PCORI Health Care Horizon Scanning System Horizon Scanning Status Report Volume 2, Issue 1 March 2020
Prepared for: Patient-Centered Outcomes Research Institute 1828 L St., NW, Suite 900 Washington, DC 20036
Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12
Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462
Investigators: Randy Hulshizer, MA, MS Damian Carlson, MS Christian Cuevas, PhD Andrea Druga, PA-C Marcus Lynch, PhD Misha Mehta, MS Brian Wilkinson, MA Donna Beales, MLIS Jennifer De Lurio, MS Eloise DeHaan, BS Eileen Erinoff, MSLIS Maria Middleton, MPH Diane Robertson, BA Kelley Tipton, MPH Rosemary Walker, MLIS Karen Schoelles, MD, SM Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI.
An intervention that potentially meets inclusion criteria might not appear in this report simply because the Horizon Scanning System has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions.
A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the Horizon Scanning System. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions.
Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflict with the material presented in this report.
Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated.
All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of PCORI or its Board of Governors. This publication was developed through a contract to support PCORI’s work. Questions or comments may be sent to PCORI at [email protected] or by mail to Suite 900, 1828 L Street, NW, Washington, DC 20036. ©2020 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org.
Suggested citation: Hulshizer R, Carlson D, Cuevas C, et al. PCORI Health Care Horizon Scanning System: 2020 Horizon Scanning Status Report: Volume 2, Issue 1. Washington, DC: Patient-Centered Outcomes Research Institute; March 2020. Prepared by ECRI Institute under Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12.
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Preface
The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning of new and emerging health care technologies and innovations with high potential for disruption to the current standard of care to better inform patient-centered outcomes research investments at PCORI. The HCHSS provides PCORI with a systematic process to identify and monitor technologies and innovations in health care that are in PCORI’s priority areas of interest and to create an inventory of interventions that have the highest potential for disruption to the current standard of care in terms of patient outcomes, health disparities, care delivery, infrastructure, access, and/or costs. It is also a tool for the public to identify information on selected new health care technologies and interventions. Any investigator or funder of research can use the PCORI HCHSS to help select research topics. The health care technologies and innovations of interest for horizon scanning are those that have yet to become part of established health care practices. These interventions are in late stages of research and development or very early phases of adoption, except in the case of new applications of already-diffused technologies. Consistent with the definitions of health care interventions provided by the National Academy of Medicine and the Federal Coordinating Council for Comparative Effectiveness Research, PCORI is interested—at present—primarily in innovations in drugs and biologics, medical devices, and procedures within its selected priority areas of interest for horizon scanning. PCORI may choose, upon future consideration, to expand its focus to include a wider range of interventions (eg, systems innovations). Horizon scanning involves 2 processes. The first is identifying and monitoring new and evolving health care interventions that purportedly hold potential to diagnose, treat, or otherwise manage a disease or condition or to improve care delivery. The second is analyzing the relevant health care context in which these new and evolving interventions would exist to understand their potential for disruption to the standard of care. The goal of the PCORI HCHSS is not to predict future utilization and costs of any health care intervention; rather, the reports are intended to help inform and guide planning and prioritization of research resources. This edition of the Status Report is the first of 4 volumes planned for 2020 and lists topics (ie, interventions intended for a specific use within a specific patient population) that have been identified and are being monitored. Content in this report is current as of March 13, 2020. The reader should be aware that, although forward-looking statements were accurate as of this currency date, no warranty is provided regarding the accuracy of these statements at the time of publication. We welcome comments on this report. Send comments by mail to William Lawrence, MD, MS, Patient-Centered Outcomes Research Institute, 1828 L St., NW, Suite 900, Washington, DC 20036, or by email to [email protected].
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Table of Contents
Introduction ...... 1 Section 1. Alzheimer’s Disease and Other Dementias: 10 Topics ...... 5 Table 1.1. Alzheimer’s Disease and Other Dementias Topics Added Since Last Status Report: 2 Topics ...... 5 Table 1.2. Currently Monitored Alzheimer’s Disease and Other Dementias Topics: 8 Topics...... 6 Section 2. Cancer: 84 Topics ...... 10 Table 2.1. Cancer Topics Added Since Last Status Report: 10 Topics ...... 10 Table 2.2. Currently Monitored Cancer Topics: 70 Topics ...... 18 Table 2.3. Cancer Topics Archived Since Last Status Report: 4 Topics ...... 73 Section 3. Cardiovascular Disease: 28 Topics ...... 76 Table 3.1. Cardiovascular Disease Topics Added Since Last Status Report: 5 Topics ...... 76 Table 3.2. Currently Monitored Cardiovascular Disease Topics: 22 Topics ...... 81 Table 3.3. Topics Archived Since Last Status Report: 1 Topic ...... 98 Section 4. Mental and Behavioral Health: 18 Topics ...... 99 Table 4.1. Mental and Behavioral Health Topics Added Since Last Status Report: 3 Topics ...... 99 Table 4.2. Currently Monitored Mental and Behavioral Health Topics: 14 Topics ...... 102 Table 4.3. Mental and Behavioral Health Topics Archived Since Last Status Report: 1 Topic ...... 114 Section 5. Rare Diseases: 107 Topics ...... 115 Table 5.1. Rare Disease Topics Added Since Last Status Report: 14 Topics ...... 115 Table 5.2. Currently Monitored Rare Disease Topics: 89 Topics ...... 127 Table 5.3. Rare Disease Topics Archived Since Last Status Report: 4 Topics ...... 208 Section 6. Potentially Disruptive Trends: 28 Trends ...... 212 Table 6.1. Trends Added Since Last Status Report: 6 Trends ...... 212 Table 6.2. Currently Monitored Trends: 22 Trends ...... 216 Appendix. Abbreviations and Acronyms ...... 230
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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 and trends currently monitored in the system and, if applicable, topics and trends archived since the last Status Report. This Status Report is organized into 6 sections—1 for each of the 5 initial PCORI-defined priority areas and 1 section for potentially disruptive trends—titled as follows: (1) Alzheimer’s Disease and Other Dementias, (2) Cancer, (3) Cardiovascular Diseases, (4) Mental and Behavioral Health, (5) Rare Diseases, and (6) Potentially Disruptive Trends. An appendix contains abbreviations and acronyms used throughout the report. The reader should note that PCORI may choose, upon future consideration, to modify or expand its list of priority areas. In addition, the PCORI HCHSS identifies and monitors disruptive trends (ie, large, high-level disruptions) occurring across or within clinical areas from a combination of factors that, taken together, create a paradigm shift in health care. Identification of these trends is not limited to PCORI’s initially defined priority areas. Each of the 6 sections contains 2 to 3 tables, depending on the topics or trends contained in that section: (1) topics or trends added since the last Status Report, (2) currently monitored topics or trends, and (3) topics or trends archived since the last Status Report. If no topics or trends fall into a given category (ie, added, monitored, archived), no table will be included for that category in that section. For Sections 1 through 5 (priority areas), tables for newly added and currently monitored topics summarize information in each row, as shown in the following columns: Potential Patient Population; Intervention Description (including names and locations of developers/manufacturers); Potential Comparators; Patient-oriented Outcome Measures (limited to those reported in clinical trials); and Regulatory Information. Information in the first 4 columns is collectively referred to as PICO (ie, patient population, intervention, comparators, and outcomes) information. In the tables of archived topics, the Regulatory Information column is replaced with a Reason for Archive column. Within each table, topics are sorted alphabetically by intervention name (ie, the second column, intervention description). Potentially disruptive trends are summarized in Section 6. Tables for newly added and currently monitored trends summarize information in each row, as shown in the following columns: Title, Description, Threats, and Opportunities. Trends are sorted alphabetically by title.
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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 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 or trend 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 include at least one patient or patient representative and provide varied perspectives and/or areas of knowledge in health care. 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; (3) the development timeline for an intervention has changed, making it unlikely that it will become clinically available within 3 years; or (4) 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 3300 leads has led to the identification of about 500 potential topics across the 5 PCORI priority areas and 80 high-level trends occurring in all areas of health care. After subjecting the potential topics to our inclusion criteria and nomination process, 247 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, 28 trends have been selected and are being actively monitored in the system. These 247 topics and 28 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 table in each priority area’s section. As topics
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advance in development, their names often change from a research name to a generic name to the brand-name product. The 247 topics included in this report represent 135 diseases/conditions and span the PCORI-defined priority areas as follows (also see Figure 1): • Alzheimer’s disease and other dementias: 10 topics (4%) • Cancer: 84 topics (34%) • Cardiovascular diseases: 28 topics (11%) • Mental and behavioral health: 18 topics (7%) • Rare diseases: 107 topics (43%) Note: Total does not equal 100% because of rounding.
Figure 1. Percentage of Topics by Priority Area
Across all priority areas, topics in this report represent the following therapeutic classes (also see Figure 2): • Cell therapy: 21 topics (9%) • Device (nonimplantable): 12 topics (5%) • Gene therapy: 21 topics (9%) • Immunotherapy: 3 topics (1%) • Implant: 8 topics (3%) • Monoclonal antibody: 9 topics (4%) • Other biotechnology: 19 topics (8%) • Pharmaceutical: 143 topics (58%) • Procedure (nonsurgical): 1 topic (0.4%) • Procedure (surgical): 1 topic (0.4%) • RNA interference: 3 topics (1%) • Viral vector therapy: 6 topics (2%) Note: Total does not equal 100% because of rounding.
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Figure 2. Percentage of Topics by Therapeutic Class
Trends are presented in alphabetical order according to title. Titles and descriptions of trends will change over time as new information becomes available. Among the 28 trends presented in this report, 4 themes have emerged (also see Figure 3): • Artificial intelligence and machine learning: 10 trends (36%) • Health information technology, apps, and smart devices: 4 trends (14%) • Innovative treatment models: 7 trends (25%) • Proteomics, genomics, and personalized medicine: 7 trends (25%)
Figure 3. Percentage of Trends by Theme
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Section 1. Alzheimer’s Disease and Other Dementias: 10 Topics
Table 1.1. Alzheimer’s Disease and Other Dementias Topics Added Since Last Status Report: 2 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 50 to 85 CT1812 (Elayta) is a small-molecule antagonist of the Cholinesterase inhibitors Cognitive performance FDA designation(s): Fast years who have mild to progesterone receptor member component 1 (PGRMC1) that is (eg, donepezil, Progression of AD Track moderate Alzheimer’s intended to slow the progression of AD. No such treatments are galantamine, Quality of life Clinical trial(s): Phase II disease (AD) available, and current treatments address only symptoms. rivastigmine) primary completion June PGRMC1 is a cell-surface protein expressed in brain synapses Memantine (off label) 2020 that acts as a receptor for oligomeric amyloid beta (Aβ) and purportedly contributes to Aβ-mediated neurotoxicity. CT1812 purportedly competes with Aβ binding to PGRMC1, potentially preventing the neurotoxicity induced by synaptic binding of Aβ in the brain. In clinical trials, patients were given CT1812 orally, at a dose of 100 or 300 mg, once daily. Developer(s): Cognition Therapeutics, Inc (Pittsburgh, Pennsylvania)
Adults aged 50 to 90 Pimavanserin (Nuplazid) is a selective serotonin inverse agonist Supportive care Psychosis symptom Submission date: years who have that is intended to treat dementia-related psychosis. No severity Supplemental New Drug dementia-related medications are FDA approved for dementia-related psychosis. Frequency of Application submission psychosis Pimavanserin is intended to improve patient health outcomes hospitalizations planned for 2020 and quality of life by reducing hallucinations and delusions, Quality of life FDA designation(s): which are experienced by about 30% of dementia patients. Breakthrough Therapy Pimavanserin purportedly preferentially inhibits the activity of Clinical trial(s): Phase III serotonin 2A (5-HT2A) receptor that is associated with dementia- HARMONY completed related psychosis. The exact mechanism of action is unknown. October 2019, pivotal In a clinical trial, pimavanserin was given orally at a dose of 20 data presented or 34 mg, once daily, and patients were followed for up to 26 December 2019 weeks or until a relapse of psychosis occurred. Note(s): Pimavanserin Developer(s): was FDA approved to Acadia Pharmaceuticals, Inc (San Diego, California) treat hallucinations and delusions associated with Parkinson’s disease psychosis in April 2016
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Table 1.1. Currently Monitored Alzheimer’s Disease and Other Dementias Topics: 8 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 50 to 85 Aducanumab (BIIB037) is a recombinant human monoclonal Cholinesterase inhibitors AD progression Clinical trial(s): Phase IIIb years who have antibody against amyloid beta (Aβ) intended as a disease- (eg, donepezil, Overall survival 221AD304 primary prodromal to mild modifying therapy for AD. According to the manufacturer, galantamine, Quality of life completion September Alzheimer’s disease (AD) aducanumab preferentially binds neurotoxic oligomeric forms rivastigmine) 2023; phase III EMERGE of Aβ, inhibits new Aβ aggregation, and promotes the Supportive care terminated August 2019, disaggregation of existing Aβ aggregates, including plaques. In topline data presented clinical trials, aducanumab was administered intravenously, at 1 December 2019; phase III of 2 unspecified doses. ENGAGE primary Developer(s): terminated August 2019, Biogen (Cambridge, Massachusetts), in collaboration with topline results presented Neurimmune AG (Schlieren-Zurich, Switzerland) and Eisai Global December 2019 (Tokyo, Japan) Note(s): This topic had been archived in the June 2019 Status Report because aducanumab’s developers had announced discontinuation of their phase III clinical trials of the drug, stating that it was unlikely to meet its primary endpoints. However, in December 2019, Biogen announced that aducanumab had met its primary goal in the subset of patients receiving a high dose of aducanumab and that the company would continue to seek FDA approval for the drug.
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 55 to 85 AGB101 is a proprietary, low-dose, extended-release formulation Supportive care Cognitive performance, Clinical trial(s): Phase III years who have mild of the antiepileptic drug levetiracetam intended to treat mild as measured by AD- HOPE4MCI primary Alzheimer’s disease (AD) cognitive impairment (MCI) due to AD. AGB101 could be the first specific clinical ratings completion November disease-modifying treatment that slows the progression and and scales 2021 delays the onset of Alzheimer’s dementia, leading to improved AD progression cognitive 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 is given orally, at a dose of 220 mg, once daily, for 78 weeks. Developer(s): AgeneBio, Inc (Baltimore, Maryland)
Adults aged 55 to 91 Brexpiprazole (Rexulti) is an atypical antipsychotic medication Antianxiety drugs Agitation, as measured Clinical trial(s): Phase III years who have that purportedly reduces agitation in patients with AD by Antidepressants by accepted clinical primary completion Alzheimer’s disease (AD)– modulating serotonin-dopamine activity in the brain. Although Antipsychotics (eg, ratings and scales November 2020; phase III associated agitation antipsychotics are sometimes used off label to treat this haloperidol) Quality of life extension primary condition, they carry an increased risk of death in patients with completion August 2021 Atypical antipsychotics dementia. Brexpiprazole might have a better safety profile than (eg, aripiprazole) Note(s): Brexpiprazole is other antipsychotics. According to the manufacturer, approved by FDA to treat Beta-adrenergics brexpiprazole is a partial agonist (ie, activator) of serotonin 1A (5- schizophrenia and as an HT1A) and dopamine D2 receptors and an antagonist of serotonin Caregiver intervention adjunctive treatment for 2A (5-HT2A) receptors. Brexpiprazole might also bind to and environmental major depressive noradrenaline α1B/2C receptors. In clinical trials, brexpiprazole is modification (eg, disorder (MDD) given orally, at a dose of 1 to 3 mg, once daily, for 10 to 14 weeks. removed or alleviated Developer(s): stressors) Otsuka Holdings Co, Ltd (Tokyo, Japan), in collaboration with H Synthetic Lundbeck A/S (Valby, Denmark) tetrahydrocannabinol
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 55 to 80 COR388 is a bacterial protease inhibitor that targets the Cholinesterase inhibitors Cognitive performance, Clinical trial(s): Phase II/III years who have mild to infectious pathogen Porphyromonas gingivalis gingipains, a (eg, donepezil, measured by Alzheimer’s GAIN primary completion moderate Alzheimer’s bacterium purportedly linked to periodontal disease and AD galantamine, Disease Assessment December 2021 disease (AD) and linked to the production of amyloid beta (Aβ) in preclinical rivastigmine) Scale-Cognitive Subscale and clinical models. P gingivalis gingipains is found in the brain Memantine (off label) 11 tissue and cerebral spinal fluid of people with AD. COR388 Progression of AD purportedly could be the first disease-modifying treatment to Quality of life reduce brain infection, 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)
Adults aged 55 to 79 Cromolyn and ibuprofen (ALZT-OP1) is a combination therapy Cholinesterase inhibitors Disease progression Clinical trial(s): Phase III years who have evidence intended to modify disease in AD. It is intended to slow or (eg, donepezil, Morbidity COGNITE primary of early Alzheimer’s reverse cognitive and functional decline in patients with early- galantamine, Mortality completion December disease (AD) stage AD. Cromolyn acts as an amyloid beta (Aβ) polymerization rivastigmine) 2020, designed under Quality of life inhibitor to purportedly block the development and spread of Supportive care Special Protocol Aβ plaques. The ibuprofen component is intended to reduce Assessment 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 up to 90 Leuco-methylthioninium dihydromethanesulfonate (LMTX) is a Cholinesterase inhibitors Brain atrophy rate Clinical trial(s): Phase II/III years who have early tau aggregation inhibitor being developed as a disease- (eg, donepezil, Cognition and memory, LUCIDITY primary Alzheimer’s disease (AD) modifying treatment for AD. It is intended to reduce levels of galantamine, as measured by accepted completion December aggregated or misfolded tau proteins in the brain, which are rivastigmine) clinical ratings and scales 2021 believed to contribute to AD pathology. In clinical trials, LMTX is Supportive care Quality of life given orally, at a dose of 8 to 16 mg, split into twice-daily doses. Developer(s): TauRx Pharmaceuticals, Ltd (Singapore, Republic of Singapore)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 55 to 85 Periodic Therapeutic Plasma Exchange, also called Alzheimer Cholinesterase inhibitors Symptom severity Clinical trial(s): Phase II/III years who have mild to Management by Albumin Replacement (AMBAR), is intended to (eg, donepezil, Cognitive function (AMBAR) completed moderate Alzheimer’s treat AD by periodically extracting plasma and exchanging the galantamine, Disease progression March 2018, topline data disease (AD) patient’s albumin with Albutein solution. Investigators theorize rivastigmine) reported October 2018, Quality of life that, because most amyloid beta (Aβ) protein is bound to Memantine (off label) data reported December albumin and circulating in plasma, plasma exchange might 2019 “flush” Aβ from the brain into the circulation, mitigating Note(s): FDA granted cognitive decline. In clinical trials, treatment groups were Biologics License assigned to receive either a high dose (total plasma exchange Application approval for once weekly, 2.5 L to 3 L plasma removal with albumin Albutein in 1978 as replacement for 6 weeks) or a low dose (low-volume plasma adjunct therapy for exchange monthly, 650 mL to 880 mL plasma removal with a patients with low dose of albumin or immunoglobulin for 12 months). hypovolemia, Developer(s): cardiopulmonary bypass Grifols SA (Barcelona, Spain) procedures, hypoalbuminemia, and plasma exchange
Adults aged 50 to 85 Troriluzole (BHV-4157) is a third-generation, tripeptide–prodrug Cholinesterase inhibitors Symptom severity, as Clinical trial(s): Phase II/III years who have mild to conjugate of riluzole being developed as a disease-modifying (eg, donepezil, measured by accepted T2 Protect AD primary moderate Alzheimer’s treatment for AD. In patients with AD, damaged brain cells are galantamine, clinical ratings and scales completion December disease (AD) susceptible to cellular injury by overactivity of the excitatory rivastigmine) Bioavailability, safety, and 2020 neurotransmitter glutamate. Riluzole is a sodium channel blocker Memantine (off label) dosing Note(s): Troriluzole is also and glutamate modulator approved by FDA to treat amyotrophic Disease progression in phase III clinical lateral sclerosis (ALS). It purportedly reduces glutamate-mediated Quality of life development to treat excitotoxicity and nerve cell deterioration by promoting spinocerebellar ataxia glutamate’s reuptake into nerve cells. Troriluzole purportedly has the same mechanism of action as riluzole but with improved bioavailability and tolerability. These factors could reduce adverse events typically associated with riluzole, such as fatigue, weakness, dizziness, and hepatotoxicity. Troriluzole purportedly decreases glutamate-mediated neuronal damage to reduce symptoms in patients with AD and delay AD progression by preventing the loss of synapses. In clinical trials, patients receive troriluzole orally at a dose of 280 mg, once daily at bedtime, for 48 weeks. Developer(s): Biohaven Pharmaceuticals, Inc (New Haven, Connecticut)
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Section 2. Cancer: 84 Topics
Table 2.2. Cancer Topics Added Since Last Status Report: 10 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 years or Cediranib plus olaparib (Lynparza) is a combination drug One or more of the Overall survival Clinical trial(s): Phase IIb older who have platinum- regimen under study for treating platinum-resistant, recurrent following: Progression-free survival CONCERTO primary resistant, recurrent ovarian cancer. Poly adenosine diphosphate-ribose polymerase Angiogenesis inhibitors Quality of life completion August 2019 ovarian cancer with no (PARP) inhibitors (eg, olaparib, rucaparib) have been approved (eg, bevacizumab) evidence of a deleterious as monotherapies for recurrent ovarian cancer; however, their Anthracyclines (eg, germline variant in the use is limited to patients with deleterious BRCA1 or BRCA2 doxorubicin, pegylated breast cancer genes, variants, which sensitize cancer cells to PARP inhibition. liposomal doxorubicin) BRCA1 or BRCA2 Research has demonstrated that cediranib, a small-molecule Taxanes (eg, docetaxel, tyrosine kinase inhibitor with activity against multiple receptor paclitaxel) tyrosine kinases, can also sensitize cancer cells to PARP inhibition by suppressing the homologous recombinational repair pathway. Therefore, clinical trials are investigating whether the combined use of cediranib and olaparib is effective in treating ovarian cancer in patients who lack deleterious BRCA1/2 variants. In clinical trials, patients receive an oral dose of cediranib at a dose of 30 mg twice daily and an oral dose of olaparib at a dose of 200 mg twice daily until disease progression or unacceptable toxicity. Developer(s): AstraZeneca (Cambridge, United Kingdom)
SECTION 2. CANCER 10
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Encorafenib (Braftovi) plus cetuximab (Erbitux) with or without Dabrafenib plus Overall survival FDA designation(s): older who metastatic binimetinib (Mektovi) is a combination therapy under study for trametinib plus an anti- Progression-free survival Priority Review colorectal cancer (CRC) treating metastatic BRAF V600E mutation–positive CRC. This EGFR antibody (eg, Quality of life (BRAFTOVI Doublet) with a mutation at V600E type of cancer is associated with poor prognosis, and patients cetuximab, Clinical trial(s): Phase III in the B-Raf proto- have a median overall survival of 4 to 6 months after failure of panitumumab) for off- BEACON CRC completed oncogene, initial therapy. Unlike other BRAF mutated cancers (eg, label use February 2019, data serine/threonine kinase melanoma), BRAF inhibitor monotherapy and BRAF/MEK FOLFIRI (ie, leucovorin published October 2019 gene, BRAF, that has inhibitor combination therapy have limited activity in BRAF [folinic acid], 5- Note(s): In June 2018, FDA progressed after one or V600E colorectal cancer due to mitogen-activated protein fluorouracil, and approved the two previous regimens kinase (MAPK) pathway reactivation through epidermal growth irinotecan) with or combination therapy of factor receptor (EGFR) signaling. Therefore, combining without anti-EGFR encorafenib and BRAF/MEK inhibitors with an EGFR inhibitor may improve antibody (eg, cetuximab, binimetinib (Braftovi and patients’ overall survival. DNA testing for somatic BRAF V600E panitumumab) Mektovi, respectively) for mutation will be needed to determine the patient’s eligibility unresectable or before starting this combination treatment. In clinical trials, metastatic melanoma patients were given encorafenib orally at 300 mg, once daily, with a BRAF V600E or and standard weekly dosing of cetuximab by infusion with or V600K mutation, as without binimetinib orally at 45 mg, twice daily. detected by an FDA- Developer(s): approved test Array BioPharma, Inc (Boulder, Colorado), a subsidiary of Pfizer, Inc (New York, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 55 years or Iomab-B (apamistamab-I-131) is an antibody–radiation One or more of the Overall survival FDA designation(s): older who have active, conjugate composed of the CD-45-specific monoclonal antibody following: Progression-free survival Orphan Drug relapsed or refractory apamistamab linked to the radioisotope iodine-131. AML is the Anthracyclines (eg, Quality of life Clinical trial(s): Phase III acute myeloid leukemia most common type of acute leukemia, and patients with daunorubicin, idarubicin) SIERRA primary (AML) with leukemic cells relapsed/refractory AML have limited treatment options and Antibody–drug completion December expressing CD45 poor outcomes. Iomab-B is under study for use as an induction conjugates (eg, 2020, preliminary data and conditioning agent before hematopoietic stem cell gemtuzumab reported October 2019, transplantation (HSCT) or other cellular therapies. ozogamicin) data presented Apamistamab binding to CD45, a receptor purportedly involved Antimetabolites (eg, December 2019 in promoting AML cell proliferation, leads to Iomab-B cytarabine, fludarabine) internalization and leukemic cell death through targeted radiation delivery. In clinical trials, Iomab-B is administered as a BCL-2 inhibitors (eg, component of a reduced-intensity conditioning regimen venetoclax) containing fludarabine and low-dose total body irradiation DNA synthesis inhibitors before allogeneic HSCT. (eg, etoposide, Developer(s): mitoxantrone) Actinium Pharmaceuticals, Inc (New York, NY) FLT3 inhibitors (eg, gilteritinib, sorafenib) Hypomethylating agents (eg, azacitidine, decitabine) IDH inhibitors (eg, enasidenib, ivosidenib)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or KTE-X19 is a chimeric antigen receptor (CAR) T-cell therapy One or more of the Overall survival PDUFA date: August 10, older who have relapsed consisting of genetically modified autologous T cells intended to following: Progression-free survival 2020 or refractory mantle cell generate specific immune responses against the CD19 antigen Cyclophosphamide Quality of life FDA designation(s): lymphoma (MCL) that has expressed on the surface of B cells. MCL is a rare form of non- Cytarabine Orphan Drug, failed to respond to or Hodgkin lymphoma that arises from cells originating in the Dexamethasone Breakthrough Therapy relapsed after at least mantle zone of the lymph node and typically affects males older Doxorubicin Clinical trial(s): Phase II one prior regimen than 60 years of age. KTE-X19 uses the same construct as the ZUMA-2 primary Methotrexate existing CAR-T therapy axicabtagene ciloleucel (FDA approved completion July 2019, for treating large B-cell lymphoma), but incorporates the Platinum agents (eg, data presented proprietary XLP manufacturing process that includes T-cell carboplatin, cisplatin) November 2019 selection and lymphocyte enrichment. These processes are Prednisone thought to be a necessary step for certain B-cell malignancies Rituximab with evidence of circulating lymphoblasts to prevent Vincristine incorporation of malignant cells into the CAR-T therapy. In clinical trials, KTE-X19 is given as a single intravenous infusion at a dose of 1 x 106 cells/kg. Developer(s): Gilead Sciences (South San Francisco, California)
Adults aged 18 years or Nadofaragene firadenovec (Instiladrin) is a gene therapy Cystectomy Overall survival Submission date: older who have recurrent intended to treat high-grade NMIBC that does not respond to Intravesical Progression-free survival Biologics License non–muscle invasive bacillus Calmette-Guérin (BCG) therapy. About half of patients chemotherapy with one Quality of life Application November bladder cancer (NMIBC) with NMIBC will have recurrent disease after BCG induction or more of the following: 25, 2019 and confirmed carcinoma therapy, and these patients are more likely to progress to a Anthracyclines (eg, FDA designation(s): in situ (CIS) only; Ta/T1 more advanced disease stage. Nadofaragene firadenovec is an epirubicin, valrubicin) Priority Review, Fast high-grade disease with adenovirus vector gene therapy containing the gene interferon Antimetabolites (eg, Track, Breakthrough concomitant CIS; or Ta/T1 alfa-2b. After its administration into the bladder, it transduces gemcitabine) Therapy high-grade disease cells in the bladder cell wall, causing them to produce and Clinical trial(s): Phase III without concomitant CIS secrete interferon alfa-2b protein, a naturally occurring protein DNA synthesis inhibitors (eg, mitomycin-C) primary completion May the body uses to fight cancer. In clinical trials, nadofaragene 2019, data reported Taxanes (eg, docetaxel) firadenovec was administered through a catheter into the December 2019 bladder every 3 months for 12 months, and patients were followed for 48 months. Developer(s): FKD Therapies Oy (Kuopio, Finland), licensed to FerGene, a company of Ferring Pharmaceuticals (Saint-Prex, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Oraxol is a novel combination therapy composed of a paclitaxel One or more of the Overall survival Submission date: New older who have locally capsule and an encequidar tablet that is administered orally following: Progression-free survival Drug Application planned advanced or metastatic rather than intravenously. Paclitaxel is a taxane that inhibits cell Anthracyclines (eg, Quality of life for March 2020 breast cancer for whom division, but it is formulated only as an intravenous infusion that doxorubicin, liposomal FDA designation(s): treatment with contains additives, which increase the risk of neuropathy and doxorubicin) Orphan Drug intravenous paclitaxel hypersensitivity. These adverse reactions often prevent patients Antimetabolites (eg, Clinical trial(s): Phase III has been recommended from completing the chemotherapy regimen, thereby reducing capecitabine, KX-ORAX-001 primary efficacy and adversely affecting health outcomes. Paclitaxel has gemcitabine) completion August 2019, been limited to intravenous administration because the drug is a Microtubule inhibitors data presented substrate of P-glycoprotein (P-gp), an active transport protein on (eg, eribulin, vinorelbine) December 2019 the gastrointestinal (GI) tract’s surface that is capable of pumping paclitaxel back into the GI tract. Encequidar is a P-gp inhibitor PARP Inhibitors (eg, that prevents P-gp-mediated efflux of paclitaxel. As an orally olaparib, talazoparib) for administered taxane, oraxol has the potential to decrease the BRCA1/2-mutated breast burden of infusion clinic visits, premedication, and potentially cancer dangerous infusion-related reactions. In clinical trials, oraxol is Taxanes (eg, docetaxel, given as an all-oral regimen of 205 mg/m2 paclitaxel plus paclitaxel) encequidar administered 3 days per week until disease progression or intolerable toxicity. Developer(s): Athenex Pharmaceuticals, Inc (Buffalo, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or OSE2101 (Tedopi) is a therapeutic cancer vaccine designed to One or more of the Overall survival Clinical trial(s): Phase III older who have locally stimulate T-cell responses against NSCLC. Patients with NSCLC following: Progression-free survival ATALANTE 1 primary advanced or metastatic that does not respond to immune checkpoint inhibitors have Angiogenesis inhibitors Quality of life completion December non–small cell lung limited treatment options and a poor prognosis, and new therapy (eg, bevacizumab, 2021, early results cancer (NSCLC) that options are needed. OSE2101 is based on a collection of neo- ramucirumab) reported April 2019 expresses HLA-A2 and epitopes, which are short peptides derived from mutant versions Antimetabolites (eg, has been previously of proteins expressed by genes mutated in cancer cells, acting as gemcitabine, treated with an immune antigens. Because neo-epitopes are expressed only in the clonal pemetrexed) checkpoint inhibitor and cancer lineage, they are not recognized by the immune system as Taxanes (eg, docetaxel) platinum-based “self” antigens and, therefore, might elicit a strong immune chemotherapy response against tumor cells expressing these antigens. OSE2101 contains 9 neo-epitopes designed to elicit cytotoxic T-cell responses and an additional neo-epitope that initiates helper T- cell responses to further activate tumor-specific T-cell responses. In clinical trials, OSE2101 is given subcutaneously at a dose of 5 mg, once every 3 weeks, for 6 cycles, then every 8 weeks for the remainder of the year, and finally every 12 weeks until disease progression or intolerable toxicity. Developer(s): OSE Immunotherapeutics SA (Nantes, France)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Pemigatinib (INCB54828) is a novel, highly potent, and selective Fluoropyrimidine-based Overall survival PDUFA date: May 30, older who have locally small-molecule inhibitor of FGFR isoforms 1, 2, and 3, which chemotherapy Progression-free survival 2020, Priority Review advanced or metastatic play an important role in cell proliferation, survival, migration, Pembrolizumab (for Quality of life FDA designation(s): cholangiocarcinoma and angiogenesis (ie, formation of new blood vessels). patients with Breakthrough Therapy harboring gene Cholangiocarcinoma is a rare cancer that forms in bile ducts, microsatellite instability– Clinical trial(s): Phase III mutations, fusions, or which carry fluid between the liver, the gallbladder, and the high or mismatch repair– FLIGHT-302 primary translocations in the small intestine. About 20% of cholangiocarcinomas harbor a deficient tumors) completion October fibroblast growth factor genetic alteration in FGFR2, which typically involves a gene 2023; phase II FLIGHT- receptor 2 gene, FGFR2, fusion/translocation that leads to constitutive FGFR2 activity. By 202 primary completion and that has previously targeting this aberrant FGFR signaling, pemigatinib purportedly June 2020, data been treated with at least prevents the growth and spread of cholangiocarcinoma tumors, presented September one line of systemic potentially improving outcomes of patients who have limited 2019 therapy treatment options. Although pemigatinib specifically binds to FGFRs 1, 2, and 3, it is designed to avoid binding to similar signaling domains in the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor. Testing for FGFR2 gene alterations will require use of a genetic test (ie, a companion diagnostic). In clinical trials, pemigatinib is given orally at an unspecified daily dose in a 2-week-on, 1-week- off schedule until disease progression or intolerable toxicity. Developer(s): Incyte Corp (Wilmington, Delaware)
Females aged 18 years or Trametinib (Mekinist) is a kinase inhibitor intended to treat low- One or more of the Overall survival Clinical trial(s): Phase II/III older who have recurrent grade serous ovarian or peritoneal cancer, a rare subtype of following: Progression-free survival GOG-0281 completed low-grade serous ovarian serous cancer characterized by changes in the mitogen- Anthracyclines (eg, Quality of life April 2019, data reported or peritoneal cancer that activated protein kinase (MAPK) signaling pathway. Recurrent pegylated liposomal October 2019 has been treated with low-grade serous ovarian or peritoneal cancer responds poorly doxorubicin) Note(s): FDA has one or more lines of to treatment with cytotoxic chemotherapy, and better Hormone therapies (eg, approved trametinib chemotherapy treatment options are needed. Trametinib purportedly shrinks letrozole, tamoxifen) (Mekinist) to treat tumors by blocking the activity of the protein MEK, a molecule Taxanes (eg, paclitaxel) advanced melanoma with that functions in the MAPK signaling pathway to regulate cell BRAF V600E or V600K Topoisomerase inhibitors growth. In a clinical trial, trametinib was given as an oral dose of mutation 2 mg daily until disease progression or unacceptable toxicity. (eg, topotecan) Developer(s): NRG Oncology (Philadelphia, Pennsylvania), in collaboration with National Cancer Institute at the National Institutes of Health (Bethesda, Maryland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or TT10 is an autologous cell therapy developed from EBV-specific One or more of the Overall survival Clinical trial(s): Phase III older who have locally T cells (EBVSTs) collected from a patient’s peripheral blood. It is following: Progression-free survival FF01 primary completion advanced or metastatic, under study for treating EBV-associated NPC, which has limited Antimetabolites (eg, 5- Quality of life December 2020 Epstein-Bar virus (EBV)– treatment options, and TT10 T cells could represent a new fluorouracil, associated, recurrent option in appropriately selected cases. In some NPC cases, EBV capecitabine, nasopharyngeal infection reprograms the nasopharyngeal epithelial cells to gemcitabine, carcinoma (NPC) that has drive cellular transformation and proliferation and, therefore, methotrexate) not been treated may be amenable to treatments targeting EBV. To create TT10, EGFR inhibitor (eg, previously with systemic autologous EBVSTs are enriched and expanded in the presence cetuximab) therapy of EBV antigen-expressing dendritic cells and cytokines to Platinum-based drugs generate large numbers of T cells that recognize specific EBV (eg, carboplatin, cisplatin) antigens in NPC cells. After being expanded to the required numbers, EBVSTs are frozen until use. TT10 cells purportedly Taxanes (eg, docetaxel, recognize and kill EBV-positive tumor cells and strengthen the paclitaxel) patient’s natural T-cell responses against cancer cells expressing EBV antigens. In clinical trials, TT10 cells are given intravenously at an unspecified dose every 2 weeks for 2 cycles after chemotherapy with gemcitabine (1000 mg/m2) plus carboplatin (AUC 2) on days 1, 8, and 15 of a 28-day cycle for 4 cycles. Six weeks after receiving 2 cycles of TT10 cells, patients receive TT10 cells every 8 weeks for 4 cycles. Developer(s): Tessa Therapeutics, Inc (Singapore, Republic of Singapore)
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Table 2.3. Currently Monitored Cancer Topics: 70 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or APR-246 is a small-molecule anticancer drug that purportedly Azacitidine Overall survival FDA designation(s): older who have restores and reactivates wild-type p53 conformation and Decitabine Progression-free survival Orphan Drug, Fast Track, myelodysplastic function in myelodysplastic cells, causing initiation of Growth factors (eg, Quality of life Breakthrough Therapy syndrome (MDS) with at programmed cell death (ie, apoptosis) in cancer cells. Triggering darbepoetin alfa, epoetin Clinical trial(s): Phase III least one genetic variant programmed cell death of myelodysplastic cells might restore alfa, filgrastim) primary completion June in the tumor protein p53 proper bone marrow function, including blood cell production 2020 gene, TP53 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Atezolizumab (Tecentriq) is a monoclonal antibody that targets One or more of the Overall survival Submission date: older who have locally programmed death-ligand 1 (PD-L1), an inhibitory surface following: Progression-free survival Supplemental Biologics advanced or metastatic molecule expressed by cells to modulate immune responses. Anthracyclines (eg, Quality of life License Application hepatocellular carcinoma HCC, an aggressive cancer, has limited treatment options and is doxorubicin) January 27, 2020 (HCC) and have had no a major cause of cancer deaths, so more effective treatment Antimetabolites (eg, 5- FDA designation(s): previous systemic options are needed. A hallmark of cancer is its ability to evade fluorouracil, gemcitabine) Orphan Drug, therapy an immune response. Several types of cancer cells, including Multikinase inhibitors (eg, Breakthrough Therapy HCC, activate an immune checkpoint pathway in T cells by lenvatinib, sorafenib) Clinical trial(s): Phase III overexpressing PD-L1, which binds to the programmed death-1 COSMIC-312 primary (PD-1) coinhibitory receptor and limits the activation of cancer- Platinum agents (eg, cisplatin, oxaliplatin) completion August 2020; specific T cells. Atezolizumab purportedly prevents the phase III IMbrave150 interaction between PD-1 and PD-L1 to release the brake on the primary completion immune checkpoint pathway. Atezolizumab treatment in November 2020, data combination with bevacizumab or cabozantinib is intended to presented November restore anticancer immunity by inhibiting vascular endothelial 2019 growth factor (VEGF)–related immunosuppression. In clinical Note(s): FDA approved trials, atezolizumab is given as an intravenous infusion at a dose atezolizumab to treat of 1200 mg on day 1 of each 21-day cycle until disease urothelial carcinoma in progression or development of unacceptable toxicity, in May 2016, to treat non– combination with intravenous bevacizumab (15 mg/kg on day 1 small cell lung cancer in of each 21-day cycle) or oral cabozantinib (40 mg daily). October 2016, to treat Developer(s): triple-negative breast Genentech, Inc (South San Francisco, California), a subsidiary of cancer in March 2019, and F Hoffman-La Roche AG (Basel, Switzerland) to treat small cell lung cancer in March 2019
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Avapritinib (BLU-285) is purportedly a potent and selective oral Tyrosine kinase inhibitors Progression-free survival Submission date: older who have advanced type 1 kinase inhibitor of mutated KIT and platelet-derived (eg, imatinib, Overall survival Supplemental New Drug systemic mastocytosis growth factor receptor A (PDGFRA) kinases. It also binds and midostaurin) Quality of life Application planned for that includes aggressive, inhibits the KIT D816V variant, the primary driver of disease in second half of 2020 indolent, or smoldering up to 95% of patients with systemic mastocytosis. Because no FDA designation(s): systemic mastocytosis FDA-approved treatments exist for this patient population, Breakthrough Therapy patients need new treatment options. Avapritinib broadly Clinical trial(s): Phase II inhibits activating mutations in KIT and PDGFRA, which drive PATHFINDER primary tumor cell division. Avapritinib is designed to act against completion May 2022; activation loop mutations in KIT and PDGFRA, which approved phase II PIONEER primary multikinase inhibitors do not inhibit. In clinical trials, avapritinib completion December 300 mg is given orally, once daily, until disease progression or 2020, data reported intolerable toxicity. December 2019; phase I Developer(s): EXPLORER primary Blueprint Medicines Corp (Cambridge, Massachusetts) completion November 2021, topline data reported December 2018, updated results reported June 2019
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Avatrombopag (Doptelet) is an oral thrombopoietin (TPO) Platelet transfusion Proportion of patients FDA designation(s): older undergoing receptor agonist (ie, activator) intended for treating severe TPO agonists (eg, who did not require a Orphan Drug chemotherapy who thrombocytopenia that occurs as a side effect of chemotherapy. eltrombopag, platelet transfusion or Clinical trial(s): Phase III develop severe About 10% of patients undergoing chemotherapy develop romiplostim; off label) reduction in primary completion thrombocytopenia, chemotherapy-induced thrombocytopenia (CIT), and no drugs chemotherapy November 2020; phase III defined as 2 platelet are approved to treat it. CIT can complicate surgical procedures Proportion of patients trial topline results 9 counts below 50 × 10 /L and chemotherapy treatment and increases the likelihood of who achieved platelet expected in first half of measured at least 24 serious bleeding events, which might require hospitalization. counts of >50 × 109/L 2020 hours apart Avatrombopag purportedly stimulates the division and after treatment Note(s): FDA approved maturation of megakaryocytes (ie, cells responsible for platelet Proportion of patients avatrombopag in May production) from bone marrow precursor cells. Avatrombopag without major or 2018 for treating activates the TPO receptor by binding to a site distinct from the nonmajor clinically thrombocytopenia in TPO binding site (ie, an allosteric site) and, therefore, does not relevant bleeding adults with chronic liver compete with naturally occurring TPO. The agent could be used disease (CLD) who are in combination with nonallosteric TPO agonists (eg, romiplostim). scheduled to undergo a Avatrombopag is administered at an initial dose of 20 mg (1 procedure and in June tablet), once daily, which is adjusted to maintain a platelet count 2019 for treating chronic 9 of 50 × 10 /L or greater without exceeding 40 mg daily. immune Developer(s): thrombocytopenia Dova Pharmaceuticals, Inc (Durham, North Carolina), a subsidiary of Swedish Orphan Biovitrum AB (Stockholm, Sweden)
Adults aged 18 years or Avisopasem manganese (GC4419) is intended to treat patients One or more of the Incidence of severe FDA designation(s): older who are at risk for who are likely to develop OM. No effective treatments are following: mucositis Breakthrough Therapy, oral mucositis (OM) after available for OM, a common side effect of anticancer therapies Localized therapy (eg, Cancer treatment Fast Track chemoradiation therapy (eg, chemotherapy, radiation). GC4419 is a small-molecule low-level laser therapy, adherence Clinical trial(s): Phase III with cisplatin and superoxide dismutase mimetic drug intended to detoxify reactive oral cryotherapy) Quality of life ROMAN primary intensity-modulated oxygen species (ROS). ROS are overproduced during Supportive care (eg, oral completion October 2020 radiation therapy for chemoradiation therapy, overwhelming endogenous superoxide hygiene protocols) locally advanced, dismutase enzymes and resulting in oxidative tissue damage that nonmetastatic head and contributes to OM. Exogenous administration of a superoxide neck cancer dismutase, such as avisopasem manganese, purportedly reduces chemoradiation-induced toxicity. In clinical trials, avisopasem manganese is given intravenously at an unspecified dose before initiating intensity-modulated radiation therapy. Developer(s): Galera Therapeutics, Inc (Malvern, Pennsylvania)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Calmangafodipir (PledOx) is a first-in-class drug candidate Oxaliplatin-based CIPN Clinical trial(s): Phase III older who have designed to prevent chemotherapy-induced peripheral chemotherapy (eg, Touch sensitivity POLAR-M primary untreated locally neuropathy (CIPN), a common and problematic toxicity caused FOLFOX) alone, without Vibration sensitivity completion March 2021 advanced or metastatic by chemotherapy-induced cell death of peripheral nerves. adjunct preventive Pain in the extremities Note(s): FDA placed colorectal cancer (CRC) Among the chemotherapy agents known to induce CIPN is therapy phase III POLAR-M on Quality of life and are considering oxaliplatin, which is a component of combination clinical hold January 23, combination chemotherapy regimens commonly used for patients with CRC. 2020 chemotherapy containing Although the exact mechanism of oxaliplatin-induced leucovorin (folinic acid), peripheral neuropathy is unclear, it purportedly involves 5-fluorouracil, and oxaliplatin metabolite generation of reactive oxygen species oxaliplatin (ie, FOLFOX) (ROS) that kill cells via oxidative stress. No treatment options to prevent oxaliplatin-related CIPN are available. Calmangafodipir purportedly acts to degrade ROS, limiting the extent of oxidative stress to cells. In clinical trials, calmangafodipir is given as an intravenous infusion at a dose of 2 or 5 µmol/kg, on day 1 of each 2-week cycle, 10 minutes before receiving FOLFOX. Treatment with calmangafodipir continues until FOLFOX treatment completes. Developer(s): PledPharma AB (Stockholm, Sweden), in collaboration with Solasia Pharma KK (Tokyo, Japan)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Canakinumab (ACZ885) is a human monoclonal antibody that One or more of the Overall survival Clinical trial(s): Phase III older who have locally binds and neutralizes the immune mediator activity of human following: Progression-free survival CANOPY-2 primary advanced or metastatic interleukin-1β (IL-1β), a member of the interleukin-1 (IL-1) family ALK inhibitors (eg, Quality of life completion February non–small cell lung of cytokines. Canakinumab is intended as an addition to the alectinib, crizotinib) if ALK 2021; phase III CANOPY-1 cancer (NSCLC) of standard of care and is designed to be a selective antibody that rearrangement positive primary completion June squamous or binds with high affinity to IL-1β, but not to any other member of ALK inhibitors (eg, 2022 nonsquamous origin that the IL-1 family or IL-1β from another species. Canakinumab ceritinib, crizotinib) if Note(s): FDA approved has not been treated or purportedly elicits an anti-inflammatory response in the tumor ROS1 rearrangement canakinumab to treat that has been previously microenvironment that blocks tumor proliferation and new positive cryopyrin-associated treated with an immune blood vessel formation (ie, angiogenesis). Under specific Angiogenesis inhibitors periodic syndromes in checkpoint inhibitor in conditions, IL-1β and other inflammatory cytokines, which are (eg, bevacizumab, June 2009; for active combination with or after produced primarily by tumor-associated macrophages, play a ramucirumab) systemic juvenile platinum-based role in the growth, vascularization, progression, and spread of idiopathic arthritis in May Anthracyclines (eg, chemotherapy cancer cells. In clinical trials, canakinumab is given as a 2013; and for tumor doxorubicin) subcutaneous injection at an unspecified dose in combination necrosis factor receptor– 2 with intravenous docetaxel at a dose of 75 mg/m or Antimetabolites (eg, associated periodic intravenous pembrolizumab at a dose of 200 mg plus platinum- gemcitabine, syndrome, based chemotherapy every 3 weeks until disease progression pemetrexed) hyperimmunoglobulin D or intolerable toxicity. EGFR inhibitors (eg, syndrome/mevalonate Developer(s): afatinib, erlotinib) if EGFR kinase deficiency, and Novartis AG (Basel, Switzerland) rearrangement positive familial Mediterranean Immune checkpoint fever in September 2016 inhibitors (eg, nivolumab, pembrolizumab) Platinum-based agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, paclitaxel) Tropomyosin kinase inhibitors (eg, larotrectinib) if NTRK rearrangement positive Vinca alkaloids (eg, vinblastine, vinorelbine)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Capmatinib (INC280) is a potent and selective, small-molecule One or more of the Overall survival Submission date: New older who have locally inhibitor of the hepatocyte growth factor (HGF) receptor. A following: Progression-free survival Drug Application advanced or metastatic receptor tyrosine kinase encoded by the MET proto-oncogene, Angiogenesis inhibitors Quality of life February 11, 2020; non–small cell lung receptor tyrosine kinase gene, MET, the HGF receptor is typically (eg, bevacizumab, Priority Review cancer (NSCLC) harboring required for tissue and organ regeneration and damage repair. ramucirumab) FDA designation(s): MET gene alterations The incidence of MET gene alterations in patients with NSCLC, Anthracyclines (eg, Orphan Drug, (MET exon 14 deletion or including MET exon 14 deletion and MET amplification, is about doxorubicin) Breakthrough Therapy MET amplification) that is 2% to 4%. MET-driven NSCLC is an aggressive disease with a Antimetabolites (eg, Clinical trial(s): Phase II untreated or that has poor prognosis and limited treatment options. Capmatinib is a gemcitabine, GEOMETRY mono-1 been previously treated novel targeted therapy intended as first-line therapy for pemetrexed) primary completion May with one or two lines of patients harboring MET alterations. Capmatinib is designed to 2021, data reported June chemotherapy interact with tyrosine 1230 and a hinge motif in the HGF Immune checkpoint inhibitors (eg, nivolumab, 2019, data reported receptor’s kinase domain, which causes it to adopt a unique October 2019 autoinhibitory shape that prevents access to its ATP binding pembrolizumab) site. Because capmatinib is highly specific for the HGF receptor, Platinum agents (eg, it purportedly has fewer off-target effects. In NSCLC cells, carboplatin, cisplatin) capmatinib purportedly blocks new blood vessel formation (ie, Taxanes (eg, docetaxel, angiogenesis), proliferation, and survival pathways by inhibiting paclitaxel) the HGF receptor’s constitutive ligand-independent signaling. Vinca alkaloids (eg, Determining eligibility for this therapy requires testing for MET vinblastine, vinorelbine) mutation status. In clinical trials, capmatinib is given orally at a dose of 400 mg, twice daily, until disease progression or intolerable toxicity. Developer(s): Novartis AG (Basel, Switzerland), licensed by Incyte Corp (Wilmington, Delaware)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 70 DCVax-L is intended to treat GBM, which has very limited Fractionated external Overall survival FDA designation(s): years who have treatment options and is associated with poor outcomes. beam radiation therapy Progression-free survival Orphan drug glioblastoma multiforme DCVax-L is an autologous immunotherapy comprising activated One or more of the Quality of life Clinical trial(s): Phase III (GBM) that has been dendritic cells loaded with patient-derived tumor antigens. It is following: GBM primary completion surgically resected and intended to improve outcomes by promoting an immune Alkylating agents (eg, November 2016, interim treated with adjuvant response against residual glioblastoma cells after surgical cyclophosphamide, data published May 2018, radiation therapy and resection. DCVax-L is manufactured using monocytes obtained lomustine, procarbazine) 3-year survival data chemotherapy from the patient through a leukapheresis process. The Angiogenesis inhibitors reported November 2018 monocytes are differentiated into dendritic cells in vitro and (eg, bevacizumab) then activated and loaded with patient-derived antigens from the patient’s tumor tissue after surgical resection. The purified mTOR inhibitors (eg, DCVax-L is then given to elicit adaptive immunity from T cells everolimus) and B cells. Treatment begins at least 2 weeks before the first Platinum agents (eg, course of DCVax-L is given and involves total or near total carboplatin, cisplatin) tumor resection followed by conventional external beam Vinca alkaloids (eg, radiation therapy and concurrent temozolomide chemotherapy. vincristine) In clinical trials, DCVax-L containing 2.5 × 106 tumor lysate– pulsed dendritic cells is given as an intradermal injection in the upper arm at days 0, 10, and 20 and at weeks 8, 16, 32, 48, 72, 96, and 120. Developer(s): Northwest Biotherapeutics, Inc (Bethesda, Maryland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 50 years or Devimistat (CPI-613) is intended to provide a new treatment One or more of the Overall survival FDA designation(s): older who have relapsed option for patients with AML, because they have very limited following: Progression-free survival Orphan drug or refractory acute options and poor outcomes. Devimistat is a small-molecule Anthracyclines (eg, Quality of life Clinical trial(s): Phase III myeloid leukemia (AML) lipoate analogue drug intended to target the altered energy daunorubicin, idarubicin) ARMADA 2000 primary metabolism unique to many cancers, including AML. The Antibody–drug conjugate completion October 2022 altered energy metabolism of cancer cells frequently depends (eg, gemtuzumab on the activity of the pyruvate dehydrogenase complex and the ozogamicin) α-ketoglutarate dehydrogenase complex. Devimistat Antimetabolites (eg, purportedly inhibits the catalytic and regulatory functions of cladribine, fludarabine) these key cancer pathways, leading to tumor cell death. In clinical trials, devimistat is being tested in combination with a Cytokine (eg, granulocyte standard induction regimen of high-dose cytarabine and colony-stimulating factor) mitoxantrone. Devimistat 2000 mg/m2 is given intravenously on DNA synthesis inhibitors days 1 to 5 of the induction regimen. (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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 75 Devimistat (CPI-613) is intended as a first-line treatment for One or more of the Overall survival FDA designation(s): years who have pancreatic cancer, because only about 5% of these patients following: Progression-free survival Orphan Drug pancreatic respond to the standard of care (ie, gemcitabine Antimetabolites (eg, 5- Quality of life Clinical trial(s): Phase III adenocarcinoma with chemotherapy). Devimistat is a small-molecule lipoate analogue fluorouracil, gemcitabine) AVENGER 500 primary distant metastases that drug intended to target the altered energy metabolism of many Chemoprotectant (eg, completion October 2021 have not been treated cancers, including pancreatic adenocarcinomas. The altered leucovorin) energy metabolism of cancer cells frequently depends on the DNA synthesis inhibitor activity of the pyruvate dehydrogenase complex and the α- (eg, irinotecan) ketoglutarate dehydrogenase complex. Devimistat purportedly downregulates metabolic pathways in cancer cells that depend EGFR inhibitor (eg, on α-ketoglutarate and acetyl-CoA. In clinical trials, devimistat is erlotinib) given by intravenous injection at a dose of 500 mg/m2 on days 1 Platinum-based agents and 3 of a 14-day cycle, followed immediately by intravenous (eg, cisplatin, oxaliplatin) modified FOLFIRINOX (ie, leucovorin [folinic acid] at 400 mg/m2, Taxanes (eg, docetaxel, 5-fluorouracil at 400 mg/m2, irinotecan at 140 mg/m2, and paclitaxel) oxaliplatin at 65 mg/m2). Developer(s): Rafael Pharmaceuticals, Inc (Cranbury, New Jersey)
