeneration, and reduces disease-related symptoms. In clinical trials, LYS-SAF302 is injected intracerebrally into both halves of the brain through image-guided tracks, once. Developer(s): Sarepta Therapeutics Inc (Cambridge, Massachusetts), in collaboration with Lysogene SA (Paris, France)
Section 2. Topics Added Since Last Status Report 181
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 1 to 17 years Maralixibat (LUM001) is an inhibitor of apical sodium- Ursodeoxycholic acid Liver function FDA designation(s): who have progressive familial dependent bile acid transporter (ASBT). It purportedly Breakthrough Therapy intrahepatic cholestasis prevents bile acids from accumulating in the liver of Need for surgical (PFIC) patients with PFIC subtypes PFIC1, PFIC2, PFIC3, and intervention Clinical trial(s): Phase II INDIGO primary PFIC4, a progressive disease that can require surgical Quality of life intervention or liver transplantation and has minimally completion December effective therapy. PFIC is characterized by mutations in 2019, preliminary data key genes leading to decreased bile acid flow through the reported April 2019; phase liver. Bile acid accumulation in the liver might lead to III MARCH-PFIC primary jaundice, intense itching, gallstones, abdominal pain, completion May 2020 nausea, vomiting, and liver damage, as well as a higher risk for hepatocellular carcinoma. Maralixibat binds to ASBTs and prevents bile acid accumulation in the liver by blocking bile acid transport from the intestine to the liver. In phase III clinical trials, maralixibat is given as an oral solution at a dose of up to 600 μg/kg, twice daily, for 26 weeks. Developer(s): Mirum Pharmaceuticals Inc (Foster City, California)
Section 2. Topics Added Since Last Status Report 182
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Infants up to 24 months with MB-107 is a bone marrow–derived gene therapy product HSC transplant Hospitalizations from FDA designation(s): X-linked severe combined intended for SCID-X1. SCID-X1 is a rare, life-threatening baseline Regenerative Medicine immunodeficiency diseases disorder caused by mutations in the IL-2 R gene that Supportive care Advanced Therapy (SCID-X1) encodes the common γ-chain, which is shared by multiple (including intravenous Immune reconstitution cytokine (immune system hormones) receptors and is immunoglobulin) Clinical trial(s): Phase I/II Serious infection rate trial primary completion necessary for the development, function, and replication from baseline of T cells, natural killer cells, and functional B cells. December 2022; phase I/II Standard care involves hematopoietic stem cell (HSC) Survival LVXSCID-ND trial primary transplants from a matched sibling donor, but matches completion August 2025, are available for fewer than 20% of patients, and preliminary data published transplants from alternative donors have an increased risk April 2019 of graft-versus-host disease and incomplete immune reconstitution. Newborns not screened before the appearance of symptoms are affected by severe opportunistic infections due to defects in immunity. MB-107 is intended to restore immune function in SCID-X1 by inserting a working copy of the interleukin-2 receptor 2 gene, IL-2R, into the DNA of a patient’s own blood-producing HSCs. MB-107 is produced by harvesting HSCs from the patient and treating them with a lentivirus vector that stably inserts the IL-2R gene into the genome of the HSC. The cells are then expanded (grown) in the laboratory and returned to the patient’s physician for infusion. In clinical trials, MB-107 is given as a single intravenous infusion into the patient following nonmyeloablative (non–bone marrow destroying) busulfan conditioning on days 2 and 3 before infusion. Developer(s): Mustang Bio (Worcester, Massachusetts), in collaboration with Fortress Biotech Inc (Waltham, Massachusetts)
Section 2. Topics Added Since Last Status Report 183
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged up to 6 years OTL-200 is a gene therapy consisting of autologous Supportive care (eg, Gross motor function, as Submission date: Biologics who have genetically CD34+ hematopoietic stem cells (HSCs) transduced ex physical, occupational, measured by accepted License Application confirmed metachromatic vivo with a lentiviral vector containing the arylsulfatase A and speech therapy; MLD clinical ratings and planned for the first half of leukodystrophy (MLD) gene, ARSA. It is intended to treat patients who have nutritional therapy) scales 2021 MLD, a progressive inherited lysosomal storage disorder caused by mutations in both alleles of ARSA. The gene Neurocognitive function, FDA designation(s): normally encodes the enzyme arylsulfatase A, which as measured by Orphan Drug, Rare breaks down sphingolipids. Lack of arylsulfatase A activity accepted MLD clinical Pediatric Disease ratings and scales leads to sphingolipid accumulation in the brain, gall Clinical trial(s): Phase III bladder, kidneys, liver, and spleen, which in turn causes Quality of life primary completion August myelin loss on nerve fibers of the central nervous system. 2022 Affected patients experience convulsions, motor disturbances, paralysis, personality changes, progressive dementia, seizures, spasticity, and visual impairment. No cure exists for MLD, and the disease is fatal; treatment consists of supportive care to manage symptoms. OTL- 200 purportedly repopulates the central nervous system with microglial cells that have restored arylsulfatase A function and thus might delay or halt disease progression. In clinical trials, patients first receive a myeloablative conditioning with busulfan, and then an unspecified dose of OTL-200 is given intravenously, once. Developer(s): Orchard Therapeutics Ltd (London, United Kingdom)
Section 2. Topics Added Since Last Status Report 184
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults who have recessive PTR-01 is a formulation of recombinant collagen type VII Supportive care for pain Change in wound size FDA designation(s): dystrophic epidermolysis (rC7) intended to improve lesions and other symptoms and infection risk from baseline Orphan Drug, Fast Track bullosa (RDEB) and complications of RDEB. It purportedly replaces defective collagen type VII with functional recombinant Evidence of collagen 7 Clinical trial(s): Phase I/II collagen at the sites of skin lesions to promote healing. anchoring in tissue primary completion December 2019 No cure exists for RDEB, and treatment relies on Time to wound closure preventing blister formation and managing symptoms. from baseline RDEB is a rare genetic disease caused by mutations in the COL7A1 gene and is characterized by widespread blistering that leads to severe scarring. The scars can lead to vision loss; disfigurement; and other serious medical problems, such as poor nutrition and slow growth from difficulty eating due to scarring in the mouth and esophagus. Individuals with RDEB are also at high risk of developing squamous cell carcinoma, an aggressive, often life-threatening form of skin cancer. PTR-01 is purported to selectively anchor the skin and other tissues affected by an absence of collagen type VII, which promotes RDEB wound healing. In clinical trials, PTR-01 is given as an intravenous infusion at a dose of 0.1 mg/kg, every 2 weeks. Developer(s): Phoenix Tissue Repair (Boston, Massachusetts)
Section 2. Topics Added Since Last Status Report 185
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 4 years or Sarizotan is a full 5-HT1A (serotonin) agonist and a Supportive care (eg, Apnea incidence and FDA designation(s): older and adults who have dopamine D2–like agonist/partial agonist being developed anticonvulsants, severity Orphan Drug Rett syndrome and breathing to treat breathing dysfunction (eg, apnea [halted assistive devices, dysfunction breathing], hyperventilation) in patients with Rett noninvasive ventilation, Hyperventilation Clinical trial(s): Phase II/III syndrome. A rare, postnatal, progressive neurologic nutritional support, incidence and severity STARS completed April 2019, results expected in disorder, Rett syndrome is caused by a mutation in the oxygen treatment, Quality of life methyl CpG binding protein 2 gene, MECP2. Located on physical and fourth-quarter 2019 the X chromosome, MECP2 encodes the MeCP2 protein occupational therapy, that normally mediates gene expression in neuronal and speech/language glial cells. Loss of MeCP2 function results in nerve cell therapy) dysfunction, which is thought to be reversible. Patients with Rett syndrome typically develop normally until 6 to 18 months of life, but then experience developmental delays and regression of previously learned motor and verbal skills. The disease eventually causes additional symptoms, such as repeated hand movements, impaired gait, slowed head growth, breathing dysfunction, and seizures. Symptom severity varies by patient and depends on the individual’s specific MECP2 mutation and the amount of mutant MeCP2 protein expression. In patients with Rett syndrome who are experiencing breathing dysfunction, sarizotan purportedly stimulates serotonin activity in the brain, which is intended to restore breathing rhythm and decrease apnea and hyperventilation incidence or severity. In clinical trials, patients receive 2 to 10 mg of sarizotan (depending on age and weight) orally, twice daily, for 24 weeks. Developer(s): Newron Pharmaceuticals SpA (Milan, Italy)
Section 2. Topics Added Since Last Status Report 186
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 8 years or Sepofarsen (formerly QR-110) is a first-in-class No approved treatment Full-field light sensitivity FDA designation(s): older and adults who have investigational RNA-based oligonucleotide that targets options Orphan Drug; Fast Track Leber congenital amaurosis homozygous or compound heterozygous mutations due Mobility course Clinical trial(s): Phase II/III 10 (LCA10) to aberrant splicing of CEP290 protein mRNA. This Quality of life aberration causes LCA10, the leading genetic cause of ILLUMINATE primary childhood blindness. Sepofarsen is intended to restore Visual acuity completion December 2020 vision in these patients. Sepofarsen purportedly repairs the RNA defect by binding to the mutated pre-mRNA sequence and causing normal pre-mRNA splicing, restoring normal (wild-type) CEP290 protein production and reversing LCA10 disease symptoms. In clinical trials, sepofarsen is given through injections into the eye at doses of 40 μg (with an 80-μg loading dose) or 80 μg (with a 160-μg loading dose) at the start of the trial, at 3 months, and every 6 months thereafter. Developer(s): ProQR Therapeutics (Leiden, the Netherlands)
Section 2. Topics Added Since Last Status Report 187
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 4 to 17 years SGT-001 is an adeno-associated viral vector (AAV9) Corticosteroids (eg, Microdystrophin protein FDA designation(s): who have genetically containing a synthetic dystrophin gene, DMD, intended to deflazacort, prednisone) production Orphan Drug, Rare confirmed Duchenne treat DMD, an inherited, X chromosome–linked genetic Pediatric Disease, Fast muscular dystrophy (DMD), disorder caused by mutations or deletions in the DMD Supportive care Track are on a stable dose of gene. DMD encodes the dystrophin protein, which helps corticosteroids, and have keep muscle cells intact. The absence of wild-type Clinical trial(s): Phase I/II levels of anti-AAV9 dystrophin protein causes progressive muscle fiber death IGNITE DMD completion antibodies below a specified and eventual widespread muscle weakness. No cure March 2020, preliminary threshold exists for DMD. First-line corticosteroid treatment data reported February manages symptoms but does not prevent disease 2019 progression and has significant side effects. FDA approved a gene therapy for patients who have a specific mutation in DMD (eg, in exon 51), but patients who have other DMD mutations do not qualify. Therefore, additional therapies are needed. The synthetic DMD gene in SGT- 001 encodes for microdystrophin, a truncated but functional protein surrogate for dystrophin, because the large size of the dystrophin protein prohibits delivery by viral vectors. In patients with DMD, SGT-001 treatment might restore skeletal muscle function and prevent or delay disease progression, independent of the patient’s mutation status. In clinical trials, 1 of 3 unspecified doses of SGT-001 is given intravenously, once. Developer(s): Solid Biosciences Inc (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 188