Adults aged 18 years or Dianhydrogalactitol (VAL-083) is a small-molecule drug that One or more of the Overall survival FDA designation(s): older who have recurrent causes N7 DNA alkylation. It is intended to treat recurrent following: Progression-free survival Orphan Drug, Fast Track malignant glioma (eg, malignant gliomas, which often become resistant to the Alkylating agents (eg, Quality of life Clinical trial(s): Phase II glioblastoma multiforme standard-of-care temozolomide therapy because the tumor carmustine, DLM-16-001 primary 6 [GBM]) expresses high levels of an enzyme (O -methylguanine-DNA- cyclophosphamide, completion September methyltransferase [MGMT]) that helps repair DNA. Patients procarbazine) 2020, data published need better treatment options, and VAL-083’s novel N7 DNA Angiogenesis inhibitors December 2019 alkylation activity is intended to overcome MGMT-mediated (eg, bevacizumab) resistance. In clinical trials, VAL-083 is given as an intravenous mTOR inhibitors (eg, infusion at a dose of 30 mg/m2 on days 1, 2, and 3 of a 21-day everolimus) treatment cycle, for up to twelve 21-day treatment cycles. Platinum-based drugs Developer(s): (eg, carboplatin, cisplatin) DelMar Pharmaceuticals, Inc (Vancouver, British Columbia, Vinca alkaloids (eg, Canada) vincristine)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Dusquetide (SGX942) is intended to treat OM, which has no One or more of the Duration of severe FDA designation(s): older who are at risk for effective treatments and is a common side effect of anticancer following: mucositis Orphan Drug, Fast Track oral mucositis (OM) therapies (eg, chemotherapy, radiation). It affects about 80% of Analgesics (eg, lidocaine, Incidence of severe Clinical trial(s): Phase III during chemoradiation patients with oropharyngeal cancer. Dusquetide is a novel narcotics) mucositis DOM-INNATE primary therapy with cisplatin synthetic, water-soluble, 5-amino-acid peptide with anti- Localized therapy (eg, Pain completion June 2020 and image-modulated inflammatory and anti-infective properties. It is a member of a low-level laser therapy, Cancer treatment Note(s): National radiation therapy for drug class called innate defense regulators. Dusquetide targets oral cryotherapy) adherence Institutes of Health locally advanced, the innate immune system and binds to an intracellular adaptor Supportive care (eg, oral selected SGX942 for its nonmetastatic squamous protein, sequestosome-1. Also called p62, this protein has a Incidence of bacterial hygiene protocols) infection Small Business cell carcinoma of the oral pivotal function in signal transduction during activation and Innovation Quality of life cavity or oropharynx control of the innate immune system. In clinical trials, Research/Small Business dusquetide is given as a 4-minute intravenous infusion at a Technology Transfer dose of 1.5 mg/mL, twice weekly, starting within 3 days after Commercialization initiating radiation therapy and continuing through 2 weeks Accelerator Program in after completing radiation therapy. September 2018 Developer(s): Soligenix, Inc (Princeton, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults who have locally Enfortumab vedotin (Padcev) provides an option for patients One or more of the Overall survival Approval date: December advanced or metastatic whose cancer has not responded to standard of care, who have following: Progression-free survival 18, 2019 urothelial cancer (mUC) limited options and poor outcomes. Enfortumab is a Alkylating agents (eg, Quality of life FDA designation(s): who have previously monoclonal antibody conjugated to a chemotherapy drug (ie, ifosfamide) Breakthrough Therapy, received a programmed vedotin), designed to bind the surface receptor nectin 4. Antimetabolites (eg, Priority Review death receptor-1 (PD-1) Vedotin is a synthetic auristatin with cytotoxic activity that gemcitabine, Clinical trial(s): Phase III or programmed death- blocks the formation of microtubules. The adhesion protein pemetrexed) EV-301 primary ligand 1 (PD-L1) inhibitor, nectin 4 is highly expressed in various types of solid tumors, Immune checkpoint completion September and a platinum- including urothelial cancer. Enfortumab vedotin purportedly inhibitors (eg, 2021; phase II EV-201 containing chemotherapy triggers internalization of the drug into the cells. This increases atezolizumab, primary completion in the vedotin’s likelihood of targeting and killing malignant cells while durvalumab) November 2020, data neoadjuvant/adjuvant, minimizing cytotoxicity on normal cells. The recommended presented September locally advanced or dose in the FDA-approved label is 1.25 mg/kg (up to a maximum Platinum agents (eg, carboplatin, cisplatin) 2019; single-arm clinical metastatic setting dose of 125 mg) given as an intravenous infusion over 30 trial results presented in Taxanes (eg, docetaxel, minutes on days 1, 8, and 15 of a 28-day cycle until disease FDA-approved labeling paclitaxel) progression or unacceptable toxicity. and prescribing Developer(s): document Seattle Genetics, Inc (Bothell, Washington), in collaboration with Note(s): This Accelerated Astellas Pharma, Inc (Tokyo, Japan) Approval requires the conduct of a further clinical trial to verify and describe Padcev’s clinical benefit
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults who have locally Erdafitinib (Balversa) is a novel, highly selective, small-molecule One or more of the Overall survival Approval date: April 12, advanced or metastatic inhibitor of 4 members of the FGFR family (ie, 1, 2, 3, and 4). following: Progression-free survival 2019 urothelial carcinoma that Erdafitinib is intended to treat unresectable, urothelial, FGFR- Antimetabolites (eg, Quality of life FDA designation(s): has susceptible FGFR3 or positive cancer after first- and second-line treatment options gemcitabine, Breakthrough Therapy FGFR2 genetic alterations have failed. Erdafitinib is designed to target FGFRs and not bind pemetrexed) Clinical trial(s): Phase III and has progressed to similar signaling domains in the vascular endothelial growth Immune checkpoint BLC3001 primary during or after at least factor receptor and the platelet-derived growth factor receptor. inhibitors (eg, nivolumab, completion November one line of platinum- Erdafitinib purportedly blocks blood vessel formation, cell pembrolizumab) 2020; phase II BLC2001 containing proliferation, and cell survival pathways in urothelial cancer Platinum agents (eg, primary completion April chemotherapy, including cells by inhibiting constitutive ligand-independent FGFR carboplatin, cisplatin) 2020, data published within 12 months of signaling. In some urothelial cancers, the presence of activating June 2019, data neoadjuvant or adjuvant FGFR gene alterations, including point mutations and gene Taxanes (eg, docetaxel, paclitaxel) presented September platinum-containing rearrangements, leads to uncontrolled cell proliferation. 2019 chemotherapy Eligibility for treatment requires patients to undergo an FDA- Note(s): This was an approved companion diagnostic to determine FGFR status. The Accelerated Approval and initial recommended dosage in the FDA-approved label is 8 mg requires the conduct of orally, once daily, with a dose increase to 9 mg daily if criteria further clinical trials to are met. The medication comes in 3-, 4-, and 5-mg tablets. verify and describe Developer(s): clinical benefits 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Etirinotecan pegol (Onzeald), a novel drug–polymer form of the One or more of the Overall survival FDA designation(s): Fast older who have advanced topoisomerase I inhibitor irinotecan, is intended to reduce following: Progression-free survival Track breast cancer with stable treatment-related adverse events in patients with breast cancer Alkylating agents (eg, Quality of life Clinical trial(s): Phase III brain metastases that and brain metastases. Etirinotecan pegol links to a cyclophosphamide) BEACON completed June has been treated with macromolecule core. This linkage purportedly renders the drug Anthracyclines (eg, 2016, pivotal data one or two cytotoxic inert in the bloodstream and allows its slow release as the doxorubicin) published November regimens patient’s body metabolizes the linkages. Slow release extends Antimetabolites (eg, 2015, quality-of-life data the time the cancer is exposed to therapeutic levels of the drug fluorouracil, gemcitabine, published May 2017; and limits high levels of drug exposure during infusion. pemetrexed) phase III ATTAIN primary Additionally, the large drug–polymer conjugate might completion July 2020 preferentially accumulate in tumor tissues because of the PARP inhibitors (eg, increased permeability of tumor vasculature. In clinical trials, niraparib, olaparib, etirinotecan pegol is given as an intravenous infusion at a dose rucaparib) of 145 mg/m2 once every 21 days until disease progression or Taxanes (eg, docetaxel, intolerable toxicity. nab-paclitaxel, paclitaxel) Developer(s): Vinca alkaloid (eg, Nektar Therapeutics, Inc (San Francisco, California) vinorelbine)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Fam-trastuzumab deruxtecan-nxki (Enhertu; previous name DS- One or more of the Overall survival Clinical trial(s): Phase III older who have locally 8201) is a monoclonal antibody conjugated with a following: Progression-free survival DESTINY-Breast04 advanced or metastatic, chemotherapy drug (ie, deruxtecan) designed to bind the Alkylating agents (eg, Quality of life primary completion hormone receptor (HR)– surface receptor HER2, a protein commonly associated with cyclophosphamide) January 2023 positive or HR-negative, certain subtypes of breast cancer. Front-line therapy for breast Anthracyclines (eg, Note(s): FDA approved human epidermal growth cancers expressing low HER2 levels relies on single-agent doxorubicin, epirubicin, fam-trastuzumab factor receptor 2 (HER2)– chemotherapy, but no therapies are approved specifically for liposomal doxorubicin) deruxtecan-nxki to treat low breast cancer that low HER2-expressing tumors, and fam-trastuzumab Antimetabolites (eg, 5- HER2-positive breast has progressed or deruxtecan-nxki might provide a new option for these patients. fluorouracil, cancer in December 2019 recurred after one or two Deruxtecan inhibits the activity of topoisomerase I, an enzyme capecitabine, prior lines of systemic that relieves DNA supercoiling, leading cells to cease their cell gemcitabine, therapy cycle and die because of replication-dependent, site-selective, methotrexate, DNA double-strand breaks. Fam-trastuzumab deruxtecan-nxki pemetrexed) purportedly binds to HER2 and triggers internalization of the drug into the cells. This increases the likelihood that deruxtecan Immune checkpoint will target and kill malignant cells while minimizing toxicity on inhibitors (eg, normal cells. In clinical trials, fam-trastuzumab deruxtecan-nxki atezolizumab) is given intravenously at a dose of 5.4 mg/kg once every 21 days Microtubule inhibitors until disease progression or intolerable toxicity. (eg, eribulin, ixabepilone) Developer(s): PARP inhibitors (eg, Daiichi Sankyo Co, Ltd (Tokyo, Japan), in collaboration with olaparib, talazoparib) 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 Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Idasanutlin (RG7388) is a nutlin-class small-molecule drug that One or more of the Progression-free survival FDA designation(s): older who have blocks interactions between the mouse double minute 2 following: Overall survival Orphan Drug relapsed/refractory acute homolog protein (MDM2) and p53, a tumor suppressor protein Anthracyclines (eg, Quality of life Clinical trial(s): Phase III myeloid leukemia (AML) thought to be involved in up to half of AML cases. No FDA- daunorubicin, idarubicin) MIRROS primary that has not responded approved agents exist for restoring p53 activity. Standard AML Antibody–drug conjugate completion September to or has relapsed after chemotherapy lacks specificity, leading to a range of side effects (eg, gemtuzumab 2020 one or two induction and disease relapse over time, as well as poor responses in ozogamicin) regimens elderly patients. In some AML cases, MDM2 is thought to reduce Antimetabolites (eg, the amount of p53 by promoting its destruction through the cladribine, fludarabine) ubiquitin-proteasome system and by turning off p53’s transcriptional activation. Idasanutlin purportedly targets a Cytokine (eg, granulocyte small hydrophobic pocket on MDM2 that normally binds to p53. colony-stimulating factor) Idasanutlin purportedly stabilizes p53 by blocking the MDM2– DNA synthesis inhibitors p53 interaction, potentially activating downstream (eg, etoposide, transcriptional targets that keep AML cells from dividing, and mitoxantrone) initiates programmed cell death. In clinical trials, idasanutlin is FLT3 inhibitor (eg, given orally twice daily, at a dose of 300 mg in combination with gilteritinib) 2 cytarabine (1000 mg/m ) for the first 5 days of a 28-day cycle, Hypomethylating agents until complete remission or disease progression. (eg, azacitidine, Developer(s): decitabine) Genentech, Inc (South San Francisco, California), a subsidiary of IDH inhibitors (eg, F Hoffman-La Roche, Ltd (Basel, Switzerland) enasidenib, ivosidenib) Multikinase inhibitor (eg, sorafenib)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor One or more of the Overall survival Submission date: older who have relapsed (CAR) T-cell therapy that has been engineered to target the B- following: Progression-free survival Biologics License and refractory multiple cell maturation antigen (BCMA) using autologous T cells isolated Alkylating agents (eg, Quality of life Application planned for myeloma (RRMM) that from a patient’s blood sample. Patients whose disease has bendamustine, first half of 2020 has been treated with 3 progressed after 3 prior treatment lines have a very poor cyclophosphamide) FDA designation(s): or more lines of prognosis and no options, so they need new and better Anthracyclines (eg, Orphan Drug, chemotherapy that treatments. The collected T cells are genetically modified with a doxorubicin) Breakthrough Therapy included a protease lentiviral vector (ie, transduction) encoding CARs with a unique Glucocorticoids (eg, Clinical trial(s): Phase II inhibitor, an anti-BCMA single-chain variable fragment (ie, BB2121) fused to dexamethasone) KarMMa primary immunomodulatory the hinge and transmembrane domains of CD8α, the completion November agent, and an anti-CD38 costimulatory domain (ie, 4-1BB) of CD137, and the signaling Immunomodulatory agents (eg, lenalidomide, 2024, data reported antibody domains of CD3ζ. The BB2121 CAR-transduced T cells that December 2019; phase III comprise ide-cel are proliferated and then reintroduced into pomalidomide, thalidomide) KarMMa-3 primary the patient. Ide-cel purportedly targets malignant BCMA- completion June 2025 expressing plasma cells in patients with multiple myeloma cells Monoclonal antibodies and promotes robust cellular activity against these cells to treat (eg, daratumumab, the disease. BCMA has been proposed as a biomarker for elotuzumab) targeting multiple myeloma because it is highly expressed in Proteasome inhibitors malignant plasma cells. In clinical trials, ide-cel is given as a (eg, bortezomib, single intravenous infusion at a dose ranging from 1.5 × 108 to carfilzomib, ixazomib) 8 4.5 × 10 anti-BCMA CAR-T cells. Topoisomerase inhibitors Developer(s): (eg, etoposide) bluebird bio, Inc (Cambridge, Massachusetts), in collaboration with Bristol-Myers Squibb Co (New York, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Infigratinib (BGJ398) is a novel, highly selective, small-molecule One or more of the Overall survival FDA designation(s): older who have locally inhibitor of 3 members of the FGFR family (1, 2, and 3). following: Progression-free survival Orphan Drug, Fast Track advanced or metastatic, Cholangiocarcinoma is a rare cancer that forms in bile ducts, Antimetabolites (eg, Quality of life Clinical trial(s): Phase III recurrent which carry fluid between the liver, the gallbladder, and the gemcitabine) PROOF primary cholangiocarcinoma that small intestine. Because about 20% of cholangiocarcinoma Platinum agents (eg, completion September harbors fusions or cases contain FGFR2 genetic alterations, using infigratinib for cisplatin, oxaliplatin) 2023 translocations in the targeting only FGFRs has the potential to improve outcomes of fibroblast growth factor patients with limited treatment options, who usually have poor receptor 2 gene, FGFR2 health outcomes. Infigratinib is designed to specifically target FGFRs (with limited activity against FGFR4) and not bind to similar signaling domains in the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor. Infigratinib purportedly blocks new blood vessel formation (ie, angiogenesis), proliferation, and survival pathways in biliary tract cancer cells by inhibiting constitutive ligand-independent FGFR2 signaling. In some cholangiocarcinoma cases, the presence of activating FGFR alterations, including gene fusions and chromosome translocations, leads to uncontrolled cell proliferation. Eligibility for the therapy requires testing for FGFR2 gene rearrangements. In clinical trials, infigratinib is given daily 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Ivosidenib (Tibsovo) is a small-molecule inhibitor of a mutant One or more of the Overall survival Submission date: older who have locally form of the enzyme IDH1 that occurs in about 25% of following: Progression-free survival Supplemental New Drug advanced or metastatic intrahepatic cholangiocarcinomas. Cholangiocarcinoma is a rare Fluoropyrimidine-based Quality of life Application planned for cholangiocarcinoma that cancer that forms in bile ducts, which carry fluid between the chemotherapy fourth quarter of 2020 harbors a rearrangement liver, the gallbladder, and the small intestine. IDH1’s mutant Pembrolizumab (for FDA designation(s): in the isocitrate form causes a tumor-inducing metabolite (ie, D-2- patients with Orphan Drug dehydrogenase 1 gene, hydroxyglutarate) to accumulate while decreasing levels of microsatellite instability– Clinical trial(s): Phase III IDH1, and has been IDH1’s normal metabolite (ie, α-ketoglutarate). This metabolite high or mismatch repair ClarIDHy trial primary treated with at least one imbalance causes histone modification and DNA methylation deficient tumors) completion January 2019, previous line of systemic that dedifferentiates cells (ie, makes them lose specialized data presented therapy characteristics) and might lead to a neoplastic state (ie, cells September 2019 that divide more than normal). By inhibiting IDH1’s mutant Note(s): FDA approved form, ivosidenib purportedly prevents uncontrolled cell division ivosidenib to treat by leading cholangiocarcinoma cells to differentiate. Ivosidenib relapsed or refractory is given orally at a dose of 500 mg each day until disease IDH1-mutated acute progression or intolerable toxicity. myeloid leukemia (AML) Developer(s): in July 2018 and for newly Agios Pharmaceuticals, Inc (Cambridge, Massachusetts) diagnosed IDH1-mutated AML in May 2019
Adults aged 18 years or Lifileucel (LN-144) is an autologous cell therapy that uses T cells One or more of the Overall survival Submission Date: older who have locally isolated from the patient’s melanoma tumor. Lifileucel uses a following: Progression-free survival Biologics License advanced or metastatic personalized therapy strategy that relies on naturally occurring Alkylating agents (eg, Quality of life Application planned for melanoma that has T cells that can penetrate cancerous tumors and are called dacarbazine, fourth quarter of 2020 progressed after one or tumor-infiltrating lymphocytes (TILs). The extracted TILs are temozolomide) FDA designation(s): more previous lines of expanded in culture until reaching a count of billions of cells. BRAF inhibitors (eg, Orphan Drug, Fast Track, standard systemic Lifileucel is intended as a tumor-specific therapy to overcome dabrafenib, vemurafenib) Regenerative Medicine therapy the tumor’s immune-suppressive environment and promote its Immunotherapy (eg, Advanced Therapy elimination. In clinical trials, lifileucel is given as an intravenous ipilimumab, nivolumab, Clinical trial(s): Phase II C- infusion followed by up to 6 doses of interleukin-2 (IL-2) to pembrolizumab) 144-01 primary support growth and activation of TILs. MEK inhibitors (eg, completion March 2020, Developer(s): trametinib) safety and efficacy data Iovance Biotherapeutics, Inc (San Carlos, California), in presented May 2019, Platinum-based agents collaboration with the National Cancer Institute at the National data reported November (eg, carboplatin) Institutes of Health (Bethesda, Maryland) 2019 Taxane agents (eg, paclitaxel)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 years or LN-145 is an autologous T-cell therapy that uses cells isolated One or more of the Overall survival Submission date: older who have from the patient’s cervical cancer. LN-145 relies on naturally following: Disease-free survival Biologics License recurrent, metastatic, or occurring T cells called tumor infiltrating lymphocytes (TILs) that Alkylating agents (eg, Quality of life Application planned for persistent cervical cancer can penetrate cancerous tumors. TILs isolated from a patient’s ifosfamide) second half of 2020 that is unsuitable for tumor are expanded in culture until reaching a count of billions Angiogenesis inhibitors FDA designation(s): surgical resection and/or of cells. LN-145 is intended as a tumor-specific therapy that can (eg, bevacizumab) Breakthrough Therapy, radiation therapy. overcome the tumor’s immune-suppressive environment and Antimetabolites (eg, 5- Fast Track Patients must have promote its elimination. In clinical trials, LN-145 is given as an fluorouracil, gemcitabine, Clinical trial(s): Phase II received at least 1 and no intravenous infusion followed by up to 6 doses of interleukin-2 pemetrexed) innovaTIL-04 primary more than 3 prior (IL-2) to support growth and activation of TILs. DNA synthesis inhibitors completion December systemic therapy Developer(s): (eg, mitomycin-C) 2021, data presented regimens. Iovance Biotherapeutics, Inc (San Carlos, California) May 2019 Immune checkpoint inhibitor (eg, pembrolizumab) Taxanes (eg, albumin- bound paclitaxel, docetaxel) Topoisomerase inhibitors (eg, irinotecan)
Males aged 18 years or 177Lu-PSMA-617 is a novel small-molecule radioligand therapy Supportive care Overall survival Clinical trial(s): Phase III older who have comprising a high-affinity targeting ligand specific for PSMA that is Progression-free survival VISION primary 177 progressive prostate- chemically linked with a radionucleotide called lutetium-177 ( Lu). Time to first symptomatic completion August 2020; 177 specific membrane Lu-PSMA-617 is intended to deliver systemic and targeted skeletal event phase II primary antigen (PSMA)–positive, radiation, causing cell death to prostate cancer cells. PSMA protein completion April 2020, Quality of life metastatic, castration- is highly expressed on the surface of most prostate cancer cells but data presented May 2019 resistant prostate cancer absent on most normal cells. Eligibility for treatment requires a positive result from a 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) scan. After 177Lu- PSMA-617 purportedly attaches to prostate cancer cells via binding to PSMA, the 177Lu component emits beta-particle radiation intended to induce cytotoxic DNA damage to the tumor cells. In clinical trials, 177Lu-PSMA-617 is given intravenously at a dose of 7.4 GBq (±10%) every 6 weeks for a maximum of 6 cycles. Developer(s): Advanced Accelerator Applications (Millburn, New Jersey), a subsidiary of Novartis AG (Basel, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Lurbinectedin (Zepsyre) is a synthetic, marine-derived Chemoradiation therapy Overall survival PDUFA date: August 16, older who have compound that selectively inhibits transactivated RNA Platinum-based agents Progression-free survival 2020, Priority Review extensive-stage small cell polymerase II transcription. Patients with SCLC that is refractory (eg, carboplatin, cisplatin) Quality of life FDA designation(s): lung cancer (SCLC) to platinum chemotherapy have limited treatment options and Topoisomerase inhibitors Orphan Drug refractory to a single a poor prognosis, and they need new therapy options. (eg, etoposide, Clinical trial(s): Phase III platinum-containing Lurbinectedin selectively inhibits RNA polymerase (Pol) II activity topotecan) ATLANTIS primary regimen during the elongation phase of messenger RNA (mRNA) completion February synthesis. Although lurbinectedin interacts with RNA Pol II, it 2020; phase II PM1183-B- does not affect the activity of RNA Pol I, mitochondrial RNA Pol, 005-14 primary or basal transcription machinery. Lurbinectedin’s binding to completion January 2020, RNA Pol II and inhibition of mRNA synthesis purportedly data presented June 2019 induces cancer cell death by reducing the expression of cellular Note(s): New Drug factors involved in tumor progression. In clinical trials, Application filed under lurbinectedin is given intravenously at a dose of 4 mg once Accelerated Approval every 3 weeks in combination with doxorubicin until disease regulations progression or intolerable toxicity. Developer(s): Pharma Mar SA (Madrid, Spain), in collaboration with Jazz Pharmaceuticals plc (Dublin, Ireland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or MDNA55 is a cytokine that specifically targets the interleukin-4 One or more of the Overall survival FDA designation(s): older who have a receptor (IL-4R), a surface receptor reported to be following: Progression-free survival Orphan Drug, Fast Track recurrent malignant overexpressed in different types of cancer stem cells, including Alkylating agents (eg, Quality of life Clinical trial(s): Phase II glioma (eg, astrocytoma, those in GBM tumors. MDNA55 offers a novel approach for cyclophosphamide, MDNA55-05 primary glioblastoma multiforme treating IL-4R-expressing tumors because GBM does not temozolomide) completion December [GBM]) respond well to standard therapy, and patients need better Angiogenesis inhibitors 2019, data reported therapy options. MDNA55 is a genetically engineered fusion (eg, bevacizumab) January 2020 protein composed of a circularly permuted interleukin-4 mTOR inhibitors (eg, molecule fused to the catalytic domain of the bacterial everolimus) Pseudomonas aeruginosa exotoxin A (PE) protein. The fusion protein functions as a molecular decoy by binding IL-4R and Platinum agents (eg, triggering receptor-mediated endocytosis to deliver the carboplatin, cisplatin) cytotoxic PE payload into the cytoplasm. MDNA55 purportedly Vinca alkaloids (eg, has high specificity and affinity for IL-4R-expressing tumors to vincristine) deliver cell-killing payloads to cancer stem cells and immunosuppressive cells of the tumor microenvironment. MDNA55 has the potential to not only kill the tumor cells, but also “unblind” the immune system to cancer. MDNA55 is given as an infusion via convection-enhanced delivery (CED). Purportedly providing a safer, targeted delivery, CED uses a pressure gradient at the infusion catheter’s tip to push the therapeutic agent across the blood–brain barrier, through the brain’s interstitial spaces, and to the delivery site. In clinical trials, MDNA55 is infused at a single, unspecified dose. Developer(s): Medicenna Therapeutics Corp (Toronto, Ontario, Canada)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 74 Metformin is a biguanide drug (ie, a drug class that prevents Active surveillance Disease-free survival Clinical trial(s): Phase III years without diabetes glucose production in the liver) often used to treat type 2 Overall survival MA32 primary mellitus who have diabetes mellitus (T2DM). Some researchers think the drug Quality of life completion February localized breast cancer might benefit patients with breast cancer because retrospective 2022 that has been treated studies of patients with diabetes taking metformin and window- with surgical resection of-opportunity studies in the neoadjuvant breast cancer setting and neoadjuvant or have shown that metformin might have anticancer effects. adjuvant chemotherapy Metformin purportedly exerts its anticancer effects by activating adenosine monophosphate (AMP)–activated protein kinase, which limits downstream components of the mTOR pathway. Additionally, metformin’s actions in reducing circulating insulin levels and improving insulin resistance in patients without diabetes might be antineoplastic because of insulin’s potential growth-stimulating activity. In clinical trials, metformin is being given orally at a dose of 850 mg, twice daily, for up to 5 years in the absence of disease progression. Developer(s): Canadian Cancer Trials Group (Kingston, Ontario, Canada)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 78 Motixafortide (BL-8040) is a high-affinity antagonist for the CXC Stem cell transplantation Overall survival Clinical trial(s): Phase III years who have newly chemokine receptor 4 (CXCR4). This receptor is overexpressed after high-dose Progression-free survival GENESIS primary diagnosed multiple in about 70% of cancers, including multiple myeloma, and is chemotherapy with one Quality of life completion April 2019, myeloma and are eligible associated with disease severity. Motixafortide is intended to or more of the following: data reported March for autologous stem cell mobilize hematopoietic stem cells (HSCs) for autologous (ie, Alkylating agents (eg, 2019 transplantation self-donated) transplantation and delay multiple myeloma bendamustine, Note(s): BioLineRx progression after primary high-dose therapy. Motixafortide is a cyclophosphamide) anticipates that topline biostable, synthetic, cyclic peptide with 14 amino acid residues Anthracyclines (eg, results from GENESIS will that binds CXCR4 with high affinity. Expression of CXCR4 in doxorubicin) be available in the CD34+ HSCs is directly involved in their retention in the bone Glucocorticoids (eg, second half of 2020 marrow via binding to the CXCL12 chemokine protein. However, dexamethasone) in multiple myeloma, CXCR4 expression is also involved in tumor progression, angiogenesis, metastasis, and cell survival. Immunomodulatory As a CXCR4 antagonist, motixafortide purportedly leads to the agents (eg, lenalidomide, mobilization of CD34+ HSCs, multiple myeloma cells, and pomalidomide, immune cells into peripheral blood. Although mobilized CD34+ thalidomide) HSCs can be collected through apheresis for autologous Proteasome inhibitors transplantation, mobilized multiple myeloma cells are no longer (eg, bortezomib, protected in the bone marrow and are sensitive to maintenance carfilzomib, ixazomib) therapy after transplantation. In clinical trials, motixafortide is Topoisomerase inhibitors given as a single subcutaneous injection at a dose of 1.25 mg/kg (eg, etoposide) on day 1 in combination 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 × 106 cells/kg), treatment can be extended up to 2 days for motixafortide and up to 8 days for G-CSF. Developer(s): BioLineRx, Ltd (Tel Aviv, Israel), in collaboration with Biokine Therapeutics, Ltd (Rehovot, Israel)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or N-803 (formerly ALT-803) is a novel interleukin-15 (IL-15) One or more of the Overall survival FDA designation(s): Fast older who have bacillus superagonist complex. NMIBC is unresponsive to standard BCG following: Progression-free survival Track, Breakthrough Calmette-Guérin (BCG)– treatment in about half of affected patients, whose disease then Anthracyclines (eg, Quality of life Therapy unresponsive, high- progresses. N-803 is intended to provide an option after BCG epirubicin, valrubicin) Clinical trial(s): Phase II grade, non–muscle treatment has failed. N-803 purportedly generates rapid and Antimetabolites (eg, QUILT-3.032 primary invasive bladder cancer durable immune responses against NMIBC by simultaneously gemcitabine) completion December (NMIBC) mobilizing both innate and adaptive immune cells to infiltrate DNA synthesis inhibitors 2019, preliminary data the tumor. While IL-15 and IL-15α enhance cytotoxic T-cell (eg, mitomycin-C) presented May 2019 proliferation, immunoglobulin G1 Fc domain (IgG1 Fc) activates NK (natural killer) cell–specific, antibody-dependent, cell- Taxanes (eg, docetaxel) mediated cytotoxicity. In clinical trials, N-803 is mixed with BCG and given as an intravesical (ie, within the bladder) instillation at an unspecified dose weekly for 6 consecutive weeks. At month 3, patients receive either a 3-week maintenance course or a 6- week reinduction course. Subsequently, patients receive 3-week maintenance treatment at 6, 9, 12, and 18 months. Developer(s): ImmunityBio (Miramar, Florida), in collaboration with AGC Biologics, Inc (Bothell, Washington)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Nanoparticle albumin-bound sirolimus (nab-sirolimus; ABI-009) One or more of the Overall survival Submission date: New older who have locally is an mTOR inhibitor associated with human albumin following: Progression-free survival Drug Application planned advanced or metastatic nanoparticles through noncovalent hydrophobic interactions. Alkylating agents (eg, Quality of life for second quarter of perivascular epithelioid Nab-sirolimus has been developed to block the mTOR pathway, dacarbazine, 2020 cell tumor (PEComa) which is involved in cell proliferation frequently activated in temozolomide, FDA designation(s): PEComas by genetic mutations in the TSC complex subunit 1 trabectedin) Orphan Drug, Fast Track, and/or 2 genes, TSC1 and/or TSC2. PEComa is a rare type of Anthracyclines (eg, Breakthrough Therapy sarcoma originating from the soft tissues lining organs, such as doxorubicin, epirubicin, Clinical trial(s): Phase II the intestines, lungs, and stomach. PEComas are malignant in liposomal doxorubicin) AMPECT primary rare cases and have potential to spread to other body parts. No Antimetabolites (eg, completion September approved treatments exist for PEComas, and standard sarcoma gemcitabine, ifosfamide) 2020, data reported cytotoxic chemotherapies have minimal survival benefit. Nab- November 2019 sirolimus purportedly enters proliferating tumor cells via Microtubule inhibitors endocytosis and macropinocytosis to have higher accumulation (eg, eribulin, vinorelbine) and better efficacy than other mTOR inhibitors. Testing for mTOR inhibitors (eg, TSC1/2 mutation status will require use of a companion everolimus, sirolimus, diagnostic. In clinical trials, nab-sirolimus is given by temsirolimus) intravenous infusion at a weekly dose of 100 mg/m2 in a 2- Multikinase inhibitors (eg, week-on, 1-week-off schedule until disease progression or imatinib, pazopanib, intolerable toxicity. regorafenib, sorafenib, Developer(s): sunitinib) Aadi Bioscience, Inc (Pacific Palisades, California)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Napabucasin (BBI608) is a small-molecule inhibitor of the One or more of the Overall survival Clinical trial(s): Phase III older who have mitogenic signal transducer and activator of the transcription 3 following: Progression-free survival CanStem303C primary metastatic colorectal (STAT-3) pathway. Napabucasin’s novel mechanism of action is Angiogenesis inhibitors Quality of life completion June 2020; cancer (CRC) that has intended to treat CRC that does not respond to second-line (eg, bevacizumab, phase III primary been treated with a chemotherapy, by purportedly targeting and killing cancer stem ramucirumab) completion November single systemic cells in tumors. Cancer stem cells are associated with treatment Antimetabolites (eg, 5- 2021 chemotherapy regimen resistance, metastasis, and poor prognosis. In clinical trials, fluorouracil, Note(s): Napabucasin is based on napabucasin is given orally at a dose of 240 mg twice daily in capecitabine) also being evaluated for fluoropyrimidine and combination with the multiagent cytotoxic chemotherapy EGFR antibodies (eg, metastatic pancreatic oxaliplatin regimen FOLFIRI (ie, leucovorin [folinic acid], 5-fluorouracil, and cetuximab, cancer and multiple solid irinotecan), with or without the addition of bevacizumab, until panitumumab) malignancies. FDA disease progression or intolerable toxicity. granted Orphan Drug FOLFIRI Developer(s): status for pancreatic FOLFOX (ie, leucovorin Boston Biomedical, Inc (Cambridge, Massachusetts), a cancer. [folinic acid], 5- subsidiary of Sumitomo Dainippon Pharma Co, Ltd (Osaka, fluorouracil, and Japan) oxaliplatin) 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 Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 22 years or NovoTTF-100L is a device intended to treat solid tumors by One or more of the Overall survival Clinical trial(s): Phase III older who have exposing them to low-intensity, intermediate-frequency, following: Progression-free survival LUNAR primary metastatic non–small cell alternating electric fields (ie, tumor-treating fields [TTFs]). TTFs Immune checkpoint Quality of life completion December lung cancer (NSCLC) that purportedly disrupt cell division through effects on charged inhibitors (eg, 2021 has progressed after macromolecules and organelles within cancer cells, potentially atezolizumab, nivolumab) first-line, platinum-based limiting tumor growth. NovoTTF-100L is a battery-powered field Taxanes (eg, docetaxel) therapy generator coupled to an electrode array that is attached to the skin of the patient’s torso as a noninvasive device. The patient applies TTF therapy in the home setting 24 hours a day, 7 days a week. The therapy is intended for use in combination with standard systemic therapies for metastatic NSCLC. Developer(s): Novocure, Ltd (St Helier, Jersey, United Kingdom)
Adults aged 18 years or NovoTTF-100M is a device intended to treat solid tumors by Radiation therapy (eg, Overall survival Clinical trial(s): Phase III older who have exposing them to low-intensity, intermediate-frequency, stereotactic radiosurgery, Progression-free survival METIS primary metastatic non–small cell alternating electric fields (ie, tumor-treating fields [TTFs]). TTFs whole-brain Quality of life completion December lung cancer (NSCLC) and purportedly disrupt cell division through effects on charged radiotherapy) 2020 newly diagnosed brain macromolecules and organelles within cancer cells, potentially In lieu of upfront metastases that have limiting tumor growth. The NovoTTF-100M device is a battery- radiation therapy, been treated with powered field generator coupled to 4 electrically insulated systemic therapy with stereotactic radiosurgery electrode arrays attached to the skin of the patient’s head. In one of the following: clinical trials, TTF therapy is given in the home setting 24 hours ALK inhibitors (eg, a day, 7 days a week and is intended for use in combination alectinib, brigatinib, with the best supportive treatment available until disease ceritinib) if ALK progression or intolerable toxicity. rearrangement positive Developer(s): EGFR inhibitors (eg, NovoCure, Ltd (St Helier, Jersey, United Kingdom) osimertinib) if EGFR variant positive Immune checkpoint inhibitors (eg, nivolumab, pembrolizumab) if PD-L1 positive
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 4 years or NY-ESO-1 SPEAR T cells (GSK3377794) are an autologous cell One or more of the Overall survival FDA designation(s): older and adults who therapy engineered from T cells collected from a patient’s following: Progression-free survival Breakthrough Therapy have locally advanced or peripheral blood. Patients with synovial sarcoma have limited Alkylating agents (eg, Quality of life Clinical trial(s): Phase I/II metastatic synovial treatment options, and NY-ESO-1 SPEAR T cells could represent dacarbazine, 208466 primary sarcoma that has not a new option. In this therapy, T cells are genetically modified temozolomide) completion December been previously treated with a retroviral vector (ie, transduction) encoding a T-cell Anthracyclines (eg, 2019, data published or has progressed or receptor that recognizes a specific antigen in NY-ESO-1 (New doxorubicin, epirubicin) August 2018, data recurred after one line of York esophageal squamous cell carcinoma-1), a protein with Antimetabolites (eg, published October 2019; chemotherapy restricted expression in testis and ovaries that is reexpressed in gemcitabine, ifosfamide) phase II 208467 primary up to 80% of synovial sarcomas. Successfully transduced cells completion January 2022 are activated, expanded, and then frozen until use. NY-ESO-1 DNA synthesis inhibitors SPEAR T cells purportedly strengthen the patient’s natural T-cell (eg, mitomycin-C) responses against cancer cells expressing NY-ESO-1. In clinical Microtubule inhibitors trials, after thawing, NY-ESO-1 SPEAR T cells are given as an (eg, eribulin, vinorelbine) intravenous infusion at an initial dose ranging from 1 × 109 to Multikinase inhibitors (eg, 6 × 109 cells. Patients who have a confirmed response or stable pazopanib, sorafenib) disease for 3 or more months might receive a second NY-ESO-1 Tropomyosin receptor SPEAR T-cell infusion. kinase inhibitor (eg, Developer(s): larotrectinib) GlaxoSmithKline plc (Brentford, United Kingdom)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 years or Ofranergene obadenovec (VB-111) is an adeno-associated viral One or more of the Overall survival Clinical trial(s): Phase III older who have vector therapy intended for recurrent platinum-resistant ovarian following: Progression-free survival OVAL primary completion recurrent, platinum- cancer. It is intended to induce programmed cell death in Angiogenesis inhibitors Quality of life December 2022 resistant ovarian cancer angiogenic endothelial cells in the tumor microenvironment as (eg, bevacizumab) Note(s): European well as inducing cellular immune responses against the tumor. Anthracyclines (eg, Commission has granted Patients with recurrent platinum-resistant ovarian cancer have a doxorubicin, pegylated ofranergene obadenovec poor prognosis and need more effective treatment options. VB- liposomal doxorubicin) Orphan Drug designation 111 purportedly penetrates and introduces a propriety Taxanes (eg, docetaxel, angiogenesis-specific promoter that specifically induces cell death paclitaxel) in angiogenic endothelial cells in the tumor 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 × 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)
Males aged 18 to 99 Olaparib (Lynparza) is a small-molecule drug intended to inhibit Abiraterone alone Progression-free survival Clinical trial(s): Phase III years who have poly adenosine diphosphate-ribose polymerase (PARP), which Docetaxel Overall survival PROpel primary metastatic, castration- functions in a DNA repair pathway. Olaparib might provide a Enzalutamide Quality of life completion April 2021 resistant prostate cancer novel and potentially synergistic mechanism of action when Note(s): FDA approved (mCRPC) that is being used with abiraterone to treat newly diagnosed mCRPC. olaparib to treat ovarian treated with androgen- Cancers are often deficient in a DNA repair pathway, and when cancer in December 2014 deprivation therapy but PARP is also inhibited, the loss of 2 types of DNA repair results and to treat breast has not yet been treated in cancer cell death in response to DNA damage. Preclinical cancer in January 2018 with chemotherapy or a studies have indicated that cross-talk might exist between newer hormonal agent androgen receptor signaling pathways and PARP. In clinical (ie, abiraterone or trials, olaparib is being studied in combination with the enzalutamide) at the hormone synthesis inhibitor abiraterone. Olaparib is given mCRPC stage orally, at a dose of 300 mg, twice daily, in addition to abiraterone, until disease progression or intolerable toxicity. Developer(s): AstraZeneca plc (Cambridge, United Kingdom), in collaboration with Merck & Co, Inc (Kenilworth, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Males aged 18 years or Olaparib (Lynparza) is a small-molecule drug intended to inhibit Abiraterone Overall survival PDUFA date: second older who have poly adenosine diphosphate-ribose polymerase (PARP), which Cabazitaxel Progression-free survival quarter of 2020 metastatic, castration- functions in a DNA repair pathway. Olaparib might improve Docetaxel Quality of life FDA designation(s): resistant prostate cancer patients’ overall survival as a single agent and when used in a Enzalutamide Breakthrough Therapy (mCRPC) that harbors a combination by potentially providing a synergistic mechanism Pembrolizumab for Clinical trial(s): Phase III mutation in 1 of 15 genes of action for treating prostate cancer in patients with poor PROfound primary involved in homologous overall outcomes. Cancers are often deficient in a DNA repair tumors that are microsatellite instability– completion June 2019, recombination repair and pathway, and with the addition of PARP inhibition, the loss of 2 data reported August has been treated with types of DNA repair results in cancer cell death in response to high or mismatch repair deficient 2019, data presented one or more newer DNA damage. Olaparib purportedly induces cell death in October 2019; phase II Radium 223 (for bone- hormonal agents (ie, prostate tumors that harbor germline mutations in one of completed July 2012, data predominant disease abiraterone and/or several genes involved in the homologous recombination repair published January 2015; with no organ enzalutamide) (HRR) pathway, providing a way to treat tumors for patients phase II completed involvement) with limited options. Treatment eligibility will require testing for December 2019; phase III specific germline gene mutations. In clinical trials, olaparib is primary completion given orally, at a dose of 300 mg, twice daily until disease October 2021; phase II progression or intolerable toxicity. TRAP primary completion Developer(s): November 2021 AstraZeneca plc (Cambridge, United Kingdom), in collaboration Note(s): Myriad Genetics, with Merck & Co, Inc (Kenilworth, New Jersey) Inc (Salt Lake City, Utah), has expanded its collaboration with the developers and will work to identify germline mutations in males enrolled in the PROfound study. FDA approved olaparib to treat BRCA- mutated ovarian cancer in December 2018.
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 12 years or Omidubicel (NiCord) is an allogeneic stem cell therapy derived Allogeneic bone marrow Bone marrow FDA designation(s): older and adults aged up from umbilical cord blood that has been multiplied in a transplantation engraftment rate Orphan Drug, to 65 years who have a laboratory using proprietary nicotinamide (NAM) technology. Pooled unexpanded cord Neutrophil recovery rate Breakthrough Therapy hematologic malignancy Omidubicel is intended as a curative approach for high-risk blood transplantation Platelet recovery rate Clinical trial(s): Phase III (ie, acute lymphoblastic blood cancers in patients who have no fully matched donor Unexpanded cord blood Overall survival primary completion leukemia, acute available. The therapy is intended to efficiently and quickly transplantation December 2019 myelogenous leukemia, restore blood and immune cells and improve resistance to Note(s): Gamida Cell chronic myelogenous infections and related complications. NAM purportedly expects to report topline leukemia, or prevents umbilical cord blood cells from differentiating rapidly phase III data in the + – – myelodysplastic in culture, resulting in increased stem cells (CD34 CD38 Lin ). second quarter of 2020 syndrome) 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)
Children aged 3 years or ONC201 is a small-molecule imipridone (a class of anticancer One or more of the Overall survival FDA designation(s): Fast older and adults who compounds) that acts as an antagonist of the G-protein coupled following: Progression-free survival Track have a recurrent high- receptor dopamine D2 receptor. ONC201 has a novel mechanism Alkylating agents (eg, Quality of life Clinical trial(s): Phase II grade glioma that of action intended to provide an option for patients who have few carmustine, ONC013 primary harbors a K27M effective treatment options and poor prognosis after recurrence. temozolomide) completion December rearrangement in the ONC201-mediated antagonism of D2 receptor purportedly Angiogenesis inhibitors 2020; phase II ONC006 histone gene, H3 inactivates the ras pathway, a driver of cell growth and (eg, bevacizumab) primary completion proliferation, and activates the integrated stress response, which Vinca alkaloids (eg, December 2020, data can activate cell death pathways. Patients with gliomas harboring vincristine) published January 2020; K27M variants in the H3 gene have a poor prognosis, and unphased Expanded preclinical data have indicated these gliomas might be susceptible Access Program, data to treatment with a D2 antagonist. Eligibility for the therapy will published October 2019 require testing for the H3 K27M variant. In clinical trials, ONC201 is given orally at an unspecified dose and time frame. Developer(s): Oncoceutics, Inc (Philadelphia, Pennsylvania)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Oportuzumab monatox (Vicinium) is an antibody–drug Cystectomy Time to cystectomy Submission date: Rolling older who have non– conjugate comprising a humanized monoclonal antibody Transurethral resection Overall survival Biologics License muscle invasive bladder fragment specific for the epithelial cell adhesion molecule of bladder tumor (TURBT) Disease-free survival Application initiated cancer (NMIBC) that is (EpCAM) linked to a truncated form of Pseudomonas aeruginosa December 2019 Intravesicular Quality of life refractory to, or has exotoxin A (PE). PE is a cytotoxic agent that inhibits protein chemotherapy with one FDA designation(s): Fast relapsed after, at least 2 synthesis through inactivation of elongation factor-2. EpCAM is or more of the following: Track intravesicular treatments highly expressed by bladder cancer cells. Oportuzumab Anthracyclines (eg, Clinical trial(s): Phase III with bacillus Calmette- monatox is intended to preferentially deliver the linked valrubicin) VISTA primary Guérin (BCG) exotoxin to these cells and delay the time to major surgery (ie, completion December cystectomy) and surgery’s associated side effects (eg, urinary Antimetabolites (eg, gemcitabine) 2020, preliminary data diversion). In clinical trials, oportuzumab monatox is given reported August 2019 intravesically (ie, into the bladder) at a dose of 30 mg in an DNA synthesis inhibitors office setting. In a clinical trial, treatment involves a 12-week (eg, mitomycin-C) induction phase (12 twice-weekly instillations followed by 6 weekly instillations) and a maintenance phase of instillations once every 2 weeks for up to 2 years. Developer(s): Sesen Bio (Cambridge, Massachusetts)
Adults aged 18 to 99 Pamiparib (BGB-290) is a small-molecule inhibitor of 2 enzymes One or more of the Overall survival Clinical trial(s): Phase III years who have involved in DNA repair, the poly adenosine diphosphate-ribose following: Progression-free survival PARALLEL 303 primary inoperable, locally polymerases I and II (PARP1/2). Pamiparib’s inhibition of Anthracyclines (eg, Quality of life completion June 2020 advanced or metastatic PARP1/2 causes mitotic defects such as centrosome epirubicin) gastric cancer or amplification, multipolar spindles, chromosome misalignment, Antimetabolites (eg, 5- gastroesophageal premature loss of cohesion, metaphase arrest, anaphase DNA fluorouracil, junction cancer that has bridges, lagging chromosomes, and micronuclei. Patients with capecitabine) responded to a previous advanced gastric cancer usually experience recurrence and HER2 antibodies (eg, line of platinum-based need effective options to delay progression. Maintenance trastuzumab) chemotherapy therapy with pamiparib purportedly mediates death of gastric cancer cells that survived platinum-based chemotherapy Platinum-based agents regimens by inhibiting PARP1/2’s DNA repair. In clinical trials, (eg, carboplatin, cisplatin, pamiparib 60 mg is given orally twice daily until disease oxaliplatin) progression or intolerable toxicity. Taxanes (eg, docetaxel, Developer(s): paclitaxel) BeiGene, Ltd (Shanghai, China)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Patidegib (BBP-009) is a hedgehog pathway inhibitor intended to Radiation therapy Overall survival FDA designation(s): older with Gorlin-Goltz treat basal cell carcinomas and reduce disease burden and Surgical resection Progression-free survival Orphan Drug, syndrome, also known as symptoms in patients with BCCNS. Basal cell carcinoma is usually Systemic chemotherapy Quality of life Breakthrough Therapy basal cell carcinoma treated with surgery, radiation, or chemotherapy (topical or (eg, vismodegib) Clinical trial(s): Phase III nevus syndrome systemic), all of which have limited efficacy, can be hard to Topical chemotherapy Pelle-926-301 primary (BCCNS), who have tolerate, and might not prevent new tumor growth. Patients with (eg, 5-fluorouracil, completion May 2020 developed basal cell BCCNS harbor a mutation in the patched 1 gene, PTCH1, which imiquimod) carcinomas encodes a negative regulator (PTC1) of hedgehog pathway protein Smoothened (Smo). Without functional PTC1 to block Smo, the hedgehog pathway becomes active and causes basal cells to multiply uncontrollably into tumors. Patidegib is designed to inhibit this pathway and, in so doing, purportedly reduces tumor burden and BCCNS-associated symptoms in patients who cannot receive or experience serious side effects from standard treatment. In clinical trials, patidegib is used as a 2% topical gel applied twice daily to the face for at least 12 months. Developer(s): PellePharm, Inc (San Francisco, California), a subsidiary of BridgeBio, Inc (Palo Alto, California), in collaboration with LEO Pharma A/S (Ballerup, Denmark)
Adults aged 18 years or Pegargiminase (ADI-PEG 20) is a pegylated preparation of the One or more of the Overall survival FDA designation(s): older who have enzyme arginine deiminase, which catalyzes the hydrolysis of following: Progression-free survival Orphan Drug malignant pleural arginine, depleting the supply of this essential amino acid from Antimetabolites (eg, Quality of life Clinical trial(s): Phase II/III mesothelioma that has the bloodstream. Cells of many tumor types cannot pemetrexed) ATOMIC primary not been treated with autonomously synthesize arginine and, therefore, might be Platinum agents (eg, completion October 2020 systemic therapies and sensitive to arginine depletion. In particular, tumor cells that cisplatin) exhibits low expression express low levels of ASS1 (involved in cellular arginine of the argininosuccinate synthesis) might be dependent on exogenous arginine. This is synthase 1 gene, ASS1 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults 18 years or older Pembrolizumab (Keytruda) is a monoclonal antibody that BCG monotherapy Overall survival Approval date: January 8, who have bacillus targets the programmed death-1 (PD-1) coinhibitory receptor Cystectomy Progression-free survival 2020 Calmette-Guérin (BCG)– expressed by activated T cells. About half of patients with Intravesical Quality of life Clinical trial(s): Phase III unresponsive, high-risk, NMIBC will have recurrent disease after BCG induction therapy, chemotherapy with one KEYNOTE-676 primary non–muscle invasive and the disease in these patients is more likely to advance. or more of the following: completion May 2022; bladder cancer (NMIBC) Pembrolizumab might provide a treatment option. A hallmark Anthracyclines (eg, phase II KEYNOTE-057 with carcinoma in situ of cancer is its ability to evade an immune response. Several epirubicin, valrubicin) primary completion June (CIS) with or without types of cancer cells, including NMIBC, activate an immune 2022, data presented Antimetabolites (eg, papillary tumors and who checkpoint pathway in T cells by overexpressing the February 2019 gemcitabine) are ineligible for or have programmed death-ligand 1 (PD-L1), which binds to PD-1 and Note(s): FDA has DNA synthesis inhibitors elected not to undergo limits the activation of cancer-specific T cells. Pembrolizumab approved (eg, mitomycin-C) cystectomy purportedly prevents the interaction between PD-1 and PD-L1 pembrolizumab to treat to release the brake on the immune checkpoint pathway. Taxanes (eg, docetaxel) many other cancers. See Pembrolizumab in combination with BCG may overcome FDA-approved labeling NMIBC’s immune tolerance by enhancing cancer-specific T-cell and prescribing responses. An oncologist prescribes pembrolizumab. The document for all recommended regimen in the FDA-approved label is an approved indications. intravenous infusion at a dose of 200 mg, once every 3 weeks, until disease progression or unacceptable toxicity; or up to 24 months without disease progression in combination with BCG induction therapy administered as an intravesical instillation at a weekly dose of 50 mg, for 6 consecutive weeks. Subsequently, patients receive a 3-week maintenance course of BCG at months 3, 6, 9, 12, 18, 24, 30, and 36. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Clinical trial(s): Phase III older who have locally targets the programmed death-1 (PD-1) coinhibitory receptor following: Progression-free survival KEYNOTE-590 primary advanced or metastatic expressed by activated T cells. Front-line therapy for Anthracyclines (eg, Quality of life completion May 2022 esophageal carcinoma or esophageal carcinoma relies on platinum-based chemotherapy, epirubicin) Note(s): FDA has esophagogastric junction but response rates are low and no second-line therapies exist. Antimetabolites (eg, 5- approved (EGJ) carcinoma that is Pembrolizumab is intended to provide an option for these fluorouracil, pembrolizumab to treat unsuitable for surgery patients. A hallmark of cancer is its ability to evade an immune capecitabine) many other cancers. See and has not been response. Several types of cancer cells, including esophageal HER2 antibodies (eg, FDA-approved labeling previously treated and EGJ carcinomas, activate an immune checkpoint pathway in trastuzumab) and prescribing T cells by overexpressing the programmed death-ligand 1 (PD- document for all Platinum agents (eg, L1), which binds to PD-1 and limits the activation of cancer- approved indications. specific T cells. Pembrolizumab purportedly prevents the carboplatin, cisplatin, interaction between PD-1 and PD-L1 to overcome the immune oxaliplatin) tolerance of esophageal and EGJ carcinomas by enhancing Taxanes (eg, docetaxel, cancer-specific T-cell responses. In clinical trials, paclitaxel) pembrolizumab is given as an intravenous infusion at a dose of 200 mg, once every 3 weeks, for up to 24 months. Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival Approval date: June 11, older who have locally targets the programmed death-1 (PD-1) coinhibitory receptor following: Progression-free survival 2019 advanced or metastatic, expressed by activated T cells. Because most patients with Antimetabolites (eg, 5- Quality of life Clinical trial(s): Phase III recurrent head and neck HNSCC have disease recurrence after treatment with standard fluorouracil, KEYNOTE-048 primary squamous cell carcinoma platinum-based chemotherapy, pembrolizumab is intended to capecitabine, completion February (HNSCC) provide an option for these patients. A hallmark of cancer is its gemcitabine, 2019, data published ability to evade an immune response. Several types of cancer methotrexate) October 2019 cells, including HNSCC, activate an immune checkpoint pathway EGFR inhibitor (eg, Note(s): FDA has in T cells by overexpressing PD-L1, which binds to PD-1 and cetuximab) approved limits the activation of cancer-specific T cells. Pembrolizumab Platinum-based drugs pembrolizumab to treat purportedly prevents the interaction between PD-1 and PD-L1 (eg, carboplatin, cisplatin) many other cancers. See in an effort to overcome the immune tolerance of HNSCC by FDA-approved labeling enhancing cancer-specific T-cell responses. The recommended Taxanes (eg, docetaxel, paclitaxel) and prescribing regimen in the FDA-approved label is an intravenous infusion at document for all a dose of 200 mg, once every 3 weeks, until disease progression approved indications. or unacceptable toxicity; or up to 24 months without disease progression. Pembrolizumab is also given in combination with intravenous cisplatin (100 mg/m2) or carboplatin (AUC 5) plus 5- fluorouracil (1000 mg/m2). Developer(s): Merck & Co, Inc (Kenilworth, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Pembrolizumab (Keytruda) is a monoclonal antibody that One or more of the Overall survival FDA designation(s): older who have stage IV targets the programmed death-1 (PD-1) coinhibitory receptor following: Progression-free survival Breakthrough Therapy colorectal cancer (CRC) expressed by activated T cells. Pembrolizumab is intended to Angiogenesis inhibitors Quality of life Clinical trial(s): Phase III that is microsatellite provide a targeted option for patients with MSI-H or dMMR (eg, bevacizumab) KEYNOTE-177 primary instability–high (MSI-H) or colorectal cancers, which make up 15% to 20% of nonhereditary Antimetabolites (eg, 5- completion December mismatch repair deficient cases and most hereditary cases. A hallmark of cancer is its fluorouracil, 2021 (dMMR) and has not ability to evade an immune response. Several types of cancer capecitabine) Note(s): FDA has been previously treated cells, including colorectal cancer cells, activate an immune EGFR antibodies (eg, approved checkpoint pathway in T cells by overexpressing the cetuximab, pembrolizumab to treat programmed death-ligand 1 (PD-L1), which binds to PD-1 and panitumumab) many other cancers. See limits the activation of cancer-specific T cells. Pembrolizumab FOLFIRI (ie, leucovorin FDA-approved labeling purportedly prevents the interaction between PD-1 and PD-L1 and prescribing to overcome CRC’s immune tolerance by enhancing cancer- [folinic acid], 5- fluorouracil, and document for all specific T-cell responses. Tumors with MSI-H or dMMR are also approved indications. purportedly more susceptible to pembrolizumab than tumors irinotecan) with low MSI. In clinical trials, pembrolizumab is given as an FOLFOX (ie, leucovorin intravenous infusion at a dose of 200 mg, once every 3 weeks, [folinic acid], 5- for up to 24 months. fluorouracil, and Developer(s): oxaliplatin) Merck & Co, Inc (Kenilworth, New Jersey) Multikinase inhibitors (eg, regorafenib) Platinum-based agents (eg, oxaliplatin) Topoisomerase inhibitors (eg, irinotecan)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 years or Pembrolizumab (Keytruda) plus lenvatinib (Lenvima) is a One or more of the Overall survival Approval date: older who have advanced combination therapy consisting of an anti-PD-1 (programmed following: Progression-free survival September 17, 2019 endometrial carcinoma death-1) monoclonal antibody (ie, pembrolizumab) and a Anthracyclines (eg, Quality of life FDA designation(s): (EC) that is not multikinase inhibitor (ie, lenvatinib). Pembrolizumab and doxorubicin) Breakthrough Therapy microsatellite instability– lenvatinib purportedly inhibit cancer growth and/or survival by mTOR inhibitors (eg, Clinical trial(s): Phase III high (MSI-H) or mismatch inhibiting immune checkpoint and receptor tyrosine kinase– everolimus, KEYNOTE-775 primary repair deficient (dMMR), mediated neoplastic signaling, respectively. Neither drug has temsirolimus) completion February who have disease shown high levels of efficacy as a single agent when used in Taxanes (eg, docetaxel, 2022; phase I/II primary progression following patients with EC who are not selected by genetic testing for paclitaxel) completion April 2020, prior systemic therapy biomarkers. However, investigators hypothesize that combined interim data published and are not candidates use of these agents might improve outcomes. This hypothesis is Platinum agents (eg, carboplatin, cisplatin) May 2019, data for curative surgery or based not only on the additive nature of the 2 agents, but also presented September radiation. on lenvatinib’s purported inhibition of vascular endothelial 2019 growth factor receptor (VEGFR)–mediated immunosuppression, Note(s): The Accelerated which might induce a pembrolizumab immune response. An Approval was based on oncologist prescribes the combination therapy. The tumor response rate and recommended regimen in the FDA-approved label is an durability of response. intravenous infusion at a dose of 200 mg, once every 3 weeks, Continued approval may until disease progression or unacceptable toxicity, or up to 24 be contingent on months without disease progression, in combination with oral verification and lenvatinib at a dose of 20 mg daily. description of clinical Developer(s): benefit in the Merck & Co, Inc (Kenilworth, New Jersey), in collaboration with confirmatory trials. FDA Eisai Co, Ltd (Tokyo Japan) has approved pembrolizumab to treat many other cancers. See FDA-approved labeling and prescribing document for all approved indications.