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 4 to 15 years SRP-9003, formerly known as MYO-101, is a Exercise Mobility FDA designation(s): who have genetically recombinant, adeno-associated viral vector carrying the Orphan Drug, Rare confirmed, early symptomatic human sarcoglycan beta gene, SGCB. It is intended to Physical therapy Muscle strength Pediatric Disease limb-girdle muscular treat LGMD2E (also called β-sarcoglycanopathy), a Supportive care 100-meter timed walk Clinical trial(s): Phase I/II dystrophy type 2E (LGMD2E) progressive inherited neuromuscular disorder caused by test a mutation in SGCB. The gene normally encodes the IRB17-00253 primary protein β-sarcoglycan, which is part of a complex involved Quality of life completion December in muscle function, regulation, and repair. Without β- 2020 sarcoglycan function, these patients develop weakness and atrophy of muscles connected to the limb girdles (ie, bony structures in the shoulder and the pelvis). Early symptoms include difficulty running, jumping, and climbing stairs, but as the disease progresses, patients typically become wheelchair dependent and develop more severe symptoms such as scoliosis, joint contractures, respiratory impairment, and heart problems. SRP-9003 purportedly restores β-sarcoglycan production in muscle cells to improve disease-related symptoms or to prevent symptoms from occurring before disease onset. In clinical trials, patients receive SRP-9003 at a dose of 5 × 1013 or 2 × 1014 viral genomes per kilogram of body weight (vg/kg) intravenously, once. Developer(s): Sarepta Therapeutics Inc (Cambridge, Massachusetts)
Section 2. Topics Added Since Last Status Report 189
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Valoctocogene roxaparvovec is an adeno-associated Emicizumab Bleeding episodes Submission date: Biologics who have hemophilia A and virus vector gene therapy intended to cure hemophilia A. License Application residual Factor VIII levels of 1 It is intended to eliminate or reduce the need for repeated Factor VIII replacement Quality of life planned for fourth-quarter (human plasma–derived IU/dL or lower despite stable treatments with Factor VIII replacement or emicizumab. Survival 2019 Factor VIII replacement Valoctocogene roxaparvovec purportedly delivers a or recombinant, porcine therapy functional copy of the gene encoding for coagulation recombinant) Treatment-related FDA designation(s): Factor VIII to correct deficient Factor VIII levels inherent adverse events Orphan Drug, Breakthrough Therapy in hemophilia A. In clinical trials, the agent is given as a single intravenous infusion at a dose of 1 × 413 to 1 × 613 Clinical trial(s): Phase III viral genomes per kilogram of body weight (vg/kg). primary completion Developer(s): December 2022; phase III primary completion BioMarin Pharmaceutical Inc (San Rafael, California) December 2022; phase I/II primary completion February 2022; phase I/II in patients with AAV5 antibodies primary completion June 2024
Section 2. Topics Added Since Last Status Report 190
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 4 years to Vamorolone (VBP15) is a dissociative steroid (ie, a Corticosteroids (eg, Ambulatory function, as FDA designation(s): younger than 7 years who steroid lacking gene transactivation activity) intended to deflazacort, prednisone) measured by accepted Orphan Drug, Fast Track have genetically confirmed treat DMD, an inherited, X chromosome–linked genetic clinical ratings or scales Duchenne muscular disorder caused by mutations or deletions in the (eg, 6-minute walk test, Clinical trial(s): Phase II dystrophy (DMD) dystrophin gene, DMD. DMD encodes the dystrophin North Star Ambulatory extension completed April protein, which helps keep muscle cells intact. The Assessment, time to 2018, data published absence of wild-type dystrophin protein causes run/walk/climb) August 2019; phase II progressive muscle fiber death and eventual widespread primary completion May muscle weakness. No cure exists for DMD, and while Muscle function, as 2020 FDA approved a dystrophin-replacement gene therapy for measured by the Time to patients who have a specific mutation in DMD (eg, in Stand Test exon 51), patients with other mutations do not qualify. First-line corticosteroid treatment (eg, deflazacort) decreases inflammation but does not prevent disease progression. Corticosteroids typically cause severe side effects such as hyperglycemia, muscle breakdown, and impaired hormone production. These side effects result from increased gene transactivation that is distinct from corticosteroids’ anti-inflammatory properties. Because dissociative steroids such as vamorolone purportedly lack gene transactivation activity while retaining anti- inflammatory function, they might have improved safety profiles versus typical corticosteroids. In clinical trials, patients receive vamorolone 2 or 6 mg/kg/day, orally, for up to 48 weeks. Developer(s): ReveraGen BioPharma Inc (Rockville, Maryland)
Section 2. Topics Added Since Last Status Report 191
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 7 to 13 years Viltolarsen (NS-065/NCNP-01) is a morpholino antisense Corticosteroids (eg, Ambulatory function, as Submission date: Rolling with Duchenne muscular oligonucleotide intended to treat DMD, an inherited, deflazacort, prednisone) measured by accepted New Drug Application dystrophy (DMD) who have a X chromosome–linked genetic disorder caused by clinical ratings and began December 2018, deletion in the DMD gene mutations or deletions in the dystrophin gene, DMD. DMD scales expected completion involving exon 53 and are on encodes the dystrophin protein, which helps keep muscle September 2019 a stable dose of cells intact. The absence of wild-type dystrophin protein Muscle strength corticosteroids causes progressive muscle fiber death and eventual FDA designation(s): 6-minute walk test Orphan Drug, Fast Track, widespread muscle weakness. No cure exists for DMD, distance and first-line corticosteroid treatment (eg, deflazacort) Rare Pediatric Disease manages symptoms but does not prevent disease Time to climb 4 stairs Clinical trial(s): Phase II progression and has significant side effects. FDA Time to run/walk 10 study completed April approved a gene therapy for patients who have a specific meters 2018, data reported mutation in DMD (eg, in exon 51), but patients who have October 2018; phase II other DMD mutations do not qualify. Therefore, additional Time to stand extension primary therapies are needed. Viltolarsen purportedly binds exon completion December 53 of dystrophin pre-mRNA (precursor RNA composed of 2020 introns and exons) and promotes skipping of exon 53 during mRNA processing, which allows for synthesis of an internally truncated but functional dystrophin protein. Therefore, viltolarsen treatment might promote skeletal muscle function and prevent or delay disease progression in patients who have mutations in DMD exon 53. In clinical trials, viltolarsen 40 or 80 mg/kg is given intravenously, once weekly, for up to 144 weeks. Developer(s): NS Pharma Inc (Paramus, New Jersey), a subsidiary of Nippon Shinyaku Co Ltd (Kyoto, Japan), in collaboration with the Cooperative International Neuromuscular Research Group (Washington, DC) and TRiNDS (Washington, DC)
Section 2. Topics Added Since Last Status Report 192
Section 3. Topics Archived Since Last Status Report: 7 Topics
Table 11. Cancer: 7 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures
Women aged 18 years or Axalimogene filolisbac (AXAL) is an immunotherapy External beam radiation Disease-free survival On June 27, 2019, the older who have locally comprising live, attenuated Listeria monocytogenes (Lm) therapy alone or with one developer announced advanced cervical cancer at bacteria engineered to express the E7 protein of human or more of the following: Overall survival discontinuation of its high risk of recurrence and papilloma virus type 16 (HPV 16), which has a crucial role Quality of life AIM2CERV phase III have completed adjuvant in cervical oncogenesis. The transforming protein E7 Antimetabolites (eg, 5- clinical trial, stating that the treatment with cisplatin and gene, E7, is cloned in a plasmid containing a truncated fluorouracil) recent FDA partial clinical radiation fragment of listeriolysin O gene, tLLO, that is introduced Platinum agents (eg, hold and the estimated into Lm, which will express and secrete the tLLO-E7 carboplatin, cisplatin) cost and time to fusion protein. Although E7 peptides presented on the complete AIM2CERV led surface of antigen-presenting cells stimulate CD4+ and company officials to CD8+ T cells, tLLO modulates cells involved in immune believe the best path suppression. According to the company, no forward would be to focus immunotherapy is available that has shown activity for on the company’s treating cervical cancer. AXAL is intended to reduce the neoantigen programs. risk for disease recurrence by promoting a cellular immune response against residual HPV 16–infected cervical cancer cells. In clinical trials, AXAL is given as an intravenous infusion at a dose of 1 × 109, 3.3 × 109, or 1 × 1010 colony-forming units every 3 weeks for 3 doses for the first 3 months and then every 8 weeks for a total of 5 doses or until disease recurrence. Developer(s): Advaxis Inc (Princeton, New Jersey)
Section 3. Topics Archived Since Last Status Report 193
Potential Patient Intervention Description Potential Comparators Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Dilanubicel (NLA101) is an allogeneic (unrelated donor) Growth factors (eg, Overall survival On July 4, 2019, the who have untreated de novo “off-the-shelf" cell therapy made up of pooled CD34+ filgrastim, granulocyte developer terminated its or secondary acute myeloid hematopoietic stem and progenitor cells (HSPCs) derived colony-stimulating factor) Progression-free survival phase II (LAUNCH) trial. Its leukemia (AML) and are from the cord blood of screened and tested healthy Quality of life development plan is under eligible for 2 or more lines of donors. Dilanubicel is intended to prevent opportunistic review. standard chemotherapy infections by providing temporary bone marrow function until blood and immune cell populations recover after chemotherapy. Unlike other hematopoietic-based cell therapies, dilanubicel might bypasses the need for a tissue-compatible donor. HSPCs are cultured in the presence of Delta1Ext-IgG, an engineered form of the Notch ligand Deltat1, to promote their division and maturation in culture. Dilanubicel can be manufactured ahead of time and cryopreserved until needed. In clinical trials, dilanubicel is given as a single intravenous infusion (unspecified dose) after the first chemotherapy cycle and up to 2 additional infusions after subsequent chemotherapy cycles. Developer(s): Nohla Therapeutics Inc (Seattle, Washington)
Section 3. Topics Archived Since Last Status Report 194
Potential Patient Intervention Description Potential Comparators Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older HSV-TK T-cell therapy (Zalmoxis) is a haploidentical (half Chemotherapy Chronic GVHD- On June 27, 2019, the who have acute match; parent, child, or sibling) stem cell therapy derived free/relapse-free survival developer suspended its lymphoblastic leukemia (ALL) from donor lymphocytes for graft-versus-leukemia Hematopoietic stem cell phase III TK008 trial when or acute myeloid leukemia treatment. Treatment is intended to provide antileukemia transplant Cumulative incidence of an unplanned interim acute or chronic GVHD (AML) that is in complete activity, promote early and sustained reconstitution of the Targeted therapy analysis revealed that the response (first, second, or immune system, and reduce transplant-related death in Cumulative incidence of treatment was ineffective subsequent), relapse (first or patients who achieved a compete response to therapy. relapse after treating 50% of second), or primary refractory Donor peripheral blood mononuclear cells are cultured planned patients. status with leukemic cells in the presence of cytokines to select Disease-free survival for T cells with reactivity against leukemic cells. Reactive Engraftment rate T cells are then transduced with a retrovirus vector containing the herpes simplex virus tyrosine kinase gene, Immune reconstitution HSV-TK, and a truncated rat low-affinity receptor for the Incidence and duration of nerve growth factor gene, Lngfr, for selection. HSV-TK infections expression in T cells acts as a suicide gene to prevent the cell therapy from causing graft-versus-host disease Overall survival (GVHD). HSV-TK phosphorylates the prodrug ganciclovir into its active form, which will kill cells expressing HSV-TK Quality of life only. In clinical trials, HSV-TK T-cell therapy is given as an intravenous infusion between days 21 and 49 after haploidentical hematopoietic stem cell transplant. At the first sign of symptoms suggestive of GVHD, patients are treated with ganciclovir to prevent GVHD from developing. Developer(s): MolMed SpA (Milan, Italy)
Section 3. Topics Archived Since Last Status Report 195