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Pexidartinib (Turalio) is a small-molecule multikinase inhibitor. It Imatinib (off label) Response rate Approval date: August 2, older who have a exhibits activity against several receptor tyrosine kinases, including Radiation therapy Patient-reported physical 2019 symptomatic colony-stimulating factor 1 receptor (CSF1R), FMS-like tyrosine function (PROMIS FDA designation(s): tenosynovial giant cell kinase 3, and KIT. No FDA-approved interventions are available to [Patient-reported Orphan Drug, tumor (TGCT) that is treat TGCT, and patients need effective options. TGCTs typically Outcomes Measurement Breakthrough Therapy associated with severe overexpress colony-stimulating factor 1 (CSF1), which is an Information System] Clinical trial(s): Phase III morbidity or functional activating ligand for CSF1R. TGCT-expressed CSF1 leads to physical function scale) ENLIVEN primary limitations and is not recruitment of CSF1R-expressing cells, such as osteoclasts, Patient-reported pain completion March 2017, amenable to macrophages, and mast cells, which initiate an inflammatory and stiffness data published August improvement with reactive process that contributes to TGCT pathogenesis. Therefore, Quality of life 2019 surgery inhibiting CSF1R by pexidartinib might limit CSF1/CSF1R-driven attraction via chemotaxis of inflammatory cells and limit the proinflammatory process underlying TGCT. The recommended dose in the FDA-approved label states an oral dose of 200 mg is to be taken twice daily for a total of 400 mg until disease progression or intolerable toxicity. The medication is to be taken on an empty stomach, at least 1 hour before or 2 hours after a meal or snack. Developer(s): Daiichi Sankyo, Inc (Tokyo, Japan)
Adults aged 18 years or Plinabulin is a marine fungus–derived microtubule inhibitor Myelosuppressive Neutropenia Submission date: New older who have advanced intended to prevent chemotherapy-induced neutropenia (ie, loss of chemotherapy with Thrombocytopenia Drug Application planned or metastatic cancer (eg, neutrophils), which occurs in most patients with cancer who are adjunctive long-lasting G- Infection incidence for fourth quarter of breast cancer, non–small receiving myelosuppressive chemotherapy. Neutropenia renders CSF (eg, pegfilgrastim) 2020 Quality of life cell lung cancer, prostate patients susceptible to complications, including infection, because Clinical trial(s): Phase II/III cancer) that has the cytotoxic regimens they receive also deplete blood-forming Protective-1 primary progressed after at least cells in the bone marrow. Unlike granulocyte colony-stimulating completion February one previous line of factor (G-CSF) that promotes growth of white blood progenitor cells 2020, data reported treatment to restore neutrophils, plinabulin’s novel mechanism of action (ie, November 2019; phase targets microtubules differently from taxanes and vinca alkaloids) II/III Protective-2 primary purportedly facilitates the release of cytokines that protect completion March 2020, neutrophils from programmed cell death (ie, apoptosis). In clinical data presented February trials, plinabulin is given as an intravenous infusion at a dose from 2020 5 to 40 mg/m2. Treatment with plinabulin continues until completion of systemic chemotherapy. Developer(s): BeyondSpring Pharmaceuticals, Inc (New York, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Pracinostat is an oral histone deacetylase (HDAC) inhibitor. Antibody–drug conjugate Complete remission rate FDA designation(s): older who have newly HDACs act as epigenetic regulators (ie, functioning peripherally (eg, gemtuzumab Overall survival Orphan Drug, diagnosed acute myeloid to the genetic code) that chemically modify the DNA structure ozogamicin) Quality of life Breakthrough Therapy leukemia (AML), cannot or its associated chromosomal proteins (eg, histones). Glasdegib in combination Clinical trial(s): Phase III tolerate intensive Abnormal activity of epigenetic regulators is thought to with low-dose cytarabine PRIMULA primary remission induction contribute to upregulating the accessibility and expression of Low-dose cytarabine completion May 2021 chemotherapy, and have tumor-promoting genes, contributing to the pathogenesis of Low-intensity therapy (eg, Eastern Cooperative AML, the most common type of acute leukemia. AML has a poor azacitidine and Oncology Group (ECOG) prognosis, and patients who cannot tolerate high doses of decitabine) performance status of 2 chemotherapy need other options. Pracinostat might improve with significant patient health outcomes in the first-line setting for AML by Venetoclax alone or in cardiovascular disease or restoring normal chromosomal structure and gene expression combination with are older than 75 years patterns in AML cells. Pracinostat purportedly inhibits class I, II, azacitidine or low-dose and IV HDACs and works synergistically in combination with a cytarabine hypomethylating agent, such as azacitidine. In a clinical trial, pracinostat was given orally, as a 60-mg capsule, once daily, 3 times weekly for 3 weeks, followed by 1 week of rest for each 28-day cycle, in combination with azacitidine given as a subcutaneous or intravenous injection at a dose of 75 mg/m2 daily for 7 days of each 28-day cycle. Developer(s): MEI Pharma, Inc (San Diego, California), in collaboration with Helsinn Group (Lugano, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Males aged 18 years or ProstAtak is a gene-mediated cytotoxic immunotherapy Radiation therapy with or Disease-free survival Clinical trial(s): Phase III older who have localized consisting of an adenovirus vector containing a herpes simplex without androgen- Overall survival PrTK03 primary prostate cancer that is virus thymidine kinase gene (ie, aglatimagene besadenovec) that deprivation therapy Quality of life completion December deemed to be is injected into tumors and leads infected cells to express 2022, designed under intermediate or high risk thymidine kinase. After viral injection, a low dose of a synthetic Special Protocol based on one factor and guanosine analogue (eg, valacyclovir) activated by thymidine Assessment; phase II has been treated with kinase is given, potentially killing tumor cells expressing the ULYSSES primary radiation transgene (ie, aglatimagene besadenovec). The intervention is completion September intended to provide antitumor effects while preserving critical 2020 structures around the prostate. Release of tumor-associated antigens by dying tumor cells purportedly leads to an antitumor immune response. ProstAtak is given as 3 rounds of intratumoral aglatimagene besadenovec injection coupled with systemic valacyclovir administration in addition to standard radiation therapy with or without androgen-deprivation therapy. Developer(s): Advantagene, Inc (Auburndale, Massachusetts)
Adults aged 18 years or ProTmune is a next-generation allogeneic (ie, from a donor), off- Standard hematopoietic Progression-free survival FDA designation(s): older who have a the-shelf hematopoietic peripheral blood cell transplant (HPBCT). stem cell transplantation Overall survival Orphan Drug, Fast Track hematologic malignancy It is developed from donor-sourced, mobilized, peripheral blood Quality of life Clinical trial(s): Phase I/II (acute lymphoblastic T cells that have been cultured in the laboratory in the presence PROTECT primary leukemia, acute myeloid of 2 small-molecule stem cell modulators (ie, FT1050 and FT4145) completion April 2020, leukemia, chronic that guide cell differentiation. Many patients with hematologic initial data reported myelogenous leukemia, malignancies seek curative therapy through HPBCT, but about March 2018, expanded or myelodysplastic 50% of patients undergoing HPBCT die or experience disease enrollment May 2019 syndrome) that will be recurrence within the first 2 years. Most deaths are unrelated to treated with allogeneic the disease itself; rather, death is caused by graft-versus-host hematopoietic peripheral disease (GVHD) arising from the transplant or infection from a blood cell transplantation compromised immune system. ProTmune is intended to decrease GVHD incidence and severity while maintaining therapeutic activity against hematologic malignancies. Clinical trials do not specify ProTmune’s delivery route; however, it is likely given as an intravenous infusion. Developer(s): Fate Therapeutics, Inc (San Diego, California)
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Adults aged 18 years or PVSRIPO is a Sabin type 1 strain of poliovirus genetically Fractionated external Overall survival FDA designation(s): older who have recurrent engineered to not harm or kill normal cells. PVSRIPO uses a beam radiation therapy Progression-free survival Orphan Drug, malignant glioma (eg, novel oncolytic virus approach intended for patients whose One or more of the Quality of life Breakthrough Therapy glioblastoma multiforme cancer has recurred and who have limited options after following: Clinical trial(s): Phase II [GBM], anaplastic standard therapy. It selectively infects and replicates tumor cells Alkylating agents (eg, Pro00077024 primary astrocytoma) that has that express the poliovirus receptor nectin-like protein 5 carmustine, completion May 2021 been treated with (CD155), which is expressed in most types of solid tumor cyclophosphamide, surgery, adjuvant cancers and in other immune cells, including dendritic cells and lomustine, procarbazine, radiation, and macrophages. In tumor cells, PVSRIPO infection causes temozolomide) temozolomide neuronal incompetence that results in cytotoxicity and death. In Angiogenesis inhibitors contrast, PVSRIPO infection of immune cells facilitates induction (eg, bevacizumab) of an antitumor immune response that does not kill or limit immune function of dendritic cells and macrophages. Although mTOR inhibitors (eg, immune cells infected by PVSRIPO initiate a type I interferon- everolimus) mediated response, this will not destroy the oncolytic virus. Platinum agents (eg, PVSRIPO purportedly targets and destroys cells in brain tumors carboplatin, cisplatin) and activates tumor-specific immune responses by stimulating Vinca alkaloids (eg, dendritic cell activity and immune function. In clinical trials, vincristine) PVSRIPO is given as a single intratumoral injection at a dose from 7 × 106 to 7 × 109 plaque-forming units. Developer(s): Istari Oncology, Inc (Durham, North Carolina), in collaboration with the Preston Robert Tisch Brain Tumor Center at Duke University (Durham, North Carolina)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 12 years or Relatlimab (BMS-986016) is a novel human immunoglobulin G4 One or more of the Overall survival Clinical trial(s): Phase II/III older and adults who (IgG4) monoclonal antibody against lymphocyte-activator gene- following: Progression-free survival primary completion have melanoma that is 3 (LAG-3), a coinhibitor receptor primarily expressed on Alkylating agents (eg, Quality of life January 2021 unsuitable for surgery or exhausted tumor-infiltrating lymphocytes (TILs). Relatlimab is dacarbazine, is metastatic and has not intended to enhance activity of immune checkpoint inhibitors temozolomide) been previously treated by stimulating TILs. As an adjunct to a checkpoint inhibitor, BRAF inhibitors (eg, with systemic therapy relatlimab might also increase treatment-related costs. dabrafenib, encorafenib, Relatlimab’s binding to LAG-3 prevents inhibitory T-cell vemurafenib) responses of TILs via interaction with major histocompatibility Immune checkpoint complex class-II (MHC-II) on dendritic cells and melanoma cells. inhibitors (eg, Relatlimab purportedly promotes innate immune responses ipilimumab, nivolumab, and FAS-mediated programmed cell death (ie, apoptosis) in pembrolizumab) melanoma cells expressing high MHC-II. Relatlimab also synergizes with programmed death-1 immune checkpoint MEK inhibitors (eg, inhibitors that might encourage melanoma-specific immune binimetinib, cobimetinib, responses. In clinical trials, relatlimab is given intravenously at a trametinib) dose of 160 mg in combination with intravenous nivolumab at a Platinum agents (eg, dose of 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 Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Infants and children aged Remestemcel-L (Ryoncil) is an allogeneic mesenchymal Photopheresis alone or Overall survival Submission date: Rolling 2 months to 17 years precursor cell therapy that uses donor bone marrow and combined with 8- Progression-free survival Biologics License who have acute graft- selectively expands mesenchymal stem cells. It is intended for methoxypsoralen Quality of life Application initiated May versus-host disease GVHD that does not respond to steroid treatment. GVHD is a One or more 29, 2019, completed (GVHD) that has not life-threatening immune disorder that is a frequent immunosuppressants: February 3, 2020 responded well to complication of allogeneic hematopoietic stem cell Alkylating agents (eg, FDA designation(s): steroids transplantation and affects many organ systems. It arises when cyclophosphamide) Orphan Drug, Fast Track donor T cells recognize host cells as foreign by virtue of their Antibodies (eg, Clinical trial(s): Phase III expression of alloantigens and mount an immune response. alemtuzumab, MSB-GVHD001 Remestemcel-L purportedly secretes growth factors and anti- antithymocyte globulin) completed April 2018, inflammatory cytokines that facilitate tissue repair by 180-day survival data downregulating immune and inflammatory responses of Calcineurin inhibitors (eg, cyclosporine, tacrolimus) reported September immunocompetent T cells contained in the graft. In clinical 2018, efficacy and safety Corticosteroids (eg, trials, remestemcel-L is given by intravenous infusion, at a dose data reported January 6 methotrexate, of 2 × 10 cells/kg, twice a week for 4 consecutive weeks. 2020 Developer(s): mycophenolate mofetil, prednisone) Mesoblast, Ltd (Melbourne, Australia, and New York, New York) mTOR inhibitors (eg, sirolimus)
Adults aged 18 to 81 Rigosertib (Estybon) is a small-molecule, multikinase inhibitor Immunomodulatory Complete remission rate FDA designation(s): years who have with activity against both the α and β isoforms of agents (eg, lenalidomide) Overall survival Orphan Drug myelodysplastic phosphoinositide 3 kinase (PI3K) and polo-like kinase 1 (PLK1). No Quality of life Clinical trial(s): Phase III syndrome that has effective treatment is available for resistant myelodysplastic INSPIRE primary exhibited primary syndrome, and patients generally have a poor prognosis when completion March 2019, resistance to the syndrome has not responded to treatment with a designed under Special hypomethylating agents hypomethylating agent. Inhibiting PI3K is intended to disrupt cell Protocol Assessment (ie, disease progression signaling that promotes cell growth and survival. Inhibiting PLK1 without attaining a might disrupt cell division, leading to cell cycle arrest in cancerous complete or partial cells. In clinical trials, rigosertib is given intravenously at a dose of response or hematologic 1800 mg daily for 3 days every 2 weeks for 8 cycles, then every 4 improvement) weeks until disease progression or intolerable toxicity. Developer(s): Onconova Therapeutics, Inc (Newtown, Pennsylvania)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 years or Robotic-assisted nipple-sparing mastectomy using the da Vinci Open surgical Patient satisfaction Clinical trial(s): Phase II older who have invasive system has been pioneered by a few European investigators to mastectomy Tissue necrosis (nipple- MARCI primary breast cancer or ductal improve cosmesis and patient satisfaction and reduce length of areola complex) completion November carcinoma in situ and are stay after total mastectomy compared with open surgery. Local tumor recurrence 2019, preliminary data undergoing total Compared with open surgery, da Vinci robotic-assisted published September Distant tumor recurrence mastectomy with mastectomy purportedly facilitates the performance of 2018; unphased immediate breast technically challenging laparoscopic procedures, enhances Overall survival comparing robotic- reconstruction cosmesis, reduces length of stay, and improves patient Disease-free survival assisted and open satisfaction. In clinical trials, surgeons performing the surgery Quality of life mastectomy primary avoid the nipple-areola tissue by removing the target breast completion March 2022 cancer tissue through a small incision under the arm (ie, axillary Note(s): FDA issued a access). After the robotically assisted steps, a surgeon manually safety communication on reconstructs the breast using a conventional breast implant and February 28, 2019 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)
Children aged 12 years or Ruxolitinib phosphate (Jakafi) inhibits the Janus kinases (JAKs) One or more of the Treatment response rate Approval date: May 24, older and adults with JAK1 and JAK2, which mediate signaling for several cytokines following: Mortality 2019 steroid-refractory acute and growth factors involved in white blood cell formation and Alemtuzumab Quality of life FDA designation(s): graft-versus-host disease immune function. JAK1 and JAK2 are implicated in GVHD, a life- α1-Antitrypsin Orphan Drug, (GVHD) after allogeneic threatening complication of ASCT for cancer. Patients receiving Antithymocyte globulin Breakthrough Therapy, stem cell transplantation ASCT are at high risk of GVHD, and steroids are first-line therapy Priority Review (ASCT) to treat cancer but do not work in some patients. Effective options are needed. Calcineurin inhibitors (eg, cyclosporine, tacrolimus) Clinical trial(s): Phase III Ruxolitinib provides a new option by inhibiting JAK1 and JAK2 REACH2 primary Cyclophosphamide and purportedly decreasing production of inflammatory completion July 2019, data cytokines and reducing immune cell migration to the Etanercept reported October 2019; gastrointestinal tract, which is frequently involved in GVHD. For Extracorporeal phase III REACH3 primary GVHD, the FDA-approved label states the recommended photopheresis completion May 2020 starting dose is 5 mg (tablet) orally, twice daily. Methotrexate Note(s): Ruxolitinib Developer(s): Mycophenolate mofetil phosphate is also Incyte Corp (Wilmington, Delaware) Pentostatin approved for 2 other indications. See full FDA- Sirolimus approved labeling and prescribing document.
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Adults aged 18 years or Sacituzumab govitecan-hziy (IMMU-132) is an antibody–drug One or more of the Overall survival PDUFA date: June 2, 2020 older who have locally conjugate consisting of a monoclonal antibody coupled via a following: Progression-free survival FDA designation(s): Fast advanced or metastatic cleavable linker to an active metabolite of the chemotherapy Alkylating agents (eg, Quality of life Track, Breakthrough triple-negative breast drug irinotecan. The monoclonal antibody is specific for cyclophosphamide) Therapy cancer and have received trophoblast cell-surface antigen 2 (Trop-2), and the irinotecan Anthracyclines (eg, Clinical trial(s): Phase III at least 2 prior systemic metabolite is called SN-38. Trop-2 is a cell-surface protein doxorubicin) ASCENT primary therapy regimens for overexpressed by several epithelial cancers, including triple- Antimetabolites (eg, completion April 2020; locally advanced or negative breast cancers. Upon binding to Trop-2, sacituzumab fluorouracil, gemcitabine) phase I/II IM-T-IMMU- metastatic disease govitecan-hziy is internalized and the linker is cleaved, releasing Microtubule 132-01 primary the chemotherapy drug. By targeting delivery of SN-38 to Trop- completion June 2020, 2-expressing cells, sacituzumab govitecan-hziy purportedly polymerization inhibitors (eg, eribulin) data published October delivers therapeutic doses of the drug to cancer cells while 2019 limiting exposure of noncancer cells. In clinical trials, PARP inhibitors (eg, Note(s): An FDA sacituzumab govitecan-hziy is given as an intravenous infusion olaparib) Complete Response at a dose of 10 mg/kg on days 1 and 8 of each 21-day treatment Taxanes (eg, docetaxel, Letter (CRL) was received cycle until disease progression or intolerable toxicity. paclitaxel) January 2019 citing issues Developer(s): Vinca alkaloid (eg, related to “chemistry, Immunomedics, Inc (Morris Plains, New Jersey) vinorelbine) manufacturing and control matters”
Children aged 12 years or Selpercatinib (LOXO-292) is a novel, highly selective, ATP- One or more of the Overall survival PDUFA date: Third older and adults who competitive small-molecule RET inhibitor intended to provide a following: Progression-free survival quarter of 2020, priority have locally advanced or targeted treatment option to patients with recurrent medullary Anthracyclines (eg, Quality of life review metastatic medullary thyroid cancer and a RET gene alteration. The receptor tyrosine doxorubicin) FDA designation(s): thyroid cancer that kinase RET can be oncogenically activated by gene fusions or point Antimetabolite agents Breakthrough Therapy harbors an alteration in rearrangements, and activating RET point rearrangements affect (eg, 5-fluorouracil) Clinical trial(s): Phase III the rearranged during about 60% of metastatic medullary thyroid cancers. Unlike Tyrosine kinase inhibitors LIBRETTO-531 primary transfection gene, RET, multikinase inhibitors that target specific alterations, selpercatinib (eg, cabozantinib, completion February and has progressed after has been designed to inhibit diverse RET fusions, activating gene vandetanib) 2023; phase I/II treatment with variants, and acquired-resistance variants with nanomolar potency. LIBRETTO-001 primary cabozantinib and/or Selpercatinib targets and purportedly inhibits RET-variant tumor completion March 2022, vandetanib cells. Eligibility for the therapy will require testing for a RET gene data presented alteration. In clinical trials, selpercatinib is given orally at an September 2019 undetermined dose and time frame. Developer(s): Loxo Oncology, Inc (Stamford, Connecticut), a subsidiary of Eli Lilly and Co, Inc (Indianapolis, Indiana)
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Children aged 1 month to Sodium thiosulfate (Pedmark) is intended to reduce the risk of Platinum-based Ototoxicity Submission date: Rolling 18 years who have cisplatin-induced ototoxicity, a common side effect in children chemotherapy (eg, Hearing ability New Drug Application localized, nonmetastatic, that can damage hearing and for which no effective treatment cisplatin) alone, without Quality of life initiated December 2018, solid tumors eligible for is available. It is a proprietary formulation that inactivates the adjuvant preventive expected completion cisplatin chemotherapy metabolic byproducts of systemic platinum-based (ie, cisplatin) therapy mid-2020 chemotherapy. Sodium thiosulfate purportedly acts only on FDA designation(s): cisplatin metabolites in general circulation and does not Orphan Drug, Fast Track, interfere with cisplatin effectiveness within targeted tumor cells. Breakthrough Therapy In clinical trials, sodium thiosulfate is given intravenously at a Clinical trial(s): Phase III 2 dose of 16 g/m or 533 mg/kg, 6 hours after receiving cisplatin- completed April 2015, based chemotherapy. Treatment with sodium thiosulfate data published January continues until completion of cisplatin treatment. 2017; phase III SIOPEL6 Developer(s): completed September Fennec Pharmaceuticals, Inc (Research Triangle Park, North 2017, data published Carolina) June 2018
Adults aged 18 years or Synthetic hypericin (SGX301) is a photosensitizing agent for use Chemotherapy Overall survival FDA designation(s): older who have newly with visible light to treat CTCL. Standard care for CTCL often Ultraviolet A Damage to tumor- Orphan Drug, Fast Track diagnosed patch/plaque- requires photodynamic therapy with ultraviolet light, which can phototherapy with adjacent tissue Clinical trial(s): Phase III phase cutaneous T-cell damage surrounding tissue and lead to skin burns, increased psoralen Progression-free survival FLASH primary lymphoma (CTCL) that pigmentation, or secondary skin cancer. SGX301 purportedly Ultraviolet B Quality of life completion December has not been treated with clears CTCL lesions without increasing the patient’s risk for skin phototherapy 2019 systemic therapy burns. In clinical trials, SGX301 is applied topically to the CTCL lesion twice weekly (covered with an opaque bandage for 12 to 24 hours) followed by fluorescent light activation of the compound. Developer(s): Soligenix, Inc (Princeton, New Jersey)
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Children and adults of Tabelecleucel (Tab-cel) is a chimeric antigen receptor (CAR) T- One or more of the Progression-free survival Submission date: any age who have cell immunotherapy engineered to provide specific immune following: Overall survival Biologics License received an allogeneic responses against EBV using unrelated and haploidentical (half Adrenocortical steroid Quality of life Application planned for hematopoietic cell match; eg, parent, child, or sometimes a sibling) cytotoxic T (eg, prednisolone) second half of 2020 transplant or solid organ lymphocytes (CTLs). Tabelecleucel purportedly provides Alkylating agent (eg, FDA designation(s): transplant and developed immunity against EBV-associated cancers in patients who have cyclophosphamide, Orphan Drug, Epstein-Barr virus– received a hematopoietic cell transplant or organ transplant. dacarbazine) Breakthrough Therapy associated EBV+PTLD can be hard to treat with standard therapies, and Anthracyclines (eg, Clinical trial(s): Phase III posttransplant treatment is associated with many comorbidities. CAR genes doxorubicin) MATCH primary lymphoproliferative are delivered to the CTLs with an adenovirus vector (AdE1- completion November disorder (EBV+PTLD) that LMPpoly), which targets specific regions of the EBV nuclear Antitumor antibiotic (eg, bleomycin) 2020; phase III ALLELE does not respond to antigen 1, latent membrane protein 1, and latent membrane primary completion Vinca alkaloid (eg, rituximab protein 2A. AdE1-LMPpoly also encodes for a programmed November 2020, vinblastine, vincristine) death-1 (PD-1)-dominant negative receptor to shield the CAR preliminary data CTLs from being downregulated (ie, checkpoint inhibition). The reported March 2020 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children and adults aged Tazemetostat (Tazverik) is a first-in-class, small-molecule EZH2 One or more of the Overall survival Approval date: January 16 years or older who inhibitor intended to treat epithelioid sarcoma, a rare and following: Progression-free survival 23, 2020 have metastatic or locally aggressive type of soft-tissue sarcoma. Most epithelioid Alkylating agents (eg, Quality of life FDA designation(s): advanced epithelioid sarcoma cases exhibit increased EZH2 activity that results in dacarbazine, Orphan Drug sarcoma not eligible for many genes being turned off, in particular those involved in temozolomide, Clinical trial(s): Phase III complete resection differentiation and cell cycle arrest. Tazemetostat purportedly trabectedin) EZH-301 primary improves health outcomes in patients with limited treatment Anthracyclines (eg, completion September options by restoring antitumorigenic gene expression that doxorubicin, epirubicin, 2020; phase II EZH-202 prevents epithelioid sarcoma cells from proliferating. According liposomal doxorubicin) primary completion to the FDA-approved label, tazemetostat is taken orally at a Antimetabolites (eg, January 2022, safety and dose of 800 mg, twice daily with or without food, until disease gemcitabine, ifosfamide) efficacy data presented progression or intolerable toxicity. Microtubule inhibitors June 2019 Developer(s): (eg, eribulin, vinorelbine) Note(s): This Accelerated Epizyme, Inc (Cambridge, Massachusetts) mTOR inhibitors (eg, Approval is based on everolimus, sirolimus, overall response rate and temsirolimus) duration of response. Continued approval Multikinase inhibitors (eg, might be contingent imatinib, pazopanib, upon verification and regorafenib, sorafenib, description of clinical sunitinib) benefit in a confirmatory trial.
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Tesetaxel is being developed as the only oral formulation in the One or more of the Overall survival Clinical trial(s): Phase III older who have human taxane drug class (eg, docetaxel, nab-paclitaxel, paclitaxel). following: Progression-free survival CONTESSA primary epidermal growth factor Taxanes inhibit mitosis (ie, duplicative cell division) and are Anthracyclines (eg, Quality of life completion September receptor 2 (HER2)– frequently used to treat breast cancer. However, available doxorubicin, liposomal 2020 negative, hormone taxanes are formulated only as intravenous infusions and are doxorubicin) receptor (HR)–positive, frequently associated with hypersensitivity reactions because of Antimetabolites (eg, locally advanced or additives needed as part of the taxane infusion solution. These capecitabine, metastatic breast cancer reactions can prevent completion of a taxane regimen, gemcitabine) previously treated with a potentially reducing efficacy. Breast cancer also develops Microtubule inhibitors taxane in the resistance over time to these infused taxanes, but oral tesetaxel (eg, eribulin, vinorelbine) neoadjuvant or adjuvant has demonstrated anticancer activity in tumors that have setting previously been exposed to other taxanes and developed PARP Inhibitors (eg, resistance. Thus, oral tesetaxel might provide a more olaparib, talazoparib) for convenient and comfortable administration route that improves BRCA1/2-mutated breast adherence, as well as a treatment option when other taxanes cancer become ineffective. In clinical trials, tesetaxel (27 mg/m2 once Taxanes (eg, docetaxel, every 21 days on day 1 of each cycle) is being used in an all-oral paclitaxel) regimen in combination with low-dose capecitabine until disease progression or intolerable toxicity. Developer(s): Odonate Therapeutics, Inc (San Diego, California)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or UGN-101 (MitoGel) is a proprietary form of the small-molecule Endoscopic management Overall survival PDUFA date: April 18, older with low-grade, drug mitomycin-C (MMC) intended to treat low-grade upper- Surgery (ie, Progression-free survival 2020 noninvasive, upper-tract tract urothelial cancer. No treatments are approved for this nephroureterectomy; Quality of life FDA designation(s): urothelial cancer cancer type, and patients need effective options. This hydrogel- might require ongoing Orphan Drug, based formulation is intended to enable longer exposure of dialysis or organ Breakthrough Therapy, MMC to urinary tract tissue to enable nonsurgical treatment of transplantation) Fast Track, Priority tumors. UGN-101 purportedly kills bladder cell tumors by One or more of the Review inhibiting DNA synthesis, which is required for the cells to divide following: Clinical trial(s): Phase III and tumors to grow. Health care personnel administer 4 mg of Alkylating agents (eg, OLYMPUS primary UGN-101 per 1 mL of TheraCoat-3 gel with a maximum dose of ifosfamide) completion April 2019, 15 mL in a once-weekly instillation given a total of 6 times using pivotal data reported a standard urethral catheter. Antimetabolites (eg, gemcitabine, May 2019, final analysis Developer(s): methotrexate) of primary endpoint data UroGene Pharma, Ltd (New York, New York) reported September Immune checkpoint 2019; phase III primary inhibitors (eg, completion December atezolizumab, avelumab) 2020 Platinum agents (eg, carboplatin, cisplatin) Taxanes (eg, docetaxel, paclitaxel)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 75 Uproleselan (GMI-1271) inhibits E-selectin, a transmembrane One or more of the Overall survival FDA designation(s): years who have relapsed glycoprotein that functions as a cell adhesion molecule. following: Progression-free survival Orphan Drug, or refractory acute Uproleselan might provide a new treatment option for a Anthracyclines (eg, Quality of life Breakthrough Therapy, myeloid leukemia (AML) population of patients with typically poor prognosis and daunorubicin, idarubicin) Fast Track outcomes. E-selectin retains AML cells within the vascular Antibody–drug conjugate Clinical trial(s): Phase III niches of the bone marrow, where these cells are less (eg, gemtuzumab primary completion susceptible to cytotoxic chemotherapy. Uproleselan ozogamicin) December 2020 purportedly inhibits E-selectin’s cell adhesion activity, mobilizing Antimetabolites (eg, AML cells out of bone marrow and into the bloodstream and cladribine, clofarabine, rendering them more sensitive to chemotherapy. In clinical cytarabine, fludarabine) trials, uproleselan is being given in combination with standard induction chemotherapy regimens (ie, mitoxantrone, etoposide, Cytokine (eg, granulocyte and cytarabine [MEC] or fludarabine, cytarabine, and idarubicin colony-stimulating factor) [FAI]). Uproleselan is given intravenously at a dose of 10 mg/kg. DNA synthesis inhibitors Developer(s): (eg, etoposide, 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 Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 to 99 Veliparib (ABT-888) is a small-molecule inhibitor of poly For a first-line treatment Overall survival Clinical trial(s): Phase III years who have stage III adenosine diphosphate-ribose polymerase (PARP), an enzyme setting, combination Progression-free survival VELIA M13-694 primary or IV, high-grade, involved in DNA repair. Veliparib is the first PARP inhibitor regimens with the Quality of life completion July 2020, epithelial ovarian, studied in the first-line treatment setting and is intended to following agents include data published fallopian tube, or primary delay disease progression in the maintenance setting. By the following: September 2019 peritoneal carcinoma not inhibiting PARP’s DNA repair, veliparib might potentiate the Angiogenesis inhibitors previously treated with anticancer activity of cytotoxic chemotherapy drugs whose (eg, bevacizumab) systemic therapy mechanism of action induces DNA damage. Additionally, PARP Anthracyclines (eg, inhibition might exhibit synthetic lethality with cells harboring doxorubicin, pegylated loss-of-function genetic rearrangements in the breast cancer 1 liposomal doxorubicin) gene, BRCA1, and/or the breast cancer 2 gene, BRCA2 (an Platinum agents (eg, ovarian cancer predisposition gene that is also involved in DNA carboplatin, cisplatin) repair); ovarian cancers frequently harbor such genetic variants. Eligibility for treatment will require testing for BRCA variant Taxanes (eg, docetaxel, status. In clinical trials, veliparib is given orally at an unspecified paclitaxel) dose each day in combination with carboplatin and paclitaxel For a maintenance for 6 cycles of 21 days. Veliparib maintenance therapy is given treatment setting, the for up to 30 additional 21-day cycles. recommended options Developer(s): include the following: AbbVie, Inc (North Chicago, Illinois) Observation Bevacizumab for patients who received bevacizumab as part of primary first-line therapy Olaparib for patients with germline or somatic BRCA1/2 mutations
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 years or VGX-3100 is a DNA-based immunotherapy vaccine containing Colposcopy followed by Incidence of cervical HSIL Clinical trial(s): Phase III older who have cervical plasmids that include expression cassettes for HPV proteins E6 one of the following Incidence of cervical REVEAL 1 primary high-grade squamous and E7. It is intended to offer a nonsurgical approach to treat procedures to remove cancer completion April 2020; intraepithelial lesion certain precancerous cervical lesions that are typically treated cervical lesions: Incidence of infection phase III REVEAL 2 (HSIL) and confirmed surgically. As a noninvasive intervention, VGX-3100’s optimized Carbon dioxide laser with HPV-16 and/or HPV- primary completion April infection with human DNA is delivered into cells, where it is translated into the E6 and ablation 18 2021 papillomavirus (HPV) type E7 proteins that act as antigens to induce targeted T-cell and Cold knife cone biopsy Quality of life Note(s): VGX-3100 is also 16 and/or 18 antibody responses. VGX-3100 purportedly uses this immune Laser cone biopsy being studied to treat system response to clear HPV-16 and HPV-18 infections and vulvar and anal HSIL precancerous lesions, enabling patients to avoid the risks Loop electrosurgical associated with surgery, such as loss of reproductive health and excision 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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Table 2.4.Cancer Topics Archived Since Last Status Report: 4 Topics
Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Atezolizumab (Tecentriq) is a monoclonal antibody that One or more of the Overall survival Atezolizumab to treat older who have targets PD-L1, an inhibitory surface molecule expressed by following: Progression-free survival TNBC was FDA-approved programmed death- cells to modulate immune responses. A hallmark of cancer is Alkylating agents (eg, Quality of life in March 2019. Because it ligand 1 (PD-L1)–positive, its ability to evade an immune response. Several types of cyclophosphamide) has been clinically locally advanced or cancer cells, including TNBC, activate an immune checkpoint Anthracyclines (eg, available for more than 1 metastatic triple-negative pathway in T cells by overexpressing PD-L1, which binds to doxorubicin) year, it is no longer within breast cancer (TNBC) the programmed death-1 (PD-1) coinhibitory receptor and the time scope for the Antimetabolites (eg, limits the activation of cancer-specific T cells. Atezolizumab PCORI Health Care fluorouracil, pemetrexed) purportedly prevents the interaction between PD-1 and PD- Horizon Scanning L1 to release the brake on the immune checkpoint pathway. PARP inhibitors (eg, System. The time scope is Treatment with atezolizumab is intended to overcome niraparib, olaparib) defined as 3 years before TNBC’s immune tolerance by enhancing cancer-specific T-cell Taxanes (eg, docetaxel, an intervention becomes responses. According to the FDA approval, atezolizumab is paclitaxel) clinically available outside given as an intravenous infusion at a dose of 840 mg on days Vinca alkaloid (eg, of the research setting to 1 and 15 of a 28-day cycle in combination with nab-paclitaxel vinorelbine) 1 year after an (100 mg/m2) until disease progression or unacceptable intervention becomes toxicity. clinically available. Developer(s): Genentech, Inc (South San Francisco, California), a subsidiary of F Hoffman-La Roche AG (Basel, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 70 ATIR101 is a T-lymphocyte immunotherapy derived from mature Photopheresis alone or Progression-free survival In November 2019, Kiadis years who have acute immune cells from a haploidentical (half match; eg, parent, child, or combined with 8- Overall survival Pharma NV announced myeloid leukemia, acute sibling) donor’s peripheral blood. ATIR101 is intended as an methoxypsoralen Quality of life discontinuation of lymphoblastic leukemia, immunotherapy adjunct to allogeneic HSCT to provide immediate One or more of the ATIR101 development. or myelodysplastic immunity against infectious agents and residual cancer during the following: syndrome and have 6 to 12 months after HSCT. During this time, the patient’s immune Alkylating agent (eg, received allogeneic system is repopulating, and ATIR101 is intended to minimize cyclophosphamide) hematopoietic stem cell patient risk for graft-versus-host disease (GVHD). Because patients Antibodies (eg, transplantation (HSCT) receiving ATIR101 purportedly do not require a perfect donor alemtuzumab, match, it might enable rapid access to HSCT and eliminate the need antithymocyte globulin) for prophylactic immune suppression. The donor’s immune cells also undergo a proprietary photodepletion procedure that Calcineurin inhibitors (eg, eliminates T cells responsible for causing GVHD. In clinical trials, cyclosporine, tacrolimus) ATIR101 is delivered as an intravenous infusion at a single dose of Corticosteroids (eg, 2 × 106 cells/kg given between 28 and 32 days after allogeneic HSCT. methotrexate, Developer(s): prednisone) Kiadis Pharma NV (Amsterdam, the Netherlands) mTOR inhibitor (eg, sirolimus)
Adults aged 18 years or Avelumab (Bavencio) is an immune checkpoint inhibitor Maintenance therapy Overall survival In November 2019, the older who have consisting of a fully human, monoclonal antibody specific for with one or more of the Progression-free survival developers of avelumab unresectable, locally programmed death-ligand 1 (PD-L1). The drug is proposed for following: Quality of life (Bavencio) reported that advanced, or metastatic use as maintenance therapy to delay disease progression after Anthracyclines (eg, the phase III trial adenocarcinoma of the primary chemotherapy. Immune tolerance is a cancer hallmark epirubicin) (NCT02625610) failed to stomach or that might be mediated by binding of PD-L1 to its receptor, Antimetabolites (eg, 5- meet its primary gastroesophageal programmed death-1 (PD-1), an action that inhibits T cells and fluorouracil, endpoint of overall junction anticancer immune responses. Preventing PD-L1–PD-1 capecitabine) survival. interaction by binding of avelumab purportedly inhibits (ie, HER2 antibodies (eg, releases) this immune checkpoint, potentially leading to an trastuzumab) anticancer immune response. Patients are given avelumab after completing one line of induction-phase cytotoxic Platinum-based agents chemotherapy. In clinical trials, avelumab is given intravenously (eg, carboplatin, cisplatin, at a 10-mg/kg infusion once every 2 weeks until disease oxaliplatin) progression or unacceptable toxicity. Taxanes (eg, docetaxel, Developer(s): paclitaxel) Pfizer, Inc (New York, New York), in collaboration with Merck KGaA (Darmstadt, Germany)
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Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 55 years or Romyelocel-L (CLT-008) is a myeloid progenitor cell therapy Growth factors (eg, Progression-free survival Clinical development of older who have acute product. It consists of allogeneic, bone marrow–derived, filgrastim, granulocyte Overall survival romyelocel-L appears to myeloid leukemia (AML) hematopoietic stem cells that are differentiated, multiplied in colony-stimulating factor) Quality of life be halted. The Phase II that has not previously the laboratory, and frozen for storage before use. In patients CLT008-03 trial was been treated and will be with AML, romyelocel-L is intended to treat chemotherapy- completed September treated with induction induced neutropenia, a side effect of treatment that can lead to 2017, with data last therapy with cytarabine opportunistic infections. Romyelocel-L purportedly prevents reported in November alone or combined with opportunistic infections by introducing a population of myeloid 2018. No additional other antileukemic progenitor cells able to produce granulocytes, neutrophils, clinical trials were agents (eg, monocytes, macrophages, red blood cells, and platelets that registered. Additionally, anthracyclines, permanently engraft in the bone marrow. It does so while the manufacturer has not daunorubicin, etoposide, producing few, if any, B lymphocytes and T lymphocytes, which released news on any idarubicin, purine could lead to graft-versus-host complications. In clinical trials, interventions in its nucleoside inhibitors) patients receive a single intravenous infusion of romyelocel-L at pipeline, or any news an unspecified dose. related to business Developer(s): activities in 2019. Cellerant Therapeutics, Inc (San Carlos, California)
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Section 3. Cardiovascular Disease: 28 Topics
Table 3.5. Cardiovascular Disease Topics Added Since Last Status Report: 5 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 80 Revivent TC Transcatheter Ventricular Enhancement System is Baroreflex activation NYHA heart failure FDA designation(s): years who have intended to improve cardiac function in patients with heart therapy (ie, Barostim neo functional class Breakthrough Device symptomatic New York failure by restoring a more normal shape to an enlarged left device) Exercise tolerance Clinical trial(s): Phase II/III Heart Association (NYHA) ventricle. The procedure, called transcatheter ventricular Cardiac contractility Heart failure–related ALIVE primary functional class III or IV restoration, could allow more patients to undergo ventricular modulation (ie, Optimizer hospitalization completion December heart failure despite restoration by offering a less invasive, and purportedly safer, device) Survival 2020; unphased REVIVE- optimal guideline- procedure than open surgical ventricular restoration, a HF primary completion Guideline-directed Quality of life directed medical therapy, procedure that is typically not covered by health insurers. The medical therapy (eg, December 2020 left ventricular ejection Revivent TC system consists of 2 polyester-covered titanium angiotensin-converting fraction less than 45%, anchors connected by a tether. To perform the procedure, an enzyme [ACE] inhibitors, and heart attack–induced interventional cardiologist inserts a delivery catheter into the diuretics, hydralazine, left ventricular aneurysm patient’s jugular vein in the neck to access the heart’s right ivabradine, scar tissue with viable ventricle and implant the internal anchor along the anterior sacubitril/valsartan) myocardium (ie, heart septum (ie, the wall separating the left and right ventricles). A Open surgical ventricular muscle) remote from cardiac surgeon then makes a 4-cm (1.6-inch) incision in the reduction/restoration area of intended chest to implant the external anchor over the opposite end of surgery treatment the tether, on the left ventricle’s outside wall, before tightening the tether. Physicians typically implant 2 to 3 pairs of tethered anchors to exclude the scar tissue from healthy myocardium (ie, heart muscle) by placing the left ventricular wall in proximity to the anterior septum. Isolating the scar tissue reduces the size of the left ventricle and purportedly allows the remaining healthy myocardium to pump blood more effectively. Developer(s): BioVentrix, Inc (San Ramon, California)
SECTION 3. CARDIOVASCULAR DISEASE 76
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Shockwave Intravascular Lithotripsy System is intended to Laser atherectomy Target vessel FDA designation(s): older who have break up hardened calcium deposits within coronary artery Mechanical atherectomy revascularization Breakthrough Device previously untreated, walls, purportedly making arteries less stiff. Reducing their Major adverse cardiac Clinical trial(s): Unphased calcified lesions with at stiffness could make performing balloon angioplasty and stent events (MACE; eg, heart single-arm pivotal least 50% narrowing (ie, placement easier with a lower risk of complications. Such attack, stroke, death) DISRUPT CAD III primary stenosis) and evidence of complications include vascular perforation or rupture that can Lithotripsy-related completion August 2020; restricted blood flow (ie, occur with use of atherectomy catheters that cut or scrape adverse events unphased single-arm ischemia) in the coronary away calcium deposits that line the coronary arteries. The Quality of life DISRUPT CAD IV primary arteries, that are suitable system consists of a rechargeable generator and energy completion July 2020; for percutaneous delivery catheter. To perform intravascular lithotripsy, a unphased randomized coronary intervention (ie, physician uses standard cardiac catheterization techniques to BALI primary completion balloon angioplasty with place a proprietary balloon catheter incorporating multiple January 2023 stent implantation) lithotripsy emitters within the target calcium deposit in the coronary artery. The catheter produces pulsatile sonic pressure waves that purportedly deliver their energy selectively to hardened calcium deposits in the medial and intimal layers of the artery walls and pass through soft tissue without damage. The pressure waves purportedly create microfractures in the calcium embedded within artery walls, thus reducing vessel wall stiffness. After treatment, the calcium deposits remain embedded in the arterial wall. Developer(s): Shockwave Medical, Inc (Santa Clara, California)
SECTION 3. CARDIOVASCULAR DISEASE 77
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Stereotactic body radiotherapy (SBRT) is an established No comparators exist. VT episode incidence Clinical trial(s): Phase I/II older who have sustained treatment for several solid-tumor cancers (eg, breast, SBRT for VT is being Survival ENCORE-VT primary ventricular tachycardia prostate, liver, kidney) that is designed to deliver high-dose explored as a last-resort, Quality of life completion July 2018, (VT) refractory to or radiation noninvasively to precise targets in the body while salvage therapy for preliminary data unsuitable for avoiding damage to healthy adjacent tissue. Investigators selected patients with published January 2019, conventional catheter have begun evaluating whether SBRT could offer a recurrent VT despite additional data presented ablation of arrhythmias noninvasive therapeutic alternative for VT, a potentially fatal existing ICDs. November 2019; phase I/II or additional medical irregular heartbeat, that has not responded to conventional NIRA-VT primary management and treatments. Although several radiation therapy systems are completion December documented, recurrent FDA cleared for SBRT for various tumors, SBRT for VT would 2019; RAVENTA (phase VT episodes despite an be an off-label use. SBRT for refractory VT would represent a not stated) primary existing implantable dramatic shift in arrhythmia treatment that would require completion June 2021; cardioverter-defibrillator substantial collaboration among clinicians in different clinical phase I/II STRA-MI-VT (ICD) service lines (eg, interventional cardiology and radiation primary completion physics) who do not typically have reason to collaborate. To September 2022; phase perform an SBRT-for-VT procedure, patients undergo detailed I/II SABR for refractory VT electrocardiographic imaging studies that combine cardiac primary completion electrical mapping with anatomic imaging, which purportedly December 2022; STAR-VT allows physicians to pinpoint the VT source and possible (phase not stated) arrhythmia trajectory. In one early study, physicians delivered primary completion a total dose of 25 Gray in a single fraction (ie, session) without December 2022; STAR sedation or anesthesia, with an average treatment time of less VTM (phase not stated) than 15 minutes. VT episodes may occur within the first 6 primary completion weeks after treatment due to radiation-induced inflammation; December 2023 however, VT episodes are expected to decline substantially Note(s): As a procedure, after radiation-associated inflammation resolves. rather than a drug or Developer(s): medical device, SBRT for Washington University School of Medicine in St Louis (St Louis, VT would not be subject Missouri) to FDA approval or University of California at Los Angeles (Los Angeles, California) clearance. US investigators typically Varian Medical Systems, Inc (Palo Alto, California) perform the procedure off label using radiotherapy systems that have FDA clearance to perform SBRT for various solid-tumor cancers.
SECTION 3. CARDIOVASCULAR DISEASE 78
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Therapeutic Intra-vascular Ultrasound (TIVUS) System is Guideline-directed Exercise capacity FDA designation(s): older who have intended to treat PAH by ablating (ie, destroying) the nerves in medical therapy (eg, PAH worsening Breakthrough Device pulmonary arterial the pulmonary arteries in a process called pulmonary artery ambrisentan, riociguat, Survival Clinical trial(s): Unphased hypertension (PAH) denervation. As an interventional procedure to treat PAH, tadalafil, treprostinil) Quality of life single-arm TROPHY II TIVUS would disrupt standard PAH treatment, which relies Atrial septostomy (for primary completion July primarily on medical management (ie, drugs). Studies have drug-resistant PAH) 2020; unphased single- suggested that baroreceptors and sympathetic nerve fibers Lung transplantation (for arm TROPHY1-US near the bifurcation (ie, branching) of the main pulmonary advanced drug-resistant primary completion April artery may contribute to the elevated blood pressures seen in PAH) 2019, preliminary data PAH. Therefore, ablating the nerves embedded in the main, reported May 2019; left, and right pulmonary arteries might reduce high blood unphased single-arm
pressure in the pulmonary arteries and lungs in patients with TROPHY1 primary PAH. To perform pulmonary artery denervation, a physician completion October inserts a proprietary catheter into the jugular vein in the neck 2018, preliminary data and advances it into the right heart to access the main reported May 2019 pulmonary artery and its left and right branches. The system
delivers high-intensity, nonfocused ultrasonic energy through
the arterial walls to ablate and deactivate the pulmonary arterial nerves. Developer(s): SoniVie, Ltd (Rosh Haayin, Israel)
SECTION 3. CARDIOVASCULAR DISEASE 79
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Vitaria is an implant intended to treat heart failure by Cardiac contractility NYHA heart failure FDA designation(s): older who have electrically stimulating the vagus nerve in the neck. This modulation (ie, Optimizer functional class Breakthrough Device symptomatic New York approach, called autonomic regulation therapy, purportedly implant) Exercise tolerance Clinical trial(s): Unphased Heart Association (NYHA) treats heart failure by correcting an imbalance in the Guideline-directed Heart failure–related ANTHEM-HFrEF pivotal functional class III heart autonomic nervous system caused by overactive sympathetic optimal drug therapy (eg, hospitalizations primary completion failure, or NYHA class II nerves and underactive parasympathetic nerves. Vagal nerve diuretics, angiotensin- Survival December 2021 heart failure with a heart stimulation (VNS) could disrupt standard-of-care drug therapy converting enzyme [ACE] Quality of life failure–related for many patients with heart failure. VNS therapy could also inhibitors, hydralazine, hospitalization in the past compete with the recently introduced Optimizer implantable ivabradine, 6 months, and whose device for treating some subsets of patients with heart failure. sacubitril/valsartan) heart is in normal sinus To deploy the device, a surgeon places a pacemaker-like rhythm with left stimulator under the skin in the right chest and tunnels the ventricular ejection stimulator’s electrode lead under the skin to the right vagus fraction of 35% or less nerve in the neck. Device implantation is typically performed despite stable, guideline- as an outpatient procedure that takes about 1 hour to directed optimal drug perform with the patient under general anesthesia. therapy Developer(s): LivaNova plc (London, United Kingdom)
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Table 3.6. Currently Monitored Cardiovascular Disease Topics: 22 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults who have Bempedoic acid (Nexletol; previous name ETC-1002) is a small- Bile acid–binding resins Major adverse cardiac Approval date: February heterozygous familial molecule prodrug converted to an active drug primarily in the Ezetimibe events (MACE) 21, 2020 hypercholesterolemia or liver and designed to inhibit ATP citrate lyase (ACL), a key Fibrates Survival Clinical trial(s): Phase III established enzyme involved in cholesterol and fatty acid synthesis in the Niacin CLEAR Outcomes primary atherosclerotic liver. Bempedoic acid might be more cost effective and more completion December PCSK9-inhibiting cardiovascular disease widely accepted than injectable proprotein convertase subtilisin 2021; results of 2 monoclonal antibodies who require additional kexin type 9 (PCSK9) inhibitors for managing disease in patients multicenter randomized lowering of low-density who cannot tolerate statins or who do not achieve sufficiently controlled trials reported lipoprotein cholesterol low cholesterol levels. By inhibiting ACL, bempedoic acid in the FDA-approved (LDL-C) purportedly reduces cholesterol synthesis, thereby prescribing information upregulating LDL receptors and increasing clearance of LDL cholesterol from the bloodstream. The FDA-approved label is a dosage of 180 mg orally, once daily, taken with or without food as an adjunct to diet and maximally tolerated statin therapy. Developer(s): Esperion Therapeutics, Inc (Ann Arbor, Michigan)
SECTION 3. CARDIOVASCULAR DISEASE 81
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 21 to 80 CardiAMP cell therapy is a regenerative medicine that uses a Enhanced external Angina incidence Clinical trial(s): Phase III years who have Canadian patient’s own bone marrow–derived mononuclear cells to counterpulsation Coronary adverse events CardiAMP CMI primary Cardiovascular Society transplant into damaged heart muscle to improve heart Guideline-directed drug Exercise tolerance completion December class III or IV chronic function and exercise capacity. The developer asserts that 2022 therapy (eg, aspirin, beta Survival refractory angina from improving heart function could also reduce angina incidence in blockers, calcium channel Quality of life obstructive coronary patients who are not candidates for conventional blockers, nitrates, artery disease that is revascularization procedures for ischemic coronary artery ranolazine) unsuitable for disease. CardiAMP therapy purportedly improves heart function conventional through 2 mechanisms: direct and indirect regeneration. In revascularization direct regeneration, the transplanted cells purportedly travel to injured heart muscle (ie, myocardium) and transform into new functional heart cells. In indirect regeneration, the transplanted cells purportedly secrete stimulatory cytokines to instruct resident stem cells to regenerate heart tissue. Clinicians first collect about 15 cc of bone marrow and send it to a partner laboratory for proprietary molecular analysis to estimate a candidate’s likelihood of successful cell therapy. If test results are positive, patients return to the cardiac catheterization laboratory after 3 or more days to undergo the procedure. Clinicians collect about 60 cc of bone marrow from the patient to concentrate a sufficient dose of autologous cells at the point of care and inject the prepared cell product into the myocardium, using a proprietary needle-injection catheter. Patients are discharged the same or next day. Developer(s): BioCardia, Inc (San Carlos, California)
SECTION 3. CARDIOVASCULAR DISEASE 82
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 21 to 90 CardiAMP cell therapy is a regenerative medicine that Baroreflex activation NYHA HF functional class Clinical trial(s): Phase III years who have New York transplants a patient’s own bone marrow–derived mononuclear therapy (ie, Barostim neo Exercise tolerance CardiAMP primary Heart Association (NYHA) cells into damaged heart muscle. It is intended to improve heart implant) HF-related completion June 2020 functional class II or III function and exercise capacity through 2 mechanisms: direct Cardiac contractility hospitalizations heart failure (HF) with and indirect regeneration. In direct regeneration, the modulation (ie, Optimizer Survival chronic ischemic left transplanted cells purportedly travel to injured heart muscle (ie, implant) Quality of life ventricular dysfunction myocardium) and transform into new functional heart cells. In Guideline-directed secondary to myocardial indirect regeneration, the transplanted cells purportedly secrete optimal drug therapy (eg, infarction and ventricular stimulatory cytokines to instruct resident stem cells to angiotensin-converting ejection fraction between regenerate heart tissue. Clinicians first collect about 15 cc of enzyme [ACE] inhibitors, 20% and 40% that is bone marrow and send it to a partner laboratory for diuretics, hydralazine, stable and being treated proprietary molecular analysis to estimate a candidate’s ivabradine, with guideline-directed likelihood of successful cell therapy. If test results are positive, sacubitril/valsartan) medical and device patients return to the cardiac catheterization laboratory after 3 therapy or more days to undergo the procedure. Clinicians collect about 60 cc of bone marrow from the patient to concentrate a sufficient dose of autologous cells at the point of care and inject the prepared cell product into the myocardium, using a proprietary needle-injection catheter. Patients are discharged the same or next day. Developer(s): BioCardia, Inc (San Carlos, California)
SECTION 3. CARDIOVASCULAR DISEASE 83
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 21 to 80 CLBS14 is an autologous CD34+ cell therapy intended to Enhanced external Angina incidence FDA designation(s): years who have Canadian reduce angina by stimulating growth of new microvasculature counterpulsation Exercise capacity Regenerative Medicine Cardiovascular Society (ie, angiogenesis) in ischemic myocardial tissue. CLBS14 is Guideline-directed Major adverse coronary Advanced Therapy class III or IV chronic intended to improve medical therapy for patients with drug- optimal drug therapy (eg, events (MACE) Clinical trial(s): Phase III refractory angina and resistant angina for whom conventional revascularization is aspirin, beta blockers, Survival RENEW completed obstructive coronary ineffective or unsuitable. During the proprietary process, calcium channel blockers, November 2015, pivotal Quality of life disease unsuited for patients receive granulocyte colony-stimulating factor (5 nitrates, ranolazine) data published August conventional mg/kg subcutaneous injection) for about 4 days to mobilize 2016 revascularization their own CD34+ cells before apheresis (ie, plasma exchange) on day 5 to collect cells from peripheral blood. Clinicians ship peripheral blood to a processing laboratory to isolate CD34+ cells and prepare the cell therapy product for transport back to the treating facility. After about 3 to 4 days, clinicians administer the cell product into ischemic heart muscle via catheter-based intramyocardial injection. Developer(s): Caladrius Biosciences, Inc (Basking Ridge, New Jersey), which acquired exclusive worldwide license from Shire plc (Dublin, Ireland), now part of Takeda Pharmaceutical Co, Ltd (Osaka, Japan)
SECTION 3. CARDIOVASCULAR DISEASE 84
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 45 years or Dalcetrapib is an inhibitor of cholesteryl ester transfer protein Guideline-directed Major cardiovascular Clinical trial(s): Phase III older who have a (CETP), a plasma protein responsible for lipid transport. optimal drug therapy (eg, adverse events (MACE), dal-GenE primary confirmed AA Dalcetrapib was originally intended to raise high-density angiotensin-converting including cardiovascular completion January 2021 polymorphism at the lipoprotein levels by modulating CETP activity. It is also enzyme [ACE] inhibitors, death, myocardial rs1967309 location in the intended to lower cardiovascular risk by helping lower levels aspirin, beta blockers, infarction, and stroke adenylate cyclase type 9 of harmful low-density lipoproteins. However, although calcium channel blockers, gene, ADCY9, and were dalcetrapib failed to reduce cardiovascular events in large statins) recently hospitalized for phase III trials, patients treated with dalcetrapib who carried Proprotein convertase acute coronary syndrome the AA polymorphism at the rs1967309 location of the ADCY9 subtilisin kexin type 9 gene showed a 39% drop in cardiovascular adverse events. (PCSK9) inhibitors 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, at a dose of 600 mg, once daily. Developer(s): DalCor Pharmaceuticals (Montreal, Québec, Canada), in collaboration with F Hoffmann-La Roche, Ltd (Basel, Switzerland)
Adults aged 18 years or Inclisiran is an RNA interference (RNAi) therapeutic designed to Bile acid sequestrants Major adverse Clinical trial(s): Phase III older who have target and reduce the expression of proprotein convertase Ezetimibe cardiovascular events ORION-10 primary atherosclerotic subtilisin kexin type 9 (PCSK9) to treat hypercholesterolemia (ie, Fibrates (MACE) completion October cardiovascular disease high cholesterol). Inhibiting PCSK9 production purportedly 2019, preliminary data Niacin Survival (coronary, peripheral, or increases the number of LDL receptors that are recycled and reported November other arteries) and are available on cell surfaces to remove LDL particles from PCSK9-inhibiting 2019; phase III ORION-8 elevated low-density extracellular fluid. Inclisiran is intended to simplify the dosing monoclonal antibodies single-arm long-term lipoprotein (LDL) regimen as a subcutaneous (ie, under the skin) injection every 3 Statins extension primary cholesterol (ie, greater to 6 months rather than an injection of alirocumab or completion August 2023 than 70 mg/dL) despite evolocumab every 2 to 4 weeks. In clinical trials, 300 mg of an optimal dose of inclisiran is given subcutaneously on days 1 and 90 and then statins or other lipid- every 6 months. lowering therapies if Developer(s): statin-intolerant The Medicines Company (Parsippany, New Jersey), a subsidiary of Novartis AG (Basel, Switzerland), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)
SECTION 3. CARDIOVASCULAR DISEASE 85
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Inclisiran is an RNA interference (RNAi) therapeutic designed to Bile acid sequestrants Major adverse Submission date: New older who have target and reduce the expression of proprotein convertase Ezetimibe cardiovascular events Drug Application planned heterozygous familial subtilisin kexin type 9 (PCSK9) to treat hypercholesterolemia. Fibrates (MACE) for fourth quarter of hypercholesterolemia Inhibiting PCSK9 production purportedly increases the number 2019 Niacin Survival and an elevated low- of LDL receptors that are recycled and are available on cell Clinical trial(s): Phase III PCSK9-inhibiting density lipoprotein (LDL) surfaces to remove LDL particles from extracellular fluid. ORION-9 primary monoclonal antibodies cholesterol level despite Inclisiran is intended to simplify the dosing regimen as a completion September maximum lipid-lowering subcutaneous (ie, under the skin) injection every 3 to 6 months Statins 2019, preliminary data therapies rather than an injection of alirocumab or evolocumab every 2 to reported November 2019 4 weeks. In clinical trials, inclisiran is given subcutaneously at a dose of 300 mg on days 1 and 90 and then every 6 months. Developer(s): The Medicines Company (Parsippany, New Jersey), a subsidiary of Novartis AG (Basel, Switzerland), in collaboration with Alnylam Pharmaceuticals (Cambridge, Massachusetts)
Adults aged 40 years or InterAtrial shunt device (IASD) is intended to relieve heart Cardiac contractility NYHA functional class FDA designation(s): older who have failure symptoms by reducing elevated left atrial pressure, a modulation (ie, Optimizer Exercise tolerance Breakthrough Device symptomatic New York common feature of heart failure that causes a backup of implant) Heart failure–related Clinical trial(s): Unphased Heart Association (NYHA) blood in the lungs, leading to pulmonary congestion and Guideline-directed hospitalization pivotal REDUCELAPHF-II class III or ambulatory breathing difficulty. IASD implantation would disrupt optimal drug therapy (eg, Survival primary completion class IV heart failure, left management for patients with heart failure with preserved angiotensin-converting December 2020; phase II Quality of life ventricular ejection left ventricular ejection fraction (ie, greater than 40%), which enzyme [ACE] inhibitors, REDUCELAPHF-I primary fraction greater than relies on drug therapy prescribed in an outpatient office diuretics, hydralazine, completion December 40%, and elevated left setting. IASD implantation might also compete with ivabradine, 2016, data published atrial pressure despite implantation of the recently introduced Optimizer electronic sacubitril/valsartan) October 2018; stable guideline-directed implant in a subset of patients with left ventricular ejection REDUCELAPHF-III optimal drug therapy fraction between 40% and 45%. To implant the IASD, a European postmarket physician inserts a specialized catheter in the femoral vein at observational primary the groin and threads it up to the right atrium to create an completion July 2021 opening in the septum, the wall separating the heart’s left and right atrial chambers. The stent-like scaffold is designed to keep the transseptal puncture open. This new opening purportedly lowers left atrial pressure and helps reduce pulmonary congestion by allowing blood to cross into the low- pressure right atrium. Developer(s): Corvia Medical, Inc (Tewksbury, Massachusetts)
SECTION 3. CARDIOVASCULAR DISEASE 86
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Neovasc Reducer is a stent-like implant intended to treat Enhanced external Angina incidence Submission date: older who have Canadian chronic angina by improving blood flow to ischemic heart counterpulsation Exercise tolerance Premarket Approval Cardiovascular Society tissue. This implanted device could provide an option for Guideline-directed Device-related adverse Application December 31, class III or IV chronic patients whose angina persists despite optimal medical medical therapy for events 2019 angina from obstructive therapy and who are unable to undergo conventional bypass ischemic heart disease Survival FDA designation(s): coronary artery disease surgery. Physicians implant the Neovasc Reducer in the (eg, aspirin, beta Breakthrough Device Quality of life that is resistant to coronary sinus, the large vein that drains blood from heart blockers, calcium channel Clinical trial(s): Unphased optimal medical therapy muscle, to create a pressure backflow that purportedly blockers, nitrates, REDUCER-1 prospective- and who are unsuitable modulates blood flow through the coronary sinus and ranolazine) retrospective for conventional redistributes blood to areas of heart muscle with poor observational primary revascularization circulation. To implant the balloon-expandable, hourglass- completion December shaped device, a physician inserts the delivery catheter at the 2022, preliminary data jugular vein in the neck and advances it into the coronary presented October 2019; sinus, located on the external heart wall between the left unphased single-arm atrium and left ventricle. Implantation purportedly takes interventional primary about 20 minutes with patients under local anesthesia. completion December Developer(s): 2028 Neovasc, Inc (Richmond, British Columbia, Canada)
Adults aged 18 to 85 Omecamtiv mecarbil is a cardiac myosin activator intended to Guideline-directed NYHA heart failure Clinical trial(s): Phase III years who have chronic increase the duration of cardiac muscle contractility and optimal drug therapy (eg, functional class GALACTIC-HF primary heart failure; New York improve cardiac muscle performance. The mechanism of action angiotensin-converting Improved exercise completion January 2021, Heart Association (NYHA) purportedly improves cardiac muscle performance without enzyme [ACE] inhibitors, tolerance designed under Special functional class II to IV; increasing cellular calcium concentrations that can occur with diuretics, hydralazine, Heart failure–related Protocol Assessment; left ventricular ejection other common heart failure drugs, thereby avoiding risk of ivabradine, hospitalization phase III METEORIC-HF fraction of 35% or less increasing heart rate, blood pressure, and arrhythmias. In sacubitril/valsartan) primary completion Survival despite maximally clinical trials, omecamtiv mecarbil is given orally at 25 to 50 mg, February 2021 tolerated, guideline- twice daily. Quality of life directed medical therapy; Developer(s): and elevated levels of B- Cytokinetics, Inc (South San Francisco, California), in type natriuretic peptide collaboration with Amgen, Inc (Thousand Oaks, California) (BNP) or N-terminal pro B-type natriuretic peptide (NTproBNP)
SECTION 3. CARDIOVASCULAR DISEASE 87
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Optimizer is a cardiac implant that uses a process called cardiac Guideline-directed NYHA heart failure Approval date: March 21, older who have New York contractility modulation (CCM) to deliver nonexcitatory optimal drug therapy (eg, functional class 2019 Heart Association (NYHA) electrical pulses during the myocardial absolute refractory angiotensin-converting Exercise tolerance FDA designation(s): class III heart failure and period to improve systolic contraction. The FDA-approved label enzyme [ACE] inhibitors, Heart failure–related Breakthrough Device remain symptomatic states the device is indicated to improve 6-minute hall walk diuretics, hydralazine, hospitalization Clinical trial(s): Unphased despite guideline- distance, quality of life, and functional status. CCM purportedly ivabradine, Survival FIX-HF-5C2 completed directed medical therapy, normalizes phosphorylation of regulatory proteins to improve sacubitril/valsartan) Quality of life October 2019; unphased are in normal sinus calcium handling—ultimately interrupting the remodeling FIX-HF-5CA completed rhythm, are not indicated cascade (ie, changes in size and shape) to reverse enlargement November 2019; for cardiac of the left ventricle—and to improve left ventricular contractile unphased postapproval resynchronization (ie, pumping) strength. The Optimizer Smart model replaced all registry primary therapy, and have a left earlier Optimizer versions (ie, II, III, IV) used in clinical trials since completion December ventricular ejection 2016. Physicians implant the pulse generator under the skin in 2023 fraction ranging from the right pectoral region similarly to standard pacemaker or 25% to 45% defibrillator implantation. Two standard pacemaker leads are placed through major blood vessels into the right ventricle on the right ventricular septum to sense local electrical activity and deliver CCM. An improved, second-generation device (FDA supplemental approval in October 2019) purportedly no longer requires an optional atrial lead placed in the right atrium for additional electrical sensing. The device delivers pulses at regular intervals during the day, purportedly unnoticed by patients. Patients recharge the pulse generator at home for 60 to 90 minutes once a week, using a noninvasive charging system placed over the implant. Developer(s): Impulse Dynamics (Mt Laurel, New Jersey)
SECTION 3. CARDIOVASCULAR DISEASE 88
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Organ Care System (OCS) is intended to maintain a donor organ Conventional cold Graft organ survival Submission date: April older who are candidates in a warm, functioning state outside the body for an extended storage Overall survival 14, 2014 for heart transplantation period to optimize donor organ health and allow for continuous Quality of life Clinical trial(s): Unphased clinical evaluation before transplantation. The OCS Heart is EXPAND Heart completed optimized for preserving donor hearts. Many donor hearts are December 2019, never transplanted because their condition degrades quickly preliminary data after harvesting, and thus fewer patients receive the heart published April 2019; transplant they need. OCS Heart would represent a substantial unphased HEART change to pretransplant procedures for potential donor organ EXPAND continued assessment, procurement, and transport compared with static access protocol primary cold storage, which is the current standard. OCS Heart completion January 2020; purportedly could increase the volume of heart unphased Donors After transplantations, enabling longer-distance transport and giving Circulatory Death clinicians more clinical data to better assess donor organ primary completion suitability. The manufacturer has developed similar technology August 2021; unphased to preserve lung and liver grafts. The OCS device comprises 2 observational clinical use principal components: a portable battery-powered console and cohort primary an organ-specific perfusion kit that function together as an completion December integrated system. The system perfuses donor organs with a 2021 proprietary blood-based solution to replenish oxygen and Note(s): FDA approved essential nutrients. When physicians harvest the donor heart, OCS Lung for standard- they place it in the perfusion module and revive it to a beating criteria lung preservation state. The self-contained perfusion module maintains the in March 2018 and for proper temperature and humidity, protects the organ from expanded-criteria lung external contaminants, and allows sterile ultrasound preservation in June assessment of heart function and sterile blood sampling for 2019; OCS Liver is under laboratory analysis. A wireless monitor allows clinicians to investigation assess the organ’s status and control system functions. Developer(s): TransMedics, Inc (Andover, Massachusetts)
SECTION 3. CARDIOVASCULAR DISEASE 89
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 75 Paradise Renal Denervation System is a catheter-based device Guideline-directed Blood pressure Clinical trial(s): years who have essential intended to ablate the sympathetic nerves that line the main optimal antihypertensive Cardiovascular adverse RADIANCE-HTN primary hypertension controlled renal arteries connecting the kidneys to the aorta. Deactivating drug therapy with one or events completion March 2020, on one or two the renal sympathetic nerves can purportedly help reduce more agents (eg, Survival interim data published medications or difficult-to-manage, treatment-resistant hypertension. An angiotensin-converting March 2019; RADIANCE-II Quality of life uncontrolled interventional procedure would shift care away from standard enzyme [ACE] inhibitors, pivotal primary hypertension on 0 to 2 office-based medical management for most patients with angiotensin-receptor completion December medications (average uncontrolled hypertension. A physician inserts the proprietary blockers [ARBs], calcium 2020 office blood pressure balloon catheter into the femoral artery in the groin and channel blockers, between 140/90 and advances it into the left and right renal arteries, alternately, to thiazide diuretics) 180/110 mm Hg) deliver 2 to 4 applications of circumferentially delivered ultrasound energy, about 7 seconds each, to each artery. The liquid-cooled balloon purportedly protects the artery walls from thermal damage while the sympathetic nerves are ablated. The physician removes the catheter using standard interventional techniques after treating both renal arteries. Developer(s): ReCor Medical, Inc (Palo Alto, California)
Adults aged 45 to 99 Placental expanded cells to treat peripheral artery disease (PLX- Guideline-directed Wound healing in the FDA designation(s): Fast years who have critical PAD) are mesenchymal-like adherent stromal cells derived from optimal drug therapy (eg, treated leg Track, Expanded Access limb ischemia and full-term human placentas and cultured in a proprietary angiotensin-converting Ischemic pain Program (EAP), EAP Cost ischemic lesions with bioreactor. PLX-PAD cells purportedly release cytokines, enzyme [ACE] inhibitors, Major amputation Recovery minor tissue loss up to chemokines, and growth factors to promote new blood vessel aspirin, cilostazol, Clinical trial(s): Phase III the ankle level growth (ie, angiogenesis) and increase circulation in ischemic clopidogrel, statins) PACE primary completion (Rutherford category 5) tissue, induce muscle tissue regeneration, and modulate Proprotein convertase May 2020 and are deemed inflammation to reduce connective tissue deposition and subtilisin kexin type 9 unsuitable for peripheral scarring. The cell product is given by intramuscular injection to (PCSK9) inhibitors artery revascularization the affected leg. by any conventional Developer(s): method Pluristem Therapeutics, Inc (Haifa, Israel)
SECTION 3. CARDIOVASCULAR DISEASE 90
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 90 Pressure-controlled intermittent coronary sinus occlusion Standard percutaneous Change in size/volume of FDA designation(s): years who have ST- (PiCSO) system consists of a proprietary catheter, console, and coronary intervention (ie, myocardial infarct (ie, Breakthrough Device segment elevation monitor intended to be used to preserve at-risk heart muscle balloon angioplasty with dead heart muscle) Clinical trial(s): Unphased myocardial infarction during an acute heart attack. PiCSO is intended to be used as an stenting) Heart function randomized PiCSO-AMI-I (STEMI) adjunct to the standard percutaneous coronary intervention for primary completion STEMI, balloon angioplasty plus stenting. It could disrupt September 2020; phase II current management by adding procedural steps and capital nonrandomized OxAMI- equipment. During a percutaneous coronary intervention PICSO primary procedure, PiCSO therapy is initiated after blood flow has been completion October 2020 restored. Physicians insert the PiCSO balloon catheter in the femoral vein at the groin and advance it into the coronary sinus vein in the heart using standard catheter-based techniques. Using a proprietary algorithm that continuously monitors coronary sinus pressure changes, a computerized PiCSO console inflates and deflates the balloon to intermittently block the coronary sinus. This process purportedly redistributes blood to areas of oxygen-starved heart muscle, improves the removal of free radicals and other harmful agents that are released when circulation is restricted, and increases expression of vascular endothelial growth factor in heart muscle. PiCSO adds an estimated 20 to 30 minutes, on average, to the standard catheter-based intervention for heart attack. Developer(s): Miracor Medical SA (Awans, Belgium)
SECTION 3. CARDIOVASCULAR DISEASE 91
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 80 Rexlemestrocel-L (Revascor) is a regenerative cellular therapy Guideline-directed NYHA heart failure Clinical trial(s): Phase III years who have chronic made from human bone marrow–derived, allogeneic adult optimal drug therapy (eg, functional class DREAM HF-1 primary (at least 6-month mesenchymal precursor cells (MPCs). Standard medical ACE inhibitors, diuretics, Exercise tolerance completion December duration) ischemic or therapy for heart failure attempts to slow disease progression hydralazine, ivabradine, Heart failure–related 2019 nonischemic New York and relieve symptoms. Rexlemestrocel-L purportedly releases sacubitril/valsartan) hospitalizations Note(s): FDA granted Heart Association (NYHA) a range of factors that induce functional recovery within Survival rexlemestrocel-L Orphan functional class II or III damaged heart tissue by activating multiple pathways to Drug designation in June Quality of life heart failure while being induce new blood vessel growth, reduce inflammation, reduce 2019 for preventing treated with maximally fibrosis and scar tissue formation, and regenerate heart mucosal bleeding after tolerated doses of a beta muscle. Rexlemestrocel-L is isolated from bone mononuclear implantation of a left blocker, an angiotensin- cells with antistromal precursor antigen (STRO)-3 antibodies, ventricular assist device converting enzyme (ACE) expanded in a laboratory, and cryopreserved until it is given (LVAD) in adults with end- inhibitor or angiotensin- to the patient. The product is intended to be an off-the-shelf stage heart failure receptor blocker (ARB), therapy given as a single injection of 25 million to 150 million and/or an aldosterone cells delivered into the endocardium using standard cardiac antagonist, plus a diuretic catheterization techniques. Developer(s): Mesoblast, Ltd (Melbourne, Australia)
SECTION 3. CARDIOVASCULAR DISEASE 92
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Rexlemestrocel-L (Revascor) is a regenerative cellular therapy LVAD implantation alone Mucosal and GI bleeding FDA designation(s): older who have New York made from human bone marrow–derived, allogeneic adult Functional capacity Orphan Drug, Heart Association (NYHA) mesenchymal stem cells. Patients who have end-stage heart Treatment-related Regenerative Medicine functional class IIIB or IV failure and require LVAD implantation face a high risk of serious adverse events Advanced Therapy heart failure that has GI bleeding and repeated hospitalizations. A phase II trial of Survival Clinical trial(s): Phase II been unresponsive to patients who received an LVAD found adding rexlemestrocel-L randomized primary Quality of life optimal medical significantly reduced the incidence of major GI bleeding by completed August 2018, management and who about 76% compared with a control group, although it did not data published March are at risk of increase the rate of successfully weaning patients from LVAD 2019 gastrointestinal (GI) therapy (the trial’s primary outcome). For patients with end- Note(s): Future bleeding after stage heart failure requiring an LVAD, rexlemestrocel-L given confirmatory phase III is implantation of a left immediately after LVAD implantation is intended to reduce the planned (no date stated) ventricular assist device risk of GI bleeding and related hospitalization. Rexlemestrocel-L to support future (LVAD) purportedly releases a range of factors that induce functional Biologics License recovery of damaged heart tissue by activating multiple Application for end-stage pathways to induce new blood vessel growth, reduce heart failure in patients inflammation, reduce fibrosis and scar tissue formation, and with an LVAD implant regenerate heart muscle. Rexlemestrocel-L is isolated from bone mononuclear cells with antistromal precursor antigen (STRO)-3 antibodies, expanded in a laboratory, and cryopreserved until it is given to the patient. The product is intended as an off-the-shelf therapy given as a single injection of 25 million to 150 million cells into the endocardium using standard cardiac catheterization techniques. Developer(s): Mesoblast, Ltd (Melbourne, Australia)
SECTION 3. CARDIOVASCULAR DISEASE 93
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 80 RT-100 (Ad5.hAC6) is an adenovirus-based gene therapy Baroreflex activation Exercise tolerance FDA designation(s): Fast years who have New York product intended to improve heart function in patients with therapy (ie, Barostim neo Heart failure–related Track Heart Association (NYHA) chronic heart failure by increasing expression of the adenylyl device) hospitalizations Clinical trial(s): Phase III functional class II to IV cyclase type 6 (AC6) protein. AC6 helps regulate heart function Cardiac contractility NYHA heart failure FLOURISH withdrawn heart failure and left but is underexpressed in heart muscle cells of patients with modulation (ie, Optimizer functional class June 2019 to reevaluate ventricular ejection heart failure. RT-100 is an adenovirus vector (ie, human device) Survival product development fraction between 10% adenovirus 5 encoding human AC6 [Ad5.hAC6]) modified to strategy Guideline-directed Quality of life and 35% despite prevent it from replicating. It is designed to enter heart cells to optimal drug therapy (eg, guideline-directed deliver the gene encoding for AC6. A physician uses standard angiotensin-converting optimal medical therapy cardiac catheterization techniques to administer a single dose enzyme [ACE] inhibitors, of RT-100 into the coronary arteries using an infusion catheter. diuretics, hydralazine, In a phase II trial, patients received 1 of 5 ascending doses from ivabradine, 9 12 3.2 × 10 to 3.2 × 10 virus particles. Dose levels in the phase III sacubitril/valsartan) trial have not yet been reported. Developer(s): Renova Therapeutics (San Diego, California)
Adults aged 20 to 80 Symplicity Spyral is a catheter-based device intended to ablate Guideline-directed Blood pressure Clinical trial(s): SPYRAL years who have 24-hour the sympathetic nerves that line the main renal arteries optimal antihypertensive Cardiovascular adverse HTN-OFF MED pivotal average ambulatory connecting the kidneys to the aorta. Deactivating the renal drug therapy with one or events primary completion June systolic blood pressure of sympathetic nerves purportedly can help reduce difficult-to- more agents (eg, Mortality 2020, preliminary proof- at least 140 mm Hg and manage hypertension. An interventional procedure would shift angiotensin-converting of-concept data Quality of life less than 170 mm Hg care from standard office-based medical management for most enzyme [ACE] inhibitors, published November patients with uncontrolled hypertension. A physician inserts the angiotensin-receptor 2017, further preliminary helical ablation catheter into the femoral artery in the groin and blockers [ARBs], calcium data published January advances it into the left and right renal arteries, alternately, to channel blockers, 2019, data presented deliver radiofrequency energy in a spiral pattern, about 1 thiazide diuretics) September 2019, post minute per application, to one or more sections of each artery. hoc data presented The physician removes the catheter using standard November 2019; SPYRAL interventional techniques after treating both renal arteries. HTN-ON MED primary Developer(s): completion November Medtronic plc (Dublin, Ireland) 2020, preliminary data published June 2018
SECTION 3. CARDIOVASCULAR DISEASE 94
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Tafamidis (Vyndaqel, Vyndamax) is a first-in-class Loop diuretics Cardiovascular-related Approval date: May 6, older who have transthyretin stabilizer designed to selectively bind to Supportive care for heart hospitalizations 2019 hereditary or wild-type transthyretin, purportedly stabilizing the tetramer of the failure Survival FDA designation(s): amyloid transthyretin- transthyretin transport protein and slowing amyloidosis Quality of life Orphan Drug, Fast Track, mediated (amyloid accumulation) in organs and tissues. In ATTR-CM, Priority Review, cardiomyopathy (ATTR- amyloidosis gradually stiffens heart muscle, leading to heart Breakthrough Therapy CM) failure. A treatment that targets the underlying disease Clinical trial(s): Phase III process could provide a disease-modifying option and slow completed November progression to advanced heart failure. The FDA-approved 2019; phase III long-term label for tafamidis states it is intended to treat safety primary cardiomyopathy associated with inherited or wild-type (ie, completion December not linked to a known genetic mutation) amyloidosis to 2024 reduce cardiovascular death and cardiovascular-related hospitalizations. Tafamidis is available in 2 nonsubstitutable oral formulations with the following FDA-approved label recommended dosages: tafamidis meglumine 80 mg once daily, taken as four 20-mg capsules, and tafamidis 61 mg once daily, taken as a single capsule (purportedly for patient convenience). Developer(s): Pfizer, Inc (New York, New York)
SECTION 3. CARDIOVASCULAR DISEASE 95
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 99 V-Wave interatrial shunt is intended to relieve heart failure Baroreflex activation NYHA functional class FDA designation(s): years who have New York symptoms by reducing elevated left atrial pressure, a therapy (ie, Barostim neo Exercise tolerance Breakthrough Device Heart Association (NYHA) common feature of heart failure that causes a backup of implant) Heart failure–related Clinical trial(s): Unphased class III or ambulatory blood in the lungs, leading to pulmonary congestion and Cardiac contractility hospitalization randomized RELIEVE-HF class IV heart failure breathing difficulty. V-Wave device implantation would modulation (ie, Optimizer Survival primary completion despite guideline- disrupt patient management for heart failure, which implant) October 2021 Quality of life directed optimal drug traditionally relies on office-based drug therapy. V-Wave Guideline-directed therapy and regardless of implantation might also compete with implantation of 2 optimal drug therapy (eg, left ventricular ejection recently introduced electronic devices for heart failure: the angiotensin-converting fraction Barostim neo and Optimizer implants. To implant the V- enzyme [ACE] inhibitors, Wave shunt, a physician inserts a specialized catheter in the diuretics, hydralazine, femoral vein at the groin and threads it up to the right ivabradine, atrium to create an opening in the septum, the wall sacubitril/valsartan) separating the left and right atrial chambers. The stent-like scaffold is designed to keep the transseptal puncture open. This new opening purportedly lowers left atrial pressure and helps reduce pulmonary congestion by allowing blood to cross into the low-pressure right atrium. Developer(s): V-Wave, Ltd (Caesarea, Israel, and Agoura Hills, California)
SECTION 3. CARDIOVASCULAR DISEASE 96
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Wireless Stimulation Endocardially for Cardiac Conventional NYHA heart failure FDA designation(s): older who have heart Resynchronization Therapy (WiSE-CRT) is a system that biventricular functional class Breakthrough Device failure and New York purportedly improves on conventional CRT devices. It replaces pacing/cardiac Exercise tolerance Clinical trial(s): IDE pivotal Heart Association (NYHA) epicardial left ventricular pacing stimulation from an electrode resynchronization Heart failure–related (SOLVE CRT) primary class I or IIa guideline lead placed within the coronary sinus vein along the left therapy with epicardial hospitalizations completion September indication for ventricular wall with endocardial left ventricular pacing from a left ventricular lead Survival 2019; CT Guided WiSE- conventional cardiac wireless electrode implanted inside the left ventricle. A Guideline-directed CRT primary completion Quality of life resynchronization conventional pacemaker implanted under the skin in the chest optimal drug therapy (eg, December 2020; WiCS-LV therapy (CRT) and whose senses and paces the right ventricle with a conventional right angiotensin-converting postmarket registry disease has not atrial lead and a right ventricular lead. A wireless electrode enzyme [ACE] inhibitors, primary completion responded to CRT or was (2.7 × 16.3 mm) anchored in the left ventricular wall paces the diuretics, hydralazine, September 2019 previously untreatable left ventricle. A wireless transmitter placed under the skin in the ivabradine, (ie, had an implanted CRT chest senses the right ventricular pacing and sends ultrasound sacubitril/valsartan) system turned off due to energy to the implant to generate endocardial left ventricular electrode lead failure or pacing synchronized with right-sided pacing. A battery pack relative contraindications placed under the skin along the patient’s ribs and under the to an implanted lead) arm powers the wireless transmitter via a thin cable tunneled under the skin. Developer(s): EBR Systems, Inc (Sunnyvale, California)
SECTION 3. CARDIOVASCULAR DISEASE 97
Table 3.7. Topics Archived Since Last Status Report: 1 Topic
Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Apabetalone (RVX-208) is a novel epigenetic selective inhibitor Guideline-directed drug MACE On January 13, 2020, older who have type 2 of bromodomain extra-terminal (BET) proteins intended to therapy (eg, aspirin, beta All-cause death Resverlogix Corp diabetes mellitus (T2DM) reduce incidence of major adverse cardiac events (MACE) in blockers, calcium channel Kidney function announced it would and high-risk coronary high-risk patients with T2DM. By blocking BET proteins at the blockers, nitrates, reformulate apabetalone artery disease (ie, acute transcription level, apabetalone purportedly slows the ranolazine) as a combination therapy coronary syndrome with abnormally increased production of dysregulated, disease- with standard oral myocardial infarction or associated proteins, moving them closer to normal levels. antidiabetic drugs (eg, unstable angina within Apabetalone is intended to reduce MACE by reducing various dipeptidyl peptidase 4 the past 90 days) and a mediators that promote vascular inflammation, calcium [DPP4] inhibitors) after low level of high-density deposition, coagulation cascade, and other mechanisms, the phase III BETonMACE lipoprotein cholesterol including metabolism, cholesterol transport, and the trial failed to reach its complement cascade. In clinical trials, apabetalone is given as a primary endpoints, thus 100-mg capsule twice daily. diminishing its disruptive Developer(s): potential. Resverlogix Corp (Calgary, Alberta, Canada)
SECTION 3. CARDIOVASCULAR DISEASE 98
Section 4. Mental and Behavioral Health: 18 Topics
Table 4.8. Mental and Behavioral Health Topics Added Since Last Status Report: 3 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Pimavanserin is a selective serotonin inverse agonist and Antidepressants (eg, Negative symptoms and Clinical trial(s): Phase II ADVANCE
older who have antagonist targeting serotonin 2A (5-HT2A) receptors. It is selective serotonin symptom severity of (negative symptoms) completed schizophrenia with intended to be used as an adjunct to antipsychotic reuptake inhibitors schizophrenia October 2019, topline data predominant negative medication to treat negative symptoms of schizophrenia. [SSRIs]; off label) Quality of life released November 2019; phase symptoms Pimavanserin might improve patient health outcomes and Atypical antipsychotics III ENHANCE-I (positive and quality of life, because no FDA-approved treatments exist (ie, cariprazine, negative symptoms) completed specifically for negative symptoms of schizophrenia. risperidone) June 2019, topline data released Negative symptoms of schizophrenia include loss of interest, Psychosocial July 2019; phase III extension lack of expression, emotional withdrawal, and cognitive interventions (eg, arts study (positive and negative impairment. Although positive symptoms of schizophrenia therapy, cognitive symptoms) primary completion (eg, hallucinations, distorted thinking) are typically seen as behavioral therapy August 2020 more urgent to treat, negative symptoms more commonly [CBT]) Note(s): The developer intends to impact patients’ ability to live independently, hold jobs, and commence a second pivotal trial maintain relationships. It is thought that 5-HT2A receptors with the 34-mg dose in the first play an important role in psychosis, schizophrenia, half of 2020. Pimavanserin was depression, and other neuropsychiatric disorders. Although FDA approved to treat the exact mechanism of action is unknown, pimavanserin hallucinations and delusions purportedly exerts its effects by acting on 5-HT2A receptors associated with Parkinson’s in the brain. Pimavanserin, FDA approved to treat disease psychosis in April 2016. hallucinations and delusions associated with Parkinson’s FDA responded to safety disease, carries a warning for QT interval prolongation. In concerns over the use of clinical trials, pimavanserin is taken by mouth at a dose of pimavanserin in patients with 10, 20, or 34 mg once daily as an adjunct to the patient’s hallucinations and delusions background antipsychotic medication. associated with Parkinson’s Developer(s): disease in September 2018. Acadia Pharmaceuticals, Inc (San Diego, California) Pimavanserin is in phase III development to treat dementia- related psychosis, with a New Drug Application submission planned for 2020.
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 55 Psilocybin is a psychoactive ingredient found in some Antidepressants (eg, Depression symptoms FDA designation(s): years who have species of mushroom. COMP360 is a synthetic form of monoamine oxidase and severity Breakthrough Therapy treatment-resistant psilocybin. When used in combination with psychological inhibitors [MAOIs], Quality of life Clinical trials: Phase II P-TRD depression support from trained therapists, it might improve patient selective serotonin primary completion August 2020 health outcomes and disrupt the paradigm of depression reuptake inhibitors treatment. Recent research has found a link between mental [SSRIs], serotonin and health disorders and hyperconnected, dysfunctional, neural norepinephrine networks in the brain. Psilocybin purportedly disrupts those reuptake inhibitors dysfunctional networks and helps restore healthier [SNRIs], tricyclic connectivity in the brain, thus improving depression antidepressants [TCAs]) symptoms. Psilocybin is thought to exert its effects primarily Brain stimulation (eg, through its metabolite, psilocin, which demonstrates agonist deep brain stimulation or partial agonist activity at serotonin 2A (5-HT2A) receptors. [DBS], electroconvulsive It produces marked changes in sensory perception, emotion, therapy [ECT], thought, and sense of self. In phase I clinical trials, synthetic transcranial magnetic psilocybin was taken orally at doses of 10 or 25 mg, before stimulation [TMS], vagal receiving 1-to-1 psychological support from an assisting nerve stimulation [VNS]) therapist throughout a session of unspecified duration. In Ketamine (off label) phase II clinical trials, psilocybin is taken orally at Psychotherapy (eg, unspecified, differing doses (stated as low dose, medium cognitive behavioral dose, and high dose) before receiving one-on-one therapy [CBT]) psychological support. The number or frequency of treatment sessions a patient might receive is unspecified. Developer(s): Compass Pathways (London, United Kingdom)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 21 to 65 Psilocybin is a psychoactive ingredient found in some Pharmacotherapy (eg, Depression symptoms FDA designation(s): years who have species of mushroom. Synthetic psilocybin, when used in selective serotonin and severity Breakthrough Therapy moderate to severe combination with support from session facilitators, might reuptake inhibitors Quality of life Clinical trial(s): Phase II PSIL201 major depressive improve patient health outcomes and disrupt the [SSRIs], serotonin and primary completion February disorder (MDD) paradigm of depression treatment. Recent research has norepinephrine 2021 found a link between mental health disorders and reuptake inhibitors hyperconnected, dysfunctional, neural networks in the [SNRIs]) brain. Psilocybin is purported to disrupt those Psychotherapy (eg, dysfunctional networks and help restore healthier cognitive behavioral connectivity in the brain, thus improving depression therapy [CBT]) symptoms. Psilocybin is thought to exert its effects primarily through its metabolite, psilocin, which demonstrates agonist or partial agonist activity at
serotonin 2A (5-HT2A) receptors. It produces marked changes in sensory perception, emotion, thought, and sense of self. In clinical trials, synthetic psilocybin is taken orally at a dose of 25 mg. Participants meet with session facilitators before dosing, undergo a session with facilitators and monitoring for 8 hours after dosing, and undergo 3 postdose integration sessions to discuss intervention experiences with facilitators. Developer(s): Usona Institute (Madison, Wisconsin)
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Table 4.9. Currently Monitored Mental and Behavioral Health Topics: 14 Topics
Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 8 to 14 years AKL-T01 (Project Evo) is a proprietary videogame digital Behavior therapy (eg, ADHD symptoms and Submission date: FDA 510(k) who have attention- therapy used on a computer tablet that is intended to applied behavior analysis severity August 2018 deficit/hyperactivity improve attention and impulse control in children with [ABA], cognitive behavioral Attentional functioning Clinical trial(s): Unphased disorder (ADHD) ADHD. This novel prescription intervention might provide therapy [CBT]) Executive functioning STARS-ADHD completed a nonpharmacologic alternative for treating ADHD that External trigeminal nerve Spatial working August 2017, data presented can be delivered at home. Through gameplay, the device stimulation (eTNS) memory October 2018; unphased purportedly delivers sensory and motor stimuli to Nonstimulant medications primary completion selectively targeted areas of the brain that are known to (eg, atomoxetine, clonidine, September 2019, data be responsible for cognitive deficiencies. The software guanfacine) reported January 2020, data provides a personalized experience through use of Stimulant medications (eg, published February 2020 adaptive algorithms. In trials, participants played the dexmethylphenidate, game at home for 30 minutes, 5 times a week, for 4 lisdexamfetamine, weeks. AKL-T01 is being studied alone and in combination methylphenidate) with a stimulant medication. Developer(s): Akili Interactive Labs, Inc (Boston, Massachusetts)
Children aged 5 years or Balovaptan (RG7314) is a small-molecule antagonist of the Atypical antipsychotics (eg, Change in adaptive FDA designation(s): older and adults who have vasopressin 1a (V1A) receptor intended to improve aripiprazole, risperidone) behavior (eg, Breakthrough Therapy high-functioning (IQ ≥ 70) emotional processing and reduce social deficits in Behavioral therapy (eg, communication and Clinical trial(s): Phase III autism spectrum disorder patients with ASD. Impairments of social interaction and applied behavior analysis socialization) primary completion (ASD) communication are core symptoms of ASD that cause [ABA]) Adverse events December 2020; phase II multiple challenges and affect quality of life. The Quality of life primary completion neuropeptide vasopressin is an endocrine hormone that February 2020; phase II is implicated in the regulation of both aggression and VANILLA completed affiliation. Blocking vasopressin might reduce aggression September 2016, data and anxiety and promote social bonding in patients with published 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)
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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 55 years Dasotraline is a serotonin, dopamine, and norepinephrine Lisdexamfetamine Binge eating frequency PDUFA date: May 14, 2020 who have moderate to reuptake inhibitor that is intended to treat BED by Pharmacotherapies (eg, and severity Clinical trial(s): Phase II/III severe binge eating disorder reducing the frequency of binge eating episodes. BED is a antiepileptics, Anxiety symptoms and completed October 2016; (BED) mental health disorder characterized by recurring norepinephrine reuptake severity phase III completed May episodes in which a person consumes large amounts of inhibitors [NRIs], serotonin- Depression symptoms 2018, pivotal phase III data food in a short time and feels loss of control; physical norepinephrine reuptake and severity reported July 2018; phase III discomfort from overeating; and shame, guilt, or inhibitors [SNRIs]; off label) extension completed June depression. It is thought to be caused by underlying 2019 anxiety, depression, or other psychological factors. Dasotraline purportedly increases the amount of serotonin, dopamine, and norepinephrine in the brain, which helps 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 at a dose of 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 (deep TMS) is a Psychotherapy (eg, PTSD symptoms and Clinical trial(s): Phase I/II who have moderate to noninvasive outpatient treatment that uses directed cognitive behavioral severity completed July 2011, data severe posttraumatic stress electromagnetic fields to target and stimulate the therapy [CBT], eye Change in cognitive published May 2013; disorder (PTSD) prefrontal cortex region of the brain to treat PTSD. A new movement desensitization function unphased primary coil design purportedly allows for deeper stimulation at and reprocessing [EMDR] Quality of life completion December 2020 safe levels to try to reduce PTSD symptoms and severity. therapy, prolonged Note(s): FDA approved deep The manufacturer asserts that the H1 coil used in the exposure therapy [PET]) TMS for treatment-resistant device stimulates deeper regions of the prefrontal cortex Repetitive transcranial depression in January 2013, than the figure-8 coil used in repetitive TMS. The magnetic stimulation and for obsessive- treatment is intended as an adjunct to pharmacologic (rTMS; off label) compulsive disorder in and/or psychologic treatment. In an ongoing trial, deep Selective serotonin August 2018 TMS is given in 20-minute sessions, 3 times a week for 4 reuptake inhibitors (eg, weeks, with a booster treatment at week 5 and another at paroxetine, sertraline) week 9, totaling 14 treatment sessions. At least 8 sessions are required for treatment. Developer(s): BrainsWay, Ltd (Hackensack, 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 75 years External trigeminal nerve stimulation (eTNS) sends Psychotherapy (eg, PTSD 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 Depression severity data published April 2016; which has limited effective treatment options. This small, movement desensitization and symptoms pivotal unphased primary portable device is intended to improve symptom severity and reprocessing [EMDR] Functional capacity completion September 2019 and quality of life. The eTNS system is a cell phone–sized therapy, prolonged Quality of life Note(s): FDA approved eTNS electrical pulse generator that delivers mild electrical exposure therapy [PET]) in April 2019 for pediatric signals via 2 wires connected to a small single-use electric Selective serotonin attention- patch that adheres to the forehead. The therapy is reuptake inhibitors (SSRIs; deficit/hyperactivity disorder intended to be used by the patient at home nightly for 8 eg, paroxetine, sertraline) (ADHD) hours while sleeping. The eTNS therapy purportedly changes the neuronal activity in key regions of the brainstem, thalamus, and cortex, increasing activity in underactive regions. It is used in conjunction with pharmacotherapy. Developer(s): Neurosigma (Los Angeles, California), in collaboration with University of California (Los Angeles, California)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Children aged 5 years or Full-spectrum microbiota (FSM) therapy, an oral route of Dietary modifications and Autism symptoms and FDA designation(s): Fast older and adults aged up to stool transplantation, introduces key strains of nutritional counseling severity Track 60 years who have autism purportedly beneficial bacteria to increase microbial Fecal microbiota Aberrant behavior Clinical trial(s): Phase II spectrum disorder (ASD) biodiversity within the gut using gut bacteria collected transplantation by other Social responsiveness SPROUT primary completion with gastrointestinal (GI) from healthy human donors. About half of individuals means GI symptoms May 2020; phase II MTT-ASD symptoms with ASD have chronic GI symptoms, such as constipation, primary completion October diarrhea, and abdominal pain. This treatment is intended 2020; phase II primary to improve both GI symptoms and core symptoms in completion June 2021 individuals with ASD. Research has found that individuals with ASD are more likely to have an abnormal gut microbiome than healthy controls, which might affect neurologic health in addition to GI symptoms. One course of FSM therapy purportedly improves autism symptoms for as long as 2 years. The oral capsules are made by processing feces until only bacteria remain, then encapsulating the bacteria concentrate inside a 3-layer gelatin capsule. In trials, a capsule of gut bacteria from healthy human donors is taken by mouth daily for 8 weeks. In one trial, patients also receive the antibiotic vancomycin and a bowel cleanse before FSM therapy. Developer(s): Finch Therapeutics (Somerville, Massachusetts), in collaboration with Arizona State University (Tempe, Arizona)
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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 65 years Ketamine is an N-methyl-D-aspartate (NMDA) receptor Psychotherapy (eg, PTSD symptoms and Clinical trial(s): Phase II who fulfill DSM-5 criteria for antagonist intended to treat PTSD symptoms in adults. cognitive behavioral severity completed September 2013 current civilian or combat- Glutamate, an excitatory neurotransmitter that binds to therapy [CBT], eye Depression symptoms (single dose), data published related posttraumatic stress NMDA receptors, is purported to be highly involved in the movement desensitization and severity June 2014; phase II/III disorder (PTSD) stress response and formation of traumatic memories in and reprocessing [EMDR] Quality of life primary completion PTSD. By decreasing glutamate’s excitatory activity and therapy, prolonged February 2020 (repeated thus reducing stress-related synaptic activity that exposure therapy [PET]) dose) contributes to PTSD symptoms, ketamine is intended to Repetitive transcranial improve PTSD symptoms and patient quality of life magnetic stimulation quicker than currently approved PTSD therapies, including (rTMS; off label) psychotherapy and selective serotonin reuptake Selective serotonin inhibitors. Ketamine purportedly provides rapid and reuptake inhibitors (SSRIs; sustained therapeutic effects for patients with PTSD. Its eg, paroxetine, sertraline) use for this purpose is off label. In clinical trials, participants are given 0.2 or 0.5 mg/kg doses of ketamine intravenously for a variable number of infusions (6 to 8) over 2 to 4 weeks. After treatment, patients must be monitored for at least 4 hours before discharge. Developer(s): Icahn School of Medicine at Mount Sinai (New York, New York), in collaboration with the Department of Veterans Affairs’ (VA’s) Office of Research and Development (Washington, DC)
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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 65 years Ketamine (NRX-100)/cyclurad (NRX-101) is a sequential Electroconvulsive therapy Suicidal ideation FDA designation(s): who have severe bipolar drug plan that includes a single infusion of ketamine (ECT) Attempted suicide Breakthrough Therapy, Fast depression with acute followed by an oral, fixed dose of 2 FDA-approved drugs. IV ketamine (off label) Completed suicide Track suicidal ideation and These 2 drugs, combined within NRX-101, are lurasidone Lurasidone (monotherapy Depression symptoms Clinical trial(s): NRX- behavior (Latuda), a serotonin 2A (5-HT2A) receptor antagonist, and or in combination with and severity 100/NRX-101: Pivotal phase d-cycloserine (DCS), an N-methyl-D-aspartate (NMDA) lithium or valproate) II STABIL-B completed receptor modulator. This combination therapy Time to relapse Olanzapine/fluoxetine November 2018, data purportedly extends ketamine’s antidepressant and combination reported May 2019; NRX- antisuicidal effects and is intended to provide both rapid- 101: phase II/III primary Quetiapine onset and sustained treatment effects. The therapy can completion March 2019, be given in the outpatient setting after a single dose of Supportive care (eg, designed under Special ketamine in a clinical setting. Lurasidone, alone or in hospitalization) Protocol Assessment; phase combination with lithium or valproate, is an approved II/III primary completion treatment for bipolar depression. DCS, an agent used in September 2020, designed tuberculosis therapy, acts as a partial or full agonist of under Special Protocol NMDA receptors. Studies of its use as a cognitive Assessment; NRX-100: phase enhancer with other psychosocial interventions have had III primary completion mixed results in various psychiatric disorders. In trials, September 2020 one 40-minute intravenous infusion of ketamine (0.5 Note(s): FDA has approved mg/kg) is given followed by administration of NRX-101 Latuda to treat depressive twice daily, adjusted to a combined dose of 950/66 episodes in bipolar mg/day for 6 weeks. Patient observation is required after depression ketamine infusion. Developer(s): NeuroRx, Inc (Wilmington, Delaware)
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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 3,4-Methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy (eg, PTSD symptoms and FDA designation(s): older who have severe psychotherapy involves treatment with MDMA during an cognitive behavioral severity Breakthrough Therapy posttraumatic stress 8-hour standardized nondirective psychotherapy session therapy [CBT], eye Depression symptoms Clinical trial(s): Phase III disorder (PTSD) performed by a therapist team. In the context of therapy, movement desensitization and severity MAPP1 primary completion MDMA administration is intended to reduce avoidance and reprocessing [EMDR] June 2020, designed under and hyperarousal, purportedly leading to a desirable therapy, prolonged Special Protocol Assessment; psychological state that enhances the therapeutic process exposure therapy [PET]) phase III MAPP2 primary for patients with severe PTSD, which has limited effective Selective serotonin completion June 2021; phase treatment options. MDMA, known by the street names reuptake inhibitors (SSRIs; II completed September Ecstasy and Molly, is a psychedelic compound that is eg, paroxetine, sertraline) 2010; phase II completed known to release serotonin, norepinephrine, and February 2011; phase II dopamine in the brain and to indirectly increase oxytocin completed November 2016; and cortisol levels. MDMA is intended to reduce anxiety phase II completed April and emotional distress and increase prosocial behaviors, 2017; phase II completed including communication, compassion, and introspection. June 2017; phase II According to the Diagnostic and Statistical Manual of completed September 2017, Mental Disorders, 5th edition (DSM-5), PTSD’s 4 main phase II pooled data symptom categories are arousal and reactivity, avoidance published May 2019 of triggers, negative thoughts and feelings, and intrusive thoughts and nightmares. In trials, a flexible dose of MDMA is given orally once a month for 3 months, during an 8-hour psychotherapy session. An initial dose (80 to 120 mg) is given, followed by a supplemental half-dose (40 or 60 mg) 1.5 to 2.0 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)
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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 65 years Oxytocin is a naturally occurring hormone in the brain Antidepressants (eg, Social cognition Clinical trial(s): Unphased who have schizophrenia that is known for its association with social bonding and, selective serotonin Negative completed August 2012, when given intranasally, purportedly improves social reuptake inhibitors [SSRIs], schizophrenia data published July 2013; cognition in patients with schizophrenia. Studies have serotonin and symptoms phase II CIDAR-3 completed shown that patients with schizophrenia have lower norepinephrine reuptake Quality of life July 2014; phase II oxytocin levels, which has been associated with impaired inhibitors [SNRIs]) completed November 2015, trust, empathy, and ability to interpret mental states. Antipsychotics (oral and data published April 2016; Current antipsychotic drugs have been used successfully injectable) phase II completed March to treat the positive symptoms of patients with Combination therapy 2017 schizophrenia but have minimal effects on negative Electroconvulsive therapy symptoms and cognitive deficits. Increasing oxytocin levels might reduce negative symptoms and normalize Mood stabilizers social dysfunction associated with schizophrenia. It is Psychotherapy (eg, being studied as both a standalone and adjunct cognitive behavioral treatment. In the most recent clinical trial, oxytocin was therapy [CBT]) used in combination with risperidone. In this study, oxytocin is given intranasally at a dose of three 4-IU puffs per nostril for a total dose of 24 IU. Other trials used doses of 24 to 80 IU/day, for 1 to 6 weeks, and a dose- range study evaluated doses of 6 to 84 IU. Trials have studied single-dose treatments as well as daily treatment for up to 4 weeks. Developer(s): Emory University (Atlanta, Georgia), in collaboration with Atlanta Veterans Administration (VA) Health Care System (Atlanta, Georgia)