Potential Patient Intervention Description Potential Comparators Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Lefitolimod (MGN1703) is a DNA molecule developed to One or more of the Overall survival In August 2019, Mologen who have metastatic act as an agonist of Toll-like receptor 9 (TLR9), a following: announced that colorectal cancer that has component of the innate immune system. Lefitolimod Progression-free survival lefitolimod failed to meet its Angiogenesis inhibitors responded to first-line offers a novel mechanism intended to induce immune Quality of life primary endpoint of overall chemotherapy responses against cancer cells and improve patient (eg, bevacizumab, survival in the pivotal health outcomes. Activating TLR9 signaling promotes ramucirumab) phase III trial immune system activation, possibly through dendritic cell Antimetabolites (eg, 5- (NCT02077868). The maturation or differentiation of B cells into antibody- fluorouracil, developer continues secreting plasma cells, or both. Immune-response capecitabine) to analyze data from the activation by lefitolimod is intended to overcome immune phase III trial to develop tolerance to tumor-associated antigens, potentially EGFR antibodies (eg, future combinations for this leading to an anticancer immune response. Lefitolimod cetuximab, patient population. purportedly prevents or delays disease recurrence by panitumumab) stimulating cancer-specific immune responses in the FOLFIRI (ie, leucovorin, maintenance setting. In clinical trials, lefitolimod solution 5-fluorouracil, irinotecan) has been given as a 60-mg subcutaneous injection twice weekly until disease progression or intolerable toxicity. FOLFOX (ie, leucovorin, 5-fluorouracil, oxaliplatin) Developer(s): Multikinase inhibitors Mologen AG (Berlin, Germany) (eg, regorafenib) Platinum agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival A similar drug who have extensive-stage targets the programmed death-1 (PD-1) co-inhibitory following: (atezolizumab) in the same small cell lung cancer (SCLC) receptor expressed by activated T cells. Front-line Progression-free survival class has been approved Platinum-based agents that has progressed after 2 or therapy for SCLC relies on platinum-based Quality of life for this patient population more lines of systemic chemotherapy, but because response rates are low (eg, carboplatin, in the first-line setting. chemotherapy and disease becomes resistant to subsequent lines cisplatin) Therefore, the subsequent of treatment, pembrolizumab might improve health Topoisomerase inhibitors approval of pembrolizumab outcomes, change patient management, and increase (eg, etoposide, for later-line therapy would treatment-related costs. A hallmark of cancer is its ability topotecan) no longer be considered to evade an immune response. Several types of cancer disruptive. cells, including SCLC, activate an immune checkpoint pathway in T cells by overexpressing the programmed death-ligand 1 (PD-L1), which binds to PD-1 and limits the activation cancer-specific T cells. Pembrolizumab purportedly prevents the interaction between PD-1 and PD-L1 in an effort to overcome the immune tolerance of SCLC by enhancing cancer-specific T-cell responses. In clinical trials, pembrolizumab is given as an intravenous infusion at a dose of 200 mg, once every 3 weeks for up to 24 months, in combination with etoposide (100 mg/m2) plus carboplatin (AUC 5) or cisplatin (75 mg/m2). Developer(s): Merck & Co Inc (Kenilworth, New Jersey)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival In May 2019, Merck who have stage IV targets the PD-1 co-inhibitory receptor expressed by following: announced that its phase or M1 metastatic triple- activated T cells. Because TNBC is not amenable to Progression-free survival III KEYNOTE-119 did not Alkylating agents (eg, negative breast cancer endocrine therapy or targeted therapies, pembrolizumab Quality of life meet its primary endpoint (TNBC) that has progressed might improve health outcomes, change patient cyclophosphamide) of superior overall survival after 1 or 2 lines of systemic management, and increase treatment-related costs. A Anthracyclines (eg, compared with chemotherapy hallmark of cancer is its ability to evade an immune doxorubicin) chemotherapy (ie, response. Several types of cancer cells, including TNBC, capecitabine, eribulin, activate an immune checkpoint pathway in T cells by Antimetabolites (eg, gemcitabine, or overexpressing the PD-L1, which binds to PD-1 to limit fluorouracil, gemcitabine, vinorelbine). In addition, a the activation of cancer-specific T cells. Pembrolizumab pemetrexed) similar drug (atezolizumab) purportedly prevents the interaction between PD-1 and Poly adenosine in the same class has been PD-L1 in an effort to overcome the immune tolerance of diphosphate-ribose approved for this patient TNBC by enhancing cancer-specific T-cell responses. In polymerase inhibitors population in the first-line clinical trials, pembrolizumab is given as an intravenous (eg, olaparib) setting. Therefore, the infusion at a dose of 200 mg, once every 3 weeks, until subsequent approval of disease progression or intolerable toxicity. Taxanes (eg, docetaxel, pembrolizumab for later- nab-paclitaxel, paclitaxel) line therapy would no Developer(s): longer be considered Vinca alkaloid (eg, disruptive. Merck & Co Inc (Kenilworth, New Jersey) vinorelbine)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Outcome Measures
Adults aged 18 years or older Pexastimogene devacirepvec (Pexa-Vec) is a Wyeth Systemic therapy with Overall survival On August 2, 2019, the who have advanced strain of vaccinia virus that has had its viral thymidine one or more of the developers announced that hepatocellular carcinoma kinase gene, TK, disrupted to selectively infect and following: Progression-free survival they had terminated their (HCC) and have received no replicate in tumor cells, which commonly express high TK Quality of life phase III PHOCUS trial systemic therapy levels. HCC has historically responded poorly to systemic Anthracyclines (eg, after an analysis by an therapies, and patients with advanced disease had very doxorubicin) independent data poor prognoses until the approvals of sorafenib (2007) Antimetabolites (eg, 5- monitoring committee and lenvatinib (2018) showed some improvement in fluorouracil, gemcitabine) showed that the trial was survival. Pexa-Vec is intended to have a synergistic effect unlikely to meet its primary with sorafenib to eliminate HCC cells and further improve Multikinase inhibitors endpoint of overall survival. outcomes. Pexa-Vec has also been engineered to (eg, cabozantinib, express human granulocyte-macrophage colony- lenvatinib, regorafenib, stimulating factor (GM-CSF) and β-galactosidase. sorafenib) Although GM-CSF induces an antitumor immune Platinum agents (eg, response and disrupts the tumor’s vascularization, cisplatin, oxaliplatin) presentation of β-galactosidase peptides stimulates T-cell responses. Pexa-Vec purportedly targets and destroys cells in liver tumors and tumor-associated blood vessels, and activates tumor-specific immune responses. In clinical trials, Pexa-Vec is given as 3 biweekly intratumoral injections at a dose of 1 × 109 plaque-forming units on day 1 and weeks 2 and 4. At week 6 after the first dose of Pexa-Vec, sorafenib treatment begins at a dose of 400 mg, twice daily. Developer(s): SillaJen Inc (Busan, South Korea) Green Cross Corp (Yongin, South Korea), regional partner Transgene SA (Strasbourg, France), regional partner Lee’s Pharmaceutical Holdings Ltd (Sha Tin, Hong Kong), regional partner