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adolescents aged 13 years SEP-363856 is a psychotropic medication intended to treat Antipsychotics (first and Schizophrenia FDA designation(s): or older and adults aged up schizophrenia through a different mechanism from second generation) symptoms (positive Breakthrough Therapy to 65 years who have currently approved antipsychotics by not binding to Psychotherapy (eg, and negative) and Clinical trial(s): Phase III schizophrenia dopamine D2 or serotonin 2A (5-HT2A) receptors. Although cognitive behavioral severity DIAMOND 1 primary the exact way it works is unknown, SEP-363856 is thought therapy [CBT]) Frequency and completion September 2021; to activate trace amine-associated receptor 1 (TAAR1) and duration of psychotic phase III DIAMOND 2 the serotonin 1A (5-HT1A) receptor. Many options for episodes primary completion October treating schizophrenia address only the positive or Social functioning 2021; phase III DIAMOND 4 negative symptoms. This drug is intended to improve both Quality of life primary completion March positive and negative symptoms without the serious side 2022; phase III DIAMOND 3 effects of currently available antipsychotics. In clinical primary completion trials, flexibly dosed SEP-363856 was given orally at a dose November 2022; phase II of 25, 50, 75, or 100 mg, once daily, for up to 52 weeks. completed July 2018, pivotal Developer(s): data presented December Sunovion (Marlborough, Massachusetts), a subsidiary of 2018, data reported October Sumitomo Dainippon Pharma (Osaka, Japan) 2019; phase II completed January 2019, data reported December 2019 Note(s): SEP-363856 is in phase II studies to treat Parkinson’s disease psychosis
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Potential Patient Intervention Description Potential Comparators Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Outcome Measures
Adolescents aged 12 years Sodium benzoate (NaBen) is a prescription-strength Antidepressants (eg, Schizophrenia FDA designation(s): Orphan or older and adults aged up formulation of the sodium salt used as a common food selective serotonin symptoms (positive Drug, Breakthrough Therapy to 55 years who have a preservative and is intended to treat schizophrenia’s reuptake inhibitors [SSRIs], and negative) Clinical trial(s): Phase IIb/III confirmed DSM-IV or DSM-5 positive and negative symptoms. Existing drugs for serotonin and Efficacy of primary completion diagnosis of schizophrenia treating schizophrenia have limited efficacy in reducing norepinephrine reuptake antipsychotics December 2018; phase IIb/III and are clinically stable with both positive and negative symptoms, and many are inhibitors [SNRIs]) Quality of life primary completion residual symptoms; and associated with serious side effects. A key dysfunction Antipsychotics (oral and December 2018; phase IIb/III adults aged 18 to 55 years related to schizophrenia is the reduced function of the N- injectable) primary completion June who have treatment- methyl-D-aspartate (NMDA) receptor in the brain. NaBen Combination therapy 2019 refractory schizophrenia addresses this by inhibiting D-amino acid oxidase (DAAO) Mood stabilizers metabolism to increase DAAO activity, leading to production of more D-serine, which increases NMDA Psychotherapy (eg, activity in the hypothalamus. In ongoing phase IIb trials cognitive behavioral for patients with clinically stable schizophrenia, 500-mg therapy [CBT]) NaBen oral tablets are given twice daily at a total dose of 1000 mg/day for 6 to 8 weeks. Participants’ current antipsychotic medication regimens remain unchanged for at least 8 weeks before study screening and during the study. In an ongoing phase 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 randomly selected sample of these participants. Developer(s): SyneuRx International Corp (New Taipei City, Taiwan)
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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 65 years Zonisamide (Zonegran) is a sulfonamide anticonvulsant Pharmacotherapy (eg, Alcohol consumption Clinical trial(s): Pilot who have alcohol use demonstrated to modulate gamma-aminobutyric acamprosate, disulfiram, Alcohol cravings unphased completed March disorder (AUD) acidergic (GABAergic) and glutamatergic naltrexone) Alcohol withdrawal 2009; pilot phase IV neurotransmission. Approved medications to treat AUD Psychotherapy (eg, symptoms completed May 2009; phase have shown limited effectiveness; only one-third of III primary completion cognitive behavioral Relapse patients achieve full remission with available therapies. therapy [CBT]) February 2021 Zonisamide is intended to reduce alcohol consumption Health outcomes in patients with heavy drinking behaviors or AUD; associated with treatment with zonisamide might also ameliorate the abstinence symptoms of alcohol withdrawal syndrome. Its exact Quality of life mechanism of action is unknown, but zonisamide purportedly reduces GABAergic and glutamatergic neurotransmission in the brain, which is signaling involved with alcohol’s effect on the brain. In clinical trials, zonisamide is given orally, at doses of up to 500 mg daily. Developer(s): Department of Veterans Affairs’ (VA’s) Office of Research and Development (Washington, DC)
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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 Zuranolone (SAGE-217) is a positive allosteric modulator Pharmacotherapy (eg, Depression symptoms FDA designation(s):
who have major depressive of gamma-aminobutyric acid receptor A (GABAA) intended selective serotonin and severity Breakthrough Therapy disorder (MDD) to treat MDD and yield benefits in about half the time of reuptake inhibitors [SSRIs], Quality of life Clinical trial(s): Phase II standard pharmacotherapies (ie, 2 weeks or sooner vs 4 serotonin and completed October 2017, to 6 weeks). The manufacturer asserts that zuranolone norepinephrine reuptake data presented October might improve symptoms within a few days. Reduced inhibitors [SNRIs]) 2018, data published brain concentrations of the inhibitory neurotransmitter Psychotherapy (eg, September 2019; phase III gamma-aminobutyric acid (GABA) as well as alterations in cognitive behavioral primary completion the subunit composition of GABAA (ie, deficits in therapy [CBT]) September 2019, topline GABAergic transmission) are thought to contribute to data reported December MDD. Zuranolone purportedly works by amplifying GABAA 2019; phase III primary receptor activity. Investigators postulate that competing completion April 2021; standard-of-care antidepressants might similarly, but phase III (open label) more slowly, reduce GABAergic deficits due to primary completion downstream effects. The manufacturer states that December 2021 (see note) zuranolone is given orally, once daily (dose unspecified), Note(s): A phase III open- for a target treatment length of 2 weeks. label trial of zuranolone was Developer(s): suspended in January 2020 Sage Therapeutics, Inc (Cambridge, Massachusetts) by the developer to evaluate “potential amendments to the study”
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Table 4.10. Mental and Behavioral Health Topics Archived Since Last Status Report: 1 Topic
Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 or older Esketamine HCL nasal spray (Spravato) is the (S+)–enantiomer of Antidepressants (eg, Depression symptoms Esketamine (Spravato) who have treatment- ketamine, delivered through a single-use intranasal device. The monoamine oxidase and severity was FDA approved in resistant major drug is indicated for use in combination with an oral inhibitors [MAOIs], Anxiety symptoms and March 2019. Because it depressive disorder antidepressant for treatment-resistant depression in adults. selective serotonin severity has been clinically (MDD) that has not Esketamine is absorbed by the lining of the nasal passages and reuptake inhibitors Suicidal thoughts available for more than 1 abated after 2 or more into the bloodstream, purportedly leading to rapid (ie, within [SSRIs], serotonin and year, it is no longer within Suicide attempts courses of hours) improvement in depression symptom severity in norepinephrine reuptake the time scope for the antidepressants at patients with MDD. Esketamine works through noncompetitive inhibitors [SNRIs], tricyclic Quality of life PCORI Health Care adequate dose and antagonism of the N-methyl-D-aspartate (NMDA) receptor. antidepressants [TCAs]) Horizon Scanning duration during the Blocking activation of the NMDA receptor facilitates sensory Brain stimulation (eg, System. The time scope is current moderate-to- input; moderates emotional responses; and might increase deep brain stimulation defined as 3 years before severe episode of dopamine, norepinephrine, and serotonin levels in the brain. [DBS], electroconvulsive an intervention becomes depression The single-use nasal spray device contains 28 mg of esketamine therapy [ECT], clinically available outside HCL and delivers two 14-mg sprays per device. Treatment is transcranial magnetic of the research setting to initiated in the induction phase at weeks 1 to 4 at a dose of 56 stimulation [TMS], vagal 1 year after an mg on day 1 and at a dose of 56 or 84 mg subsequently, twice nerve stimulation [VNS]) intervention becomes weekly. During the maintenance phase, from weeks 5 to 8, Ketamine (intravenous; clinically available. esketamine is given at a dose of 56 or 84 mg once weekly, and off label) from week 9 and after, it is given at a dose of 56 or 84 mg every Psychotherapy (eg, one or two weeks. Esketamine is a Schedule III controlled cognitive behavioral substance. therapy [CBT]) Developer(s): Janssen Research & Development, LLC, a unit of Johnson & Johnson (New Brunswick, New Jersey)
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Section 5. Rare Diseases: 107 Topics
Table 5.11. Rare Disease Topics Added Since Last Status Report: 14 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Afamelanotide (Scenesse) is a melanocortin 1 receptor (MC1-R) Beta-carotene Duration of sunlight Approval date: October 8, older who have a history agonist indicated to increase pain-free light exposure in adults supplementation tolerated without pain 2019 of phototoxic reactions who have EPP. A rare genetic metabolic disorder, EPP causes Lifestyle modification (ie, Number and severity of FDA designation(s): from erythropoietic phototoxicity and anaphylactoid reactions when the patient’s sunlight avoidance) phototoxic reactions Orphan Drug, Priority protoporphyria (EPP) skin is exposed to light. The drug is a chemical analogue of Quality of life Review alpha-melanocyte stimulating hormone (α-MSH), a naturally Clinical trial(s): Phase III occurring peptide hormone released by skin cells in response to completed July 2013, data ultraviolet radiation (UVR). α-MSH stimulates melanocytes to published July 2015; express melanin. Afamelanotide is a linear, 13-amino-acid phase III completed May peptide with 2 modified amino acids intended to increase the 2011 peptide’s half-life. The peptide analogue purportedly increases the melanin content of skin without requiring exposure to damaging UVR. Melanin absorbs, scatters, and quenches ultraviolet light, and so increased skin melanin levels are purportedly photoprotective. The peptide is administered as a controlled-release subcutaneous implant (16 mg) that is about the size of a grain of rice. The FDA-approved label states it “should be administered by a healthcare professional who is proficient in the subcutaneous implantation procedure and has completed training prior to administration” and uses “implantation devices that have been determined by the manufacturer to be suitable for implantation.” The implant is given every 2 months. Developer(s): Clinuvel, Ltd (Melbourne Australia)
SECTION 5. RARE DISEASES 115
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 to 55 AT-007 is a small-molecule inhibitor of the enzyme aldose Lifestyle modification (eg, Galactitol concentration Submission date: New years who have classic reductase. Galactosemia is a rare genetic disease that affects avoidance of dairy in plasma from baseline Drug Application planned galactosemia confirmed patients’ ability to metabolize galactose, a simple sugar found in products and other Cognitive decline from for second half of 2020 by evidence of absent or foods and produced during normal metabolism. Elevated sources of galactose) baseline FDA designation(s): significantly decreased circulating galactose is converted by aldose reductase into Cataract formation from Orphan Drug galactose-1 phosphate galactitol, a toxic metabolite that causes long-term baseline Clinical trial(s): Phase II uridyl transferase (GALT) complications including central nervous system damage (eg, Sepsis incidence from ACTION-Galactosemia activity convulsions, irritability, lethargy, developmental delays) and baseline pivotal primary cataracts. Galactosemia has no cure or approved treatments. completion December AT-007 purportedly penetrates tissues, including the central 2019; topline results nervous system, to inhibit aldose reductase, thereby reducing reported January 2020 toxic galactitol levels and limiting disease complications. In clinical trials, AT-007 was administered orally once daily at a dose of up to 20 mg/kg. Developer(s): Applied Therapeutics, Inc (New York, New York)
Children aged 12 years or Benralizumab (Fasenra) is a monoclonal antibody that targets Corticosteroids Annualized rate of HES FDA designation(s): older and adults who the interleukin-5 (IL-5) receptor α-chain expressed on the Cytotoxic drugs (eg, flares from baseline Orphan Drug have hypereosinophilic surface of eosinophils. The receptor’s ligand is IL-5, a cytokine cyclophosphamide, Fatigue score from Clinical trial(s): Phase III syndrome (HES) responsible for promoting the activation and inflammatory hydroxyurea, vincristine) baseline NATRON trial primary responses of eosinophils. HES is a group of rare inflammatory Imatinib Overall survival completion June 2022 disorders characterized by the chronic overproduction of Quality of life eosinophils. These eosinophils infiltrate tissues and may cause damage to organs, such as the heart and lungs, which can negatively affect quality of life and mortality risk. Treatment options are limited. Benralizumab purportedly binds the IL-5α receptor and attracts natural killer (NK) cells that induce rapid and near-complete eosinophil depletion via apoptosis (ie, programmed cell death). In clinical trials, benralizumab was given by subcutaneous injection at a dose of 30 mg every 4 weeks. Developer(s): AstraZeneca plc (Cambridge, United Kingdom)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Females aged 18 to 45 Blarcamesine (ANAVEX2-73) is a small-molecule sigma-1 Supportive care (eg, Behavioral symptom FDA designation(s): years who have receptor activator intended to treat adult females who have anticonvulsants, assistive severity, as measured by Orphan Drug, Fast Track, genetically confirmed Rett syndrome, a rare, postnatal, progressive neurologic devices, noninvasive accepted clinical ratings Rare Pediatric Disease Rett syndrome disorder. Rett syndrome is caused by a mutation in the methyl ventilation, nutritional and scales Clinical trial(s): Phase II CpG binding protein 2 gene, MECP2. Located on the X support, oxygen Seizure frequency primary completion chromosome, MECP2 encodes the MeCP2 protein that normally treatment, physical and Sleep quality and March 2020, preliminary mediates gene expression in neuronal and glial cells. Loss of occupational therapy, duration (Part A) data presented MeCP2 function results in nerve cell dysfunction, which is speech/language September 2019; phase II thought to be reversible. Patients with Rett syndrome develop therapy) AVATAR primary normally until 6 to 18 months of age and subsequently completion June 2020 experience developmental delays and regression of previously Note(s): Blarcamesine is learned motor and verbal skills. The disease eventually causes also in clinical additional symptoms, such as repeated hand movements, development for treating impaired gait, slowed head growth, disordered breathing, and Alzheimer’s disease, seizures. Symptom severity varies by patient and depends on dementia in Parkinson’s the individual’s specific MECP2 mutation and the amount of disease, infantile spasms, mutant MeCP2 protein expression. No cure exists, and fragile X syndrome, and treatment generally consists of supportive care for managing Angelman syndrome symptoms. By activating the cellular sigma-1 receptor, blarcamesine purportedly reduces protein misfolding, inflammation, oxidative stress, and mitochondrial dysfunction, all of which might contribute to the symptoms of Rett syndrome and other neurodegenerative disorders (eg, Alzheimer’s disease). By promoting normal nerve cell function, blarcamesine may reduce disease symptoms. In clinical trials, patients take or caregivers give a liquid solution containing 5 mg of blarcamesine, once daily by mouth, for up to 19 weeks. Developer(s): Anavex Life Sciences Corp (New York, New York)
SECTION 5. RARE DISEASES 117
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Males aged 18 to 65 Fidanacogene elaparvovec (PF-06838435) is an adeno- Factor IX replacement Bleeding episodes FDA designation(s): years who have associated viral vector gene therapy under development to therapy (human plasma Treatment-related Orphan Drug, moderate to severe treat hemophilia B. As a single-treatment gene therapy, derived or recombinant) complications Breakthrough Therapy hemophilia B (factor IX fidanacogene elaparvovec could eliminate the need for Survival Clinical trial(s): Phase III activity 2% or less) who repeated injections of coagulation-factor replacement. Quality of life single-arm BENEGENE-2 have been receiving Fidanacogene elaparvovec uses an adeno-associated viral primary completion July routine factor IX vector to deliver a high-activity factor IX gene whose expression 2021 replacement therapy for is driven by a liver-specific apolipoprotein E (Apo E) at least 6 months enhancer/α1-antitrypsin (hAAT) promoter. In clinical trials, fidanacogene elaparvovec is administered as a single intravenous infusion (dose not stated). Developer(s): Pfizer, Inc (New York, New York)
SECTION 5. RARE DISEASES 118
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 12 years or Mepolizumab (Nucala) is a monoclonal antibody specific for Corticosteroids Annualized rate of HES Submission date: New older and adults who interleukin-5 (IL-5), a cytokine responsible for promoting Cytotoxic drugs (eg, flares from baseline Drug Application planned have hypereosinophilic eosinophil activation and inflammatory responses. HES is a cyclophosphamide, Fatigue score from for 2020 syndrome (HES) group of rare inflammatory disorders characterized by the hydroxyurea, vincristine) baseline FDA designation(s): chronic overproduction of eosinophils. These eosinophils Imatinib Overall survival Orphan Drug, Fast Track infiltrate tissues and might damage organs such as the heart Quality of life Clinical trial(s): Phase III and lungs, which can negatively impact quality of life and risk of completed December mortality. Treatment options are limited. Mepolizumab 2019; phase III completed purportedly binds to IL-5 and prevents it from binding to the IL- August 2019, data 5 receptor on the surface of eosinophils, which inhibits reported November inflammatory signaling and reduces eosinophil levels in 2019; phase III completed circulation without completely depleting them from the body. In September 2010 clinical trials, mepolizumab was given as a subcutaneous Note(s): FDA approved injection of 300 mg every 4 weeks. mepolizumab to treat Developer(s): severe asthma in GlaxoSmithKline plc (Brentford, United Kingdom) November 2015, to treat eosinophilic granulomatosis with polyangiitis (Churg- Strauss syndrome) in December 2017, for self- administration in June 2019, and for children aged 6 to 11 years with severe eosinophilic asthma in September 2019
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Narsoplimab (OMS721) is a fully human monoclonal antibody Eculizumab (off label) Inflammation biomarkers Submission date: Rolling older who have specific for mannan-binding lectin-associated serine protease-2 Rituximab with from baseline Biologics License developed hematopoietic (MASP-2) that is being investigated as a treatment for HSCT- plasmapheresis Red blood cell Application initiated stem cell transplantation TMA. About 10% to 25% of HSCTs lead to TMA and, in high-risk Supportive care (eg, transfusion requirements October 2019 (HSCT)–associated patients (eg, patients with comorbid graft-versus-host disease antibiotics, from baseline FDA designation(s): thrombotic whose TMA has not responded to modification of antihypertensives, Platelet requirements Orphan Drug, microangiopathy (TMA) immunosuppressive therapy), the death rate is more than 90%. erythropoietin, from baseline Breakthrough Therapy No treatments are FDA approved for HSCT-TMA. TMA is thrombopoietin) Survival Clinical trial(s): Phase II characterized by the formation of blood clots in small blood study primary vessels throughout the body that can progressively damage completion October organs, including the kidneys, and carries a high risk of 2019, preliminary data morbidity and mortality. In addition, TMA is characterized by reported December 2019 excessive activation of the immune system’s complement system. MASP-2 is a key enzyme in the lectin pathway responsible for activating the complement system in response to tissue damage or microbial infection. By binding and inhibiting MASP-2, narsoplimab purportedly reduces excessive complement-mediated inflammation and endothelial damage characteristic of TMA while leaving other complement system functions intact. In clinical trials, narsoplimab has been administered as an intravenous infusion at an unspecified loading dose followed by daily unspecified low, medium, or high doses as subcutaneous injections. Developer(s): Omeros Corp (Seattle, Washington)
SECTION 5. RARE DISEASES 120
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 12 years or Narsoplimab (OMS721) is a fully human monoclonal antibody Eculizumab Platelet count change FDA designation(s): older and adults who specific for mannan-binding lectin-associated serine protease-2 Plasma therapy (ie, from baseline Orphan Drug, Fast Track have primary atypical (MASP-2), the effector enzyme of the lectin pathway in the plasma infusion or Glomerular filtration rate Clinical trial(s): Phase III hemolytic uremic complement system. An ultra-rare genetic disease, aHUS results plasmapheresis) from baseline primary completion syndrome (aHUS) in chronic uncontrolled complement activation, leading to TMA events from February 2020 complement-mediated thrombotic microangiopathy (TMA). TMA baseline is characterized by the formation of blood clots in small blood Disease remission rate vessels throughout the body that can progressively damage organs, including the kidneys, and carries a high risk of morbidity and mortality. Narsoplimab is intended to reduce the excessive complement-mediated inflammation and endothelial damage characteristic of aHUS while leaving other complement system functions intact. In clinical trials, narsoplimab was administered as an intravenous infusion at an unspecified loading dose followed by daily subcutaneous injections. Developer(s): Omeros Corp (Seattle, Washington)
Adults aged 18 years or OCU300 is a proprietary nanoemulsion of brimonidine tartrate Dry eye treatment for Bulbar redness FDA designation(s): older who have ocular eye drop solution intended to treat oGVHD. No FDA-approved symptom management Dry eye symptoms Orphan Drug graft-versus-host disease treatments exist for oGVHD, and patients are sometimes given (off label) Ocular discomfort Clinical trial(s): Phase III (oGVHD) off-label dry eye treatment to manage symptoms. A debilitating Light sensitivity primary completion July immune disorder, oGVHD is a frequent complication of 2020 allogeneic bone marrow transplants and affects the ocular Quality of life surface and tear-producing glands. OCU300 purportedly has an anti-inflammatory effect on the eye surface and mediates vasoconstriction, resulting in relief from dry eyes, eye pain, severe light sensitivity, and other clinical presentations of oGVHD. The nanoemulsion formulation of OCU300 purportedly prolongs retention of the agent on the eye surface. In clinical trials, OCU300 is given by eye drop at a dose of 0.18% twice daily for 12 weeks. Developer(s): Ocugen, Inc (Malvern, Pennsylvania)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 1 month or Ravulizumab-cwvz (Ultomiris) is a humanized, long-acting, Eculizumab Platelet count change Approval date: October older and adults who monoclonal antibody that purportedly provides immediate Plasma therapy (ie, from baseline 18, 2019 have atypical hemolytic and complete inhibition of the C5 complement protein in the plasma infusion or Glomerular filtration rate Clinical trial(s): Phase III uremic syndrome (aHUS) terminal complement cascade. aHUS, an ultra-rare genetic plasmapheresis) from baseline trial primary completion and evidence of disease, results in chronic uncontrolled complement TMA events from November 2018, data complement-mediated activation, leading to complement-mediated TMA. TMA is baseline reported January 2019; thrombotic characterized by the formation of blood clots in small blood Disease remission rate phase III primary microangiopathy (TMA) vessels throughout the body that can progressively damage completion November organs, including the kidneys, and carries a high risk of 2020 morbidity and mortality. Ravulizumab-cwvz is intended to Note(s): Ravulizumab- inhibit C5 activation leading to excessive complement- cwvz was approved to mediated inflammation and endothelial damage treat adults with characteristic of aHUS while leaving other aspects of the paroxysmal nocturnal immune system intact. Ravulizumab-cwvz is administered as hemoglobinuria (PNH) in an intravenous infusion in pediatric and adult patients, 1 December 2018 month of age or older. The FDA-approved label provides a dosing table that starts with a loading dose based on weight (600 mg for 5 kg body weight and a sliding scale up to 3000 mg for 100 kg body weight). After the loading dose, for patients weighing 5 to 20 kg, the drug is given at a maintenance dose of 300 mg or 600 mg every 4 weeks. For patients weighing 20 to 100 kg, the maintenance dose is 2100 to 3600 mg every 8 weeks. Developer(s): Alexion Pharmaceuticals (Boston, Massachusetts)
SECTION 5. RARE DISEASES 122
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or RGN-259 is a sterile and preservative-free eye drop formulation Antibiotic eye drops Visual acuity FDA designation(s): older who have stage 2 of thymosin beta 4 (Tβ4), a naturally occurring regenerative Bandage contact lenses Corneal sensitivity Orphan Drug or 3 neurotrophic peptide. RGN-259 is intended to treat neurotrophic keratitis Cenegermin eye drops Quality of life Clinical trial(s): Phase III keratopathy in at least (NK), a rare degenerative disease of the corneal epithelium that Surgery SEER-1 primary one eye currently has no effective treatments. NK is characterized by completion August 2020 decreased corneal sensitivity and poor corneal wound healing, Note(s): RGN-259 is also which makes the cornea sensitive to injury and decreases reflex in phase II/III trial tear production. RGN-259 purportedly promotes cell migration development for dry eye and laminin-5 production, reducing both cell death and syndrome inflammation in the cornea. In clinical trials, RGN-259 ophthalmic solution is given as a direct instillation into the affected eye or eyes, 5 times a day for 4 weeks. Developer(s): RegeneRx Biopharmaceuticals, Inc (Rockville, Maryland), in collaboration with RegenTree, LLC (Princeton, New Jersey)
SECTION 5. RARE DISEASES 123
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 6 years or Setmelanotide (RM-493) is a selective melanocortin-4 (MC4) Lifestyle modifications Hunger symptoms and Submission date: New older and adults who receptor agonist (ie, activator) peptide intended to treat (eg, diet, exercise) severity Drug Application have leptin receptor patients with LEPR deficiency obesity. Setmelanotide might Psychotherapy (eg, Rate of comorbidities (eg, anticipated first quarter (LEPR) deficiency genetic improve patient quality of life and health outcomes by reducing cognitive behavioral cardiovascular disease, of 2020 obesity insatiable hunger, obesity, and obesity-related complications. therapy [CBT]) diabetes mellitus, FDA designation(s): LEPR deficiency obesity is a rare, recessive, genetic disorder in obesity) Orphan Drug, which a variation in the leptin receptor gene, LEPR, results in Weight Breakthrough Therapy inadequate leptin receptors. Leptin receptors normally signal a Quality of life Clinical trial(s): Pivotal feeling of fullness (satiety) when leptin binds to them in the phase III primary hypothalamus area of the brain. Patients with LEPR deficiency completion January 2020, do not receive those signals of satiety, due to a lack of topline data released functional leptin receptors, and subsequently experience August 2019, additional insatiable hunger that leads to obesity and obesity-related data (body mass index complications. Patients are born of normal weight but often [BMI] and cardiovascular) become obese in the first few months of life. It is thought that released November 2019; MC4 receptors function downstream of leptin receptors in phase II completed controlling satiety. Setmelanotide purportedly activates MC4 January 2018, data receptors in the paraventricular nucleus and lateral published May 2018; hypothalamic nuclei areas in the brain, thereby suppressing phase II/III primary appetite. It also purportedly increases resting energy completion May 2021; expenditure. Setmelanotide might require a companion phase II/III long-term diagnostic device to determine patient eligibility. In clinical extension trial primary trials, setmelanotide is administered as an injection underneath completion March 2023 the skin once daily at an unspecified dose. Note(s): Setmelanotide is Developer(s): in phase III trials to treat Rhythm Pharmaceuticals, Inc (Boston, Massachusetts) proopiomelanocortin (POMC) deficiency obesity, Bardet-Biedl syndrome, and Alström syndrome and is in phase II trials to treat MC4R pathway heterozygous obesity and POMC epigenetic disorders
SECTION 5. RARE DISEASES 124
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Children aged 6 years or Setmelanotide (RM-493) is a selective melanocortin-4 (MC4) Lifestyle modifications Hunger symptoms and Submission date: New older and adults who receptor agonist (ie, activator) peptide intended to treat (eg, diet, exercise) severity Drug Application have patients with POMC deficiency obesity. This is a rare, recessive, Psychotherapy (eg, Rate of comorbidities (eg, anticipated first quarter proopiomelanocortin genetic disorder in which patients are often severely obese by 1 cognitive behavioral cardiovascular disease, of 2020 (POMC) deficiency year of age, remain obese for life, and experience a variety of therapy [CBT]) diabetes mellitus, FDA designation(s): genetic obesity obesity-related complications. Setmelanotide might improve obesity) Orphan Drug, patient quality of life and health outcomes by reducing Weight Breakthrough Therapy insatiable hunger, obesity, and obesity-related complications. Quality of life Clinical trial(s): Phase II POMC deficiency obesity is caused by variants in the completed January 2018, proopiomelanocortin gene, POMC, that result in insufficient data published July 2016; production of adrenocorticotropic hormone (ACTH), alpha- phase II/III primary melanocyte-stimulating hormone (α-MSH), and beta- completion January 2020, melanocyte-stimulating hormone (β-MSH). Normally, α-MSH topline data reported and β-MSH bind to MC4 receptors in the brain and help August 2019, additional suppress appetite. A lack of α-MSH and β-MSH in patients with data (body mass index POMC deficiency is thought to lead to excessive hunger and [BMI] and cardiovascular) obesity. Setmelanotide purportedly activates MC4 receptors in reported November the paraventricular nucleus and lateral hypothalamic nuclei 2019; phase II/III primary areas in the brain to suppress appetite. Setmelanotide also completion May 2021; purportedly increases resting energy expenditure. phase II/III long-term Setmelanotide might require a companion diagnostic device to extension trial primary determine patient eligibility. In clinical trials, setmelanotide is completion March 2023 administered as an injection underneath the skin at an Note(s): Setmelanotide is unspecified dose, once daily. in phase III trials to treat Developer(s): leptin receptor (LEPR) Rhythm Pharmaceuticals, Inc (Boston, Massachusetts) deficiency obesity, Bardet-Biedl syndrome, and Alström syndrome and is in phase II trials to treat melanocortin-4 receptor pathway heterozygous obesity and POMC epigenetic disorders
SECTION 5. RARE DISEASES 125
Potential Patient Intervention Description Potential Patient-oriented Regulatory Population Developer(s)/Manufacturer(s) Comparators Outcome Measures Information
Adults aged 18 years or Tildacerfont (SPR001) is a small-molecule antagonist of the Glucocorticoids (eg, Disease progression FDA designation(s): older who have corticotropin-releasing factor type 1 (CRF1) receptor. It might dexamethasone, Measures of disease Orphan Drug congenital adrenal help improve health outcomes in patients with CAH by reducing hydrocortisone, severity (eg, serum levels Clinical trial(s): Phase II hyperplasia (CAH) due to symptoms associated with adrenal enlargement and excessive prednisone) of 17- completed May 2019, 21-hydroxylase deficiency androgen production and reducing chronic treatment with hydroxyprogesterone, data reported March high-dose steroids. CAH is a group of genetic disorders androstenedione, and 2019; phase II completed characterized by abnormal hormone production in the adrenal ACTH) September 2019, data gland. Accounting for approximately 95% of cases, CAH due to Symptom severity reported September 21-hydroxylase deficiency occurs when variations in the Quality of life 2019 CYP21A2 gene cause a deficiency of 21-hydroxylase, an enzyme necessary for the production of cortisol and aldosterone in the adrenal gland. The result is reduced or absent cortisol and aldosterone production, and, indirectly, elevated levels of adrenocorticotropic hormone (ACTH) that cause enlargement of the adrenal gland and increased production of adrenal androgens. Depending on severity, patients experience risk for adrenal crisis, salt-losing, growth failure, atypical genitalia, virilization, menstrual dysfunction, and infertility. Tildacerfont
binding to CRF1 receptors on the pituitary gland in the brain purportedly decreases the release of ACTH, which helps decrease adrenal enlargement and adrenal androgen production in patients with CAH. In clinical trials, tildacerfont is taken orally at a dose of 400 mg, once daily, for 12 weeks in addition to baseline glucocorticoid therapy. Developer(s): Spruce Biosciences (San Francisco, California)
SECTION 5. RARE DISEASES 126
Table 5.12. Currently Monitored Rare Disease Topics: 89 Topics
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 6 months ABO-101 is a recombinant adeno-associated viral vector Supportive care Cognitive and motor FDA designation(s): Orphan Drug, or older and adults who carrying a wild-type copy of the N-acetyl-alpha- function, as measured Rare Pediatric Disease, Fast Track have Sanfilippo glucosaminidase gene, NAGLU. The therapy is intended for by validated clinical Clinical trial(s): Phase I/II syndrome type B (also Sanfilippo syndrome type B, a childhood-onset, progressive, ratings and scales Transpher B primary completion called inherited metabolic disorder caused by a mutation in NAGLU enzyme activity October 2020 mucopolysaccharidosis NAGLU. Sanfilippo syndrome type B (about 30% of all Heparan sulfate levels type III B [MPSIIIB]) Sanfilippo syndrome cases) has no cure, and patients typically do not survive beyond their 20s. Treatment consists of supportive care. Patients with the disorder 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 intravenously via a peripheral-limb vein, at a low dose (2 × 1013 vg/kg) or high dose (5 × 1013 vg/kg), once. Developer(s): Abeona Therapeutics, Inc (Dallas, Texas)
SECTION 5. RARE DISEASES 127
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 6 months ABO-102 is a recombinant adeno-associated viral vector Bone marrow Age-related FDA designation(s): Orphan Drug, or older who have carrying a wild-type copy of the N-sulfoglucosamine transplantation developmental scores Fast Track, Rare Pediatric Sanfilippo syndrome sulfohydrolase gene, SGSH. It is intended to treat Sanfilippo Supportive care Behavior, as measured Disease, Regenerative Medicine type A (also called syndrome type A, a childhood-onset, progressive, inherited by accepted clinical Advanced Therapy mucopolysaccharidosis metabolic disorder caused by a mutation in SGSH. Patients ratings and scales Clinical trial(s): Phase I/II type III A [MPSIIIA]) and with the disorder cannot break down the polysaccharide Brain, liver, and spleen Transpher A primary completion a minimum cognitive heparan sulfate, a process normally mediated by the SGSH- volume December 2022 (MPSIIIA disease developmental quotient encoded enzyme heparan-N-sulfamidase. Buildup of Cognitive and motor phase unspecified), interim data (DQ) of 60 or above, or heparan sulfate in cells of the central nervous system causes function, as measured reported July 2019, interim data children or adults (age degeneration that manifests as behavioral problems, by accepted clinical presented October 2019; phase unspecified) who have sleeplessness, loss of speech and cognitive skills, mental ratings and scales I/II primary completion middle- or advanced- retardation, heart problems, seizures, and loss of mobility. December 2022 (patients with Heparan sulfate levels phase MPSIIIA and a DQ No cure exists for Sanfilippo syndrome type A (about 60% of middle- or advanced-phase below 60 all Sanfilippo syndrome cases), and patients typically do not Sleep quality and MPSIIIA) survive past their 20s. Treatment consists of supportive duration care. In patients with Sanfilippo syndrome type A, ABO-102 Sulfamidase enzyme purportedly restores sulfamidase enzyme function, blocks activity central nervous system degeneration, and reduces disease- Quality of life related symptoms. In clinical trials, ABO-102 is given intravenously via a peripheral-limb vein, at a low dose (0.5 × 1013 vg/kg), middle dose (1.0 × 1013 vg/kg), or high dose (3.0 × 1013 vg/kg), once. Developer(s): Abeona Therapeutics, Inc (Dallas, Texas)
SECTION 5. RARE DISEASES 128
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or ACE-083 is a locally acting, follistatin protein–based therapy Foot surgery Muscle volume FDA designation(s): Orphan Drug, older who have intended for CMT disease types 1 or X. Most patients with Supportive care (eg, Muscle strength Fast Track genetically confirmed CMT1 overexpress PMP22 protein due to an extra copy of analgesics, mobility Muscle function (eg, Clinical trial(s): Phase II primary Charcot-Marie-Tooth the peripheral myelin protein 22 gene, PMP22. Most patients aids, orthotic devices, walk/run time, walk completion January 2020; phase (CMT) disease type 1 or with CMT type X underexpress connexin-32 protein due to physical and distance) II open-label extension primary X alterations in the gap junction protein beta 1 gene, GJB1. occupational therapy) Balance and fall risk completion June 2022 Disruption of PMP22 or connexin-32 expression degrades Quality of life Note(s): Topline results expected the protective myelin sheath on nerve fibers, leading to in early 2020 peripheral nerve dysfunction, eventual nerve conduction loss, and muscle weakness in the hands and lower limbs. No curative or disease-modifying treatments are available for any type of CMT disease, and patients typically receive supportive care to lessen functional disability and neuropathic pain. Therefore, additional therapies are needed. ACE-083 is a recombinant fusion protein consisting of a modified form of human follistatin linked to the human immunoglobulin G2 Fc (IgG2 Fc) domain that purportedly binds to and inhibits specific proteins in the transforming growth factor beta (TGF-beta) protein superfamily that reduce muscle growth, such as activins and myostatin. Thus, ACE-083 is intended to increase muscle mass and strength in the areas where the drug is given. In clinical trials, patients receive an injection of up to 250-mg ACE-083, injected bilaterally into the tibialis anterior (ie, lower leg) muscle, once every 3 to 4 weeks, up to 24 times. Developer(s): Acceleron Pharma, Inc (Cambridge, Massachusetts)
SECTION 5. RARE DISEASES 129
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 6 to 16 Amifampridine (Ruzurgi), also known as 3,4-diaminopyridine, Immunoglobulins Ambulatory function (ie, Approval date: May 6, 2019, years who have is a potassium channel blocker approved by FDA for treating Immunosuppressive Triple Timed Up & Go Priority Review Lambert-Eaton children who have LEMS, a rare autoimmune neuromuscular drugs (eg, prednisone) [3TUG] test) FDA designation(s): Orphan Drug, myasthenic syndrome disorder. About 60% of patients with LEMS also have small Off-label Fast Track (LEMS) cell lung cancer, but the disorder can occur in patients acetylcholinesterase Clinical trial(s): Unphased without cancer. Pediatric onset of LEMS is rare. Patients with inhibitors (eg, expanded access, unphased LEMS develop antibodies that attack the body’s own cells pyridostigmine) expanded access and disrupt normal signaling between nerve cells and muscles. Muscle weakness first develops in the legs and arms and can progress to the shoulders, feet and hands, and head and throat. Patients may also experience dry mouth and eyes, constipation, weight loss, and reduced reflex response. LEMS has no cure, and treatment is intended to relieve symptoms. Ruzurgi purportedly improves muscle function by promoting normal nerve cell– muscle signaling. Its manufacturer formerly made the drug freely available to adults with LEMS through a compassionate use program. In November 2018, FDA approved a competing drug, the phosphate salt of amifampridine (Firdapse), for treating adults with LEMS. Because Firdapse contains the same active ingredient as Ruzurgi, its mechanism of action is likely similar. However, the 2 drugs’ wholesale acquisition costs (WACs) differ significantly: Ruzurgi’s monthly maximum-dose WAC ranges from $12 000 to $24 000 (depending on dosing), while Firdapse’s monthly maximum-dose WAC is about $43 000. According to Ruzurgi’s FDA-approved label, patients take the drug orally. Depending on patient weight, patients receive 7.5 to 30.0 mg initially in 2 to 3 divided doses and gradually increase to a maximum daily maintenance dose of 50 to 100 mg daily in up to 5 divided doses. Developer(s): Jacobus Pharmaceutical Co, Inc (Princeton, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Apremilast (Otezla) is a small-molecule anti-inflammatory Corticosteroids Pain, frequency, or Approval date: July 19, 2019 older who have oral oral drug that inhibits phosphodiesterase type 4 (PDE4). Immunosuppressants duration of oral ulcers FDA designation(s): Orphan Drug ulcers associated with Behçet’s disease is a rare disease caused by blood vessel (eg, azathioprine, from baseline Clinical trial(s): Phase III primary Behçet’s disease inflammation that can cause skin symptoms, including oral cyclosporine) Disease progression completion September 2017, ulcers. Few effective treatment options (ie, Nonsteroidal anti- Quality of life data published November 2019 immunosuppressant therapy) exist for affected patients. inflammatory drugs Note(s): FDA approved Investigators have linked Behçet’s disease to overactive T (NSAIDs) apremilast in March 2014 to treat helper 17 cells and increased interleukin-17 (IL-17) psoriatic arthritis and in production. Apremilast’s PDE4 inhibitory activity purportedly September 2014 to treat plaque increases cyclic adenosine monophosphate in immune cells psoriasis to decrease production of proinflammatory mediators, such as tumor necrosis factor (TNF)-alpha, IL-17, and IL-23, which purportedly alleviates blood vessel inflammation and symptoms. The FDA-approved label recommends a 5-day titration period of an initial oral dose of 10 mg on day 1, gradually increased by day 5 to 20 mg in the morning and 30 mg in the evening. Thereafter, the maintenance dosage is 60 mg daily (30 mg in morning and 30 mg in evening). This titration is intended to reduce the gastrointestinal (GI) symptoms associated with initial therapy. Developer(s): Celgene Corp (Summit, New Jersey), a subsidiary of Bristol- Myers Squibb (New York, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Arimoclomol (BRX-345) is a small-molecule amine intended Edaravone Disability Submission date: New Drug older who have to treat ALS by helping regulate proteins involved with the Riluzole Disease progression Application planned for second amyotrophic lateral disease. ALS is a rare and fatal neurodegenerative disease in Supportive care Functional capacity half of 2021 sclerosis (ALS) which the death of nerve cells (ie, neurons) in the brain and Survival FDA designation(s): Orphan Drug spinal cord leads to a loss of voluntary muscle function, Clinical trial(s): Phase II/III wasting of muscle mass, and eventual death. While the exact (patients with SOD1 mutation) cause is unknown, it is thought to be caused by completed November 2016, data accumulations of abnormal proteins in neural cells. published February 2018; phase Arimoclomol might reduce abnormal protein accumulation III ORARIALS-01 primary and help deconstruct abnormal proteins, slowing disease completion December 2020; progression and improving patient quality of life by phase III ORARIALS-2 open-label prolonging motor function. The exact cause of abnormal extension primary completion protein collection in ALS is unknown, although patients with August 2022 inherited forms of ALS could have variants in other genes Note(s): Headline results are that might contribute, such as the copper-zinc superoxide expected in the first half of 2021 dismutase 1 gene, SOD1. FDA-approved drugs to treat the disease (eg, edaravone, riluzole) might decrease symptom severity but do not prevent disease progression. Arimoclomol purportedly increases the activity of heat shock factor 1, a transcription factor that promotes expression of heat shock proteins (HSPs). These proteins are thought to regulate normal protein folding and deconstruct abnormal proteins. In clinical trials, patients take arimoclomol by mouth. One recent trial reported giving a 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 45 years or Arimoclomol (BRX-345) is a small-molecule drug intended to Immunosuppressants Disease progression Submission date: New Drug older who have treat sIBM by increasing the production of reparative heat (eg, azathioprine, Functional capacity Application planned for second sporadic inclusion body shock proteins (HSPs) in damaged muscle cells. A methotrexate, Survival half of 2021 myositis (sIBM) degenerative muscle disease of unknown cause, sIBM prednisone) Quality of life FDA designation(s): Orphan Drug, develops most often after 50 years of age and causes Supportive care Fast Track progressive loss of muscle strength and volume over 10 to Clinical trial(s): Pivotal phase II/III 15 years. No cure or treatment is available. Patients primary completion December progress to severe disability, requiring the use of a 2021; phase II/III completed wheelchair and help with daily activities. Complications, September 2012, data published including aspiration pneumonia, can increase the risk of March 2016; phase III open-label death. Investigators suspect that sIBM-induced muscle extension primary completion degeneration might be caused by the accumulation of May 2022 abnormal and misfolded proteins in muscle cells. Note(s): Pivotal trial final results Arimoclomol purportedly increases the activity of heat shock expected first half of 2021 factor 1, a transcription factor that promotes HSP expression in cells experiencing stress or toxicity. HSPs protect against the accumulation of misfolded proteins and other toxic waste products by restoring functional protein shapes and degrading abnormal protein aggregates. In clinical trials, arimoclomol is given orally at a dose of 400 mg (two 200-mg pills), 3 times daily, for a daily dose of 1200 mg. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children and adults Arimoclomol (BRX-345) is a small-molecule drug intended to Miglustat Disability Submission date: New Drug aged 2 to 18 years who treat NPD-C by amplifying the production of reparative heat Supportive treatment Disease progression Application planned for first half have Niemann-Pick shock proteins (HSPs) that are purported to slow disease (eg, bowel regimen, Disease symptoms and of 2020 disease type C (NPD-C) progression. Niemann-Pick disease (NPD) is a neurovisceral bronchoalveolar lavage, severity FDA designation(s): Orphan Drug, disorder that stems from a genetic variant affecting lipid bronchodilation Survival Fast Track, Breakthrough metabolism in the body. No cure or effective treatment is therapy, gastrostomy Therapy Quality of life available. NPD-C, a subtype of NPD, is characterized by tube, physical therapy) Clinical trial(s): Phase II/III mutations in the NPC intracellular cholesterol transporter primary completion June 2018, genes, NPC1 and NPC2, resulting in impaired cellular data reported January 2019, data processing and transport of low-density lipoprotein reported January 2020 cholesterol. The 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 at a dose of 150 to 600 mg (based on patient weight) 3 times daily. Developer(s): Orphazyme US, Inc (Newton, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 5 to 18 Ataluren (Translarna) is a small-molecule drug intended to Corticosteroids (eg, Ambulatory function Submission date: New Drug years who have treat DMD, an inherited, X chromosome–linked genetic deflazacort, prednisone) (eg, 6-minute walk test Application (NDA) resubmission Duchenne muscular disorder caused by point mutations or deletions in the distance, time to run or planned for mid-2020 dystrophy (DMD) and dystrophin gene, DMD. DMD encodes dystrophin, a protein walk 10 meters, climb 4 FDA designation(s): Orphan Drug harbor a nonsense that helps promote muscle function. In patients with DMD, stairs, North Star Clinical trial(s): Phase III primary dystrophin mutation the absence of wild-type dystrophin protein causes Ambulatory completion March 2020 (patients progressive muscle fiber death and eventual widespread Assessment) not previously treated with muscle weakness. No cure exists for DMD, and first-line Pulmonary function ataluren); phase III open-label corticosteroid treatment (eg, deflazacort) manages Time to loss of primary completion December symptoms but does not prevent disease progression and ambulation 2020 (patients previously treated has significant side effects. FDA approved 2 gene therapies with ataluren); long-term for patients who have a specific mutation in DMD (ie, in exon observational cohort study 51 or exon 53), but patients who have other DMD mutations (STRIDE registry) primary are ineligible for these therapies. Therefore, additional completion May 2025, data therapies are needed. In about 10% to 15% of patients with published January 2020; phase III DMD, the DMD gene harbors a nonsense mutation. These ACT DMD completed August nonsense mutations encode a premature stop signal (ie, 2015, data published July 2017; stop codon) in the messenger RNA (mRNA) encoding phase III extension study dystrophin, preventing the production of full-length completed June 2018, data functional dystrophin protein. Ataluren purportedly published August 2018 promotes premature stop codon read-through by the cell’s Note(s): The manufacturer translational machinery, thereby producing full-length initially submitted an NDA to FDA dystrophin. Therefore, by restoring dystrophin function, in March 2017. In October 2017, ataluren might prevent or delay disease progression. FDA issued a Complete Response Ataluren’s premature stop codon read-through activity was Letter (CRL) stating that data determined empirically, and no specific molecular target of from additional trials were the drug has been identified. In clinical trials, patients needed. Ataluren has been receive an oral suspension of ataluren 3 times a day for up approved to treat children who to 144 weeks. In the morning and afternoon, patients have DMD in the European receive a dose of 10 mg/kg, and in the evening, a dose of 20 Union, Iceland, Liechtenstein, mg/kg, for a total of 40 mg/kg/day. Norway, and Brazil. Developer(s): PTC Therapeutics, Inc (South Plainfield, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 75 Autologous mesenchymal stem cells secreting neurotrophic Edaravone Disease progression FDA designation(s): Orphan Drug, years who have rapidly factors (MSC-NTF; NurOwn) is bone marrow–derived therapy Riluzole Disability Fast Track progressing intended to treat ALS. A rare and fatal neurodegenerative Supportive care Quality of life Clinical trial(s): Phase III BCT-002 amyotrophic lateral disease, ALS is characterized by the death of nerve cells (ie, primary completion October sclerosis (ALS) neurons) in the brain and spinal cord that leads to a loss of 2020, topline data expected voluntary muscle function, wasting of muscle mass, and fourth quarter of 2020; phase II eventual death. In patients with ALS, the presence of completed September 2015, data abnormal proteins in the brain and spinal cord causes published March 2016, data neuronal death and contributes to disease progression. The published November 2017; exact cause of these aggregates is unknown. FDA-approved phase II completed July 2016, drugs to treat the disease (eg, riluzole, edaravone) decrease data published November 2019 symptom severity in some patients but do not prevent Note(s): BrainStorm Cell neuronal injury and ALS progression. NurOwn grows the Therapeutics met with FDA in patient’s bone marrow cells in a proprietary culture media to February 2020 to discuss a differentiate mesenchymal stromal cells into astrocyte-like regulatory pathway and possible cells. The cultured cells purportedly secrete neurotrophic expedited pathway. NurOwn is and growth factors, including glial-derived neurotrophic also in phase II development to factor, brain-derived neurotrophic factor, vascular treat progressive multiple endothelial growth factor, and hepatocyte growth factor, sclerosis. which have immunomodulatory characteristics intended to protect neurons and glial cells from toxins and facilitate tissue repair. Thus, MSC-NTF could delay or prevent neuronal injury in patients with rapidly progressing ALS. In clinical trials, MSC-NTF is given intrathecally (ie, into the spinal cord) at an unspecified dose every other month, 3 times. Developer(s): BrainStorm Cell Therapeutics (New York, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Avacopan (CCX168) is a small-molecule anti-inflammatory Prednisone with Remission FDA designation(s): Orphan Drug older who have newly drug that purportedly binds and inhibits the complement cyclophosphamide Response time Clinical trial(s): Phase III diagnosed or relapsed anaphylatoxin C5a from triggering inflammatory reactions followed by Estimated glomerular ADVOCATE completed November antineutrophil through C5 receptors, which are associated with AAV azathioprine filtration rate 2019, topline data reported cytoplasmic antibody pathogenesis. Patients with AAV have limited treatment Prednisone with Vasculitis Damage Index November 2019 (ANCA)–associated options and increased risk of death from inflammatory rituximab followed by Quality of life vasculitis (AAV) vascular complications arising in various organs (often the azathioprine requiring treatment kidneys). Avacopan might reduce inflammation, vascular with cyclophosphamide tissue damage, and subsequent organ failure that occurs in or rituximab many patients with poorly managed AAV. AAV is caused by autoantibodies called antineutrophil cytoplasmic antibodies that increase vascular adhesion molecules and contribute to alternative complement pathway (including C5) activation and formation of immune complexes in blood vessels. These inflammatory effects trigger the homing and inflammatory processes of granulocytes (particularly neutrophils), causing tissue damage in areas of high cell and complex accumulation. Avacopan is intended to inhibit the activity of C5 and its role in downstream inflammatory effects. In clinical trials, avacopan is given orally at an unspecified dose in combination with rituximab or in combination with cyclophosphamide followed by azathioprine. Developer(s): ChemoCentryx, Inc (Mountain View, California), in collaboration with Vifor Fresenius Medical Care Renal Pharma (St Gallen, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 5 years Bercolagene telserpavec (B-VEC) is a herpes simplex virus 1 Supportive care to Wound healing FDA designation(s): Orphan Drug, or older and adults who (HSV-1) vector-based gene therapy intended for chronic or minimize and manage Quality of life Fast Track, Rare Pediatric have dystrophic recurring wounds in patients with DEB. This rare, debilitating skin wounds Disease, Regenerative Medicine epidermolysis bullosa connective tissue disorder has no approved treatments. Advance Therapy (DEB) who have at least Patients with DEB carry a Clinical trial(s): Phase II GEM-1 one wound between 10 genetic variant in the collagen type VII alpha 1 chain gene, primary completion March 2019, 2 and 20 cm in size COL7A1. This variant prevents cells from producing type VII data reported October 2019 collagen, causing severe, painful, and/or itchy epidermal wounds that can affect a patient’s longevity and quality of life. Bercolagene telserpavec is a recombinant, replication- incompetent, HSV-1 vector that contains a full-length copy of the human COL7A1 gene to correct the expression of type VII collagen. By restoring type VII collagen production in keratinocytes, bercolagene telserpavec purportedly anchors the skin’s dermal and epidermal layers to prevent blistering and promote wound healing without heavy scarring. In clinical trials, bercolagene telserpavec is administered topically over a skin wound on days 1 through 5 and again on days 30, 60, and 90. Developer(s): Krystal Biotech, Inc (Pittsburgh, Pennsylvania)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 12 years Berotralstat (BCX7353) is a plasma kallikrein inhibitor C1 esterase inhibitors Number of angioedema PDUFA date: December 3, 2020 or older and adults who intended to treat type I or II HAE. A rare inherited genetic (eg, Cinryze, Haegarda) attacks FDA designation(s): Orphan Drug, have type I or type II disorder, HAE is caused by a mutation in the gene Plasma kallikrein Quality of life, as Fast Track hereditary angioedema encoding the C1 esterase inhibitor protein (C1-INH). inhibitors (eg, measured by accepted Clinical trial(s): Phase III APeX-2 (HAE) Berotralstat is intended to prevent the onset of HAE lanadelumab-flyo) clinical ratings and primary completion April 2019, attacks by providing an oral alternative to injectable HAE scales data reported November 2019 treatments, which might improve treatment adherence. C1-INH normally regulates production and activity of the plasma serine protease kallikrein, which in turn regulates production and activity of the inflammatory mediator bradykinin. Unregulated kallikrein and bradykinin activity due to the absence of C1-INH causes fluid leakage from blood vessels and swelling of surrounding tissues. Patients with type I or II HAE, also known as C1 inhibitor deficiency, typically experience severe swelling (ie, edema) of the hands, abdomen and gastrointestinal (GI) tract, upper and lower extremities, and throat. Symptoms are triggered by stress, injury, illness, or hormone fluctuations. Swelling of the abdomen and intestines causes severe abdominal pain and GI upset, and swelling of the throat can lead to asphyxiation. In clinical trials, patients receive berotralstat orally at a dose of 110 or 150 mg, once daily, for up to 48 weeks. Developer(s): BioCryst Pharmaceuticals, Inc (Durham, North Carolina)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 10 years or BIIB112 (NSR-RPGR) is a recombinant adeno-associated viral Supportive care Best corrected visual Clinical trial(s): Phase II/III XIRIUS older who have retina vector that delivers a codon-optimized form of the retinitis Vitamin and nutritional acuity (BCVA) primary completion August 2020, specialist–confirmed pigmentosa GTPase regulator-open reading frame 15 gene, supplementation Retinal sensitivity preliminary safety and efficacy chromosome X–linked RPGR-ORF 15. This gene encodes a full-length functional Peripheral vision data reported September 2018, retinitis pigmentosa protein intended to treat XLRP. No effective treatments are preliminary data presented May Recovery time (XLRP) and RPGR-ORF 15 approved for this rare condition, and BIIB112 could become 2019 gene variants the first retinal gene therapy to delay XLRP or reverse vision Quality of life loss. XLRP is the most common form of RP caused by variants in the eye-specific form of the RPGR gene, called RPGR-ORF 15. BIIB112 is intended to express a full-length RPGR-ORF 15 protein in retinal cells that will restore the function of cones and rods. In clinical trials, a single dose is given via subretinal injection into the eye. Developer(s): Biogen (Cambridge, Massachusetts)
Adults aged 18 years or Budesonide (Nefecon) is a synthetic corticosteroid intended to Corticosteroids Proteinuria change FDA designation(s): Orphan Drug older who have biopsy- treat IgA nephropathy. A kidney disease, IgA nephropathy Immunosuppressants from baseline Clinical trial(s): Phase III Nefigard proven immunoglobulin occurs when an antibody subtype called IgA accumulates in (eg, azathioprine, Occurrence of end- primary completion October A (IgA) nephropathy the kidneys and causes local inflammation that can gradually cyclophosphamide, stage renal disease 2020 (Berger disease) and an affect kidney function. The disease can cause end-stage mycophenolate) Change in eGFR from estimated glomerular kidney disease within 10 to 20 years in up to 40% of affected baseline filtration rate (eGFR) patients. No treatments are approved for IgA nephropathy. Change in quality of life between 45 and 90 The standard of care (ie, high-dose systemic corticosteroids) is from baseline mL/min/1.73 m2 (stage controversial because of the increased risks of adverse events 2 to 3A chronic kidney and serious infections, high blood pressure, weight gain, disease) and medically diabetes mellitus, and osteoporosis. Budesonide is intended controlled blood to avert these systemic side effects. Treatment is targeted to pressure the Peyer patches of the small intestine, where IgA complexes are thought to originate, via the manufacturer’s proprietary TARGIT technology. Drug tolerability is purportedly optimized by the drug’s low bioavailability (about 90% is inactivated in the liver before reaching the circulation) compared with corticosteroids. In clinical trials, budesonide is taken orally at a dose of 16 mg, once daily, for 9 months. Developer(s): Calliditas Therapeutics AB (Stockholm, Sweden)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 10 years or CAP-1002 is a cell-based therapy intended for DMD, an Corticosteroids (eg, Ambulatory function, as FDA designation(s): Orphan Drug, older who have inherited, X chromosome–linked genetic disorder caused by deflazacort, prednisone) measured by accepted Rare Pediatric Disease, genetically confirmed rearrangements or deletions in the dystrophin gene, DMD. clinical ratings and Regenerative Medicine Advanced Duchenne muscular DMD encodes the dystrophin protein, which helps promote scales (eg, time to Therapy dystrophy (DMD), are muscle function. The absence of wild-type dystrophin stand, time to Clinical trial(s): Phase II HOPE-2 ambulatory or protein causes progressive muscle fiber death and eventual run/walk/climb; 6- primary completion December nonambulatory, and are widespread muscle weakness. No cure for DMD exists, and minute walk test, North 2019, interim data reported July receiving stable doses first-line corticosteroid treatment addresses symptoms but Star Ambulatory 2019 and October 2019 of systemic does not prevent disease progression and has significant Assessment) glucocorticoids side effects. FDA approved 2 gene therapies for patients Muscle strength and who have a specific mutation in DMD (ie, in exon 51 or exon function (eg, 53); however, patients who have other DMD mutations are Performance of Upper ineligible for these therapies. CAP-1002 contains Limb [PUL] clinical cardiosphere-derived cells (CDCs) from donor heart tissue. scale) The CDCs in CAP-1002 purportedly secrete growth factors Cardiac function 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 7 to 23 Casimersen (SRP-4045) is a phosphorodiamidate Corticosteroids (eg, Ambulatory function, as FDA designation(s): Orphan Drug years who have morpholino oligomer (PMO; DNA analogue) intended to deflazacort, prednisone) measured by accepted Clinical trial(s): Phase III ESSENCE Duchenne muscular treat DMD, an inherited, X chromosome–linked genetic clinical ratings and trial primary completion May dystrophy (DMD) with a disorder caused by rearrangements or deletions in the DMD scales 2022 (children aged 7 to 13 rearrangement in the gene. DMD encodes the dystrophin protein, which is Quality of life years), topline data reported dystrophin gene, DMD, involved in muscle function, and the absence of wild-type March 2019; phase III open-label that involves exon 45 dystrophin protein causes progressive muscle fiber necrosis extension primary completion and who are on a stable and eventual widespread muscle weakness. Casimersen August 2026 (children aged 7 to dose of corticosteroids purportedly binds exon 45 of dystrophin pre-messenger 17 years and adults aged 18 to RNA (mRNA; ie, precursor RNA composed of introns and 23 years) exons) and promotes skipping of exon 45 during mRNA Note(s): In November 2019, processing. This allows for synthesis of an internally casimersen’s manufacturer truncated, but functional, dystrophin protein. Casimersen announced that it intended to treatment is intended to promote skeletal muscle function address issues outlined in a and prevent or delay disease progression in patients with Complete Response Letter (CRL) DMD who have DMD exon 45 variants. In clinical trials, from FDA regarding its New Drug casimersen is given intravenously at a dose of 30 mg/kg, Application (NDA) for golodirsen, once weekly, for up to 144 weeks. also in development for treating Developer(s): DMD, before pursuing regulatory Sarepta Therapeutics, Inc (Cambridge, Massachusetts) approval for casimersen. Before receiving the CRL for golodirsen, it had planned to file an NDA for casimersen in the first half of 2020.
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 16 years Crizanlizumab-tmca (Adakveo) is a humanized Blood transfusions Amount and length of Approval date: November 15, or older and adults who immunoglobulin G2 (IgG2) antibody against P-selectin, which Hematopoietic (blood intravenous opioid use 2019 have sickle cell disease promotes the inflammation and adhesion involved in vaso- cell–generating) stem Frequency of VOCs FDA designation(s): Orphan Drug, (SCD) occlusive crises (VOCs). Crizanlizumab-tmca is intended to cell transplantation Hospital length of stay Breakthrough Therapy, Priority improve treatment efficacy by blocking P-selectin to prevent Hydroxyurea Rehospitalizations Review abnormal red blood cell clumping in small blood vessels and Pharmaceutical-grade l- within 3 days of Clinical trial(s): Phase III STAND maintain blood flow. In SCD, sickled red blood cells are more glutamine (ie, Endari) discharge primary completion May 2022; susceptible to oxidative damage, inappropriate clumping (ie, Voxelotor (ie, Oxbryta) Quality of life phase II SUSTAIN data published adhesion), and vessel blockage, leading to VOCs that cause February 2017, post hoc data severe pain, requiring hospitalization. VOC complications presented November 2019 can include circulating blood clots, stroke, organ failure, or Note(s): FDA approval is based early death, and available treatments are often ineffective. on phase II SUSTAIN data Hydroxyurea, which has been a mainstay of treatment for VOC, can reduce its incidence but is ineffective in about one- third of adult patients. The FDA-approved label states the drug is indicated to reduce the frequency of VOCs in patients with SCD and is administered intravenously at a dose of 5 mg/kg over 30 minutes on week 0, week 2, and every 4 weeks after that. Developer(s): Novartis AG (Basel, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 4 years Diazoxide choline controlled release (DCCR) is an Cognitive behavioral Hyperphagia symptoms FDA designation(s): Orphan Drug, or older and adults with investigational, proprietary crystalline salt formulation of therapy (CBT) and severity Fast Track Prader-Willi syndrome diazoxide, a potassium channel activator that inhibits insulin Diet and food intake Rate of comorbidities Clinical trial(s): Phase III DESTINY (PWS) with hyperphagia secretion. It is intended to treat hyperphagia (abnormally control (eg, cardiovascular PWS/C601 primary completion increased appetite) in patients with PWS. PWS is a rare Exercise disease, diabetes May 2020; phase III C602 open- genetic disease (about 8000-11 000 US patients) caused by Glucagon-like peptide 1 mellitus, obesity) label extension primary lack of expression of several genes on chromosome 15. It is (GLP-1) receptor agonist Mortality completion April 2021; phase III often managed with off-label diazoxide (Proglycem), which is (eg, exenatide or Quality of life C603 open-label primary approved to treat low blood sugar. However, patients with liraglutide; off label) completion March 2023 PWS require a lower 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 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Eculizumab (Soliris) is a recombinant humanized Azathioprine Functional impairments Approval date: June 27, 2019 older who have monoclonal antibody that binds with high affinity to the Hematopoietic stem cell (eg, vision, mobility, and FDA designation(s): Orphan Drug neuromyelitis optica complement protein C5 (a soluble component of the innate transplantation bowel or bladder Clinical trial(s): Phase III PREVENT spectrum disorder immune system). Eculizumab is intended to relieve the Intravenous incontinence) change completed July 2018, data (NMOSD) and who test autoimmune and neurodegenerative symptoms and corticosteroids from baseline published May 2019; phase III positive for anti- pathology of neuromyelitis optica by binding C5 and Mycophenolate mofetil Incidence of relapse open-label extension primary aquaporin-4 (AQP4) inhibiting its cleavage to C5a and C5b. This action prevents from baseline Plasmapheresis completion June 2020 antibodies the downstream formation and activation of the cell-lysing Quality-of-life change Rituximab terminal complement complex C5b-9, which damages cell from baseline membranes targeted with the complexes. C5b-9 complex Thymus transplantation production is thought to directly drive the uncontrolled (donor matched) complement activation that promotes some autoimmune reactions. The FDA-approved label recommends 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, and 1200 mg every 2 weeks thereafter. Developer(s): Alexion Pharmaceuticals, Inc (Boston, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 4 to 7 years Edasalonexent (CAT-1004) is a small-molecule inhibitor of Corticosteroids (eg, Ambulatory function Submission date: New Drug who have Duchenne nuclear factor kappa-light-chain-enhancer of activated B deflazacort, prednisone) (eg, North Star Application anticipated in early muscular dystrophy cells (NF-kB). It is intended to treat DMD, an inherited X Supportive care Ambulatory 2021 (DMD) chromosome–linked genetic disorder caused by Assessment, 4-stair FDA designation(s): Orphan Drug, rearrangements or deletions in the dystrophin gene, DMD. climb velocity, stand Fast Track, Rare Pediatric Disease DMD encodes the dystrophin protein that helps keep muscle from supine velocity, Clinical trial(s): Pivotal phase III cells intact. The absence of wild-type dystrophin protein 10-meter walk/run PolarisDMD primary completion causes progressive muscle fiber death and eventual velocity) June 2020 (boys aged 4 to widespread muscle weakness and purportedly leads to the Muscle strength younger than 8 years), topline persistent activation of NF-kB, which contributes to disease data expected in fourth quarter progression. DMD has no cure, and first-line corticosteroid of 2020; phase III GalaxyDMD treatment (eg, deflazacort) manages symptoms but does not open-label extension primary prevent disease progression and has significant side effects. completion June 2022 (boys aged FDA approved 2 gene therapies for patients who have a 4 to 12 years); phase II specific mutation in DMD (ie, in exon 51 or exon 53), but MoveDMD completed August patients who have other DMD variants are ineligible for 2019, data published April 2018 these therapies. Therefore, additional therapies are needed. Note(s): Catabasis Edasalonexent therapy is intended for all patients with DMD Pharmaceuticals is investigating regardless of genetic variant status. By blocking NF-kB edasalonexent to treat activity, edasalonexent purportedly improves skeletal nonambulatory DMD, in muscle function, preserves cardiac function, and reduces partnership with Duchenne UK the risk of bone fracture in patients with DMD. In clinical trials, patients receive edasalonexent orally at a dose of 100 mg/kg/day (divided into 3 equal doses) for up to 104 weeks. Developer(s): Catabasis Pharmaceuticals, Inc (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 75 Elafibranor is a first-in-class dual agonist (ie, activator) of Obeticholic acid Overall survival FDA designation(s): Orphan Drug, years who have primary peroxisome proliferator-activated receptor (PPAR) alpha Rate of progression to Breakthrough Therapy biliary cholangitis (PBC) (PPARα) and PPAR delta (PPARδ) intended to treat PBC. An liver failure Clinical trial(s): Phase II and had an inadequate autoimmune disease, PBC damages the liver’s bile ducts, Symptom relief (eg, completed October 2018, data response to causing bile to accumulate in the liver and leading to diarrhea due to fat reported April 2019 ursodeoxycholic acid irreversible liver scarring and potentially liver failure. malabsorption, fatigue, (UDCA) treatment Elafibranor is intended to provide a safer alternative to itching) obeticholic acid (Ocaliva) for treating PBC in patients for Quality of life whom initial therapy with UDCA is inadequate. Elafibranor purportedly reduces bile acid synthesis, improves bile detoxification in the bile duct, and acts as an anti- inflammatory agent. Further, elafibranor might reduce itching (ie, pruritus), a major symptom of PBC that is not addressed by any existing PBC treatments. In a phase II clinical trial, elafibranor is administered as 80- or 120-mg tablets, taken twice daily, for 12 weeks. Developer(s): GENFIT Corp (Paris, France)
SECTION 5. RARE DISEASES 147
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 16 years Elamipretide is a peptide compound designed to treat PMM Supportive care, Exercise tolerance FDA designation(s): Orphan Drug, or older and adults by restoring cellular energy production. No curative or especially to address Fatigue Fast Track aged up to 80 years disease-modifying treatments exist for the disease. In PMM, cardiovascular, Quality of life Clinical trial(s): Phase III who have primary DNA mutations impair the mitochondria’s ability to produce neurologic, or MMPOWER-3 primary mitochondrial energy by metabolizing lipids, especially cardiolipin. The respiratory completion December 2019, myopathy (PMM) impaired energy production causes muscle degeneration. complications topline data reported December Tissues composed of cells with the highest energy 2019; phase II open-label requirements (eg, skeletal muscle, heart, brain) are most extension primary completion affected. Prognosis worsens if disease onset is early and December 2021 depends on the number of organs affected. Elamipretide purportedly penetrates mitochondrial membranes to bond reversibly to cardiolipin, thereby normalizing the inner mitochondrial membrane structure and improving mitochondrial function. Elamipretide is thought to enhance energy generation through increased production of ATP, a critical component in energy transport, and to potentially lower levels of reactive oxygen species that can damage cardiolipin. In clinical trials, patients receive elamipretide as under-the-skin (ie, subcutaneous) injections at a dose of 40 mg (0.5 mL), once daily, for up to 168 weeks. Developer(s): Stealth Biotherapeutics, Inc (Newton, Massachusetts), in collaboration with Alexion Pharmaceuticals, Inc (Boston, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 12 years or Elamipretide is a peptide compound designed to treat Supportive care Exercise tolerance FDA designation(s): Orphan Drug, older who have mitochondrial dysfunction disorders by restoring cellular directed at relieving Fatigue Fast Track genetically confirmed energy production. Barth syndrome is a chromosome X– individual symptoms Quality of life Clinical trial(s): Phase II/III Barth syndrome and a linked mitochondrial disorder characterized by degeneration (eg, bacterial infection, TAZPOWER primary completion baseline body weight of of heart muscle (ie, dilated cardiomyopathy) and skeletal heart failure) October 2018, preliminary data more than 30 kg and muscle (ie, myopathy), recurrent infections due to reported April 2019, additional estimated glomerular neutropenia (ie, low white cells), and short stature. Barth data presented November 2019 filtration rate (eGFR) syndrome is managed primarily with supportive care greater than 90 because no pharmacologic therapies have yet demonstrated mL/min/1.73 m2 or clinical benefits. In Barth syndrome, mutations in the body weight of more tafazzin gene, TAZ, result in the production of dysfunctional than 40 kg and eGFR tafazzin protein. This protein ensures adequate levels of greater than 60 but less functional cardiolipin, a lipid required for normal than 90 mL/min/1.73 m2 mitochondrial structure, function, and energy production. Tissues with the highest energy demands (eg, heart and skeletal muscle) are most affected. Elamipretide purportedly penetrates mitochondrial membranes to bond reversibly to cardiolipin, thereby normalizing the inner mitochondrial membrane structure and improving mitochondrial function. Elamipretide is thought to enhance energy generation through increased production of ATP, a critical component in energy transport, and to potentially lower levels of reactive oxygen species that can damage cardiolipin. In clinical trials for Barth syndrome, patients receive subcutaneous injections of elamipretide at a dose of 40 mg once daily for 12 weeks. Developer(s): Stealth Biotherapeutics, Inc (Newton, Massachusetts), in collaboration with Alexion Pharmaceuticals, Inc (Boston, Massachusetts)
SECTION 5. RARE DISEASES 149
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 12 years Elexacaftor/tezacaftor/ivacaftor (Trikafta) and ivacaftor is a CFTR modulator dual Respiratory function Approval date: October 21, 2019 or older and adults who regimen of triple combination therapy intended to treat CF therapy (ie, Survival FDA designation(s): Orphan Drug, have cystic fibrosis (CF) in patients who have a F508del variant in the CFTR gene. The lumacaftor/ivacaftor, Quality of life Fast Track, Breakthrough with a F508del variant therapy purportedly makes proteins produced by the tezacaftor/ivacaftor) Therapy, Priority Review in at least one copy of mutant CFTR gene more effective. This drug targets a much CFTR modulator Clinical trial(s): Phase III the cystic fibrosis larger population of patients with CF (ie, 90%, an estimated monotherapy (ie, completed December 2018, data transmembrane 27 000 patients in the United States) than other CF gene ivacaftor) published November 2019; conductance regulator therapies already on the market. This therapy can be used in phase III completed April 2019, gene, CFTR patients who have CF with at least one F508del variation in data published November 2019; the CFTR gene. Elexacaftor/tezacaftor/ivacaftor and ivacaftor phase III primary completion purportedly work due to a combined effect to increase the September 2020; phase III quantity and function of F508del-CFTR at the cell surface. primary completion October This results in increased CFTR activity, as measured by CFTR- 2020; phase III primary mediated chloride transport. Elexacaftor and tezacaftor bind completion June 2021; phase III to different sites on the CFTR protein and have an additive open-label primary completion effect in facilitating the cellular processing and trafficking of May 2022; phase III primary F508del-CFTR to increase the amount of CFTR protein completion August 2022 delivered to the cell surface compared with either molecule Note(s): Vertex Pharmaceuticals alone. Ivacaftor potentiates the channel open probability (or will receive a Rare Pediatric gating) of the CFTR protein at the cell surface. The FDA- Disease Priority Review Voucher approved label states the dosage is taken by mouth as 2 for developing this therapy tablets containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg in the morning and 1 ivacaftor 150-mg tablet in the evening; the morning and evening doses are to be taken about 12 hours apart and with fat-containing food. Developer(s): Vertex Pharmaceuticals, Inc (Boston, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 1 year or Epidiolex (cannabidiol oral solution) is the first prescription Anticonvulsants (eg, Change in seizure Submission Date: Supplemental older and adults aged drug approved based on plant-derived cannabidiols, and it is levetiracetam) frequency New Drug Application February up to 65 years who intended to treat seizures caused by TSC. This intervention Chemotherapy (eg, Cognitive and 3, 2020 have inadequately purportedly reduces seizure frequency, which is a significant everolimus) developmental effects FDA designation(s): Orphan Drug controlled seizures cause of illness and death in this patient population. TSC is a Epilepsy surgery Hospitalizations Clinical trial(s): Phase III associated with rare autosomal-dominant genetic condition that is caused Vagal nerve stimulation Survival completed February 2019, tuberous sclerosis by mutations in either subunit of the TSC complex gene, (VNS) Quality of life pivotal data reported May 2019, complex (TSC) TSC1 or TSC2. The disease is characterized by noncancerous data reported December 2019 tumor growth in many different organs, including the brain, Note(s): FDA approved Epidiolex and is the leading cause of genetic epilepsy and autism in to treat seizures associated with children. Although the exact mechanism of action is Lennox-Gastaut syndrome and unknown, Epidiolex might impart an overall anticonvulsant Dravet syndrome in June 2018 effect by modulating several neuronal pathways when used in combination with antiepileptic drug treatment. In clinical trials, Epidiolex is given at a low (25 mg/kg/day) or high (50 mg/kg/day) dose; drug is split into a twice-daily dose taken in an oral solution. Developer(s): GW Pharmaceuticals plc (Wiltshire, United Kingdom)
Males aged 18 years or Etranacogene dezaparvovec (AMT-061) gene therapy consists Factor IX replacement Bleeding episodes FDA designation(s): Orphan Drug, older who have of adeno-associated viral vector serotype 5 (AAV5) containing therapy (human Treatment-related Breakthrough Therapy moderate to severe a codon-optimized human factor IX Padua gene (AAV5-hFIXco- plasma–derived or complications Clinical trial(s): Phase III HOPE-B congenital (ie, inherited) Padua). The adeno-associated viral vector delivers a copy of recombinant) Survival primary completion March 2020; hemophilia B and are the Padua variant of the factor IX gene, F9 or FIX. It Quality of life single-arm phase II primary receiving factor IX purportedly has an 8-fold increase in activity compared with completion October 2018, data prophylaxis with more wild-type (ie, not caused by any known genetic variant) factor published October 2019, further than 150 days’ exposure IX to provide sustained coagulation. As a single-treatment data presented December 2019 to factor IX protein gene therapy, AMT-061 could eliminate the need for repeated treatment coagulation-factor replacement. The manufacturer asserts that nearly all patients screened in clinical trials, potentially even patients with some preexisting antibodies to the AAV5 viral vector, are eligible for therapy. In clinical trials, AMT-061 is given as a single intravenous infusion at a dose of 2 × 1013 genome copies (gc)/kg. Developer(s): uniQure NV (Amsterdam, the Netherlands)
SECTION 5. RARE DISEASES 151
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 7 years FCX-007 is a cell-based gene therapy consisting of patient- Supportive care for pain Change in wound size FDA designation(s): Orphan Drug, or older and adults who derived dermal fibroblasts (skin cells) treated to produce a and infection risk from baseline Fast Track, Rare Pediatric have recessive functional copy of the collagen type VII alpha 1 chain gene, Time to wound closure Disease, Regenerative Medicine dystrophic COL7A1. The cell therapy is delivered by injection into the from baseline Advanced Therapy epidermolysis bullosa patient’s skin lesions to promote wound healing. RDEB is a Clinical trial(s): Phase III trial (RDEB) rare genetic disease caused by mutations in the collagen planned, primary completion COL7A1 protein, which is needed for maintaining proper December 2020; phase I/II FI- skin integrity. Loss of COL7A1 expression in RDEB leads to FCX-007 primary completion June widespread blistering, resulting in severe scarring, vision 2020, interim data reported May loss, disfigurement, and other serious medical problems. 2018; phase III primary FCX-007 is intended to prevent blistering and promote completion December 2020 wound healing without heavy scarring by delivering transduced COL7A1-expressing fibroblasts into poorly healing lesions. The therapy is thought to form anchoring fibrils that hold the layers of skin together to prevent RDEB- caused wounds. In clinical trials, FCX-007 was injected directly at an unspecified dose into the papillary dermis of blisters and wounds. Developer(s): Fibrocell Technologies, Inc (Exton, Pennsylvania), in collaboration with Castle Creek Pharmaceuticals, LLC (Parsippany-Troy Hills, New Jersey)
SECTION 5. RARE DISEASES 152
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 2 years Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, Monthly convulsive PDUFA date: June 25, 2020 or older and adults amphetamine derivative intended as an adjunctive therapy clobazam, stiripentol, seizure frequency FDA designation(s): Orphan Drug, aged up to 35 years for Dravet syndrome. A rare, severe, infantile-onset form of topiramate, valproate) (MCSF) Fast Track who have Dravet epilepsy, Dravet syndrome is usually caused by a variant in Ketogenic diet Convulsive seizure Clinical trial(s): Phase III syndrome and are the sodium voltage-gated channel alpha subunit 1 gene, Plant-derived CBD duration completed January 2019, data taking one or more SCN1A. Fintepla is intended as an option for patients who Seizure-free interval published December 2019; antiepileptic drugs have prolonged seizures that are difficult to control with Functional capacity phase III primary completion July available antiepileptic drugs. In addition, patients typically Quality of life 2020; phase III primary experience cognitive impairment, behavioral problems, completion July 2020, pooled muscle weakness, and sleep disorders. FDA has approved data published December 2019; cannabidiol (CBD) to treat the disease, but it can cause phase III open-label extension hepatic impairment, especially when used in conjunction primary completion December with certain antiepileptics; the drug also can cause 2020, data presented December sleepiness, sedation, and suicidal behavior. In patients with 2018, data presented October Dravet syndrome, fenfluramine hydrochloride low-dose 2019; phase III long-term follow- purportedly promotes serotonin release and stabilizes nerve up primary completion April activity in the brain, which might decrease seizure frequency 2023 and duration. In clinical trials, patients take or caregivers Note(s): FDA issued a Refusal to give the drug by mouth at a dose of 0.2, 0.4, or 0.8 File letter on April 8, 2019, citing mg/kg/day (up to a maximum of 20 mg/day) for the duration missing and incorrect data. FDA of the trial. The drug is intended to be taken daily, on an rescinded Breakthrough Therapy ongoing basis. designation because criteria Developer(s): were no longer met with the Zogenix, Inc (Emeryville, California) approval of 2 drugs for Dravet syndrome. Zogenix resubmitted a New Drug Application in November 2019.
SECTION 5. RARE DISEASES 153
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 2 years Fenfluramine hydrochloride low-dose (Fintepla) is an Antiepileptics (eg, Frequency of seizures FDA designation(s): Orphan Drug or older and adults amphetamine derivative intended as an adjunctive therapy clobazam, stiripentol, that result in drops Clinical trial(s): Pivotal phase III aged up to 35 years for Lennox-Gastaut syndrome. The syndrome is a rare, topiramate, valproate) Duration of seizures primary completion December who have Lennox- severe, infantile- or childhood-onset form of epilepsy. Ketogenic diet that result in drops 2020, topline data reported Gastaut syndrome that Fintepla might improve health outcomes in patients with Plant-derived CBD Seizure-free interval February 2020; phase II primary is being treated with 1 Lennox-Gastaut syndrome, who often experience multiple Functional capacity completion September 2018, to 4 antiepileptic drugs types of seizures (eg, atonic, tonic, atypical absence, drop data published August 2018; Quality of life attacks) difficult to control with FDA-approved antiepileptic phase III long-term follow-up drugs. In addition, patients typically experience cognitive primary completion April 2023 impairment, intellectual disability, behavioral problems, Note(s): Fintepla to treat Dravet delayed development, and muscle weakness. FDA has syndrome is under Priority approved cannabidiol (CBD) to treat the disease, but it might Review by FDA cause hepatic impairment, especially when used in conjunction with certain antiepileptics; the drug can also cause sleepiness, sedation, and suicidal behavior. In patients with Lennox-Gastaut syndrome, Fenfluramine hydrochloride low-dose purportedly promotes serotonin release and stabilizes nerve activity in the brain, which might decrease seizure frequency and duration. In clinical trials, patients take the drug by mouth at a dose of 0.2 or 0.8 mg/kg/day (up to a maximum of 20 mg/day) for up to 52 weeks. The drug is intended to be taken daily on an ongoing basis. Developer(s): Zogenix, Inc (Emeryville, California)
SECTION 5. RARE DISEASES 154
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adolescents aged 16 Fezagepras (PBI-4050; 3-pentylbenzeneacetic acid sodium Organ transplantation Change from baseline in FDA designation(s): Orphan Drug, years or older and salt) is a novel, synthetic, medium-chain fatty acid derivative, Supportive care skin pathology Rare Pediatric Disease adults who have oral antifibrotic (ie, reduces scar tissue formation) intended to Change from baseline in Clinical trial(s): Phase II/III Alström syndrome treat Alström syndrome, a rare genetic syndrome. The fasting plasma glucose primary completion July 2020, syndrome is characterized by obesity in childhood or over time preliminary data reported April adolescence and type 2 diabetes mellitus (T2DM), often with Change from baseline in 2018; pivotal phase III planned severe insulin resistance, dyslipidemia, hypertension, and plasma insulin over severe life-threatening multiorgan fibrosis involving the time bladder, kidney, liver, and heart. Progressive loss of vision and Change from baseline in hearing, dilated cardiomyopathy, and short stature might also glycated hemoglobin occur. Fezagepras is intended to alleviate development of (HbA ) over time insulin resistance, dyslipidemia, and hypertension and severe 1c multiorgan fibrosis. The drug purportedly has stimulating and Change from baseline in inhibiting activity toward the G-protein coupled receptors blood glucose, as GPR40 and GPR84, respectively, which reduce fibrotic activity measured by weekly 4- in macrophages, fibroblasts and myofibroblasts, and point profile epithelial cells. In clinical trials, fezagepras was given as four Change from baseline in 200-mg capsules (800 mg total), once daily. liver stiffness Developer(s): Liminal Biosciences (Laval, Québec, Canada)
Males aged 12 years or Fitusiran (ALN-AT3) is an RNA interference (RNAi) therapeutic Emicizumab Bleeding episodes Clinical trial(s): Phase III ATLAS- older who have under development for hemophilia A and B. Fitusiran (hemophilia A) Treatment-related INH primary completion hemophilia A or B purportedly reduces expression of antithrombin, an enzyme Factor VIII replacement complications February 2020; phase III ATLAS- that inactivates several other enzymes in the blood-clotting (human plasma–derived Survival A/B primary completion April cascade. This inactivation promotes sufficient thrombin 2020; phase III ATLAS-PPX or recombinant, porcine Quality of life generation to restore hemostasis and prevent bleeding. recombinant; primary completion November Fitusiran therapy would replace regular intravenous blood hemophilia A) 2021; phase II/III ATLAS-PEDS (in factor infusions with a monthly subcutaneous injection. In Factor IX replacement young children) primary clinical trials, fitusiran is given as a subcutaneous (ie, under (human plasma–derived completion February 2023; the skin) injection at a dose of 80 mg once monthly for up to or recombinant; phase III ATLAS-OLE primary 20 months. hemophilia B) completion October 2025 Developer(s): Note(s): FDA lifted a clinical hold Alnylam Pharmaceuticals (Cambridge, Massachusetts), in on fitusiran studies in December collaboration with Sanofi Genzyme (Cambridge, 2017 Massachusetts)
SECTION 5. RARE DISEASES 155
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Neonates aged up to 28 Fosdenopterin (BBP-870, ORGN001) is a synthetic version of Anticonvulsants Ability to sit upright Submission date: Rolling New days who have cyclic pyranopterin monophosphate (cPMP). It is intended to Supportive care independently for at Drug Application initiated molybdenum cofactor restore molybdenum cofactor (MoCo) levels and sulfite Ventilator (ie, breathing) least 30 seconds at 12 December 3, 2019 deficiency (MoCD) type oxidase activity to enable clearance of sulfite from patients support months FDA designation(s): Orphan Drug, A with MoCD type A. An ultra-rare genetic metabolic disorder, Bayley Scales of Infant Breakthrough Therapy, Rare MoCD type A causes catastrophic and irreversible neurologic Development at 12 Pediatric Disease damage within the first weeks of life. MoCD type A has no months Clinical trial(s): Phase II/III effective treatments and is caused by a mutation in the Pediatric Evaluation of primary completion December molybdenum cofactor synthesis 1 gene, MOCS1, which turns Disability Inventory 2020 guanosine triphosphate to cPMP, an intermediate in the (PEDI) at 12 months body’s production of MoCo. MoCo is a key component of the Survival at 12 months sulfite oxidase enzyme, which clears the neurotoxic metabolic byproduct sulfite from the body. In a clinical trial, fosdenopterin is given intravenously, at a dose of 80 to 320 μg/kg, daily. Developer(s): Origin Biosciences (Palo Alto, California), a subsidiary of BridgeBio Pharma (Palo Alto, California)
SECTION 5. RARE DISEASES 156
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 2 years Gaboxadol (OV101), also known as THIP, is a small-molecule Supportive care (eg, Motor function, as FDA designation(s): Orphan Drug, or older and adults derivative of muscimol, a compound found in the anticonvulsants for measured by accepted Fast Track aged up to 49 years mushroom Amanita muscaria. It is intended to treat seizures, assistive clinical ratings and Clinical trial(s): Pivotal phase III who have genetically Angelman syndrome, a rare, noninherited, X chromosome– devices, scales NEPTUNE primary completion confirmed Angelman linked neurodevelopmental disorder caused by a mutation benzodiazepines for Time to sleep onset July 2020 (children); phase II syndrome in the ubiquitin protein ligase E3a gene, UBE3A. UBE3A sleep disturbances, Total sleep time completed June 2018 (children encodes the UBE3A protein, which mediates cellular protein occupational therapy, Behavioral and adults), data presented degradation and is expressed in both excitatory and physical therapy, disturbances, as October 2018, data reported May inhibitory neurons in the brain. Normally, the brain can speech/language measured by accepted 2019; phase II ELARA open-label differentiate between excitatory and inhibitory signals, a therapy) clinical ratings and extension primary completion process called tonic inhibition, that is partially mediated by scales July 2020 (children and adults) gamma-aminobutyric acid (GABA) receptors. In a mouse Note(s): Gaboxadol is also in model of Angelman syndrome in which the animals lacked phase II clinical development to UBE3A and UBE3A expression, loss of tonic inhibition treat fragile X syndrome disrupted nerve cell function and normal brain activity, resulting in motor dysfunction. Patients with Angelman syndrome experience severe developmental delays, intellectual disability, impaired speech and motor function, behavioral and sleep disturbances, and seizures. No cure exists, and treatment consists of supportive care. If effective, gaboxadol could decrease symptom severity in patients with the disease. Because the drug is a delta-selective, gamma-
aminobutyric acid receptor A (GABAA) receptor agonist (ie,
activator) that selectively activates GABAA receptors, it purportedly restores the process of tonic inhibition and normalizes brain activity in patients with Angelman syndrome. In clinical trials, patients receive gaboxadol 10 to 25 mg, once or twice daily, for up to 52 weeks. Developer(s): Ovid Therapeutics, Inc (New York, New York)
SECTION 5. RARE DISEASES 157
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 13 to 22 Gaboxadol (OV101) is a small-molecule derivative of Supportive care (eg, Aberrant behavior FDA designation(s): Orphan Drug, years who have fragile X muscimol, a compound found in the mushroom anticonvulsants for incidence and severity, Fast Track syndrome Amanita muscaria. It is intended to treat fragile X syndrome, seizures and/or as measured by Clinical trial(s): Phase II ROCKET a rare, noninherited, X chromosome–linked behavior stabilization, accepted clinical ratings primary completion February neurodevelopmental disorder. This syndrome is caused by behavior-stabilizing and scales 2020, data expected in early mutations in the fragile X mental retardation 1 gene, medications [eg, alpha2 2020 FMR1. Expansion of the cytosine, guanine, guanine (CGG) agonists, Note(s): Gaboxadol is also in trinucleotide repeats in the 5′ untranslated region of FMR1 antidepressants, beta phase III clinical development to causes gene hypermethylation, which then silences blockers], educational treat Angelman syndrome expression of the encoded Fmr1 protein (Fmrp). Fmrp, interventions, sensory which is expressed in neurons and glial cells, is thought to integration techniques) promote synapse formation and adaptation (ie, synaptic plasticity) in the brain and is thought to be important for learning, memory, and regulating protein synthesis and transport of coding and noncoding RNA in the brain. Normally, the brain can differentiate between excitatory and inhibitory signals, a process called tonic inhibition that is partially mediated by gamma-aminobutyric acid (GABA) receptors. In patients with fragile X syndrome, loss of Fmrp function purportedly disrupts protein translation, synaptic plasticity, intracellular signaling, and GABA-mediated tonic inhibition. This leads to development of autism-like symptoms, including anxiety, irritability, aggression, hyperactivity, and restricted and repetitive behaviors. Some patients also experience seizures. Symptom severity varies by patient and is determined by gender and the number of CGG trinucleotide repeats that the patient harbors (ie, males with high numbers of CGG trinucleotide repeats typically exhibit the most severe symptoms). Because gaboxadol is a
delta-selective, GABA A (GABAA) receptor agonist (ie,
activator) that selectively activates GABAA receptors, it purportedly restores the process of tonic inhibition and normalizes brain activity in patients with fragile X syndrome. In clinical trials, patients receive an unspecified dose of gaboxadol, 1, 2, or 3 times daily, for up to 12 weeks. Developer(s): Ovid Therapeutics, Inc (New York, New York)
SECTION 5. RARE DISEASES 158
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Galcanezumab-gnlm (Emgality) is a humanized monoclonal Corticosteroids Weekly cluster Approval date: June 4, 2019 older who have episodic antibody against calcitonin gene–related peptide (CGRP) Topiramate (off label) headache frequency FDA designation(s): cluster headache intended to treat episodic cluster headache. Galcanezumab- Verapamil (off label) Cluster headache Breakthrough Therapy gnlm is the first biologic approved to treat these headaches. severity, as measured Clinical trial(s): Phase III CGAL CGRP is a neuropeptide thought to contribute to pain by accepted clinical completed February 2018, data signaling of the trigeminal sensory nerve, leading to ratings and scales published July 2019, data headache development. Galcanezumab purportedly presented September 2019 prevents CGRP from binding to its receptor, which might (abstract IHC-PO-256); phase III reduce cluster headache frequency. The FDA-approved label CGAR open-label extension states the recommended dose is 300 mg (3 consecutive primary completion November subcutaneous [ie, under the skin] injections of 100 mg each 2021 (episodic, chronic cluster patients take themselves) at the onset of the cluster period, headache), data presented and then monthly until the end of the cluster period. A September 2019 (abstract IHC- missed dose during a cluster period is recommended to be PO-247) taken as soon as possible. Note(s): FDA approved Developer(s): galcanezumab-gnlm to treat Eli Lilly and Co (Indianapolis, Indiana) migraine headache in September 2018
SECTION 5. RARE DISEASES 159
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 6 years or Givinostat is a small-molecule histone deacetylase (HDAC) Corticosteroids (eg, Ambulatory function FDA designation(s): Orphan Drug, older and adults who inhibitor intended to treat DMD, an inherited X deflazacort, prednisone) (eg, 6-minute walk test Fast Track have Duchenne chromosome–linked genetic disorder caused by mutations distance, time to rise Clinical trial(s): Phase III primary muscular dystrophy or deletions in the dystrophin gene, DMD. DMD encodes the from floor, North Star completion March 2022; phase (DMD), are ambulatory, dystrophin protein, which helps keep muscle cells intact. The Ambulatory II/III long-term follow-up primary and are receiving a absence of wild-type dystrophin protein causes progressive Assessment) completion December 2023 stable dose of muscle fiber necrosis and eventual widespread muscle Muscle strength corticosteroids 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 it might trigger inflammation. No cure exists for DMD, and first-line corticosteroid treatment (eg, deflazacort) manages symptoms but does not prevent disease progression and has significant side effects. FDA approved 2 gene therapies for patients who have a specific mutation in DMD (ie, in exon 51 or exon 53), but patients who have other DMD mutations are ineligible for these therapies. Therefore, additional therapies are needed. In patients with DMD, givinostat purportedly blocks HDAC overactivity and improves muscle regeneration and function. In clinical trials, patients receive an unspecified, weight-dependent dose of an oral suspension of givinostat, at a concentration of 10 mg/mL, twice daily with food, for up to 18 months. Developer(s): Italfarmaco SpA (Milan, Italy)
SECTION 5. RARE DISEASES 160
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults who have acute Givosiran (Givlaari) is an RNA interference (RNAi) therapeutic Carbohydrate perfusion Rate of attacks Approval date: November 20, hepatic porphyria (AHP) that reduces the expression of aminolevulinic acid synthase (acute) Rate of hemin 2019 1 (ALAS1) to treat AHP. A group of rare metabolic disorders, Hemin injection (acute) administration FDA designation(s): Orphan Drug, AHPs are caused by genetic mutations (usually autosomal Supportive therapy Pain score change from Breakthrough Therapy, Priority dominant) in enzymes that are involved in heme production (acute) baseline Review in the liver and converge in their respective metabolic Trigger avoidance Nausea score change Clinical trial(s): Phase III pathways on the ALAS1 enzyme. This is thought to increase (acute) from baseline ENVISION primary completion the production of heme intermediates in the liver that are Fatigue score change January 2019, data reported toxic to nerves and contribute to developing AHP. The September 2019 manifestations include intermittent porphyria, from baseline aminolevulinic acid dehydratase-deficiency porphyria, hereditary coproporphyria, and variegate porphyria. Common symptoms from these manifestations can include confusion; fatigue; nausea; weakness; blisters on sun- exposed skin; and severe, diffuse abdominal pain. The disorders are chronic and are associated with serious morbidity. Acute flares can be life threatening. Givosiran is designed to reduce the expression of ALAS1 enzyme in the liver, reduce buildup of neurotoxic heme intermediates, and prevent or reduce recurrent AHP attacks. It is the first treatment to obtain FDA approval to prevent attacks or treat chronic manifestations of these disorders. The FDA- approved label’s recommended dose is 2.5 mg/kg once monthly by subcutaneous injection. Developer(s): Alnylam Pharmaceuticals, Inc (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children and adults Golodirsen (Vyondys 53) is a phosphorodiamidate Corticosteroids (eg, Ambulatory capacity, as Approval date: December 12, with Duchenne morpholino oligomer (PMO; DNA analogue) intended to deflazacort, prednisone) measured by accepted 2019 muscular dystrophy treat DMD, an inherited, X chromosome–linked genetic clinical ratings and FDA designation(s): Orphan Drug (DMD) who have a disorder caused by rearrangements or deletions in the scales Clinical trial(s): Phase II confirmed mutation in dystrophin gene, DMD. DMD encodes the dystrophin protein, 6-minute walk test completed March 2019, data the DMD gene that is which helps keep muscle cells intact. The absence of wild- distance reported September 2017; phase amenable to exon 53 type dystrophin protein causes progressive muscle fiber Quality of life III ESSENCE primary completion skipping necrosis and eventual widespread muscle weakness. No May 2022; phase III open-label cure exists for DMD, and first-line corticosteroid treatment extension primary completion manages symptoms but does not prevent disease August 2026 progression and has significant side effects. FDA approved 2 Note(s): FDA approved this gene therapies for patients with a specific mutation in DMD indication under Accelerated (ie, in exon 51 or exon 53), but patients who have other DMD Approval “based on an increase variants are ineligible for these therapies. Additional in dystrophin production in therapies are needed. Golodirsen purportedly binds exon 53 skeletal muscle observed in of dystrophin pre-mRNA (ie, precursor RNA composed of patients treated with VYONDYS introns and exons) and promotes skipping of exon 53 during 53. Continued approval for this mRNA processing. This allows for synthesis of an internally indication may be contingent truncated but functional dystrophin protein. Therefore, upon verification of a clinical golodirsen treatment might promote skeletal muscle benefit in confirmatory trials.” function and prevent or delay disease progression in The trial that served as the basis patients who have mutations in DMD exon 53. The FDA- for the approval was a 2-part approved label states the recommended dosage is 30 mg/kg study on a total of 25 patients. once weekly as an intravenous infusion given over 35 to 60 minutes. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 10 years or Idebenone (Puldysa) is a small-molecule benzoquinone drug Corticosteroids (eg, Forced vital capacity Submission date: New Drug older who have intended to treat DMD, an inherited, X chromosome–linked deflazacort, prednisone) (total, percentage Application planned for second Duchenne muscular genetic disorder caused by mutations or deletions in the predicted) half of 2021 dystrophy (DMD) dystrophin gene, DMD. DMD encodes the dystrophin protein, Percentage predicted FDA designation(s): Orphan Drug, which helps keep muscle cells intact. The absence of wild- peak expiratory flow Rare Pediatric Disease, Fast Track type dystrophin protein causes progressive muscle fiber Percentage predicted Clinical trial(s): Phase III SIDEROS necrosis and eventual widespread muscle weakness. No forced expiratory primary completion August 2021; cure exists for DMD, and first-line corticosteroid treatment volume in 1 second phase III SIDEROS-E primary manages symptoms but does not prevent disease Muscle strength completion December 2023; progression and has significant side effects. FDA approved 2 Quality of life phase III DELOS completed April gene therapies for patients who have a specific mutation in 2014, data published April 2015, DMD (ie, in exon 51 or exon 53), but patients who have other additional data presented DMD variants are ineligible for these therapies. Therefore, December 2017 additional therapies are needed. Idebenone is similar to Note(s): Idebenone’s coenzyme Q10 and purportedly facilitates electron transport manufacturer formerly used the within mitochondria. According to the manufacturer, brand name Catena for its DMD maintaining correct electron balance is essential for normal indication 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 take or caregivers give idebenone by mouth at a dose of 900 mg daily, divided into 3 equal doses of two 150- mg tablets each, taken with meals. Developer(s): Santhera Pharmaceuticals (Pratteln, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 55 IMR-687 is a selective inhibitor of the enzyme Blood transfusion Frequency of vaso- FDA designation(s): Orphan Drug, years who have sickle phosphodiesterase 9 (PDE9) in development to treat SCD. Crizanlizumab-tmca (ie, occlusive crises (VOCs) Fast Track, Rare Pediatric Disease cell disease (SCD) Donor stem cell transplantation is the only potentially Adakveo) and hospitalization Clinical trial(s): Phase II curative treatment for SCD but is not widely available Hematopoietic (blood Number of blood randomized primary completion because of the difficulty of finding a closely matched donor cell–generating) stem transfusions required July 2020, initial data reported to increase the chance of success. IMR-687 could represent cell transplantation Quality of life June 2019; phase II single-arm a disease-modifying treatment that is more widely available. Hydroxyurea extension primary completion The oral drug purportedly prevents destruction of and June 2024 increases levels of cyclic guanosine monophosphate (cGMP). Pharmaceutical-grade l- Higher cGMP levels in turn increase production of fetal glutamine hemoglobin while reducing the sickling of red blood cells Voxelotor (ie, Oxbryta) and the “stickiness” of white blood cells. IMR-687 purportedly does not reduce levels of certain white blood cells that can occur with hydroxyurea use, increasing infection risks. In a phase II trial, patients take IMR-687 at either a 50- or 100-mg dose once daily for up to 24 weeks. Developer(s): Imara, Inc (Boston, Massachusetts)
Adults aged 18 years or Inebilizumab (MEDI-551) is a humanized monoclonal antibody Azathioprine Attack rate PDUFA date: June 11, 2020 older who have intended to bind to CD19+, which is expressed on a broad Eculizumab plus Functional impairments FDA designation(s): Orphan Drug, neuromyelitis optica or range of B cells. Inebilizumab is intended to bind to and immunosuppressants (eg, vision, mobility, and Breakthrough Therapy neuromyelitis optica deplete autoreactive B cells involved in the neurodegenerative Intravenous bowel or bladder Clinical trial(s): Phase II/III N- spectrum disorder disease course of NMOSD, for which no cure exists. NMOSD is corticosteroids incontinence) change MOmentum primary completion (NMOSD), including a rare autoimmune disease that affects myelin in the eyes, Mycophenolate mofetil from baseline October 2018, pivotal study data those with and without spinal cord, and other parts of the body. Patients with Hospitalizations published October 2019 aquaporin-4- NMOSD can have pain, paralysis, vision loss, and bladder and Plasmapheresis Quality-of-life change immunoglobulin G bowel problems. Approved treatments are Rituximab from baseline (AQP4-IgG) antibodies, immunosuppressants and/or add-on therapies for those with and who have had one positive aquaporin-4 (AQP4) antibodies. About 80% of relapse requiring rescue patients test positive for autoantibodies to water channel therapy in the previous protein AQP4, produced by B cells. In clinical trials, regardless year 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Pregnant females with a In utero percutaneous endoscopic repair is a surgical Fetoscopic repair with Successful repair of Clinical trial(s): Unphased single- singleton fetus of procedure to repair myelomeningocele, the most severe laparotomy and uterine spine defects arm pilot primary completion gestational age 19 to 26 form of spina bifida, in a fetus. The procedure uses cameras externalization Developmental status November 2020 weeks who has a and specialized instruments inserted through a few small Open surgical repair Survival diagnosis of incisions in the woman’s womb without surgically opening Quality of life myelomeningocele the abdomen or uterus. Although this approach is (including myeloschisis) technically more difficult than open surgical in utero that occurs at vertebral myelomeningocele repair, it purportedly reduces surgical level T1 through S1 with risks for both mother and fetus while offering outcomes hindbrain herniation similar to open surgery. The MOMS trial in 2011 established prenatal surgery for myelomeningocele as superior to postnatal surgical repair for improving quality of life and reducing long-term disability for mother and fetus. However, prenatal surgery increased short-term risks for both fetus and mother. Prenatal open surgery involved a large abdominal incision and opening the uterus (ie, hysterotomy) to access the fetal spine, which increased risk of uterine rupture. Selected centers then developed fetoscopic surgery with uterine externalization in which surgeons partially removed and exposed the uterus (temporarily) to improve surgeons’ access to the fetus. Surgeons inflated the uterus with inert gas, repaired the fetal spine defects with endoscopic tools inserted through several small incisions in the uterus, and replaced the intact uterus back in the woman’s abdomen. With this new percutaneous (ie, through the skin) approach, a few centers now seek to improve on fetoscopic surgery that required uterine externalization by testing whether they can safely and effectively perform the spinal repair without large abdominal incisions and without removing the uterus. Developer(s): Joint research collaboration among University of Southern California (Los Angeles, California), Children’s Hospital Los Angeles (Los Angeles, California), Huntingdon Hospital (Pasadena, California), Wellington Regional Medical Center (Wellington, Florida), and USFetus Consortium
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or jCell is an allogeneic (ie, unrelated donor) stem cell therapy Supportive care Best corrected visual FDA designation(s): Orphan Drug, older who have that uses human retinal progenitor cells that have been Vitamin and nutritional acuity (BCVA) Regenerative Medicine Advanced genetically confirmed cultured and expanded. No effective treatments are supplementation Retinal sensitivity Therapy retinitis pigmentosa available for RP, so jCell could be the first nonsurgical Peripheral vision Clinical trial(s): Phase II JC-02 (RP) therapy for RP. It is intended to delay RP progression or Recovery time primary completion August 2019 reverse vision loss through the release of neurotrophic factors that might rescue diseased retinal cells and possibly Quality of life differentiate into new rod cells in the retina. In clinical trials, jCell has been given as 3 × 106 or 6 × 106 human retinal progenitor cells suspended in medium. It is injected intravitreally under local anesthesia into the eye with the poorest visual acuity or, if vision is comparable in both eyes, the nondominant eye. Developer(s): jCyte, Inc (Newport Beach, California), in collaboration with California Institute of Regenerative Medicine (Oakland, California)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Lenabasum (JBT-101) is a novel synthetic anti-inflammatory Combined autologous Disease progression Submission date: Biologics older who have diffuse and antifibrotic (ie, antiscarring) medication under hematopoietic stem cell Skin fibrosis and License Application planned for cutaneous systemic investigation to treat systemic sclerosis, a rare, incurable, transplantation and inflammation 2021 sclerosis autoimmune, connective tissue disease. Conventional high-dose Mortality FDA designation(s): Orphan Drug, immunosuppressive therapy has limited efficacy in immunosuppressive Quality of life Fast Track preventing disease progression or reducing mortality rates. therapy Clinical trial(s): Phase III The disease is marked by vasculopathy, skin thickening due Low-dose (RESOLVE-1) primary completion to collagen accumulation, autoantibody formation, and immunosuppressive March 2020 inflammation, which leads to fibrosis in skin and internal therapy organs. Patients with limited cutaneous systemic sclerosis Symptom-based have fairly high survival rates but are at increased risk of palliative pulmonary arterial hypertension (PAH). Patients with diffuse pharmacotherapy (eg, cutaneous systemic sclerosis have worse survival rates. angiotensin-converting Preclinical studies suggest that lenabasum preferentially enzyme [ACE] inhibitors, activates specific immune cell cannabinoid receptors (ie, nonsteroidal anti- CB2). Lenabasum purportedly binds CB2 receptors and inflammatory drugs triggers inflammation resolution, a multifaceted process that [NSAIDs]) 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 15 years Lenadogene nolparvovec (GS010) is a gene therapy intended Supportive care Visual acuity FDA designation(s): Orphan Drug or older and adults who for LHON, a rare maternally inherited genetic disease of the Quality of life Clinical trial(s): Phase III REFLECT have Leber hereditary mitochondrial DNA that leads to irreversible vision loss. primary completion June 2020, optic neuropathy GS010 is intended to restore vision loss and quality of life in developed under Special (LHON) caused by a patients with LHON caused by a mutation in the NADH Protocol Assessment; phase III mutation in the ND4 dehydrogenase 4 gene, ND4. GS010 is an adeno-associated RESCUE completed July 2019, gene virus serotype 2 (AAV2) vector that delivers a functional copy data reported September 2019; of the ND4 gene into cells. GS010 uses a mitochondrial phase III REVERSE completed targeting sequence that carries the therapeutic messenger December 2018, data reported RNA (mRNA) transcribed from this transgene from the May 2019 nucleus of treated cells directly to the mitochondria, where the functional ND4 proteins are produced and incorporated, treating the deficiency. In clinical trials, GS010 is administered as a single intravitreal (ie, into the eye) injection at a dose of 9 × 1010 vg in 90 μL of balanced salt solution plus 0.001% Pluronic F68. Developer(s): Gensight Biologics, Inc (New York, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 17 years or Lenti-D is a bone marrow–derived gene therapy product Histocompatible stem CALD progression Submission date: Biologics younger who have intended for ALD, a rare, X chromosome–linked, inherited cell transplantation Functional disability License Application planned for active cerebral metabolic disorder caused by mutations in the ATP binding Lorenzo’s oil (4 parts Quality of life 2020 adrenoleukodystrophy cassette subfamily D member 1 gene, ABCD1. The disorder glyceryl trioleate to 1 FDA designation(s): Orphan Drug, (CALD) leads to accumulation of abnormally high levels of part glyceryl trierucate) Breakthrough Therapy unbranched, saturated, very-long-chain fatty acids in Clinical trial(s): Phase II/III patients’ brains and adrenal cortexes. Cerebral ALD (CALD) is Starbeam primary completion the most severe form and involves neurodegeneration, July 2020, data reported including the breakdown of the protective myelin sheath of September 2019; phase III nerve cells in the brain. Symptoms occur in early childhood primary completion February and progress rapidly, causing severe loss of neurologic 2023 function and eventual death. CALD can be treated with bone marrow or stem cell transplants. However, fewer than 30% of patients find matching donors, and allogenic (ie, unrelated donor) transplants can have potentially fatal side effects. Lenti-D is intended to restore expression of the adrenoleukodystrophy protein gene, ALDP, which metabolizes very-long-chain fatty acids that are thought to contribute to CALD neurodegeneration. Lenti-D consists of patient-derived CD34+ stem cells that are harvested and treated with a lentivirus vector that stably inserts a functional copy of ALDP into the cells. The cells are then multiplied in culture to facilitate uptake. In clinical trials, Lenti-D is given as a single intravenous infusion after myeloablative (ie, bone marrow destroying) conditioning with busulfan and cyclophosphamide. Developer(s): bluebird bio, Inc (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 12 years LentiGlobin (BB305) consists of patient-derived hematopoietic Blood transfusion Frequency of VOCs and FDA designation(s): Orphan Drug, or older and adults stem cells transduced with a functional copy of the human Crizanlizumab-tmca (ie, hospitalizations Regenerative Medicine Advanced aged up to 50 years hemoglobin subunit beta gene, HBB, which are then Adakveo) Number of blood Therapy who have severe sickle reintroduced to the patient. In SCD, sickled red blood cells are Hematopoietic stem cell transfusions required Clinical trial(s): Phase I/II primary cell disease (SCD) more susceptible to oxidative damage, inappropriate transplantation Quality of life completion February 2022; adhesion, and vascular obstruction, leading to vaso-occlusive Hydroxyurea interim data reported June 2019 crises (VOCs) that cause severe pain, requiring hospitalization. VOC complications can include circulating blood clots, stroke, Pharmaceutical-grade l- organ failure, or early death. LentiGlobin has a unique amino glutamine acid substitution in the HBB gene that promotes antisickling of Voxelotor (Oxbryta) red blood cells. By replacing dysfunctional human HBB genes, LentiGlobin might address SCD’s underlying cause, rather than just reduce symptoms. LentiGlobin is given by intravenous infusion as a single dose after myeloablative conditioning with busulfan. Developer(s): bluebird bio, Inc (Cambridge, Massachusetts)
Children and adults LentiGlobin (BB305) is a gene therapy intended for β- Allogeneic stem cell Transfusion need status FDA designation(s): Orphan Drug, aged up to 50 years thalassemia, an inherited blood disorder caused by a transplantation Organ function Breakthrough Therapy who have transfusion- mutation in the hemoglobin subunit beta gene, HBB. This Repeated blood Level of iron overload Clinical trial(s): Phase III dependent β- mutation causes ineffective red blood cell production, leading transfusions Quality of life NORTHSTAR-2 primary February thalassemia, also to severe anemia. Standard of care involves use of frequent 2022, interim data reported known as β-thalassemia blood transfusions and supportive care. LentiGlobin might December 2019; phase III major, with a β0/β0 provide a one-time functional cure for β-thalassemia. NORTHSTAR-3 primary + genotype (ie, no β- LentiGlobin consists of bone marrow–derived CD34 completion June 2022, globin expression) or a hematopoietic stem cells (HSCs) harvested from the patient preliminary data reported β+/β0 genotype (ie, little and treated with a lentivirus vector that stably inserts a December 2019 β-globin expression) functional copy of the HBB gene into the cells. The cells are then multiplied in culture to facilitate uptake. This autologous HSC therapy does 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 or older Liposomal cyclosporine A (L-CsA) is an immunosuppressive Immunosuppressants Disease progression FDA designation(s): Orphan Drug who develop treatment intended to reduce the inflammatory disease (eg, azithromycin, Lung retransplantation Clinical trial(s): Phase II/III bronchiolitis obliterans burden of BOS, the most common cause of chronic lung mycophenolate, Survival completed December 2014 (see syndrome (BOS) after allograft dysfunction after transplantation. No treatments tacrolimus) Quality of life note), data presented March lung transplantation are approved for BOS, and no standardized treatment Supportive care (eg, 2019, data presented April 2019, protocols are available. Cyclosporine A is a potent corticosteroids, oxygen) data presented May 2019; phase immunosuppressive drug for preventing transplant III BOSTON-2 primary completion rejection, but systemic administration has insufficient September 2021; phase III penetration into the lungs to treat BOS and carries a risk of BOSTON-1 primary completion nephrotoxicity. L-CsA uses a proprietary inhaled liposomal December 2021; phase III nanodelivery system to administer what researchers believe BOSTON-3 open-label extension to be a sufficient concentration of cyclosporine A directly to primary completion March 2023 the lung parenchyma, mediating immunosuppressive Note(s): A phase II/III trial was effects. L-CsA purportedly dampens key inflammatory T-cell terminated early because activity in the lungs thought to contribute to the chronic “Interim analysis results revealed inflammation and irreversible scarring caused by BOS, substantial increase of patient slowing or preventing disease progression. In clinical trials, number, with unfeasible study the drug is inhaled using the PARI eFlow Nebulizer system at prolongation.” a dose of 5 mg twice daily for 48 weeks for participants with a single-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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 4 years Livoletide (AZP-531) is a first-in-class analogue of unacylated Cognitive behavioral Hyperphagia symptoms FDA designation(s): Orphan Drug or older and adults ghrelin, a naturally occurring hormone intended to treat therapy (CBT) and severity Clinical trial(s): Phase IIb/III aged up to 65 years hyperphagia (ie, abnormally increased appetite) in patients Rate of comorbidities ZEPHYR pivotal primary who have Prader-Willi with PWS. Unacylated ghrelin is thought to counteract the Diazoxide (off label) (eg, cardiovascular completion June 2020 syndrome (PWS) with effects of acylated ghrelin, commonly called the “hunger Diet and food intake disease, diabetes Note(s): Topline results expected hyperphagia hormone,” which stimulates food-seeking behavior. No control mellitus, obesity) in the first half of 2020 might effective treatments are approved for PWS-associated Exercise Mortality support a New Drug Application abnormal eating behaviors. If livoletide effectively treats Glucagon-like peptide 1 Quality of life filing abnormal eating in PWS, it might reduce obesity-related (GLP-1) receptor agonist complications and improve quality of life for patients. (eg, exenatide or Livoletide is under development to treat hyperphagia liraglutide; off label) associated with PWS, a rare genetic disease (about 8000- 11 000 US patients) caused by lack of expression of several genes on chromosome 15. In addition to having intellectual disability and short stature, patients with PWS often die by about 40 years of age, mainly from obesity-related comorbidities, including cardiovascular and respiratory (eg, sleep apnea) complications and type 2 diabetes mellitus (T2DM). In clinical trials, patients receive subcutaneous injections at dosages between about 60 and 120 mcg/kg daily. Developer(s): Millendo Therapeutics (Ann Arbor, Michigan)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children and adults Lumasiran (ALN-GO1) is an RNA interference (RNAi) Diet management and Change in urinary Submission date: Rolling New who have primary therapeutic intended to reduce glycolate oxidase (GO) fluid intake oxalate excretion Drug Application initiated hyperoxaluria type 1 expression in PH1. A rare inherited disorder, PH1 is Organ transplantation Hospitalizations January 10, 2020 (PH1) characterized by kidney and bladder stones from the (ie, isolated or Quality of life for FDA designation(s): Orphan Drug, buildup of excessive oxalate. Lumasiran is intended to combined liver and patients and caregivers Breakthrough Therapy improve health outcomes in patients with PH1 by reducing kidney) Clinical trial(s): Phase III morbidity from oxalate crystals accumulating in the kidneys Renal dialysis ILLUMINATE-A primary and urinary tract. No pharmacologic treatment options are Shockwave lithotripsy completion November 2019, available for PH1. Lumasiran purportedly lowers hepatic data reported December 2019; levels of GO, which produces the substrate necessary for the phase III ILLUMINATE-B primary subsequent production of oxalate. Limiting the substrate completion March 2020; phase III necessary for oxalate production is intended to limit its ILLUMINATE-C primary buildup. In clinical trials, lumasiran is given subcutaneously completion March 2021; phase by injection at a dose of 3 mg/kg/month. I/II completed January 2019, data Developer(s): reported February 2019 Alnylam Pharmaceuticals (Cambridge, Massachusetts) Note(s): Topline data expected for ILLUMINATE-B mid-2020
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Luspatercept-aamt (Reblozyl) is an erythrocyte (ie, red blood Allogeneic stem cell Blood transfusion Approval date: November 8, older who have β- cell) maturation agent under development to treat β- transplantation dependence 2019 thalassemia that thalassemia. Luspatercept-aamt is intended to restore Repeated blood Incidence of iron FDA designation(s): Orphan Drug, requires regular red production of normal red blood cells, thus obviating the transfusions overload Fast Track, Priority Review blood cell transfusions need for repeat transfusions and the accompanying iron Organ function Clinical trial(s): Phase III BELIEVE chelation therapy. β-thalassemia is caused by a Quality of life primary completion November rearrangement in the hemoglobin subunit beta gene, HBB. 2017, data reported November This prevents normal erythrocyte maturation, resulting in 2019; phase II single-arm severe anemia requiring chronic blood transfusions for completed November 2015, data survival plus nightly iron chelation to prevent iron overload. published March 2019 Luspatercept-aamt is a first-in-class biologic that purportedly stimulates maturation of erythrocyte precursor cells differently from the body’s natural erythropoietin, thereby correcting the maturation defect and restoring normal erythrocyte production. Luspatercept-aamt is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the transforming growth factor beta (TGF-beta) superfamily involved in late-stage erythrocyte production. The FDA-approved label is an injection under the skin at a recommended dose of 1 mg/kg every 3 weeks to treat β-thalassemia-associated anemia in patients who require regular red blood cell transfusions. Developer(s): Acceleron Pharma, Inc (Cambridge, Massachusetts), in collaboration with Celgene Corp (Summit, New Jersey)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 6 months LYS-SAF302 is a viral vector–based gene therapy intended Supportive care Developmental and FDA designation(s): Orphan Drug, or older and adults who for Sanfilippo syndrome type A, a childhood-onset, cognitive delays, as Rare Pediatric Disease have genotypically progressive, inherited metabolic disorder caused by a measured by MPS Clinical trial(s): Phase II/III confirmed Sanfilippo variant in the N-sulfoglucosamine sulfohydrolase gene, clinical ratings and AAVance primary completion syndrome type A (also SGSH. Patients with the disorder cannot break down the scales January 2022 called polysaccharide heparan sulfate, a process normally Independence, as mucopolysaccharidosis mediated by the SGSH-encoded enzyme heparan-N- measured by MPS type III A [MPSIIIA]) sulfamidase. Buildup of heparan sulfate in central nervous clinical ratings and system cells causes degeneration that manifests as scales behavioral problems, sleeplessness, loss of speech and Sleep duration cognitive skills, mental retardation, heart problems, seizures, Quality of life and loss of mobility. No cure exists for Sanfilippo syndrome type A (about 60% of all Sanfilippo syndrome cases), and patients typically do not survive past their 20s. Treatment consists of supportive care. LYS-SAF302 is a recombinant adeno-associated viral vector carrying SGSH. LYS-SAF302 purportedly restores heparan-N-sulfamidase function, blocks central nervous system degeneration, and reduces disease-related symptoms. In clinical trials, LYS-SAF302 is injected intracerebrally, into both halves of the brain, through image-guided tracks, once. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts), in collaboration with Lysogene SA (Paris, France)