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Section 4. Potentially Disruptive Trends: 13 Trends
Table 12. Potentially Disruptive Trends: 13 Trends
Title Description Threats Opportunities
Artificial intelligence (AI) In this application of AI, a software program analyzes magnetic resonance Might lead, due to algorithmic Might help detect cancer at analysis of imaging imaging, computed tomography (CT), or ultrasound scans from patients detection errors, to false-negative earlier stages, thereby enabling scans to screen for or suspected of having cancer and generates a probability-of-malignancy or false-positive reports that could earlier treatment and potentially confirm a diagnosis of score. A standard risk score that could be used, for example, is the Breast have health and/or legal improving patient health cancer Imaging Reporting and Data System. The machine learning AI software (eg, implications outcomes convolutional neural networks) is used with conventional picture archiving and communications systems to learn the features of malignancy and point Might lead to overdiagnosis (ie, a Might reduce human error rates out problematic areas in images. This AI software is intended to improve true-positive diagnosis with little or in cancer detection and diagnosis radiologists’ ability to detect abnormal lumps and nodules and to help no health consequences that could determine whether they are dangerous. It does this by scanning all lead to unnecessary treatment or dimension slices at once, homing in on regions of interest, and providing a undue negative psychological cancer risk score. impact on the patient) Might be viewed by some radiologists as a threat to their autonomy as clinicians
Artificial intelligence (AI) Several researchers and companies have developed multiple AI software Might be limited to larger imaging Might improve patient health for image triage to algorithms to screen imaging scans in high volumes in hospital emergency centers with more resources outcomes if most acute cases prioritize emergency departments or other urgent care settings. The intent is to identify the most because of cost and complexity receive appropriate care sooner cases serious cases that might not be apparent based on traditionally recognized parameters or markers and suggest giving them priority review by a Might be difficult to operationalize Might improve workflow to radiologist. The AI algorithm pushes these cases to the front of the work or maintain because many prioritize higher-urgency cases queue based on identified markers learned by reviewing a multitude of software systems need to work when radiologist availability is images. Over time, some algorithms purportedly become more accurate at together limited screening as they review more images. Some products have already Might pose litigation risk for Might add a layer of protection received FDA 510(k) clearance for specific indications using conventional providers who are unable to against potential litigation for x-rays, CT, and ultrasound, including identification of probable fractures in implement these systems “missed” events or cases in the cervical spine, intracranial hemorrhage, abdominal aortic tears, and imaging brain aneurysms. Might be viewed by some radiologists as a threat to their autonomy as clinicians
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Title Description Threats Opportunities
Artificial intelligence (AI) Recent reports show potential for AI and machine learning to detect or Might lead, due to algorithmic Might enable more objective, and machine learning diagnose mental and behavioral health conditions, including depression, detection errors, to inaccurate biologically grounded diagnoses for biologically based posttraumatic stress disorder (PTSD), schizophrenia, and bipolar disorder. diagnoses that could have health of some mental and behavioral diagnosis of mental and Data analysis techniques and machine learning algorithms can be used to and/or legal implications health conditions compared with behavioral health match specific brain patterns, behavior, and genetic factors, allowing for traditional methods of diagnosis conditions biologically based, individualized prediction and diagnosis of mental and Might be more costly in the short behavioral health disorders. term than traditional methods of Might reduce the stigma diagnosis associated with mental illness by supporting a biological basis for Might be viewed by some some mental and behavioral clinicians and therapists as a health conditions threat to their autonomy Might lead to earlier treatment Might reduce or eliminate the trial-and-error nature of current methods of diagnosis Might be more cost effective in the long term than traditional methods of diagnosis
Artificial intelligence Digital voice assistants, or conversational agents, have grown into widely Might lead, due to inaccurate Might improve patient access to (AI)–based voice used AI software programs designed to respond to natural language and natural language processing, to care by providing convenient, 24- assistants for patient- simulate human conversation. These assistants are being positioned to providing patients with incorrect hour medical advice oriented health care provide patient health care support (eg, LifePod, Nuance, Aiva Health). medical advice, thereby causing applications AI-powered virtual assistants can provide 24-hour support to a wide range subsequent adverse events Might improve patient health of patients who might need access to home care on demand. For example, outcomes and reduce burden for LifePod is designed to help people follow a care plan developed by their Might pose threats to patient health care providers health data privacy provider or to contact a caregiver. Another patient voice assistant, Aiva, Might decrease costs of care by purportedly reduces response time needed to connect with the caregiving reducing doctor’s office visits team by triaging patient requests to the most appropriate caregiver.