SECTION 5. RARE DISEASES 175
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 1 year or Maralixibat (LUM001) is an inhibitor of apical sodium- Ursodeoxycholic acid Liver function FDA designation(s): Orphan Drug, older who have dependent bile acid transporter (ASBT). It purportedly (UDCA) Need for surgical Breakthrough Therapy progressive familial prevents bile acids from accumulating in the liver of patients intervention Clinical trial(s): Phase II INDIGO intrahepatic cholestasis with subtypes PFIC1, PFIC2, PFIC3, and PFIC4 of PFIC, a Quality of life primary completion February (PFIC) progressive disease that can require surgical intervention or 2020, preliminary data reported liver transplantation and has minimally effective therapy. April 2019, data presented PFIC is characterized by variants in key genes leading to November 2019; phase III decreased bile acid flow through the liver. Accumulation of MARCH-PFIC primary completion bile acid in the liver can lead to jaundice, intense itching, May 2020; phase III extension gallstones, abdominal pain, nausea, vomiting, and liver primary completion November damage, as well as a higher risk for hepatocellular 2022 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)
Children and adults MT1621 is an oral combination of the DNA building blocks Supportive care Motor function FDA designation(s): Orphan Drug, with thymidine kinase 2 deoxycytidine and deoxythymidine intended to address the assessment from Breakthrough Therapy deficiency (TK2d) due to underlying cause of TK2 deficiency. MT1621 purportedly baseline Clinical trial(s): Phase II pivotal a confirmed genetic provides cells an adequate balance of the nucleotide 6-minute walk test from primary completion January mutation in the building blocks and restores cell function in patients with baseline 2022; phase II completed May thymidine kinase 2 TK2d. A rare disorder, TK2d is caused by genetic mutations Respiratory status from 2019, data reported October gene, TK2 in mitochondrial DNA leading to mitochondrial dysfunction, baseline 2019 including inadequate energy production by cells. TK2d Health care services use causes progressive and severe muscle weakness that
impairs movement, breathing, and eating, and can be fatal. Survival No therapies are approved for TK2d. In clinical trials, MT1621 is administered orally up to 400 mg/kg daily as a Quality of life dissolved solution. Developer(s): Modis Therapeutics (Oakland, California), a subsidiary of Zogenix (Emeryville, California)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Narsoplimab (OMS721) is a fully human monoclonal Corticosteroids Renal function from FDA designation(s): Orphan Drug, older who have antibody that binds mannan-binding lectin-associated serine Immunosuppressants baseline Breakthrough Therapy immunoglobulin A (IgA) protease-2 (MASP-2). Narsoplimab is intended to reduce (eg, azathioprine, Urine protein excretion Clinical trial(s): Phase III primary nephropathy excessive complement-mediated inflammation and cyclophosphamide, from baseline completion August 2020 endothelial damage characteristic of IgA nephropathy while mycophenolate) leaving other immune system functions intact. IgA Supportive care nephropathy is a kidney disease that occurs when an antibody subtype called IgA accumulates in the kidneys and causes local inflammation that can gradually affect kidney function and cause end-stage kidney disease within 10 to 20 years in up to 40% of affected patients. No treatments are approved for IgA nephropathy. The standard of care (ie, high-dose systemic corticosteroids) is controversial because of the increased risks of adverse events and serious infections, high blood pressure, weight gain, diabetes mellitus, and osteoporosis. MASP-2 is a key enzyme for activating the lectin pathway of the body’s complement system in response to tissue damage or microbial infection. Excessive complement activation is a trait of IgA nephropathy. Targeting the lectin pathway is intended to reduce excessive inflammation while leaving other key complement functions intact. In clinical trials, narsoplimab is administered as an intravenous infusion at an unspecified loading dose followed by daily subcutaneous injections. Developer(s): Omeros Corp (Seattle, Washington)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Nintedanib (Ofev) is an oral kinase inhibitor and antifibrotic Azathioprine Breathing function Approval date: September 6, older who have drug approved by FDA to treat SSc-ILD. Patients with Cyclophosphamide Disease progression 2019 systemic sclerosis– systemic sclerosis, also known as scleroderma, have Mycophenolate mofetil Survival FDA designation(s): Orphan Drug, associated interstitial thickening and scarring of connective tissue in multiple Rituximab Quality of life Fast Track lung disease (SSc-ILD) organs. Most develop interstitial lung disease (ILD), which is Supportive care Clinical trial(s): Phase III SENSCIS the leading cause of death in these patients. No cure exists completed October 2018, data for SSc-ILD, and before Ofev’s approval, available treatments published May 2019; phase III only managed symptoms and did not prevent disease open-label extension primary progression. Nintedanib purportedly binds to and blocks completion July 2021 intracellular signaling of the following receptor tyrosine Note(s): FDA approved kinases (RTKs): platelet-derived growth factor receptor α and nintedanib to treat IPF in β, fibroblast growth factor receptor 1-3, and vascular October 2014 endothelial growth factor receptor 1-3, which are thought to contribute to lung tissue fibrosis in both ILD and a related condition, idiopathic pulmonary fibrosis (IPF). The FDA- approved label states the drug is indicated to slow “the rate of decline in pulmonary function in patients with SSc-ILD.” The recommended dosage is 150-mg capsules taken twice daily with food, about 12 hours apart. Developer(s): Boehringer Ingelheim Pharmaceuticals, Inc (Ridgefield, Connecticut)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 21 to 80 NT-501 (Renexus) is an eye implant containing genetically Vascular endothelial Neurodegeneration, as FDA designation(s): Orphan Drug, years who have macular modified human cells that secrete neuropeptide ciliary growth factor (VEGF) measured by changes in Fast Track telangiectasia (MacTel) neurotrophic factor (CNTF). No implants are approved to inhibitors macular ellipsoid zone Clinical trial(s): Phase III primary type 2 carry biologics for MacTel type 2, a neurodegenerative Macular thickness completion March 2022; phase III disorder that causes gradual central vision loss over a Visual acuity primary completion March 2022; period of 10 to 20 years. Therefore, NT-501 might represent Retinal sensitivity phase II completed April 2017, a novel treatment option for these patients. NT-501 allows data published April 2019 controlled release of biologic drugs and is intended to slow Reading speed retinal degeneration. CNTF purportedly diffuses into the retina from the cells contained within the Renexus device to stimulate retinal cell growth and protect the cells from damage. In clinical trials, Renexus is surgically implanted into the vitreous humor and contains an unspecified dose of CNTF. The implant purportedly secretes CNTF for up to 2 years after placement. Developer(s): Neurotech Pharmaceuticals (Cumberland, Rhode Island), in collaboration with Lowy Medical Research Institute (La Jolla, California)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 2 years Onasemnogene abeparvovec-xioi (AVXS-101; Zolgensma) is an Manual chest Ventilator (ie, breathing) Approval date: May 24, 2019 or younger who have adeno-associated viral vector (AAV) approved by FDA for physiotherapy for support use FDA designation(s): Orphan Drug, spinal muscle atrophy patients 2 years of age or younger with SMA (type unspecified). ineffective cough (eg, Nutritional support use Breakthrough Therapy, Fast Track (SMA) with biallelic Zolgensma contains a functional copy of SMN1, and delivery of Cough Assist or Motor function, as Clinical trial(s): Phase I START mutations in the this functional gene copy by Zolgensma might delay or halt VitalCough) measured by accepted completed December 2017, long- survival motor neuron 1 SMA disease progression. Patients receiving the treatment are Noninvasive positive clinical ratings and term follow-up data published gene, SMN1 likely to have SMA types I or II because onset of these types pressure ventilation scales February 2019, data published typically occurs before 2 years of age. SMA is a neuromuscular Nusinersen Muscle strength, as September 2019; phase III disorder caused by a genetic defect in SMN1. This defect results measured by accepted STR1VE-US primary completion in loss of the gene’s encoded SMN protein, which is critical for clinical ratings and November 2019, interim data motor neuron function and transmission of signals from the scales reported April 2019 and brain to skeletal muscles. Patients with SMA experience motor September 2019; phase III neuron loss, resulting in progressive muscle weakness and Developmental milestone achievement SPR1NT primary completion eventual paralysis. The related gene, survival of motor neuron October 2020 2, centromeric, or SMN2, can also produce low levels of SMN Mortality Note(s): One month after FDA protein. The gene’s copy number naturally varies in humans, Hospitalization rates approval, AveXis disclosed to FDA and SMA disease severity generally correlates with the number that previously submitted of SMN2 copies the patient has (ie, the more copies of SMN2, Biologics License Application data the less severe the disease). SMA is classified into 1 of 4 types were inaccurate. In August 2019 (ie, I, II, III, or IV), with type I being the most severe and having FDA stated the drug will remain the earliest onset, at about 0 to 6 months. The FDA-approved on the market during assessment label’s recommended dose of Zolgensma is 1.1 × 1014 vg/kg of of the situation. On October 30, body weight, delivered intravenously via peripheral vein, once. 2019, a Novartis press release Because patients can experience immune reactions to the viral stated that FDA placed a partial vector and/or transient changes in liver enzyme function after hold on AVXS-101 intrathecal Zolgensma treatment, patients also receive systemic (spinal injection) clinical trials for corticosteroids equivalent to oral prednisolone at 1 mg/kg of SMA due to findings in a small body weight per day, starting 1 day before Zolgensma animal study. The company said administration and continuing for a total of 30 days. After 30 “adverse events that might be days, clinicians assess patients’ liver function. Patients with expected from the preclinical normal follow-up results taper the corticosteroid dose over the findings have not been seen in a next 28 days. If liver function abnormalities persist, patients thorough review of human safety continue systemic corticosteroid treatment until laboratory data from all available sources to findings are normal and then taper the corticosteroid dose over date” and that it is working with the next 28 days. FDA on next steps. Developer(s): AveXis, Inc (Bannockburn, Illinois), a wholly owned subsidiary of Novartis AG (Basel, Switzerland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Infants and children OTL-101 is a bone marrow–derived gene therapy product Bone marrow Event-free survival Submission date: Biologics aged 30 days to 17 intended for ADA-SCID, a rare and life-threatening inherited transplantation Overall survival License Application planned for years who have disease of the immune system due to a faulty adenosine Enzyme replacement Quality of life 2020 adenosine deaminase– deaminase gene, ADA. This gene is essential for T-cell and B- FDA designation(s): Orphan Drug, severe combined cell (ie, lymphocyte) production. Patients with ADA-SCID Breakthrough Therapy, Rare immunodeficiency produce no functional lymphocytes, leading to susceptibility Pediatric Disease (ADA-SCID) and are to serious and life-threatening infections. Without enzyme Clinical trial(s): Phase II/III ineligible for allogeneic replacement therapy, patient life expectancy is short. OTL- primary completion August 2020; bone marrow 101 was designed to restore lymphocyte development and phase I/II completed September transplantation from a immunity in patients with ADA-SCID (also known as bubble 2019, initial data reported + matched family donor boy disease). OTL-101 consists of patient-derived CD34 February 2019; phase I/II primary stem cells that are harvested from the patient and treated completion December 2020 with a lentivirus vector that stably inserts a functional copy of the ADA gene into the cells. The cells are then multiplied in culture to facilitate uptake. In clinical trials, OTL-101 is given as a single intravenous infusion of an unspecified dose. Developer(s): Orchard Therapeutics, Ltd (London, United Kingdom)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children and adults OTL-103 is a bone marrow–derived gene therapy product Hematopoietic stem cell Frequency of Submission date: Biologics aged up to 65 years intended for WAS, a rare X chromosome–linked inherited transplantation immunoglobulin or License Application planned by who have Wiskott- primary immunodeficiency disorder caused by mutations in Immunoglobulin platelet infusions fourth quarter of 2021 Aldrich syndrome (WAS) the WASP actin nucleation promoting factor gene, WAS. The infusion Rate of hospitalizations FDA designation(s): Orphan Drug, WAS gene is a cytoskeleton regulator expressed only in Platelet infusion for infection or bleeding Regenerative Medicine Advanced blood-forming (ie, hematopoietic) cells. WAS deficiency leads episodes Therapy to eczema, petechiae, thrombocytopenia, reduced blood Clinical trial(s): Phase I/II TIGET- clotting, and susceptibility to infections. A bone marrow WAS completion October 2018, transplant from an allogeneic (ie, unmatched) donor can data published May 2019; phase potentially cure WAS. OTL-103 is intended to relieve WAS II primary completion February symptoms by repopulating the bone marrow with WAS- 2022 expressing hematopoietic stem cells to restore growth, replication, and functional capacities that enable immune responses to infectious agents and injury. OTL-103 consists of patient-derived CD34+ hematopoietic stem cells that are harvested from the patient and treated with a lentivirus vector that stably inserts a functional copy of the WAS gene into the cells. The cells are then multiplied in culture to facilitate uptake and frozen until needed for use. In clinical trials, the transduced OTL-103 cell product is given as a single intravenous infusion of an unspecified number of cells, after patients have received a myeloablative (ie, bone marrow destroying) conditioning regimen with busulfan, fludarabine, and anti-CD20 antibody. Developer(s): Orchard Therapeutics, Ltd (London, United Kingdom)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged up to 7 OTL-200 is a gene therapy consisting of autologous CD34+ Supportive care (eg, Gross motor function, Submission date: Biologics years who have hematopoietic stem cells transduced ex vivo with a lentiviral nutritional therapy; as measured by License Application planned for genetically confirmed vector containing the arylsulfatase A gene, physical, occupational, accepted MLD clinical first half of 2021 metachromatic ARSA. It is intended to treat patients who have MLD, a and speech therapy) ratings and scales FDA designation(s): Orphan Drug, leukodystrophy (MLD) progressive inherited lysosomal storage disorder caused by Neurocognitive Rare Pediatric Disease variants in both alleles of ARSA. The gene normally encodes function, as measured Clinical trial(s): Phase I/II primary the enzyme arylsulfatase A, which breaks down by accepted MLD completion April 2018 (fresh sphingolipids. Lack of arylsulfatase A activity leads to clinical ratings and cells), data presented March sphingolipid accumulation in the brain, gall bladder, kidneys, scales 2019, data presented September liver, and spleen, which in turn causes myelin loss on nerve Quality of life 2019; phase II primary fibers of the central nervous system. Affected patients completion August 2022 experience convulsions, motor disturbances, paralysis, (cryopreserved cells), data personality changes, progressive dementia, seizures, presented October 2019 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 myeloablative conditioning with busulfan, and then an unspecified dose of fresh or cryopreserved OTL-200 is given intravenously, once. Developer(s): Orchard Therapeutics, Ltd (London, United Kingdom)
SECTION 5. RARE DISEASES 183
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children older than 14 Palovarotene is a selective retinoic acid receptor gamma Supportive care (eg, New HO formation FDA designation(s): Orphan Drug, years and adults who (RARγ) agonist being developed to treat FOP. A rare assistive devices, Number of body Breakthrough Therapy, Fast have fibrodysplasia connective tissue disorder, FOP leads to the abnormal corticosteroids, regions with HO Track, Rare Pediatric Disease ossificans progressiva growth of bone in muscles, tendons, and ligaments, known nonsteroidal anti- Flare rate Clinical trial(s): Phase III MOVE (FOP) as heterotopic ossification (HO). Palovarotene treatment inflammatory drugs Range of motion, as primary completion September might prevent HO in patients with FOP. HO flares can occur [NSAIDs], occupational measured by accepted 2020; phase II completed May spontaneously or after physical trauma (eg, injury, infection). therapy) clinical ratings and 2016, phase II long-term Once formed, the heterotopic bone cannot be removed scales extension primary completion because tissue disruption causes additional HO episodes. March 2021 HO progressively interferes with normal body functions, Physical function, as measured by accepted Note(s): Palovarotene including walking, bending, breathing, chewing, and development has paused after a swallowing. FOP is caused by a mutation in the activin A clinical ratings and scales futility analysis reviewed by the receptor type 1 gene, ACVR1, which encodes for the Independent Data Monitoring ACVR1/ALK2 receptor. ALK2 normally regulates the bone Committee; palovarotene is morphogenetic protein (BMP) pathway, which is responsible under partial clinical hold in for cartilage regulation and bone development and growth. patients younger than 14 years. In patients with FOP, mutant ALK2 overactivates Smad 1/5/8, Palovarotene is also in phase II a group of 3 signal transduction proteins that, when development to treat multiple activated, bind DNA and initiate the transcription of genes in osteochondromas. the BMP2 pathway that promotes HO. Palovarotene purportedly binds to and activates RARγ, which promotes Smad destruction. In clinical trials, for preventive treatment, patients receive oral palovarotene 5 mg, once daily, for 24 months. For disease flares, patients receive oral palovarotene 20 mg, once daily, for 4 weeks, followed by palovarotene 10 mg, once daily, for 8 weeks. Developer(s): Clementia, an Ipsen Company (Montreal, Québec, Canada)
SECTION 5. RARE DISEASES 184
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 2 years Pegzilarginase (AEB1102) is a modified version of the human Low-arginine diet Mobility (eg, 2-minute FDA designation(s): or older and adults who arginase 1 enzyme. It is intended to treat arginase 1 Nitrogen-scavenging walk test, Functional Breakthrough Therapy, Rare have arginase 1 deficiency, a rare, inherited metabolic disorder caused by drugs (eg, sodium Mobility Assessment) Pediatric Disease deficiency mutations in the arginase 1 gene, ARG1. Lack of the ARG1- phenylacetate, sodium Adaptive behavior (eg, Clinical trials: Phase III PEACE encoded arginase enzyme, which is part of the cellular urea benzoate) Vineland Adaptive primary completion March 2021, cycle, leads to excessive nitrogen accumulation in the blood Seizure medications (eg, Behavior Scale II) topline data expected in first and cerebrospinal fluid. Affected patients typically carbamazepine, quarter of 2021; phase II primary experience seizures, growth impairment, and intellectual phenobarbital) completion June 2021, topline disability. According to the manufacturer, pegzilarginase is data reported September 2019 modified to increase enzyme activity and stability compared with native arginase. Pegzilarginase treatment purportedly restores arginase 1 activity, which might slow or halt the deficiency and disease progression. In clinical trials, patients receive intravenous infusions of an unspecified dose of pegzilarginase weekly, in conjunction with an individualized disease management regimen (eg, severe protein restriction, essential amino acid supplementation, nitrogen- scavenging drugs) for up to 150 weeks. Developer(s): Aeglea Biotherapeutics, Inc (Austin, Texas)
SECTION 5. RARE DISEASES 185
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Pitolisant (Wakix) is a selective histamine 3 (H3) receptor Amphetamines (eg, Excessive daytime Approval date: August 14, 2019 older who have antagonist/inverse agonist that is intended to treat patients dextroamphetamine, sleepiness symptoms FDA designation(s): Orphan Drug, excessive daytime with EDS from narcolepsy. A rare sleep disorder, EDS from lisdexamfetamine, and severity Fast Track sleepiness (EDS) from narcolepsy is characterized by overwhelming daytime mixed amphetamine Sleep attack frequency Clinical trial(s): Phase III narcolepsy sleepiness and sudden sleep attacks throughout the day. salts) Functional capacity HARMONY I completed Pitolisant has a novel mechanism of action compared with Methylphenidate Quality of life December 2010, data published currently approved therapies and is the first treatment for Modafinil November 2013, data published the disorder that is not scheduled as a controlled substance Solriamfetol August 2018; phase III HARMONY by the US Drug Enforcement Administration. Pitolisant 1bis completed July 2012, data purportedly works by increasing the synthesis and release of published August 2018; phase III histamine, a wakefulness-promoting neurotransmitter in the HARMONY III completed brain. The exact mechanism of action is unknown. Pitolisant September 2016, data published is taken by mouth, at a dose of 17.8 or 35.6 mg, once daily in November 2019; phase III the morning. The FDA-approved label recommends patients HARMONY IV completed August titrate up to 17.8 mg by taking 8.9 mg the first week and 2014, data published April 2019; increasing to 17.8 mg the second week. The dose may be unphased Expanded Access increased to a maximum recommended dosage of 35.6 mg, Program once daily, the third week if therapeutic effect is not reached. Developer(s): Harmony Biosciences, LLC (Plymouth Meeting, Pennsylvania), with license to develop, manufacture, and commercialize pitolisant in the United States from Bioprojet Pharma (Paris, France)
SECTION 5. RARE DISEASES 186
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 10 years Plerixafor (Mozobil) is a CXC chemokine receptor 4 (CXCR4) Granulocyte colony- Infection rate FDA designation(s): Orphan Drug or older and adults inhibitor. It purportedly prevents most leukocyte subsets stimulating factor (G- Severity of infections Clinical trial(s): Phase II/III aged up to 75 years from homing in and localizing in the bone marrow, a CSF; for infection Wart control primary completion October who have a clinical characteristic of WHIM syndrome. A rare primary prevention) Hematologic and 2020 diagnosis of WHIM immunodeficiency, WHIM syndrome is caused by several Imiquimod (to treat immunologic Note(s): In December 2008, FDA syndrome (warts, different mutations in the C-X-C motif chemokine receptor 4 warts) parameters approved plerixafor to treat hypogammaglobulinem gene, CXCR4. The mutations associated with the syndrome Intravenous Quality of life ovarian cancer and for use in ia, infections, and cause dysfunction of the immune system, which increases immunoglobulin (IVIg; combination with G-CSF to myelokathexis) with a infection risk and other complications resulting in many for infection prevention) mobilize hematopoietic stem heterozygous mutation types of bacterial infection that can be mild to severe with cells (HSCs) to the peripheral in the C-tail of CXCR4, serious sequelae. No cure exists. Standard treatment blood for collection and documented involves antibiotic prophylaxis, immune stimulation, and subsequent autologous neutropenia, and treatment of infections and their consequences. Plerixafor is transplantation in patients with history of severe or intended to reduce infection risk. In a clinical trial, it is given non-Hodgkin lymphoma and recurrent infections by injection 0.02 to 0.04 mg/kg/day for 6 months. multiple myeloma Developer(s): Sanofi Genzyme (Cambridge, Massachusetts)
Adults aged 40 to 80 PRM-151 (rhPTX-2) is a recombinant form of the innate Nintedanib Respiratory function FDA designation(s): Orphan Drug, years who have immunity protein pentraxin-2, which is active at sites of Pirfenidone Exercise capacity Breakthrough Therapy idiopathic pulmonary tissue damage and has demonstrated broad antifibrotic Mortality Clinical trial(s): Phase II fibrosis (IPF) activity in preclinical models. Unlike available therapies for Quality of life completed May 2018, data IPF that only slow the rate of disease progression, PRM-151 published June 2018, data is an agonist (ie, activator) that purportedly reverses IPF published May 2019 pathology. PRM-151 purportedly turns off the proliferation Note(s:) On February 13, 2020, pathway mediated by proinflammatory and profibrotic Promedior announced that it had macrophages that leads to fibrosis, and it helps activate the been acquired by Roche healing resolution pathway by directing the differentiation of monocytes into proresolution macrophages. In clinical trials, PRM-151 was given as an intravenous infusion of 10 mg/kg over 60 minutes on days 1, 3, and 5, then once every 4 weeks. Developer(s): Promedior, Inc (Lexington, Massachusetts), part of by F Hoffman-La Roche AG (Basel, Switzerland)
SECTION 5. RARE DISEASES 187
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 24 PTC-AADC (formerly known as GT-AADC, AGIL-AADC, and Dopamine agonists (eg, Motor function, as Submission date: Biologics months or older and AAV2-hAADC) is an adeno-associated viral vector containing bromocriptine, measured by accepted License Application planned for adults who have a functional copy of the human dopa decarboxylase gene, pramipexole, ropinirole, clinical ratings and second quarter of 2020 genetically confirmed, DDC. It is intended to treat patients who have AADCD, a rotigotine) scales FDA designation(s): Orphan Drug, symptomatic aromatic l- childhood-onset, progressive, inherited neurometabolic Monoamine oxidase Developmental delays Rare Pediatric Disease amino acid disorder. AADCD is caused by a rearrangement in DDC that inhibitors (eg, selegiline, Dyskinesia Clinical trial(s): Phase I/II primary decarboxylase results in the loss of the gene’s encoded enzyme, aromatic l- tranylcypromine) Quality of life completion December 2020, data deficiency (AADCD) amino acid decarboxylase (AADC). This enzyme is critical for Vitamin B6 published December 2017; converting neurotransmitter precursors into dopamine, phase II MIND primary epinephrine, norepinephrine, or serotonin. Patients with completion December 2020; AADCD experience symptoms including severe pooled data presented May developmental delays, weak muscle tone, involuntary 2018, pooled data presented movements of the arms and legs, and seizures. Existing October 2019 (abstracts 207, treatments only manage symptoms and do not prevent 231) disease progression. Delivery of a functional copy of DDC by PTC-AADC treatment might enhance neurotransmitter production, restore motor function, and delay or prevent other disease symptoms. In clinical trials, PTC-AADC is given intracerebrally into the bilateral putamen via stereotactic surgery, at a dose of 1.8 × 1011 or 2.4 × 1011 vg, once. Developer(s): PTC Therapeutics, Inc (South Plainfield, New Jersey)
SECTION 5. RARE DISEASES 188
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults who have PTR-01 is a formulation of recombinant collagen type VII Supportive care for pain Change in wound size FDA designation(s): Orphan Drug, recessive dystrophic (rC7) intended to improve RDEB lesions and other and infection risk from baseline Fast Track epidermolysis bullosa symptoms and complications. It purportedly replaces Time to wound closure Clinical trial(s): Phase I/II primary (RDEB) defective collagen type VII with functional recombinant from baseline completion December 2019 collagen at skin lesion sites to promote healing. No cure Evidence of collagen 7 exists for RDEB, and treatment relies on preventing blister anchoring in tissue formation and managing symptoms. RDEB is a rare genetic disease caused by mutations in the collagen type VII alpha 1 chain gene, COL7A1, and is characterized by widespread blistering that leads to severe scarring. The scars can lead to vision loss, disfigurement, and other serious medical problems, such as poor nutrition and slow growth from difficulty eating due to scarring in the mouth and esophagus. Individuals with RDEB are also at high risk of developing squamous cell carcinoma, an aggressive, often life-threatening form of skin cancer. PTR-01 is purported to selectively anchor the skin and other tissues affected by an absence of collagen type VII, which promotes RDEB wound healing. In clinical trials, PTR-01 is given as an intravenous infusion at a dose of 0.1 mg/kg, every 2 weeks. Developer(s): Phoenix Tissue Repair (Boston, Massachusetts)
SECTION 5. RARE DISEASES 189
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 16 years PXT3003 is a proprietary combination of 3 FDA-approved Analgesics Functional mobility FDA designation(s): Orphan Drug, or older and adults pharmaceuticals (ie, [RS]-baclofen, naltrexone Foot surgery Pain Fast Track aged up to 67 years hydrochloride, and D-sorbitol) intended to treat CMT1A. Mobility aids Quality of life Clinical trial(s): Phase II who have genetically Patients with CMT1A overexpress PMP22 protein because of Orthotic devices completed December 2012, data confirmed Charcot- an extra copy of the peripheral myelin protein 22 gene, published December 2014; Physical and Marie-Tooth disease PMP22. PMP22 overexpression degrades the protective phase III PLEO-CMT completed occupational therapy type 1A (CMT1A) myelin sheath on nerve fibers, leading to peripheral nerve September 2018, topline data dysfunction and eventual nerve conduction loss. No curative reported October 2018, or disease-modifying treatments exist, and patients typically additional data presented May receive supportive care to address functional disability and 2019; phase III PLEO-CMT-FU neuropathic pain. Additional therapies for CMT1A are follow-up extension primary needed. The 3 drugs in PXT3003 are all involved in completion April 2019, modulation of cellular activity in the central nervous system: preliminary data reported (RS)-baclofen is a gamma-aminobutyric acid (GABA) receptor January 2020 agonist (ie, activator) that blocks excitatory neurotransmitter Note(s): Pharnext intends to release, naltrexone hydrochloride is an opioid receptor reach agreement with FDA on a antagonist, and D-sorbitol purportedly is a muscarinic protocol for an additional phase acetylcholine receptor activator that might promote III study in the first half of 2020 expression of genes involved in myelin production. Thus, after FDA in August 2019 asked PXT3003 might improve myelination, protect nerve and the developer to conduct an muscle cell function, and prevent disease progression in additional phase III study due to patients with CMT1A. In clinical trials, patients drink a missing data caused by solution of PXT3003 twice daily with food, for 15 months. intercurrent events in the phase Developer(s): III PLEO-CMT study Pharnext SA (Paris, France)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 70 Reboxetine (AXS-12) is a selective norepinephrine reuptake Amphetamines Cataplexy attack FDA designation(s): Orphan Drug years who have inhibitor intended to treat patients who have EDS and Antidepressants (eg, frequency Clinical trial(s): Phase II CONCERT narcolepsy with cataplexy from narcolepsy, a chronic neurologic sleep selective serotonin EDS symptoms and completed November 2019, excessive daytime disorder. Narcolepsy treatments typically address either EDS reuptake inhibitors severity topline data reported December sleepiness (EDS) and or cataplexy, whereas reboxetine purportedly addresses [SSRIs], tricyclic Wakefulness 2019 cataplexy both. Narcolepsy is caused by impaired production of antidepressants [TCAs]) Quality of life Note(s): Axsome Therapeutics is hypocretin, an excitatory neuropeptide that regulates the Nonamphetamine to receive from Pfizer an sleep–wake cycle. About 60% to 70% of patients with stimulants (eg, exclusive US license to clinical narcolepsy also experience cataplexy, a disorder armodafinil, modafinil) and nonclinical reboxetine data. characterized by sudden, uncontrollable muscle weakness Sodium oxybate More than 40 countries outside or paralysis that occurs during the daytime and is often Solriamfetol of the United States have triggered by a strong emotion, such as crying, excitement, or approved reboxetine to treat laughter. Reboxetine purportedly promotes wakefulness major depressive disorder and increases the activity of the excitatory neurotransmitter (MDD). 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)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 4 months to RGX-121 is a recombinant, adeno-associated viral vector Supportive care Cognitive, behavioral FDA designation(s): Orphan Drug, 5 years who have (AAV9) carrying the human iduronate-2-sulfatase gene, IDS. and adaptive function, Fast Track, Rare Pediatric Disease Hunter syndrome (also It is intended to treat Hunter syndrome. This childhood- as measured by Clinical trial(s): Phase I/II RGX- called onset, progressive, inherited metabolic disorder is caused by accepted MPSII-specific 121-101 primary completion mucopolysaccharidosis a mutation in IDS. Patients with the disorder cannot break clinical ratings and December 2020, interim data type II [MPSII]) down the polysaccharides dermatan sulfate and heparan scales reported December 2019 sulfate, the process of which is normally mediated by the Quality of life 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 × 1010 GC/g brain mass is injected intracisternally (ie, into the cerebrospinal fluid), once. Developer(s): Regenxbio, Inc (Rockville, Maryland)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 6 years Rivipansel is a synthetic molecule that is similar in structure Analgesia (eg, Opioid use FDA designation(s): Orphan Drug, or older and adults who to a carbohydrate. It is a panselectin inhibitor that targets acetaminophen, Frequency of VOCs Fast Track have sickle cell disease inflammatory and adhesion processes that might contribute morphine, nonsteroidal Hospital stay Clinical trial(s): Phase III RESET (SCD) and are to VOC. Rivipansel is intended to reduce the duration of VOC anti-inflammatory drugs Rehospitalizations completed June 2019, designed experiencing a vaso- and hospital stays. In SCD, sickled red blood cells are more [NSAIDs]) within 3 days of under Special Protocol occlusive crisis (VOC) susceptible to oxidative damage, inappropriate adhesion, Crizanlizumab-tmca discharge Assessment, pivotal data and vascular obstruction, leading to VOCs that cause severe Hydration reported August 2019; phase III pain, requiring hospitalization. VOC complications can Quality of life Hydroxyurea extension terminated November include circulating blood clots, stroke, organ failure, or early 2019 Voxelotor death. In clinical trials, rivipansel is given by intravenous Note(s): The phase III RESET trial infusion every 12 hours for up to 15 doses. For patients failed to meet primary and key older than 12 years and heavier than 40 kg, the first dose is secondary endpoints 1680 mg and subsequent doses are 840 mg. For patients aged 6 to 12 years or weighing less than 40 kg, the first dose is 40 mg/kg up to 1680 mg and subsequent doses are 20 mg/kg up to 840 mg every 12 hours. Developer(s): GlycoMimetics, Inc (Rockville, Maryland), in partnership with Pfizer, Inc (New York, New York)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Infants and children RVT-802 is an allogeneic (ie, unmatched) donor thymus- Hematopoietic stem cell T-cell proliferation Submission date: Rolling who have primary derived, cell-based therapy intended to restore immune transplantation Survival Biologics License Application immune deficiency function in patients with primary immune deficiencies from Supportive care June 2019 from congenital congenital athymia, which includes complete DiGeorge FDA designation(s): Orphan Drug, athymia (ie, lack of a genetic anomaly, CHARGE syndrome, and FOXN1 deficiency. Rare Pediatric Disease, thymus), which includes Patients with congenital athymia have a high risk of death Breakthrough Therapy, complete DiGeorge (often by 24 months of age) due to chromosomal mutations Regenerative Medicine Advanced genetic anomaly; that disrupt T-cell production. The absence of functional Therapy coloboma, heart mature T cells or B cells severely compromises immunity. Clinical trial(s): Phase II defects, atresia choanae RVT-802 is intended to restore the patient’s ability to completed June 2019; phase II (CHARGE) syndrome; produce naïve T cells with a broad T-cell receptor repertoire, completed June 2019 and Forkhead Box N1 conferring effective immune responses. Isolated thymocytes Note(s): FDA declined to approve (FOXN1) deficiency are cultured in a manufacturing facility for 14 to 21 days. In RVT-802 because of clinical trials, RVT-802 is given by placing a cultured thymus manufacturing concerns on slice into a small hole in the quadriceps muscle, which is December 5, 2019; but on then pulled over the slice using an insoluble stitch. The dose December 27, 2019, the original is 4 to 18 g/m2 of thymus tissue per patient body weight in developer completed a strategic kilograms. alliance with Sumitomo Developer(s): Dainippon that might help Sumitovant Biopharma, Ltd (London, United Kingdom), a address the manufacturing subsidiary of Sumitomo Dainippon Pharma Co (Osaka, concerns Japan)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 4 years Sarizotan is a full serotonin 1A (5-HT1A) receptor agonist and Supportive care (eg, Apnea incidence and FDA designation(s): Orphan Drug,
or older and adults who a dopamine D2 receptor-like agonist/partial agonist being anticonvulsants; severity Rare Pediatric Disease have Rett syndrome developed to treat breathing dysfunction (eg, apnea [halted assistive devices; Hyperventilation Clinical trial(s): Phase II/III STARS and breathing breathing], hyperventilation) in patients with Rett syndrome. noninvasive ventilation; incidence and severity primary completion April 2019 dysfunction A rare, postnatal, progressive neurologic disorder, Rett nutritional support; Quality of life syndrome is caused by a mutation in the methyl CpG oxygen treatment; binding protein 2 gene, MECP2. Located on the X physical, occupational, chromosome, MECP2 encodes the MeCP2 protein that and speech/language normally mediates gene expression in neuronal and glial therapy) cells. Loss of MeCP2 function results in nerve cell dysfunction, which is thought to be reversible. Patients with Rett syndrome typically develop normally until 6 to 18 months of life but then experience developmental delays and regression of previously learned motor and verbal skills. The disease eventually causes additional symptoms, such as repeated hand movements, impaired gait, slowed head growth, breathing dysfunction, and seizures. Symptom severity varies by patient and depends on the individual’s specific MECP2 mutation and the amount of mutant MeCP2 protein expression. In patients with Rett syndrome who are experiencing breathing dysfunction, sarizotan purportedly stimulates serotonin activity in the brain, which is intended to restore breathing rhythm and decrease apnea and hyperventilation incidence or severity. In clinical trials, patients receive sarizotan orally at a dose of 2 to 10 mg (depending on age and weight), twice daily for 24 weeks. Developer(s): Newron Pharmaceuticals SpA (Milan, Italy)
SECTION 5. RARE DISEASES 195
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 75 Seladelpar (MBX-8025) is an orally administered peroxisome Obeticholic acid Overall survival FDA designation(s): Orphan Drug, years with a diagnosis proliferator-activated receptor delta (PPARδ) agonist in Rate of progression to Breakthrough Therapy of primary biliary development for treating PBC. An autoimmune disease, PBC liver failure Clinical trial(s): Phase III cholangitis (PBC) who damages the liver’s bile ducts, causing bile to accumulate in Symptom relief (eg, ENHANCE primary completion had an inadequate the liver and leading to irreversible liver scarring and diarrhea due to fat December 2020; phase II/III response to potential liver failure. Seladelpar is intended to provide a malabsorption, fatigue, primary completion December ursodeoxycholic acid safer alternative to obeticholic acid (Ocaliva) for treating PBC itching) 2020; phase II primary (UDCA) treatment or in patients for whom initial therapy with UDCA is inadequate Quality of life completion July 2019, preliminary were intolerant to UDCA or who cannot tolerate it. Seladelpar purportedly has data presented May 2019 treatment anticholestatic and anti-inflammatory effects that might Note(s): CymaBay Therapeutics reduce itching (ie, pruritus), inflammation, and destruction suspended clinical trials and of the intrahepatic bile ducts. In a phase III clinical trial, halted seladelpar development seladelpar is administered as a 5 or 10 mg tablet, once daily, after identifying abnormal liver for 52 weeks. findings in some trials Developer(s): CymaBay Therapeutics (Newark, California)
Children aged 8 years Sepofarsen (QR-110) is a first-in-class investigational RNA- Supportive care Visual acuity FDA designation(s): Orphan Drug, or older and adults who based oligonucleotide that targets homozygous or Mobility course Fast Track, Rare Pediatric Disease have Leber congenital compound heterozygous mutations due to aberrant splicing Full-field light sensitivity Clinical trial(s): Phase II/III amaurosis 10 (LCA10) of centrosome protein 290 (CEP290) protein messenger RNA Quality of life ILLUMINATE primary completion (mRNA). This aberration causes LCA10, the leading genetic December 2020 cause of childhood blindness. Sepofarsen is intended to restore 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 (ie, wild-type) CEP290 protein production and reversing LCA10 disease symptoms. In clinical trials, sepofarsen is given through injections into the eye at doses of 40 μg (with an 80-μg loading dose) or 80 μg (with a 160-μg loading dose) at the start of the trial, at 3 months, and every 6 months thereafter. Developer(s): ProQR Therapeutics (Leiden, the Netherlands)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 4 to 17 SGT-001 is an adeno-associated viral vector (AAV9) Corticosteroids (eg, Microdystrophin FDA designation(s): Orphan Drug, years who have containing a synthetic dystrophin gene, DMD, intended to deflazacort, prednisone) protein production Rare Pediatric Disease, Fast Track genetically confirmed treat DMD, an inherited, X chromosome–linked genetic Clinical trial(s): Phase I/II IGNITE Duchenne muscular disorder caused by rearrangements or deletions in the DMD DMD primary completion March dystrophy (DMD), are gene. DMD encodes the dystrophin protein, which helps 2020 (suspended), preliminary on a stable dose of keep muscle cells intact. The absence of wild-type data reported February 2019 corticosteroids, and dystrophin protein causes progressive muscle fiber death Note(s): FDA placed a clinical have levels of anti-AAV9 and eventual widespread muscle weakness. No cure exists hold on the IGNITE DMD trial in antibodies below a for DMD. First-line corticosteroid treatment manages November 2019 specified threshold symptoms but does not prevent disease progression and has significant side effects. FDA approved 2 gene therapies for patients who have a specific mutation in DMD (ie, in exon 51 or exon 53), but patients who have other DMD mutations are ineligible for these therapies. Therefore, additional therapies are needed. The synthetic DMD gene in SGT-001 encodes for microdystrophin, a truncated but functional protein surrogate for dystrophin, because the large size of the dystrophin protein prohibits delivery by viral vectors. In patients with DMD, SGT-001 treatment might restore skeletal muscle function and prevent or delay disease progression, independent of the patient’s mutation status. In clinical trials, SGT-001 is given intravenously at 1 of 3 unspecified doses, once. Developer(s): Solid Biosciences, Inc (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 4 to 15 SRP-9003, formerly known as MYO-101, is a recombinant, Exercise 100-meter timed walk FDA designation(s): Orphan Drug, years who have adeno-associated viral vector carrying the human Physical therapy test Rare Pediatric Disease genetically confirmed, sarcoglycan beta gene, SGCB. It is intended to treat LGMD2E Supportive care Mobility Clinical trial(s): Phase I/II IRB17- early symptomatic limb- (also called β-sarcoglycanopathy), a progressive inherited Muscle strength 00253 primary completion girdle muscular neuromuscular disorder caused by a mutation in SGCB. The Quality of life December 2020, interim data dystrophy type 2E gene normally encodes the protein β-sarcoglycan, which is reported October 2019 (LGMD2E) part of a complex involved in muscle function, regulation, and repair. Without β-sarcoglycan function, these patients develop weakness and atrophy of muscles connected to the limb girdles (ie, bony structures in the shoulder and pelvis). Early symptoms include difficulty running, jumping, and climbing stairs, but as the disease progresses, patients typically depend on wheelchairs and develop more severe symptoms, such as scoliosis, joint contractures, respiratory impairment, and heart problems. SRP-9003 purportedly restores β-sarcoglycan production in muscle cells to improve disease-related symptoms or to prevent symptoms from occurring before disease onset. In clinical trials, patients receive SRP-9003 intravenously at a dose of 5 × 1013 or 2 × 1014 vg/kg, once. Developer(s): Sarepta Therapeutics, Inc (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 18 years or Timrepigine emparvovec (BIIB111/AAV2-REP1) is an adeno- Low-vision aids (eg, Best corrected visual FDA designation(s): Orphan Drug, older who have associated virus serotype 2 (AAV2) vector that delivers a telescopic and acuity (BCVA) Regenerative Medicine Advanced genetically confirmed recombinant human CHM-associated gene. The gene magnifying lenses) Color vision Therapy choroideremia (CHM) encodes Rab escort protein 1 (REP1) inside the eye to treat Supportive care Contrast sensitivity Clinical trial(s): Phase III STAR choroideremia, a rare, degenerative, chromosome X–linked Retinal sensitivity primary completion November genetic retinal disorder primarily affecting males, for which 2020 no treatment is available. Timrepigine emparvovec is intended to introduce a functional choroideremia gene, CHM, designed to enhance expression of REP1. This is thought to reduce accumulation of waste products in retinal cells and slow or stop vision decline. REP1’s enhanced expression might also slow or reverse early stages of cell death in damaged retinal cells, possibly improving visual acuity in some patients. In clinical trials, timrepigine emparvovec was given by injection into the subretinal space, which is between the retina’s outer layers, at a low (1 × 1010) or high (1 × 1011) vector dose. Developer(s): Biogen (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 or older Tofersen (BIIB067) is an antisense oligonucleotide intended Edaravone Disability Clinical trial(s): Phase III primary who have amyotrophic to treat a variation in the SOD1 gene (in SOD1-ALS disease). Riluzole Disease progression completion July 2021; phase III lateral sclerosis (ALS) It does this by lowering the level of abnormal SOD1 protein Supportive care Functional capacity extension study primary and a confirmed that is thought to cause motor neuron death and contribute completion June 2023 Survival variation of the to ALS pathology. ALS is a rare and fatal neurodegenerative superoxide dismutase 1 disease in which the death of nerve cells (ie, neurons) in the gene, SOD1 brain and spinal cord leads to a loss of voluntary muscle function, wasting of muscle mass, and eventual death. While the exact cause is unknown, neuronal accumulation of abnormally formed proteins, such as variant SOD1, might contribute to the death of those cells. About 2% of patients with ALS have a SOD1 gene alteration, and it is the second most common genetic cause of ALS. Misfolded SOD1 proteins have been found in higher concentrations in the cerebrospinal fluid of patients with SOD1-ALS and are thought to contribute to SOD1-ALS pathology. FDA-approved drugs to treat the disease (eg, riluzole, edaravone) decrease symptom severity in some patients but do not prevent neuronal injury and ALS progression. Tofersen is an artificially created piece of DNA purported to bind to SOD1 mRNA and inhibit the production of SOD1 protein. In a phase I trial, tofersen was administered intrathecally (ie, into the spinal canal) during a 12-hour infusion at a dose of 0.15, 0.50, 1.5, or 3.0 mg, once. The dose in phase III trials has not been announced. Developer(s): Biogen, Inc (Cambridge, Massachusetts)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Females aged 5 years or Trofinetide (NNZ-2566) is a novel synthetic analogue of the Supportive care (eg, Symptom frequency FDA designation(s): Orphan Drug, older and adults aged amino‐terminal tripeptide of insulin-like growth factor 1 anticonvulsants; and severity, as Fast Track up to 45 years who (IGF-1) intended to treat Rett syndrome. A rare, postnatal, assistive devices; measured by accepted Clinical trial(s): Phase II Rett-001 have genetically progressive neurologic disorder, Rett syndrome is caused by noninvasive ventilation; clinical ratings and completed September 2014, data confirmed Rett a mutation in the methyl CpG binding protein 2 gene, nutritional support; scales published November 2017; syndrome MECP2. Located on the X chromosome, MECP2 encodes the oxygen treatment; Motor function, as phase II Rett-002 completed MeCP2 protein that normally mediates gene expression in physical, occupational, measured by accepted January 2017, data published neuronal and glial cells. Loss of MeCP2 function results in and speech/language clinical ratings and April 2019; phase III LAVENDER nerve cell dysfunction, which is thought to be reversible. therapy) scales primary completion September Patients with Rett syndrome develop normally until 6 to 18 2021 months of age and subsequently experience developmental delays and regression of previously learned motor and verbal skills. The disease eventually causes additional symptoms, such as repeated hand movements, impaired gait, slowed head growth, disordered breathing, and seizures. Symptom severity varies by patient and depends on the individual’s specific MECP2 mutation and the amount of mutant MeCP2 protein expression. No cure exists, and treatment generally consists of supportive care for managing symptoms. Trofinetide, because of its homology with the amino-terminal peptide tripeptide of IGF-1, which promotes neuronal and glial function, is intended to decrease symptom severity and disease progression in patients who have Rett syndrome. In clinical trials, patients receive trofinetide either orally or via a gastrostomy tube, at a dose of 35, 50, 70, 100, or 200 mg/kg, twice daily for 40 to 56 days. Developer(s): Acadia Pharmaceuticals, Inc (San Diego, California), in collaboration with Neuren Pharmaceuticals, Ltd (Camberwell, Australia) and Rettsyndrome.org (Cincinnati, Ohio)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 to 75 Troriluzole (BHV-4157) is a third-generation, tripeptide– Physical and Ataxia symptom Clinical trial(s): Phase III primary years who have prodrug conjugate of riluzole being developed for treating occupational therapy severity, as measured completion October 2020 genetically confirmed certain autosomal-dominant (ie, inherited) types of SCA. A Supportive care by accepted clinical spinocerebellar ataxia progressive neurodegenerative disease, SCA is generally Use of assistive devices ratings and scales (SCA) type 1, 2, 3, 6, 7, 8, characterized by loss of balance and motor coordination, Activities of daily living, or 10 abnormal speech, vision problems, and cognitive as measured by impairment. All autosomal-dominant forms of SCA are accepted clinical ratings caused by repeat expansions in genes normally involved in and scales neuron function, and disruption of these genes causes Daily functioning progressive neuronal damage. In patients with SCA or other capacity, as measured neurodegenerative disorders, such as amyotrophic lateral by accepted clinical sclerosis (ALS), damaged brain cells might be susceptible to ratings and scales further cellular injury mediated by overactivity of the Quality of life excitatory neurotransmitter glutamate. Another drug, riluzole (Rilutek), is a sodium channel blocker and glutamate modulator approved by FDA for treating ALS. It purportedly reduces glutamate-mediated excitotoxicity and nerve cell deterioration by promoting the neurotransmitter’s reuptake into nerve cells. Troriluzole purportedly has the same mechanism of action as riluzole but has improved bioavailability and tolerability, which could reduce adverse events typically associated with riluzole treatment (eg, fatigue, weakness, dizziness, hepatotoxicity). Troriluzole treatment might decrease glutamate-mediated neuronal damage and improve disease symptoms in patients with SCA. In clinical trials, patients take troriluzole orally, at a dose of 200 mg, once daily, for 48 weeks. Developer(s): Biohaven Pharmaceuticals, Inc (New Haven, Connecticut)
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Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Valoctocogene roxaparvovec (BMN 270), also known as Emicizumab Bleeding episodes Submission date: Biologics older who have valrox, is an adeno-associated virus vector gene therapy Factor VIII replacement Treatment-related License Application December hemophilia A and intended to cure hemophilia A. It is intended to eliminate or (human plasma–derived adverse events 23, 2019 residual factor VIII levels reduce the need for repeated treatments with factor VIII or recombinant, porcine Survival FDA designation(s): Orphan Drug, of 1 IU/dL or lower replacement or emicizumab. Valoctocogene roxaparvovec recombinant) Quality of life Breakthrough Therapy despite stable factor VIII purportedly delivers a functional copy of the gene encoding Clinical trial(s): Phase III primary replacement therapy for coagulation factor VIII to correct deficient factor VIII completion December 2022; levels inherent in hemophilia A. In clinical trials, the agent is phase III primary completion 13 13 given as an intravenous infusion at a dose of 1 × 4 to 1 × 6 December 2022; phase I/II vg/kg, once. primary completion February Developer(s): 2022, preliminary data published BioMarin Pharmaceutical, Inc (San Rafael, California) December 2017, long-term data published January 2020; phase I/II in patients with AAV5 antibodies primary completion June 2024
SECTION 5. RARE DISEASES 203
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 4 to 6 Vamorolone (VBP15) is a dissociative steroid (ie, a steroid Corticosteroids (eg, Muscle function, as FDA designation(s): Orphan Drug, years who have lacking gene transactivation activity) intended to treat DMD, deflazacort, prednisone) measured by Time to Fast Track genetically confirmed an inherited, X chromosome–linked genetic disorder caused Stand Test Clinical trial(s): Pivotal phase II Duchenne muscular by mutations or deletions in the dystrophin gene, DMD. DMD Ambulatory function, as VBP15-004 primary completion dystrophy (DMD) encodes the dystrophin protein, which helps keep muscle measured by accepted May 2020; phase II VBP15-003 cells intact. The absence of wild-type dystrophin protein clinical ratings or scales extension completed April 2018, causes progressive muscle fiber death and eventual (eg, time to data published August 2019; widespread muscle weakness. No cure exists for DMD, and run/walk/climb, 6- phase II VBP15-002 completed while FDA approved 2 dystrophin-replacement gene minute walk test, North May 2018, data published August therapies for patients who have a specific mutation in DMD Star Ambulatory 2019; phase II VBP15-LTE (eg, in exon 51 or exon 53), patients with other mutations Assessment) primary completion April 2020, are ineligible for these therapies. First-line corticosteroid data presented October 2019 treatment (eg, deflazacort) decreases inflammation but does not prevent disease progression. Corticosteroids typically cause severe side effects, such as hyperglycemia, muscle breakdown, and impaired hormone production. These side effects result from increased gene transactivation that is distinct from corticosteroids’ anti-inflammatory properties. Because dissociative steroids, such as vamorolone, purportedly lack gene transactivation activity while retaining anti-inflammatory function, they might have improved safety profiles versus typical corticosteroids. In clinical trials, patients receive vamorolone orally, 2 or 6 mg/kg/day, for up to 48 weeks. Developer(s): ReveraGen BioPharma, Inc (Rockville, Maryland), in collaboration with US National Institutes of Health (Bethesda, Maryland), US Department of Defense (Washington, DC), and European Commission’s Horizon 2020 program (Brussels, Belgium)
SECTION 5. RARE DISEASES 204
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Males aged 4 to 10 Viltolarsen (NS-065/NCNP-01) is a morpholino antisense Corticosteroids (eg, Muscle strength PDUFA date: Third quarter of years who have oligonucleotide intended to treat DMD, an inherited, X deflazacort, prednisone) 6-minute walk test 2020; Priority Review Duchenne muscular chromosome–linked genetic disorder caused by mutations Golodirsen distance FDA designation(s): Orphan Drug, dystrophy (DMD) with a or deletions in the dystrophin gene, DMD. DMD encodes the Time to climb 4 stairs Fast Track, Rare Pediatric Disease deletion in the DMD dystrophin protein, which helps keep muscle cells intact. The Time to run/walk 10 Clinical trial(s): Phase II study gene involving exon 53 absence of wild-type dystrophin protein causes progressive meters completed April 2018, data and are on a stable muscle fiber death and eventual widespread muscle Time to stand presented June 2018, data dose of corticosteroids weakness. No cure exists for DMD, and first-line presented October 2018, data Ambulatory function, as corticosteroid treatment (eg, deflazacort) manages presented October 2019; phase II measured by accepted symptoms but does not prevent disease progression and extension primary completion clinical ratings and has significant side effects. FDA approved 2 gene therapies December 2020; phase III scales for patients who have a specific mutation in DMD (ie, in exon primary completion November 51 or exon 53), but patients who have other DMD mutations 2024 are ineligible for these therapies. Therefore, additional therapies are needed. Viltolarsen purportedly binds exon 53 of dystrophin pre-mRNA (ie, precursor messenger RNA composed of introns and exons) and promotes skipping of exon 53 during mRNA processing, which allows for synthesis of an internally truncated but functional dystrophin protein. Therefore, viltolarsen treatment might promote skeletal muscle function and prevent or delay disease progression in patients who have mutations in DMD exon 53. In clinical trials, viltolarsen is given intravenously at a dose of 40 or 80 mg/kg, once weekly, for up to 144 weeks. Developer(s): NS Pharma, Inc (Paramus, New Jersey), a subsidiary of Nippon Shinyaku Co, Ltd (Kyoto, Japan), in collaboration with the Cooperative International Neuromuscular Research Group (CINRG; Washington, DC) and TRiNDS (Washington, DC)
SECTION 5. RARE DISEASES 205
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 5 to 17 Vosoritide (BMN 111) is a recombinant C-type natriuretic Human growth Health complications FDA designation(s): Orphan Drug years who have peptide analogue intended to treat achondroplasia by hormone Quality of life Clinical trial(s): Phase II achondroplasia promoting long-bone growth. Achondroplasia, the most Limb-lengthening completed October 2017; phase common form of human dwarfism, is a genetic disorder that surgery II primary completion October results in irregular bone growth, short stature, and serious 2022, height data reported health complications, including extra fluid in the brain and November 2019; unphased compression of the spinal cord. Less severe complications, primary completion October but nonetheless limiting, include bowed legs, recurrent ear 2024; pooled phase II data infections, and sleep apnea. Vosoritide might lessen published July 2019; phase III achondroplasia’s health impacts by allowing normal completed October 2019, data conversion of cartilage into bone at growth plates as a child reported December 2019; phase ages. Achondroplasia results from a defect in the fibroblast III primary completion October growth factor receptor 3 gene, FGFR3, which promotes 2024 overactivity of negative regulators of bone growth. Note(s): BioMarin Pharmaceutical Vosoritide purportedly interrupts intracellular pathways that plans to meet with health contribute to the overactivity. In clinical trials, vosoritide is authorities in the first half of given as a daily injection under the skin at a dose of 15 2020 to discuss plans for mg/kg daily. submitting a marketing Developer(s): application BioMarin Pharmaceutical, Inc (Novato, California)
SECTION 5. RARE DISEASES 206
Potential Patient Intervention Description Potential Patient-oriented Regulatory Information Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 12 years Voxelotor (Oxbryta; previous name GBT440) is intended as a Blood transfusions Opioid use for pain Approval date: November 25, or older and adults who disease-modifying agent to treat SCD. Some other recently Crizanlizumab-tmca (ie, management 2019 have sickle cell disease developed drugs may target the root cause of SCD, but they Adakveo) Frequency of VOCs FDA designation(s): Orphan Drug, (SCD) do not work in all patients and have side effects that many Hematopoietic (blood Number of blood Rare Pediatric Disease, patients cannot tolerate. In SCD, sickled red blood cells are cell–generating) stem transfusions required Breakthrough Therapy, Fast more susceptible to oxidative damage, inappropriate cell transplantation Hospitalized days Track, Priority Review clumping, and vessel blockage, leading to vaso-occlusive Hydroxyurea Quality of life Clinical trial(s): Phase III GBT crises (VOCs) that cause severe pain, requiring HOPE completed October 2019, hospitalization. Voxelotor purportedly binds mutated Pharmaceutical-grade L- glutamine (ie, Endari) pivotal data published August hemoglobin and prevents it from sickling and aggregating, 2019, post hoc data reported increasing native hemoglobin’s affinity for oxygen. Because November 2019; phase III oxygenated sickle hemoglobin does not polymerize, extension primary completion voxelotor purportedly reduces polymerization and the December 2019 resultant sickling and destruction of red blood cells. With the potential to improve hemolytic anemia and oxygen delivery, voxelotor might modify the underlying SCD disease process rather than merely decrease disease symptoms. The FDA- approved label for Oxbryta states that the drug is intended to treat SCD, based on an increase in hemoglobin, and is taken as oral tablets at a recommended dose of 1500 mg (three 500-mg tablets), once daily, with or without food. Developer(s): Global Blood Therapeutics, Inc (South San Francisco, California)
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Table 5.13. Rare Disease Topics Archived Since Last Status Report: 4 Topics
Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Male children younger AT132 is an adeno-associated virus vector that delivers a Supportive care Children’s Hospital of The primary completion than 5 years of age who functional copy of the myotubularin gene, MTM1, to treat X- Philadelphia Infant Test date for the phase I/II have chromosome X– linked myotubular myopathy. An ultra-rare, severe, debilitating of Neuromuscular ASPIRO trial of AT132 has linked myotubular condition, X-linked myotubular myopathy is caused by an MTM1 Disorders (CHOP been extended to March myopathy genetic variant that leads to muscle weakness and affects INTEND) 2024, thereby moving the children as early as birth. The gene makes a phosphatase Motor function intervention out of the enzyme thought to be involved in the development and Respiratory function time scope for the PCORI maintenance of muscle cells throughout the body. No cure Health Care Horizon Ventilator (ie, breathing) exists for the disease, and AT132 is intended to increase levels Scanning System. The support of functional myotubularin and thereby reduce symptoms. In time scope is defined as clinical trials, AT132 is given intravenously at a dose of 1 × 1014, Survival 3 years before an 3 × 1014, or 5 × 1014 vg/kg, once. Quality of life intervention becomes Developer(s): clinically available outside Audentes Therapeutics, Inc (San Francisco, California) of the research setting to 1 year after an intervention becomes clinically available.