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Title Description Threats Opportunities
Bacteriophages to treat Bacteriophages are viruses that infect only bacterial cells and might help Might add significant short-term Might lead to decreased patient bacterial infections treat bacterial infections. They were discovered more than a century ago but costs to infection treatment morbidity and mortality were not pursued as a treatment in the United States because of safety concerns and the increased availability of antibiotics. However, with Might pose a health risk for Might add to the body of scientific increasing rates of antibiotic resistance and better understanding of patients, because much is still to knowledge surrounding infection bacteriophage biology, researchers are now considering using be learned about bacteriophage and its treatment biology bacteriophages to treat infections that are multidrug-resistant or Might reduce long-term treatment characteristically hard to treat with antibiotics. Bacteriophages are in clinical Might eventually lead to costs by reducing the time trials to treat primary immune deficiency disease, hyper-IgM syndrome, bacteriophage resistance similar to patients spend in intensive care urinary tract infections, gastrointestinal tract infections, diabetic foot ulcers, antibiotic resistance units leg ulcers, wound infections, Pseudomonas aeruginosa infections, and Staphylococcus aureus infections. The Center for Innovative Phase Applications and Therapeutics (IPATH) in La Jolla, California, treats patients who have life-threatening multidrug-resistant infections with bacteriophages on a case-by-case basis through FDA’s Compassionate Use program. IPATH intends to conduct phase I/II trials for chronic infections in cystic fibrosis and infections associated with implantable hardware such as pacemakers and prosthetic joints.
Comprehensive CGP involves sequencing a panel of cancer-associated genes in DNA Might lead to overtreatment of Might improve health outcomes genomic profiling (CGP) and/or RNA isolated from a patient’s tumor or blood sample. CGP is some early-stage cancers that for patients who have limited in patients who have intended to detect actionable genomic alterations (AGAs) known to be could resolve on their own targeted therapy options cancer to identify therapeutic targets. Clinicians might use CGP to select an FDA-approved personalized targeted targeted therapy (on-label or off-label) that is most likely to benefit a patient Might have limited availability of Might strengthen collaborations therapy who has advanced cancer that harbors AGAs. CGP might also be used to coverage because third-party between genetic counselors and help enroll patients in clinical trials of investigational therapies against payers are likely to cover CGP and clinicians, promoting familiarity cancer that carries specific AGAs. targeted therapies for only specific with AGAs and identifying those indications and are unlikely to that might be drug targets cover targeted therapies for unapproved indications Might increase disparities by limiting availability to patients who are insured or able to pay for treatment out of pocket
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Title Description Threats Opportunities
Direct-to-consumer DTC genetic testing manufacturers such as 23andMe have started to Might pose significant threats to Might provide insight into the best (DTC) genetic testing examine and use their troves of patient-derived genetic data and patient health data privacy targets to pursue for drug partnerships with volunteered genetic-testing questionnaire data to drive drug development development pharmaceutical and treatment. By partnering with pharmaceutical companies, DTC genetic Might lead to a competitive companies to facilitate testing companies might provide insight into the best disease targets for disadvantage for drug developers Might enable effective and less drug development and drug companies to pursue. The databases also make it easier to identify who choose not to partner with expensive identification of treatment people who are diseased, asymptomatic, or carriers for the condition of DTC genetic testing companies patients and asymptomatic interest and enroll them in trials cost effectively. carriers for clinical trials Might lead to a more efficient drug development process for personalized medicines
Gene editing to treat or Various clinical trials using gene editing technology are underway. These Might pose significant health risks Might improve quality of life for prevent disease technologies hold great promise for treating and/or preventing several to patients because much is still patients diseases and conditions. For example, CRISPR (clustered regularly unknown about potential adverse interspaced short palindromic repeats) is a dynamic, versatile tool that can events related to gene editing Might reduce overall treatment be programmed to target specific stretches of genetic code and edit DNA at costs for patients and the health precise locations in the human genome. The technology allows researchers Might pose significant ethical and care system by providing a one- to permanently modify genes and has the potential to create therapies with societal threats (eg, unethical time, curative treatment option alteration of human embryos) a durable treatment effect. Might reduce societal burden and health care costs by preventing and/or eliminating certain genetic disorders
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Title Description Threats Opportunities
N-of-1 trials to research N-of-1 trials focus on collecting treatment-response data in a single patient Might predispose patients to being Might provide insight into the best patient-centered and might represent the optimal form of clinical evaluation for patient- treated unethically by use of precision medicines, outcomes centered medicine. Researchers design a mini-investigation for an manufacturers of poorly developed thereby improving health experimental drug’s safety and efficacy entirely around an individual investigational agents with small outcomes patient’s response, to determine whether a particular treatment works for budgets that individual. A patient might alternate between drug and placebo for a Might make patient-centered couple of weeks at a time, and researchers record the outcomes. These trial Might be viewed as a threat by comparative data more results can then be used to guide specific treatment for a patient or be some stakeholders who benefit accessible to patients and pooled with other N-of-1 trials of the same drug and same experimental from large, population-based, physicians design to obtain population-level trends. An advantage of data from N-of-1 randomized controlled trials and trials is that they can reveal how responses to treatments might vary among current data aggregation systems and within patients. N-of-1 trials are best used to evaluate treatments for chronic, slowly progressing, or frequently recurring or relapsing diseases. The ideal treatments for N-of-1 trials might display characteristics such as substantial individual differences in treatment effects, uncertainty regarding the best treatment regimen, rapid onset of drug action, or brief and safe washout periods. N-of-1 trial outcomes should be validated, repeatable measures and might include the use of biomarkers.