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Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Adults aged 18 years or Caplacizumab-yhdp (Cablivi) is a highly potent and selective Antiplatelet therapy Disease recurrence Caplacizumab-yhdp older who have acquired bivalent antibody fragment targeting von Willebrand factor and Corticosteroids Major thromboembolic (Cablivi) received FDA thrombotic designed to treat aTTP. This condition develops when the Cyclosporine A events approval on February 6, thrombocytopenic spleen produces antibodies against ADAMTS13 (ie, von 2019. Because it has Daily plasmapheresis (ie, Survival purpura (aTTP) Willebrand factor–cleaving protease), an enzyme involved in been clinically available plasma exchange) Quality of life blood clotting. Caplacizumab purportedly inhibits the for more than 1 year, it is interaction between von Willebrand factor and platelets by Rituximab no longer within the time targeting the von Willebrand factor A1 domain, potentially Splenectomy (to scope for the PCORI blocking platelet interactions mediated by ultra-large von eliminate production of Health Care Horizon Willebrand factor and the formation of string-like blood clots. It antibodies to ADAMTS13) Scanning System. The is intended to reduce aTTP recurrence and its serious, life- Vincristine time scope is defined as threatening effects. The FDA-approved label for Cablivi states 3 years before an that the biologic is intended to treat aTTP in combination with intervention becomes plasma exchange and immunosuppressive therapy. The clinically available outside recommended first dose is an 11-mg bolus intravenous of the research setting to injection at least 15 minutes before plasma exchange, with an 1 year after an 11-mg subcutaneous injection after completing plasma intervention becomes exchange, continued daily for 30 days after the last plasma clinically available. exchange. If aTTP’s signs persist after the initial treatment course (eg, suppressed ADAMTS13 activity), caplacizumab-yhdp treatment may be extended another 28 days. Developer(s): Ablynx NV (Ghent, Belgium), a Sanofi (Paris, France) company
SECTION 5. RARE DISEASES 209
Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Infants aged up to 24 MB-107 is a bone marrow–derived gene therapy product HSC transplantation Immune reconstitution Both ongoing trials months with X-linked intended for SCID-X1. A rare, life-threatening disorder, SCID-X1 Supportive care Serious infection rate (phase I/II primary severe combined is caused by mutations in the interleukin-2 receptor 2 gene, IL- (including intravenous from baseline completion December immunodeficiency 2R. This gene encodes the common γ-chain, which is shared by immunoglobulin) Hospitalizations from 2024 and phase I/II disease (SCID-X1) multiple cytokine (ie, immune system hormones) receptors and baseline LVXSCID-ND primary is necessary for the development, function, and replication of T completion August 2025) Survival cells, natural killer (NK) cells, and functional B cells. Standard are not expected to yield care involves hematopoietic stem cell (HSC) transplants from a data for more than 3 matched sibling donor, but matches are available for fewer years, thereby placing the than 20% of patients. Also, transplants from alternative donors intervention out of the have an increased risk of graft-versus-host disease and time scope for the PCORI incomplete immune reconstitution. Newborns not screened Health Care Horizon before symptoms appear are affected by severe opportunistic Scanning System. The infections due to immune deficiencies. MB-107 is intended to time scope is defined as restore immune function in SCID-X1 by inserting a working copy 3 years before an of the IL-2R gene into the DNA of a patient’s own blood- intervention becomes producing (ie, hematopoietic) stem cells. MB-107 is produced by clinically available outside harvesting HSCs from the patient and treating them with a of the research setting to lentivirus vector that stably inserts the IL-2R gene into the 1 year after an genome of the HSC. The cells are then expanded (ie, grown) in intervention becomes the laboratory and returned to the patient’s physician for clinically available. infusion. In clinical trials, MB-107 is given as a single intravenous infusion into the patient after nonmyeloablative (ie, 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)
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Potential Patient Intervention Description Potential Patient-oriented Reason for Archive Population Developer(s)/Manufacturer(s) Comparators Outcome Measures
Children aged 5 years or SB-913 is a gene-editing technology that uses an adenovirus Idursulfase IDS activity (clinical Phase I/II results failed to older and adults who vector to modify liver cells with zinc finger endonucleases. laboratory measurement) provide evidence that SB- have Hunter syndrome These endonucleases insert a functional copy of the iduronate- change from baseline 913 would have a (also called 2-sulfatase gene, IDS, into a precise location in the patient’s DNA Urine GAG levels (in ratio beneficial effect on mucopolysaccharidosis to treat Hunter syndrome. A childhood-onset, progressive, to creatinine) change patient-oriented type II [MPSII]) inherited metabolic disorder, Hunter syndrome is caused by a from baseline outcomes, suggesting mutation in IDS. IDS encodes a lysosomal enzyme of the same Frequency of idursulfase that SB-913 is unlikely to name that metabolizes glycosaminoglycans (GAGs) and administration change cause disruption. prevents their accumulation, toxicity, and widespread tissue from baseline and organ damage. No cure exists for Hunter syndrome, and the 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 containing 5 × 1013 vg/kg, and containing each of the 3 components of SB-913: zinc finger nuclease 1 (ZFN1), zinc finger nuclease 2 (ZFN2), and human iduronate-2- sulfatase (hIDS) donor gene. Developer(s): Sangamo Therapeutics (Richmond, California)
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Section 6. Potentially Disruptive Trends: 28 Trends
Table 6.14. Trends Added Since Last Status Report: 6 Trends
Title Description Threats Opportunities
Artificial intelligence (AI) Cardiac ultrasound (ie, echocardiography) is widely used to diagnose heart Might increase health Might improve outcomes by operator guidance for cardiac conditions. However, the diagnostic quality of echocardiograms is highly information technology costs making diagnostic-quality ultrasound scans dependent on the operator’s ultrasound skills. New AI algorithms have been and complexity echocardiograms available to developed that purportedly allow less-experienced operators to perform Might elevate data security more patients in lower- diagnostic-quality echocardiograms through real-time feedback that risks through increased resource areas simulates guidance in probe positioning and image capturing from an automation Might allow earlier detection of experienced sonographer. The first AI-assisted echocardiography operator Might increase workload of heart conditions that could be guidance system, Caption Guidance, received FDA De Novo marketing cardiologists and demand for effectively managed authorization on February 7, 2020. follow-up testing if high volumes of patients are referred from primary care practices
Artificial intelligence (AI)– Traditional analysis of brain tumor samples during neurosurgery requires at Might be costly to implement Might improve outcomes augmented pathology to least 30 minutes, increasing risks to patients and raising procedural costs. Might require additional through improved detection improve brain cancer This application of AI combines optical imaging and a deep convolutional information technology and classification of tumor diagnosis network to analyze digitized images of brain tumor samples to detect and infrastructure to digitize all samples in real time classify cancerous cells in the operating room in about 3 minutes. The pathology specimens Might help alleviate shortage technique uses a fiber-laser microscope to perform stimulated Raman Might increase disparities in of specialist pathologists scattering microscopy to allow sample analysis without conventional slicing improved care at centers Might facilitate personalized and staining in a pathology lab. An AI algorithm automatically classifies the without this technology cancer care by more complete brain tumor subtype, purportedly with 90% accuracy, giving surgeons specimen analysis additional near–real time information about how to proceed. Neuropathologists can review digital images to confirm AI-assisted sample analysis, potentially remotely if not available on site. AI algorithms purportedly can also increase their proficiency by learning from larger sample volumes over time. AI-assisted intraoperative analysis of brain tumors can purportedly be readily expanded to other tumor types.
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Title Description Threats Opportunities
Artificial intelligence (AI)–based Immersive AI virtual reality (AI-VR) is being developed for use anywhere in Might pose threats to data Might provide customizable virtual reality therapy model health care, including to improve patient experiences, evaluate treatment privacy if hackers gain access sessions, so patients can options, and inform treatment of various conditions, including to patients’ full-body digital progress at their own pace, posttraumatic stress disorder, anxiety, and hot flashes, as well as many tracking data while providing real-time other disorders. Several immersive AI-VR algorithms have been designed to Might increase disparities if analytics for clinicians adapt to the patient’s progress in sessions and to be used every day to insurance does not cover the Might provide a cost-effective, improve patients’ physical and psychological symptoms related to their cost of the VR treatment nonpharmacological therapy specific condition. model Might improve patient health outcomes and reduce burden for health care providers
Cannabidiol to treat brain- Cannabidiol (CBD) is a cannabinoid found in cannabis. While its exact Might pose health risks to Might improve patient health related diseases and mechanism of action is unknown, its binding to endocannabinoid receptors patients until more is known outcomes by providing a new symptoms in the brain produces sensations of calmness, relaxation, improved mood, regarding its mechanism of treatment class and paradigm reduced pain, and sleepiness. CBD has been registered in more than 200 action, safety, and efficacy Might improve understanding clinical trials to treat a variety of brain-related diseases and symptoms, of brain-related disease including anxiety, depression, substance use, posttraumatic stress disorder, pathology pain, spasms, and seizures. FDA approved the first and, so far only, CBD- containing drug in June 2018 to treat seizures associated with 2 rare forms of epilepsy: Dravet syndrome and Lennox-Gastaut syndrome.
Section 6. Potentially Disruptive Trends 213
Title Description Threats Opportunities
Immuno-positron emission Immuno-PET imaging is a noninvasive clinical tool that measures the uptake Might increase costs Might improve patient tomography (PET) to predict of radiolabeled monoclonal antibodies to predict their toxicity in normal associated with equipment, outcomes and quality of life by response to cancer-specific tissues and efficacy in tumors. The most common isotopes for labeling personnel, and radiolabeling helping optimize the selection therapeutic monoclonal monoclonal antibodies used in immuno-PET include 89-Zr, 124-I, 64-Cu, and Might have limited access and dosage of therapeutic antibodies 86-Y. In cancer cells, the uptake of a therapeutic monoclonal antibody (eg, because immuno-PET may be monoclonal antibodies atezolizumab, cetuximab, trastuzumab) is associated with the expression unavailable at most infusion Might decrease off-target levels of its target biomarker (eg, programmed death-ligand 1 [PD-L1], centers adverse events epidermal growth factor receptor [EGFR], human epidermal growth factor Might be a process that takes Might determine noninvasively receptor 2 [HER2]). However, therapeutic monoclonal antibodies also longer than normal and delays the patient’s biomarker status, accumulate in normal tissues that express the biomarker, which may lead to treatment for patients which could reduce the off-target toxicity. Immuno-PET imaging purportedly allows clinicians to number of biopsies measure noninvasively and at a whole-body level the distribution, tumor targeting, and accumulation of radiolabeled monoclonal antibodies in patients. Immuno-PET has the potential to improve patient outcomes by guiding selection and dosage of therapeutic monoclonal antibodies and helping in the design of clinical trials of novel monoclonal antibodies. Compared with immunohistochemistry, which shows a biomarker’s expression in a biopsy at a single time point, immuno-PET also has the potential to assess the biomarker expression status of patients over time and throughout the body.
Section 6. Potentially Disruptive Trends 214
Title Description Threats Opportunities
Telehealth to treat mental Telehealth, the use of digital communication modalities to provide health Might pose risks to patient Might improve individual and health conditions care, is being increasingly harnessed to provide psychiatric assessments and confidentiality if population health outcomes treatment to patients to help address access-to-care issues. A 2017 report communications are not by allowing patients quicker, found that 77% of US counties reported a severe shortage of psychiatrists. secure more convenient, and wider Recent estimates of health care provider-to-patient ratios reveal an Might pose risks to patient access to mental health care increasing scarcity of mental health resources, especially in rural areas. safety if health care providers and by allowing patients to Telehealth aims to help narrow the gap by improving patient access to aren’t as readily able as during pick providers who are best providers and helping patients receive mental health care faster and more face-to-face visits to collect suited for them conveniently, because communication takes place online. Telehealth crucial information such as Might reduce health care costs psychiatry is increasingly being used to treat behavioral health conditions vital signs for medical decision by reducing the amount of including anxiety, depression, attention-deficit/hyperactivity disorder, and making time patients are away from substance use disorders. Might be difficult to treat work, reducing money spent patients with serious health traveling to appointments, and issues like active suicidal reducing overall treatment ideation or alcohol withdrawal time from a distance, especially if providers are unfamiliar with local inpatient facilities and mental health resources Might impede a health care provider from establishing patient rapport as readily (compared with in-person visits), and providers might not understand a patient’s geographical and/or psychosocial context as well
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Table 6.15. Currently Monitored Trends: 22 Trends
Title Description Threats Opportunities
Aging treated as a disease Drugs considered to have antiaging properties can be prescribed off label Might stigmatize large Might promote research into for aging but are not covered by insurance because aging is not considered segments of the population aging-related conditions (eg, a disease. However, a new research paradigm advocates classifying aging as based on their age Alzheimer’s disease, cancer, a disease instead of the natural consequence of growing older. Some Might threaten ethical diabetes, heart disease, stroke) researchers hope to shift popular notions of aging toward a disease-based boundaries regarding how and lead to downstream model and promote antiaging therapies as a solution to the problem. Some blood and stem cell products benefits for many patients of argue that most serious diseases today are a function of aging, and they for transfusions from younger all ages think that research into these mechanisms will uncover effective antiaging people are obtained and used Might lead to downstream therapies that will improve the independence, quality of life, and Might increase disparities increases in overall life span of productivity of older people, while decreasing burden to health care and because of the high cost of patients by encouraging social systems. Antiaging treatments under investigation include metformin, antiaging therapies research into antiaging rapamycin, resveratrol, and nicotinamide, as well as blood or stem cell therapies transfusions from young people. Researchers in Singapore are purportedly examining between 10 and 15 antiaging agents.
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 scans to imaging (MRI), computed tomography (CT), or ultrasound scans from detection errors, to false- earlier stages, thereby screen for cancer or confirm a patients suspected of having cancer and generates a probability-of- negative or false-positive enabling earlier treatment and cancer diagnosis malignancy score. A standard risk score that could be used, for example, is reports that could have health potentially improving patient the Breast Imaging Reporting and Data System (BI-RADS). The machine and/or legal implications health outcomes learning AI software (eg, convolutional neural networks) is used with Might lead to overdiagnosis (ie, Might reduce human error conventional picture archiving and communications systems to learn the a true-positive diagnosis with rates in cancer detection and features of malignancy and point out problematic areas in images. This AI little or no health diagnosis software is intended to improve radiologists’ ability to detect abnormal consequences that could lead lumps and nodules and to help determine whether they are dangerous. It to unnecessary treatment or does this by scanning all dimension slices at once, homing in on regions of undue negative psychological interest, and providing a cancer risk score. impact on the patient) Might be viewed by some radiologists as a threat to their autonomy as clinicians
Section 6. Potentially Disruptive Trends 216
Title Description Threats Opportunities
Artificial intelligence (AI) and Recent reports show potential for AI and ML to detect or diagnose mental Might lead, due to algorithmic Might enable more objective, machine learning (ML) for and behavioral health conditions, including depression, posttraumatic stress detection errors, to inaccurate biologically grounded biologically based diagnosis of disorder (PTSD), schizophrenia, and bipolar disorder. Data analysis diagnoses that could have diagnoses of some mental and mental and behavioral health techniques and ML algorithms can be used to match specific brain patterns, health and/or legal behavioral health conditions conditions behavior, and genetic factors, allowing for biologically based, individualized implications compared with traditional prediction and diagnosis of mental and behavioral health disorders. Might be more costly in the methods of diagnosis short term than traditional Might reduce the stigma methods of diagnosis associated with mental illness Might be viewed by some by supporting a biological clinicians and therapists as a basis for some mental and threat to their autonomy behavioral health conditions Might lead to earlier treatment Might reduce or eliminate the trial-and-error nature of current diagnosis methods Might be more cost effective in the long term than traditional methods of diagnosis
Artificial intelligence (AI) for Several researchers and companies have each developed AI software Might be limited to larger Might improve patient health image triage to prioritize algorithms to screen imaging scans in high volumes in hospital emergency imaging centers with more outcomes if most-acute cases emergency cases departments or other urgent care settings. The intent is to identify the most resources because of the cost receive appropriate care serious cases that might not be apparent with traditionally recognized and complexity of screening sooner parameters or markers and suggest giving them priority review by a systems Might improve workflow to radiologist. The AI algorithm pushes these cases to the front of the work Might be difficult to prioritize higher-urgency cases queue based on identified markers learned by reviewing a multitude of operationalize or maintain when radiologist availability is images. Over time, some algorithms purportedly become more accurate at because many software limited screening as they review more images. Some products have already systems need to work together Might add a layer of protection received FDA 510(k) clearance for specific indications using conventional x- Might pose litigation risk for against potential litigation for rays, computed tomography (CT), and ultrasound, including identification of providers who are unable to missed events or cases in probable fractures in the cervical spine, intracranial hemorrhage, abdominal implement these systems imaging aortic tears, and 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) Approximately 50% of people with advanced (stage IV) chronic kidney Might lead some health care Might provide an actionable systems for early detection of disease are unaware of their level of kidney function impairment. This can professionals to rely too much early warning to clinicians of acute kidney injury (AKI) risk in lead to rapid progression to kidney failure and a need for dialysis in the on an AI system for patient imminent declining kidney high-risk patients emergency department, involve immediate consultation with a nephrologist, monitoring and use less of function and have generally poor outcomes. Researchers are developing AI-enabled their own clinical faculties Might improve disease diagnostics intended to monitor patients at high risk of developing AKI to Might contribute to clinicians’ management and patient provide early warning alerts to a clinician about a patient’s deteriorating alert fatigue from all of the outcomes condition. For example, DeepMind AI, in collaboration with the US clinical care tools intended to Might substantially reduce Department of Veterans Affairs, is developing AI that evaluates data from protect patients and alert clinical and financial burdens the electronic medical record (EMR) that purportedly predicts AKI in patients clinicians about potential to patients and the health care up to 48 hours earlier than current diagnostic approaches. They are harms system if these systems can designing the system to provide clinicians with a warning through an app provide early warning of AKI called Streams App. This notification indicates that a patient is a candidate that enables early intervention for earlier and more-intensive preventive treatment to avoid more-invasive and averts kidney damage procedures like dialysis. In addition, KidneyIntelX (RenalytixAI plc) is in development for evaluating the long-term risk of AKI in patients with type 2 diabetes mellitus (T2DM). KidneyIntelX purportedly identifies patients with T2DM and fast-progressing kidney disease by using machine learning (ML) algorithms that assess a combination of predictive blood-based biomarkers in combination with EMR information to identify patients at high risk of kidney disease progression.
Artificial intelligence (AI) to Researchers around the world are pursuing use of AI to develop precision Might raise patient privacy Might improve outcomes for identify personalized diagnostics and prognostic modeling to personalize treatment across the concerns TBI and reduce rehabilitative treatment options for complete TBI spectrum, from concussion to coma. For example, researchers Might create questions about care burden traumatic brain injury (TBI) from the Transforming Research and Clinical Knowledge in Traumatic Brain who owns the data Might improve quality of life Injury (TRACK-TBI) network are using machine learning (ML) to analyze a Might create controversy for patients with TBI complex data set, including imaging, blood tests, and in-person about publicly funded TBI Might inform research and assessments. These data, from 3000 patients in the TRACK-TBI study, are research that essentially treatment of other neurologic being used to identify patterns that eventually can be applied in a clinical subsidizes new proprietary TBI disorders, based on TBI setting to improve TBI outcomes. The researchers have developed a treatments marketed by research findings standardized approach to analyze imaging, clinical data, biomarkers, and private companies
treatment outcomes across research sites and will help lead clinical trials of TBI treatments in development by matching candidates to investigational interventions.
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Title Description Threats Opportunities
Artificial intelligence (AI) voice Digital voice assistants, or conversational agents, have grown into widely Might lead, due to inaccurate Might improve patient access assistants for patient-oriented used AI software programs designed to respond to natural language NLP, to providing patients with to care by providing health care applications processing (NLP) and simulate human conversation. These assistants are incorrect medical advice, convenient, 24-hour medical being positioned to provide patient health care support (eg, LifePod, thereby causing subsequent advice Nuance, Aiva Health). AI-powered virtual assistants can provide 24-hour adverse events Might improve patient health support to a wide range of patients who might need access to home care on Might pose threats to patient outcomes and reduce burden demand. For example, LifePod is designed to help people follow a care plan health data privacy for health care providers developed by their provider or to contact a caregiver. Another patient voice Might decrease costs of care assistant, Aiva, purportedly reduces the response time needed to connect by reducing doctor’s office with the caregiving team by triaging patient requests to the most visits appropriate caregiver.
Artificial intelligence (AI)– This application of AI uses machine learning (ML) and natural language Might not be covered by third- Might improve patient health enabled precision medicine for processing (NLP) to analyze electronic pathology (e-path) records, party payers for outcomes by analyzing large cancer prognosis and comprising personal and family history, clinical features, and genetic or genomic/proteomic profiling amounts of clinical, genomic, treatment decisions protein biomarkers. The intent is to manage patients’ cancer as follows: (1) or the targeted therapies if and proteomic data yielding Predict response to treatment; (2) evaluate whether subsequent treatment FDA has not approved the AI- recommendations that can might be beneficial; (3) guide targeted therapy selection (on or off label) for recommended therapies for help clinicians more quickly cancers harboring actionable genomic alterations (AGAs); and/or (4) help the cancers for which they identify targeted therapies enroll patients in clinical trials of investigational therapies. The AI algorithms were recommended and/or biomarkers likely to would need to be adapted to understand treatment paradigms for different Might increase disparities if benefit patients types of cancers. In addition, the algorithms would also need to learn to off-label therapies are Might reduce human error recognize and collect information for different e-path records, which can available only to patients who rates in cancer detection and have different formats and content. AI’s performance is compared with the have the resources to pay for diagnosis gold standard of clinicians manually reviewing e-path records. Clinicians treatments not covered by Might help identify novel then use this information to establish a management plan that is most likely their insurance prognostic markers that can to benefit patients with cancer. Might cause skepticism among be incorporated into prognosis some physicians about using assessment AI-generated treatment recommendations because of prior failed attempts in AI research to yield appropriate and reliable treatment recommendations
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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- Might lead to decreased bacterial infections treat bacterial infections. They were discovered more than a century ago term costs to infection patient illness and death but were not pursued as a treatment in the United States because of treatment Might add to the body of safety concerns and the increased availability of antibiotics. However, with Might pose a health risk for scientific knowledge increasing rates of antibiotic resistance and better understanding of patients because much is still surrounding infection and its bacteriophage biology, researchers are now considering using to be learned about treatment bacteriophages to treat infections that are multidrug-resistant or bacteriophage biology Might reduce long-term characteristically hard to treat with antibiotics. Bacteriophages are in Might eventually lead to treatment costs by reducing clinical trials to treat primary immune deficiency disease, hyper-IgM bacteriophage resistance the time patients spend in syndrome, urinary tract infections, gastrointestinal tract infections, similar to antibiotic resistance intensive care units diabetic foot ulcers, leg ulcers, wound infections, Pseudomonas aeruginosa infections, and Staphylococcus aureus infections. The Center for Innovative Phase Applications and Therapeutics (IPATH) treats patients who have life- threatening multidrug-resistant infections with bacteriophages on a case- by-case basis through FDA’s Compassionate Use program. IPATH intends to conduct phase I/II trials for chronic infections in cystic fibrosis and infections associated with implantable hardware such as pacemakers and prosthetic joints.
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Title Description Threats Opportunities
Complete omics monitoring: Complete omics monitoring is being marketed as a comprehensive wellness Might increase costs Might improve patient metabolomics, proteomics, package that includes whole genome sequencing, microbiome analyses, significantly for participants management options genomics, and transcriptomics metabolome analyses, and proteome analyses. Researchers are exploring and also for third-party Might enable clinicians to for disease prevention and complete omics monitoring as a way to screen for disease risk, detect payers that would need to more easily identify patients’ treatment diseases earlier, and identify effective treatment options for patients. The cover treatment of identified risks or early disease stages to approach is intended to improve early treatment, posttreatment, and diseases and conditions in pursue the best treatment progression monitoring of diseases such as cancers, neurodegenerative their beneficiaries options in a shorter time than diseases, and metabolic diseases. For example, Q Bio’s platform uses a 75- Might widen health disparities standard screening and minute patient evaluation visit and quarterly omics exams to gather all the further because those who diagnostic processes necessary data. The company integrates information gained from anatomic, could afford to pay for it (ie, it Might improve identification of genetic, biochemical, and biometric measurements for early health is unlikely to be covered by new drug targets and intervention and disease prevention. insurance) would have health development of effective information to inform their personalized medicines in the course of action that future individuals who could not afford wellness omics testing would not Might lead to overdiagnosis and overtreatment for health issues that could be clinically insignificant or that might resolve on their own; this might negatively impact the mental and behavioral health of participants
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Title Description Threats Opportunities
Comprehensive genomic CGP involves sequencing a large panel (ie, thousands) of cancer-associated Might lead to overtreatment Might improve health profiling (CGP) in patients who genes in DNA and/or RNA isolated from a patient’s tumor tissue or blood of some early-stage cancers outcomes for patients who have cancer to identify sample. CGP is intended to detect actionable genomic alterations (AGAs) that could resolve on their have limited targeted therapy personalized targeted therapy known to be therapeutic targets. Clinicians are using CGP (in both germline own options and somatic testing scenarios) to determine the aggressiveness and Might have limited availability Might strengthen inheritable factors of cancers upon initial diagnosis (germline testing; ie, in of insurance coverage collaborations between cells without cancer). It is used to select targeted therapies (on label or off because third-party payers genetic counselors and label) along the patient’s clinical pathway (somatic testing; ie, in cells with are likely to cover CGP and clinicians, promoting cancer) to benefit patients with cancers that harbor AGAs. CGP also is being targeted therapies for only familiarity with AGAs and used to help identify patients who are eligible for clinical trials of specific indications and are identifying those that might be investigational therapies for cancers with specific AGAs. unlikely to cover targeted drug targets therapies for unapproved indications Might increase disparities by being available only to patients who are insured or able to pay for treatment out of pocket
Direct-to-consumer (DTC) Laboratories that offer DTC genetic testing services are considering use of Might pose significant threats Might provide insight into the genetic testing partnerships patient-derived genetic data and volunteered genetic testing to patient health data privacy best targets to pursue for drug with pharmaceutical questionnaire data as a way to drive drug development and treatment. By Might lead to a competitive development companies to facilitate drug partnering with pharmaceutical companies, DTC genetic testing companies disadvantage for drug Might enable effective and development and treatment can provide large data sets that might provide insight into new disease developers that choose not to less-expensive identification of targets worth pursuing by drug companies. The databases from DTC partner with DTC genetic patients and asymptomatic testing might also make it easier for pharmaceutical companies to identify testing companies carriers for clinical trials people who have a disease, are asymptomatic, or are carriers for Might lead to a more efficient conditions of interest and recruit them for clinical trials in a cost-effective drug development process for manner. For instance, genetic testing company 23andMe has established personalized medicines collaborations with GlaxoSmithKline, and another genetic testing company, Nebula Genomics, is collaborating with EMD Serono to use consumer data to drive the drug development process.
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Title Description Threats Opportunities
Fecal microbiota FMT is the transfer of donor stool into the gastrointestinal (GI) tract of a Might pose health risks for Might improve patient health transplantation (FMT) to treat patient with the aim of repopulating a healthier GI tract microbiome. FMT patients from transmissible outcomes and quality of life as diseases associated with might change treatment paradigms and improve health outcomes for agents that could be contained a treatment option for many disturbances in the gut patients with various GI diseases and other diseases with GI involvement. in the donor stool GI, infectious, autoimmune, microbiome (ie, gut dysbiosis) FMT can be accomplished directly through colonoscopy or indirectly through Might pose legal risks for mental health, and other a nasal tube, oral feeding tube, enema, or capsule. The stool is sourced from donor banks if they can be health conditions volunteers believed to be healthy, who undergo a variety of formal, medical held liable for FMT-related Might improve understanding screening processes before donating. The stool is tested for various adverse events and health of the microbiome and its pathogens before being deemed safe for transplantation. FDA has not outcomes association with various approved FMT for any uses, although the agency allows its investigational Might significantly shift diseases and conditions use. The agency has issued guidance regarding donor screening and stool- paradigms of care and involve Might reduce use of other testing protections to avoid serious risks of infection transmission. Stool clinician learning curves and treatments, such as antibiotics banks such as OpenBiome work with clinicians to make FMT available and changes in treatment models, and biologics, which could help safer for use by screening donor stool, preparing the stool for implantation, infrastructure, and care stem antibiotic resistance and and freezing it until it is ready for use. One of the most common uses for settings, depending on the avert the risk of serious side FMT is in recurrent Clostridium difficile (C diff) infection. FMT has been found, disease or condition for which effects posed by those in randomized controlled clinical trials, to resolve 80% to 90% of infections it is used therapies caused by recurrent C diff that did not respond to antibiotics. Might be costly due to the increasing number of tests, processing, and storage required to ensure safety, and disparities in patient access to FMT might occur
Gene editing to treat or Clinical trials using gene editing technology are under way. These Might pose significant health Might improve quality of life prevent disease technologies hold great promise for treating and/or preventing several risks to patients because much for patients diseases and conditions. For example, CRISPR (clustered regularly is still unknown about Might reduce overall treatment interspaced short palindromic repeats) is a dynamic, versatile tool that can potential adverse events costs for patients and the be programmed to target specific stretches of genetic code and edit DNA at related to gene editing health care system by precise locations in the human genome. The technology allows researchers Might pose significant ethical providing a one-time, curative to permanently modify genes and has the potential to create therapies with and societal threats (eg, treatment option a durable treatment effect. unethical alteration of human Might reduce societal burden embryos) and health care costs by preventing and/or eliminating certain genetic disorders
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Title Description Threats Opportunities
Integrated electronic health Several products are available to collect physiologic data from Might generate further data Might improve outcomes if solutions to improve cardiovascular patients through wearables or smartphones and transfer security risks, as well as clinicians and patients can cardiovascular care the data to clinicians. Most products are limited in scope (eg, blood questions about who owns or interact in a timely manner pressure or electrocardiogram alone). Product availability and consumer controls the data and where to and adjust care as needed marketing has largely outpaced clinical research on the true clinical use of store it Might increase technical these technologies in cardiovascular care. Limited early data have Might increase clinical staff’s efficiencies compared with suggested some integrated digital health interventions introduced during workload significantly if the multiple separate systems that hospitalizations from heart attacks might reduce 30-day readmissions and additional patient data track blood pressure, heart related health care costs compared with historical controls. The American monitoring requirements are rate, weight, and related College of Cardiology (ACC) has issued a set of principles intended to guide substantial health statistics appropriate integration of eHealth or mobile health technologies into Might create system cardiovascular care. ACC calls for more research of digital health applied compatibility problems, to cardiovascular care to ensure patient safety, care quality, and positive potentially limiting usefulness health outcomes. ACC advises that these technologies should improve the for effective patient patient experience, care quality, patient safety, and outcomes without monitoring, depending on the hampering clinical workflow. technology and standards involved Might raise quality control concerns regarding device maintenance and data integrity Might raise concerns about who will pay for the technology upfront and for its continued maintenance and quality control Might increase disparities if the technology cost or complexity filters out poorer, older, or less technically minded patients
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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 Might provide insight into the patient-centered outcomes and might represent the optimal form of clinical evaluation for patient- being treated unethically by best use of precision centered medicine. Researchers design a mini-investigation for an manufacturers of poorly medicines, thereby improving experimental drug’s safety and efficacy entirely around an individual developed investigational health outcomes patient’s response, to determine whether a particular treatment works for agents with small budgets Might make patient-centered that individual. A patient might alternate between drug and placebo for a Might be viewed as a threat by comparative data more couple of weeks at a time, and researchers record the outcomes. These trial some stakeholders who accessible to patients and results can then be used to guide specific treatment for a patient or be benefit from large, population- physicians pooled with other N-of-1 trials of the same drug and same experimental based, randomized controlled design to obtain population-level trends. An advantage of data from N-of-1 trials and current data trials is that they can reveal how responses to treatments might vary among aggregation systems and within patients. N-of-1 trials are best used to evaluate treatments for chronic, slowly progressing conditions, or frequently recurring or relapsing diseases. The ideal treatments to test in N-of-1 trials would demonstrate substantial individual differences in treatment effects, uncertainty regarding the best treatment regimen, rapid onset of drug action, or brief and safe washout periods. N-of-1 trial outcomes should be validated, repeatable measures and might include the use of biomarkers.
Proteomic profiling to Proteomic profiling involves the systematic separation, identification, and Might add to clinician burden Might improve patient health diagnose cancer and guide characterization of proteins present in a patient’s tumor or blood sample. In by requiring them to learn outcomes by detecting cancer personalized targeted therapy patients suspected of having cancer, clinicians use proteomic profiling to about protein signatures for early and matching patients identify a cancer-associated protein signature that might confirm the different cancer types and with targeted therapies or presence and origin of a specific cancer type. For these patients, proteomic understand which could be clinical trials likely to benefit profiling helps identify overexpressed proteins that are known to be drug targets them therapeutic targets, such as those caused by chromosomal rearrangements. Might increase disparities by Clinicians then use this information to select a targeted therapy, on label or being available only to patients off label, that is most likely to benefit a patient with cancer or to help enroll who are insured or able to pay patients in clinical trials of investigational therapies. for treatment out of pocket
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Title Description Threats Opportunities
Psychedelic drugs to treat Psychedelic drugs (eg, psilocybin, lysergic acid diethylamide [LSD], N,N- Might result in negative health Might improve health mental and behavioral health dimethyltryptamine [DMT], 3,4-methylenedioxymethamphetamine [MDMA], outcomes for some patients outcomes and quality of life conditions ketamine) alter one’s state of consciousness, purportedly by altering certain and are therefore not for some patients neurotransmitters in the brain. Their use might provide the user with recommended for every Might also reduce the altered perception, increased introspection, feelings of closeness with patient prevalence of treatment- others, and positive mood states. These experiences are often reported as Might pose population health resistant mental health deeply profound and life-altering. Although most psychedelics are and legal risks related to conditions and reduce costs designated as Schedule I drugs in the United States, researchers are making controlled substances associated with long-term investigating their potential to treat a variety of mental and behavioral more accessible mental health treatment health disorders that have not responded to conventional treatments. The Might increase disparities in Might positively shift the Multidisciplinary Association for Psychedelic Studies was established in 1986 access to care if clinicians are paradigm and infrastructure of to research and provide education regarding potential therapeutic uses in hesitant to treat patients using mental health care mental health treatment. In September 2019, Johns Hopkins announced the controlled substances that Might encourage continued launch of its Center for Psychedelic and Consciousness Research to study carry stigma or a significant research into additional psychedelic drugs to treat certain mental health conditions. The number of risk of harm or mental potential therapeutic uses for clinical trials on the use of psychedelics for mental health conditions is deterioration psychedelic drugs and might increasing. Psilocybin is in clinical trials to investigate treatment for Might be costly in the short enhance understanding of depression, anorexia nervosa, obsessive-compulsive disorder, alcohol use term if significant costs are mental health conditions disorder, nicotine dependence, cocaine use disorder, and cancer-related associated with building anxiety. LSD is being explored to treat anxiety associated with life- necessary treatment threatening illness, other anxiety disorders, and depression. DMT, a drug infrastructure present in a psychoactive brew called ayahuasca, is being researched as a treatment for depression. MDMA is in phase III clinical trials for use during psychotherapy to treat posttraumatic stress disorder (PTSD) and is being investigated as therapy for social anxiety in adults with autism. Most of these psychedelic drugs are not intended for frequent or long-term use, and therapeutic effects have been reported with as few as 2 to 3 treatments (eg, MDMA-assisted psychotherapy for PTSD). Ketamine, while not traditionally considered a psychedelic drug, has some psychedelic properties and is being explored off label to treat PTSD. A closely related molecule, esketamine (Spravato), has been approved to treat depression.
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Title Description Threats Opportunities
Smart device applications to Mental health apps are intended to relieve symptoms associated with a Might decrease the likelihood Might decrease health care improve mental health variety of mental health conditions. They are available as part of curated that a patient seeks a disparities by providing more app libraries or because of consumer online searching. The apps offer diagnosis and appropriate patients with access to mental features including symptom tracking, self-monitoring, guided meditation, medical care plan health resources, especially if and talk therapy. Authors of a recent study seeking to evaluate quality Might compromise patient regional access to psychiatrists claims of mental health apps searched Android and iOS app stores and health outcomes if patients and psychologists is limited found 1435 apps for anxiety, depression, schizophrenia, self-harm, and rely solely on an app to self- Might improve patient substance abuse. Of the apps that met inclusion criteria of purporting to diagnose outcomes, augmenting be based on scientific principles (n = 73), approximately 67% claimed Might lead to breaches in existing treatment plans by effectiveness at diagnosing a mental health condition or improving personal health information, providing new and additional symptoms, mood, or self-management; 14% percent provided a which has legal and patient- support that can be accessed description that their development was based on lived experience; and centered ramifications outside of the health care only one app had a citation to published literature. FDA has not subjected Might be difficult to regulate setting any mental health apps to regulatory pathways to treat mental health and might require additional Might raise awareness of conditions. A recent meta-analysis and qualitative review suggests that infrastructure for that process mental health conditions and mental health apps might be useful adjunctive treatment for depression, reduce associated stigma noting potential benefits of increased patient access and decreased costs. Might enable patients who are More research is needed to determine the safety and efficacy of mental reluctant to reach out for or health apps and their appropriate clinical context. attend in-person therapy to get help, while preserving some discretion
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Title Description Threats Opportunities
Smartphone-guided medical An accurate diagnosis, when made in a timely manner, can provide the best Might pose security risks or Might decrease overall costs examinations and diagnostics insight into treatment options for patients. A recent telehealth and e-health expose patient health data related to both patient care for use by patients and case study highlighted a patient’s case in which acute appendicitis was inappropriately and care delivery by reducing caregivers diagnosed via telehealth, allowing timely surgery to take place. Smartphone Might, because of user or clinician’s office visits apps can deliver examinations and diagnostic services to patients in remote device errors, lead to Might reduce disparities in areas by boosting the use of smartphones as diagnostic devices for multiple misdiagnosis or mistreatment terms of access to care for age groups. These apps are accompanied by handheld examination kits that patients in rural areas allow patients or caregivers to perform guided medical examinations and Might increase patient share results with their provider for an appropriate diagnosis and treatment autonomy and satisfaction by options (eg, TytoCare [for ear infection, heart and lung sounds, throat involving patients and infection diagnosis], MoleScope [for skin screening], RetinaScope [for caregivers in the diagnostic diabetic eye disease screening]). process Might reduce burden on the health system, such as sequelae from overlooked symptoms for which patients did not have time or opportunity to seek in-person evaluation
Section 6. Potentially Disruptive Trends 228
Title Description Threats Opportunities
Tissue-of-originagnostic, Oncology drugs have traditionally been approved by FDA for cancers Might increase costs by Might provide a pathway to molecularly targeted oncology arising from specific tissues or organs (eg, breast, prostate, lung, blood). requiring more widespread FDA approval in instances of drugs With the increasing recognition that some genetic changes drive the testing of tumors using whole indications that might not be development of cancers arising across different organs or tissues, genome sequencing or very suited for traditional clinical investigators began defining patient populations in terms of their large gene panels upon initial trial designs molecular subtype. These observations were made in so-called basket diagnosis of a patient to Might create new collaboration trials or umbrella trials—the same clinical trial enrolled patients with identify all potential opportunities for laboratories cancers originating in different tissues or organs and researchers therapeutic targets and companies that offer observed a signal of efficacy for a molecular target of a drug across those Might involve a substantial whole genome and exome cancers. This led to expansion of cohorts or creation of tissue-of-origin- learning curve for providers sequencing specific trials with the intent that the manufacturer seek FDA drug Might lead to poor outcomes approval for that tissue of origin (eg, ALK inhibitors for non–small cell lung in certain patients with a cancer, BRAF inhibitors for melanoma or Erdheim Chester disease). molecular driver and tissue-of- However, FDA has recently approved 3 drugs for use in molecularly origin combination for which defined patient populations. Examples include pembrolizumab (Keytruda), the targeted therapy is which received approval to treat unresectable or metastatic, microsatellite ineffective instability-high, or mismatch repair–deficient solid tumors in adult and pediatric patients. Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) were approved to treat solid tumors that have a neurotrophic tyrosine receptor kinase gene fusion without a known acquired resistance mutation. This change in approach raises issues regarding clinical trial conduct to provide the supporting evidence for regulatory submissions. It also raises potential issues with the varied responses to molecularly targeted therapies across different cancer types, particularly for rare cancers or cancers in which a molecular target rarely occurs.
Wearable smart devices to Autism spectrum disorder is a developmental disorder defined by deficits in Might pose threats to patient Might provide a provide social support for social interaction and communication, including difficulty understanding health data privacy nonpharmacological treatment patients who have autism emotions and regulating behavior. Several wearable smart devices intended Might increase disparities by option for some patients spectrum disorder to improve social deficits in autism, such as a wrist-worn biosensor to being available only to those Might incentivize positive predict aggression and glasses equipped with facial recognition that deliver who can afford to pay for behaviors that will improve real-time social cues to improve socialization, are in development. these expensive devices health outcomes Might reduce caregiver burden and long-term costs of care Might increase patient independence
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Appendix. Abbreviations and Acronyms
AADC aromatic l-amino acid decarboxylase aHUS atypical hemolytic uremic syndrome AADCD aromatic l-amino acid decarboxylase deficiency AI artificial intelligence AAV ANCA-associated vasculitis AKI acute kidney injury AAV2 adeno-associated virus serotype 2 ALAS1 aminolevulinic acid synthase 1 AAV5 adeno-associated virus serotype 5 ALD adrenoleukodystrophy AAV9 adeno-associated virus serotype 9 ALDP adrenoleukodystrophy protein Aβ amyloid beta ALK ALK receptor tyrosine kinase ABA applied behavior analysis ALK2 activin receptor-like kinase-2; ACVR1 ABCD1 ATP binding cassette subfamily D member 1 ALS amyotrophic lateral sclerosis AC6 adenylyl cyclase type 6 AMBAR Alzheimer Management by Albumin Replacement ACC American College of Cardiology AML acute myeloid leukemia ACE angiotensin-converting enzyme AMP adenosine monophosphate ACL adenosine triphosphate citrate lyase α-MSH alpha-melanocyte-stimulating hormone ACTH adrenocorticotropic hormone ANCA antineutrophil cytoplasmic antibody ACVR1 activin A receptor type 1 Apo E apolipoprotein E AD Alzheimer’s disease AQP4 aquaporin-4 ADA adenosine deaminase AQP4-IgG aquaporin-4-immunoglobulin G ADAM a disintegrin and metalloprotease ARB angiotensin-receptor blocker ADAMTS13 ADAM metallopeptidase with thrombospondin type ARG1 arginase 1 1 motif 13 ARSA arylsulfatase A ADA-SCID adenosine deaminase/severe combined ASBT apical sodium-dependent bile acid transporter immunodeficiency ASCT allogeneic stem cell transplantation ADCY9 adenylate cyclase type 9 ASD autism spectrum disorder ADHD attention-deficit/hyperactivity disorder ASS1 argininosuccinate synthase 1 AGA actionable genomic alteration ATP adenosine triphosphate AHP acute hepatic porphyria aTTP acquired thrombotic thrombocytopenic purpura
APPENDIX. ABBREVIATIONS AND ACRONYM 230
ATTR-CM amyloid transthyretin-mediated cardiomyopathy CAH congenital adrenal hyperplasia AUC area under the curve CALD cerebral adrenoleukodystrophy AUD alcohol use disorder CAR chimeric antigen receptor BCCNS basal cell carcinoma nevus syndrome CB2 cannabinoid receptor 2 B cell bursa of Fabricius–maturing cell; B lymphocyte CBD cannabidiol BCG bacillus Calmette-Guérin CBT cognitive behavioral therapy BCL-2 BCL2 apoptosis regulator cc cubic centimeters BCMA B-cell maturation antigen CCM cardiac contractility modulation BCVA best corrected visual acuity CD3ζ cluster of differentiation 3ζ BED binge eating disorder CD8+ cluster of differentiation 8–positive BET bromodomain extra-terminal CD8α cluster of differentiation 8α BI-RADS Breast Imaging Reporting and Data System CD19 cluster of differentiation 19 BMI body mass index CD19+ cluster of differentiation 19–positive BMP bone morphogenetic protein CD20 cluster of differentiation 20 BMP2 bone morphogenetic protein 2 CD34+ cluster of differentiation 34–positive β-MSH beta-melanocyte-stimulating hormone CD38 cluster of differentiation 38 BNP B-type natriuretic peptide CD45 cluster of differentiation 45 BOS bronchiolitis obliterans syndrome CD137 cluster of differentiation 137 BRAF B-Raf proto-oncogene, serine/threonine kinase CD155 type 1 transmembrane glycoprotein; poliovirus BRCA breast cancer receptor nectin-like protein 5 BRCA1 breast cancer 1 CDC cardiosphere-derived cell BRCA2 breast cancer 2 C diff Clostridium difficile C1 complement component 1 CED convection-enhanced delivery C1-INH C1 esterase inhibitor CEP290 centrosome protein 290 C5 complement component 5 CETP cholesteryl ester transfer protein C5a complement 5a anaphylatoxin fragment CF cystic fibrosis C5b complement 5b anaphylatoxin fragment CFTR cystic fibrosis transmembrane conductance regulator C5b-9 complement 5b complex 9
APPENDIX. ABBREVIATIONS AND ACRONYM 231
CGG cytosine, guanine, guanine CTL cytotoxic T lymphocyte cGMP cyclic guanosine monophosphate CXCL12 CXC chemokine ligand 12 CGP comprehensive genomic profiling CXCR4 CXC chemokine receptor 4 CGRP calcitonin gene–related peptide CXCR4 C-X-C motif chemokine receptor 4 CHARGE coloboma, heart defects, atresia choanae CYP21A2 cytochrome P450 family 21 subfamily A member 2 CHM choroideremia D2 dopamine 2 CHOP INTEND Children’s Hospital of Philadelphia Infant Test of DAAO d-amino acid oxidase Neuromuscular Disorders DBS deep brain stimulation CIPN chemotherapy-induced peripheral neuropathy DCS d-cycloserine CIS carcinoma in situ DDC dopa decarboxylase CIT chemotherapy-induced thrombocytopenia DEB dystrophic epidermolysis bullosa CLD chronic liver disease DMD Duchenne muscular dystrophy CMT Charcot-Marie-Tooth DMD dystrophin CMT1A Charcot-Marie-Tooth disease type 1A dMMR mismatch repair deficient CNTF ciliary neurotrophic factor DMT N,N-dimethyltryptamine COL7A1 collagen DPP4 dipeptidyl peptidase 4 COL7A1 collagen type VII alpha 1 chain DQ developmental quotient cPMP cyclic pyranopterin monophosphate DSM-IV Diagnostic and Statistical Manual of Mental CRC colorectal cancer Disorders, 4th edition CRF1 corticotropin-releasing factor type 1 DSM-5 Diagnostic and Statistical Manual of Mental CRISPR clustered regularly interspaced short palindromic Disorders, 5th edition repeats DTC direct to consumer CRL Complete Response Letter E6 early expression 6 CRT cardiac resynchronization therapy E7 early expression 7 CSF1 colony-stimulating factor 1 EAP Expanded Access Program CSF1R colony-stimulating factor 1 receptor EBV Epstein-Barr virus CT computed tomography EBV+PTLD Epstein-Barr virus–associated posttransplant CTCL cutaneous T-cell lymphoma lymphoproliferative disorder
APPENDIX. ABBREVIATIONS AND ACRONYM 232
EBVST Epstein-Barr virus–specific T cells FOLFIRINOX leucovorin (folinic acid), 5-fluorouracil, irinotecan, EC endrometrial cancer and oxaliplatin ECOG Eastern Cooperative Oncology Group FOLFOX leucovorin (folinic acid), 5-fluorouracil, and oxaliplatin ECT electroconvulsive therapy FOP fibrodysplasia ossificans progressiva EDS excessive daytime sleepiness FOXN1 Forkhead Box N1 eGFR estimated glomerular filtration rate FSM full-spectrum microbiota EGFR epidermal growth factor receptor FT1050 small-molecule stem cell modulator (made by Fate EGJ esophagogastric junction Therapeutics) EMDR eye movement desensitization and reprocessing FT4145 small-molecule stem cell modulator (made by Fate EpCAM epithelial cell adhesion molecule Therapeutics) EPP erythropoietic protoporphyria GABA gamma-aminobutyric acid eTNS external trigeminal nerve stimulation GABAA gamma-aminobutyric acid receptor A EZH2 enhancer of zeste 2 polycomb repressive complex GABAergic pertaining to or affecting the neurotransmitter 2 subunit GABA F9 coagulation factor IX GAG glycosaminoglycan FAI fludarabine, cytarabine, and idarubicin GALT galactose-1 phosphate uridyl transferase Fc crystallizable fragment GBM glioblastoma multiforme FDA US Food and Drug Administration GBq gigabecquerel FGFR fibroblast growth factor receptor gc genome copies FGFR2 fibroblast growth factor receptor 2 GC/g genome copies per gram FGFR3 fibroblast growth factor receptor 3 G-CSF granulocyte colony-stimulating factor FGFR4 fibroblast growth factor receptor 4 GI gastrointestinal FIX alias for coagulation factor IX gene, F9 GJB1 gap junction protein beta 1 FLT3 fms related tyrosine kinase 3 GLP-1 glucagon-like peptide 1 FMR1 fragile X mental retardation 1 g/m2 grams per square meter of body surface area Fmrp Fmr1 protein GO glycolate oxidase FOLFIRI leucovorin (folinic acid), 5-fluorouracil, and GPR40 G-protein coupled receptor 40 irinotecan GPR84 G-protein coupled receptor 84
APPENDIX. ABBREVIATIONS AND ACRONYM 233
GTPase (guanosine triphosphate) superfamily of enzymes HSIL high-grade squamous intraepithelial lesion GVHD graft-versus-host disease HSP heat shock protein H3 histamine 3 HSV-1 herpes simplex virus 1 H3 histone 5-HT1A 5-hydroxytryptamine 1A; serotonin hAAT human α1-antitrypsin 5-HT2A 5-hydroxytryptamine 2A; serotonin HAE hereditary angioedema ICD implantable cardioverter-defibrillator HbA1c glycated hemoglobin IDE Investigational Device Exemption HBB hemoglobin subunit beta IDH icocitrate dehydrogenase HCC hepatocellular carcinoma IDH1 icocitrate dehydrogenase 1 HCHSS PCORI Health Care Horizon Scanning System IDS iduronate-2-sulfatase HCL hydrogen chloride IgA immunoglobulin A HDAC histone deacetylase IGF-1 insulin-like growth factor 1 HER2 human epidermal growth factor receptor 2 IgG1 Fc immunoglobulin G1 Fc domain HES hypereosinophilic syndrome IgG2 Fc immunoglobulin G2 Fc domain HF heart failure IgG4 immunoglobulin G4 HGF hepatocyte growth factor IgM immunoglobulin M hIDS human iduronate-2-sulfatase IL-1 interleukin-1 HLA-A2 human leukocyte antigen serotype A2 IL-1β interleukin-1β HNSCC head and neck squamous cell carcinoma IL-2 interleukin-2 HO heterotopic ossification IL-2R interleukin-2 receptor HPBCT hematopoietic peripheral blood cell transplant IL-4R interleukin-4 receptor HPV human papillomavirus IL-5 interleukin-5 HPV-16 human papillomavirus type 16 IL-5α interleukin-5 α chain HPV-18 human papillomavirus type 18 IL-15 interleukin-15 HR hormone receptor IL-15α interleukin-15α HRR homologous recombination repair IL-17 interleukin-17 HSC hematopoietic stem cell IL-23 interleukin-23 HSCT hematopoietic stem cell transplantation ILD interstitial lung disease
APPENDIX. ABBREVIATIONS AND ACRONYM 234
IPF idiopathic pulmonary fibrosis MCI mild cognitive impairment IQ intelligence quotient MCL mantle cell lymphoma IU international unit mCRPC metastatic, castration-resistant prostate cancer IU/dL international unit per deciliter MCSF monthly convulsive seizure frequency IV intravenous MDD major depressive disorder IVIg intravenous immunoglobulin MDM2 mouse double minute 2 homolog JAK Janus kinase MDMA 3,4-methylenedioxymethamphetamine JAK1 Janus kinase 1 MDS myelodysplastic syndrome JAK2 Janus kinase 2 MEC mitoxantrone, etoposide, and cytarabine KIT KIT proto-oncogene, receptor tyrosine kinase MeCP2 methyl CpG binding protein 2 LAG-3 lymphocyte-activator gene-3 MECP2 methyl CpG binding protein 2 LCA10 Leber congenital amaurosis 10 MEK alias for mitogen-activated protein kinase kinase 1 LDL low-density lipoprotein gene, MAP2K1 LEMS Lambert-Eaton myasthenic syndrome MEK mitogen-activated protein kinase kinase LEPR leptin receptor MET MET proto-oncogene, receptor tyrosine kinase LGMD2E limb-girdle muscular dystrophy type 2E mg/m2 milligrams per square meter of body surface area LHON Leber hereditary optic neuropathy MGMT O6-methylguanine-DNA-methyltransferase LSD lysergic acid diethylamide MHC-II major histocompatibility complex molecule class II 177Lu lutetium-177 μL microliter LVAD left ventricular assist device ML machine learning MACE major adverse cardiovascular events MLD metachromatic leukodystrophy MacTel macular telangiectasia MMC mitomycin-C MAOI monoamine oxidase inhibitor mm Hg millimeters of mercury MAPK mitogen-activated protein kinase MoCD molybdenum cofactor deficiency MASP-2 mannan-binding lectin-associated serine MoCo molybdenum cofactor protease-2 MOCS1 molybdenum cofactor synthesis 1 MC4 melanocortin-4 MPC mesenchymal precursor cell MC4R melanocortin-4 receptor MPS mucopolysaccharidosis
APPENDIX. ABBREVIATIONS AND ACRONYM 235
MPSII mucopolysaccharidosis type II; Hunter syndrome NRI norepinephrine reuptake inhibitor MPSIIIA mucopolysaccharidosis type III A; Sanfilippo NSAIDs nonsteroidal anti-inflammatory drugs syndrome type A NSCLC non–small cell lung cancer MPSIIIB mucopolysaccharidosis type III B; Sanfilippo NTproBNP N-terminal pro B-type natriuretic peptide syndrome type B NTRK neurotrophic tyrosine receptor kinase MRI magnetic resonance imaging NY-ESO-1 New York esophageal squamous cell carcinoma-1 mRNA messenger RNA NYHA New York Heart Association MSI microsatellite instability oGVHD ocular graft-versus-host disease MSI-H microsatellite instability–high OM oral mucositis MTM1 myotubularin p53 tumor protein 53 mTOR mammalian target of rapamycin p62 tumor protein 62; sequestosome-1 mUC metastatic urothelial cancer PAH pulmonary arterial hypertension NADH nicotinamide adenine dinucleotide PARP poly adenosine diphosphate-ribose polymerase NAGLU N-acetyl-alpha-d-glucosaminidase PARP1/2 poly adenosine piphosphate-ribose polymerases NAM nicotinamide I and II ND4 NADH dehydrogenase 4 PBC primary biliary cholangitis NDA New Drug Application PCORI Patient-centered Outcomes Research Institute NK natural killer PCSK9 proprotein convertase subtilisin kexin type 9 NK neurotrophic keratitis PD-1 programmed death-1 NLP natural language processing PDE4 phosphodiesterase type 4 NMDA N-methyl-d-aspartate PDE9 phosphodiesterase type 9 NMIBC non–muscle invasive bladder cancer PDGFRA platelet-derived growth factor receptor A NMOSD neuromyelitis optica spectrum disorder PD-L1 programmed death-ligand 1 NPC nasopharyngeal carcinoma PDUFA Prescription Drug User Fee Act NPC1 NPC intracellular cholesterol transporter 1 PE Pseudomonas exotoxin A NPC2 NPC intracellular cholesterol transporter 2 PEComa perivascular epithelioid cell tumor NPD Niemann-Pick disease PEDI Pediatric Evaluation of Disability Inventory NPD-C Niemann-Pick disease type C PET positron emission tomography
APPENDIX. ABBREVIATIONS AND ACRONYM 236
PET prolonged exposure therapy PTCH1 patched 1 PFIC progressive familial intrahepatic cholestasis PTSD posttraumatic stress disorder PFIC1 progressive familial intrahepatic cholestasis type 1 PUL Performance of Upper Limb PFIC2 progressive familial intrahepatic cholestasis type 2 PWS Prader-Willi syndrome PFIC3 progressive familial intrahepatic cholestasis type 3 QT ventricular depolarization interval from the start of PFIC4 progressive familial intrahepatic cholestasis type 4 the Q wave to the end of the T wave P-gp P-glycoprotein Rab ras genes from rat brains PGRMC1 progesterone receptor member component 1 RARγ retinoic acid receptor gamma PH1 primary hyperoxaluria type 1 ras rat sarcoma PI3K phosphoinositide-3-kinase rC7 recombinant collagen type VII PICO patient population, intervention, comparators, RDEB recessive dystrophic epidermolysis bullosa outcomes REP1 Rab escort protein 1 PLK1 polo-like kinase 1 RET rearranged during transfection PMM primary mitochondrial myopathy RNAi RNA interference PMO phosphorodiamidate morpholino oligomer ROS reactive oxygen species PMP22 peripheral myelin protein 22 ROS1 ROS proto-oncogene 1, receptor tyrosine kinase PNH paroxysmal nocturnal hemoglobinuria RP retinitis pigmentosa Pol polymerase RPGR-ORF 15 retinitis pigmentosa GTPase regulator-open Pol I polymerase I reading frame 15 Pol II polymerase II RRMM relapsed and refractory multiple myeloma POMC proopiomelanocortin RTK receptor tyrosine kinase PPAR peroxisome proliferator-activated receptor rTMS repetitive transcranial magnetic stimulation PPARα peroxisome proliferator-activated receptor alpha SBRT stereotactic body radiotherapy PPARδ peroxisome proliferator-activated receptor delta SCA spinocerebellar ataxia PROMIS Patient-reported Outcomes Measurement SCD sickle cell disease Information System SCID-X1 X-linked severe combined immunodeficiency PSMA prostate-specific membrane antigen disease PTC1 phosphatase type 2 C SCLC small cell lung cancer
APPENDIX. ABBREVIATIONS AND ACRONYM 237
SCN1A sodium voltage-gated channel alpha subunit 1 T2DM type 2 diabetes mellitus SGCB sarcoglycan beta TGCT tenosynovial giant cell tumor SGSH N-sulfoglucosamine sulfohydrolase TGF-beta transforming growth factor beta sIBM sporadic inclusion body myositis TIL tumor-infiltrating lymphocyte SMA spinal muscle atrophy TK2 thymidine kinase 2 Smad Sma/mothers against decapentaplegic homolog TK2d thymidine kinase 2 deficiency Smad1 Sma/mothers against decapentaplegic homolog 1 TMA thrombotic microangiopathy Smad5 Sma/mothers against decapentaplegic homolog 5 TMS transcranial magnetic stimulation Smad8 Sma/mothers against decapentaplegic homolog 8 TNBC triple-negative breast cancer SMN survival of motor neuron TNF tumor necrosis factor SMN1 survival of motor neuron 1 TP53 tumor protein p53 SMN2 survival of motor neuron 2, centromeric TPO thrombopoietin Smo Smoothened Trop-2 trophoblast cell-surface antigen 2 SN-38 7-ethyl-10-hydroxycamptothecin TSC tuberous sclerosis complex SNRI serotonin and norepinephrine reuptake inhibitor TSC1 TSC complex subunit 1 SOD1 superoxide dismutase 1 TSC2 TSC complex subunit 2 SSc-ILD systemic sclerosis–associated interstitial TTF tumor-treating field lung disease 3TUG Triple Timed Up & Go SSRI selective serotonin reuptake inhibitor TURBT transurethral resection of bladder tumor STAT-3 signal transducer and activator of transcription 3 UBE3A ubiquitin protein ligase E3a STEMI ST-segment elevation myocardial infarction UDCA ursodeoxycholic acid STRO antistromal precursor antigen US United States TAAR1 trace amine-associated receptor 1 UVR ultraviolet radiation TAZ tafazzin V1A vasopressin 1a Tβ4 thymosin beta 4 VA US Department of Veterans Affairs TBI traumatic brain injury VEGF vascular endothelial growth factor TCA tricyclic antidepressant VEGFR vascular endothelial growth factor receptor T cell thymus-originating cell; T lymphocyte vg viral genomes
APPENDIX. ABBREVIATIONS AND ACRONYM 238
VNS vagal nerve stimulation VOC vaso-occlusive crisis VR virtual reality VT ventricular tachycardia WAC wholesale acquisition cost WAS WASP actin nucleation promoting factor WAS Wiskott-Aldrich syndrome WASP Wiskott-Aldrich syndrome protein WHIM warts, hypogammaglobulinemia, infections, and myelokathexis XLRP X-linked retinitis pigmentosa ZFN1 zinc finger nuclease 1 ZFN2 zinc finger nuclease 2
APPENDIX. ABBREVIATIONS AND ACRONYM 239