Proteomic profiling to Proteomic profiling involves the systematic separation, identification, and Might add to clinician burden by Might improve patient health diagnose cancer and characterization of proteins present in a patient’s tumor or blood sample. In requiring them to learn about outcomes by detecting cancer guide personalized patients suspected of having cancer, clinicians use proteomic profiling to protein signatures for different early and matching patients with targeted therapy identify a cancer-associated protein signature that might confirm the cancer types and understand targeted therapies or clinical trials presence and origin of a specific cancer type. For these patients, proteomic which could be drug targets likely to benefit them profiling helps identify overexpressed proteins that are known to be therapeutic targets, such as those caused by chromosomal Might increase disparities by rearrangements. Clinicians then use this information to select an limiting availability to patients who FDA-approved targeted therapy (on-label or off-label) that is most likely are insured or able to pay for to benefit a patient with cancer or to help enroll patients in clinical trials treatment out of pocket of investigational therapies.
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Title Description Threats Opportunities
Psychedelic drugs to Psychedelic drugs (eg, psilocybin, lysergic acid diethylamide [LSD], N,N- Might face ethical, societal, Might improve patient health treat mental and dimethyltryptamine [DMT]) alter one’s state of consciousness, purportedly political, and legal hurdles to outcomes and quality of life behavioral health by altering certain neurotransmitters in the brain, providing the user with adoption because of legal issues conditions altered perception, increased introspection, feelings of closeness with and considerable controversy Might reduce prevalence of others, and positive mood states. These experiences are often reported as surrounding the use of treatment-resistant mental and deeply profound and life-altering. Although most psychedelics are psychedelics and drugs that have behavioral health conditions designated as Schedule I drugs in the United States, researchers are been used illicitly Might reduce costs related to investigating their potential to treat a variety of mental and behavioral health combat-related PTSD disorders that have not responded to conventional treatments. Psilocybin is being investigated to treat cancer-related psychological distress and Might encourage continued resistant depression. LSD is being explored to treat anxiety associated with research into potential benefits of life-threatening illness. DMT, a drug present in ayahuasca, is being psychedelic drugs to treat mental researched as a treatment for depression. Most of these psychedelics are and behavioral health and other intended for neither frequent nor long-term use, and therapeutic effects can conditions be seen with as few as 2 to 3 treatments (eg, MDMA-assisted psychotherapy for PTSD). Ketamine, while not strictly a psychedelic drug, has some psychedelic properties and is used off-label to treat PTSD. A closely related molecule, esketamine (Spravato), has been approved to treat depression. 3,4-Methylenedioxymethamphetamine (MDMA) is in phase III clinical trials for use during psychotherapy to treat PTSD and is being investigated as therapy for social anxiety in adults with autism.
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Title Description Threats Opportunities
Tissue of origin– Oncology drugs have traditionally been approved by FDA for cancers of a Might increase costs by requiring Might enable earlier access to agnostic, molecularly specific tissue of origin or pathologic subtype (ie, specific blood cancer). more widespread testing of tumors molecularly defined therapies by targeted oncology With the identification of genetic changes that drive the pathogenesis of to identify an ever-increasing providing a pathway to FDA drugs cancers arising from multiple tissues of origin, investigators began defining number of potential molecular approval in instances of rare patient populations in terms of their molecular subtype irrespective of tissue targets tissue/molecular driver of origin. Initially, these so-called basket trials or umbrella trials would combinations that might not be observe a signal of efficacy for a molecularly targeted drug in a cancer of a Might lead to poor outcomes by amenable to traditional clinical given tissue of origin, which would be followed by expansion of that cohort overlooking varied responses to trial designs and FDA approval or creation of a tissue-of-origin-specific trial, with the intent that the drug be molecularly targeted therapies pathways FDA approved for that tissue of origin (eg, ALK inhibitors for non–small cell across different tumor types lung cancer, BRAF inhibitors for melanoma or Erdheim Chester disease). More recently, FDA approved 3 drugs for use in molecularly defined patient populations irrespective of the cancer’s tissue of origin. Pembrolizumab (Keytruda) was approved to treat adult and pediatric patients with unresectable or metastatic, microsatellite instability-high or mismatch repair deficient solid tumors. Larotrectinib and entrectinib were approved to treat solid tumors that have a neurotrophic tyrosine receptor kinase gene fusion without a known acquired resistance mutation. This change in approach raises issues regarding the regulatory pathway as well as potential issues with the varied responses to molecularly targeted therapies across different cancer types, particularly for rare cancers or cancers in which the molecular target rarely occurs.
Wearable smart Autism spectrum disorder is a developmental disorder defined by deficits in Might pose threats to patient Might provide a devices to provide social interaction and communication, including difficulty understanding health data privacy nonpharmacological treatment social support for emotions and regulating behavior. Several wearable smart devices intended option for some patients patients who have to improve social deficits in autism are in development, such as a wrist-worn Might increase disparities by autism spectrum biosensor to predict aggression and glasses equipped with facial limiting availability to those who Might incentivize positive disorder recognition that deliver real-time social cues to improve socialization. can afford to pay for these behaviors that will improve health expensive devices outcomes Might reduce caregiver burden and long-term costs of care Might increase patient independence
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