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Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid BiomarkersA Review

To identify the key insights or developments described in this article

1 Credit CME

JAMA Neurology

Published Online: October 17, 2022

Review

Article Information and Disclosures

Jeremy M. Shefner, MD, PhD¹;

Richard Bedlack, MD, PhD²;

Jinsy A. Andrews, MD³;

James D. Berry, MD, PhD⁴;

Robert Bowser, PhD¹;

Robert Brown, MD, DPhil⁵;

Jonathan D. Glass, MD⁶;

Nicholas J. Maragakis, MD⁷;

Timothy M. Miller, MD, PhD⁸;

Jeffrey D. Rothstein, MD, PhD⁷;

Merit E. Cudkowicz, MD⁴

Author Affiliations

¹Barrow Neurological Institute, Phoenix, Arizona
²Duke University, Durham, North Carolina
³The Neurological Institute, Columbia University, New York, New York
⁴Healey & AMG Center ALS, Massachusetts General Hospital, Boston
⁵University of Massachusetts, Worcester
⁶Emory University, Atlanta, Georgia
⁷Johns Hopkins University, Baltimore, Maryland
⁸Washington University, St Louis, Missouri

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Abstract

Importance Clinical trial activity in amyotrophic lateral sclerosis (ALS) is dramatically increasing; as a result, trial modifications have been introduced to improve efficiency, outcome measures have been reassessed, and considerable discussion about the level of data necessary to advance a drug to approval has occurred. This review discusses what recent pivotal studies can teach the community about these topics.

Observations By restricting inclusion and exclusion criteria, recent trials have enrolled populations distinct from previous studies. This has led to efficacy signals being observed in studies that are smaller and shorter than was thought feasible previously. However, such trials raise questions about generalizability of results. Small trials with equivocal clinical results also raise questions about the data necessary to lead to regulatory approval. The ALS Functional Rating Scale–Revised remains the most commonly used primary outcome measure; this review discusses innovations in its use. Blood neurofilament levels can predict prognosis in ALS and may be a sensitive indicator of biologic effect; current knowledge does not yet support its use as a primary outcome.

Conclusions and Relevance It is now possible to use specific inclusion criteria to recruit a homogeneous patient population progressing at a specific rate; this will likely impact trials in the future. Generalizability of results on limited populations remains a concern. Although clinical outcomes remain the most appropriate primary outcome measures, fluid markers reflecting biologically important processes will assume more importance as more is learned about the association between such markers and clinical end points. The benefit of use of analytic strategies, such as responder analyses, is still uncertain.

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Article Information

Accepted for Publication: July 14, 2022.

Published Online: October 17, 2022. doi:10.1001/jamaneurol.2022.3282

Corresponding Author: Jeremy M. Shefner, MD, PhD, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85015 (jeremy.shefner@dignityhealth.org).

Author Contributions: Dr Shefner had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Shefner, Bedlack, Andrews, Bowser, Brown, Maragakis, Miller, Rothstein, Cudkowicz.

Acquisition, analysis, or interpretation of data: Bedlack, Berry, Glass.

Drafting of the manuscript: Shefner, Bedlack, Bowser.

Critical revision of the manuscript for important intellectual content: All authors.

Obtained funding: Glass.

Administrative, technical, or material support: Bedlack, Bowser, Brown, Maragakis, Cudkowicz.

Supervision: Shefner, Bedlack, Rothstein.

Conflict of Interest Disclosures: Dr Shefner reported receiving personal fees from Amylyx, Apic BiosciencesNeurosense, Cytkinetics, Denali, GlaxoSmithKline, Mitsubishi Tanabe Pharma America, Orphazyme, Orthogonal, Pinteon, RRD International, SwanBio, Helixsmith, Novartis, Sanofi, EMD Serono, and PTC Therapeutics and grants from Amylyx, Biogen, Biotie Therapies (now Acorda Therapeutics), Cytokinetics, Mitsubishi Tanabe Pharma America, Alexion, Medicinova, Alector, Ionis, and Orphazyme during the conduct of the study. Dr Bedlack reported receiving grants from ALS Association, Healey Center, Medicinova, Orion, and Neuraltus; personal fees from ALS Association, AB Science, Alexion, Amylyx, Apellis, Biogen, Biohaven, Black Swan, Brainstorm Cell, Clene, Corcept, Cytokinetics, GenieUS, Guidepoint, ITF Pharma, Mallinkrodt, MT Pharma, New Biotic, Orphazyme, Shinkei Pharma, and Woolsey Pharma; and book royalties from Springer Publishing. Dr Andrews reported receiving grants from Alexion, AZTherapies, Amylyx, Biogen, Cytokinetics, Orion, Novartis, MGH Foundation, Ra Pharma, Biohaven, Clene, and Prilenia and personal fees from Amylyx, AL-S Pharma, Affinia, Apellis, Avexis, Biogen, Cytokinetics, Denali, Orphazyme, Novartis, UCB, Sanofi, Neurosense, and Wave Life Sciences outside the submitted work. Dr Berry reported receiving grants from Alexion Pharmaceuticals, Biogen, MT Pharma of America, MT Pharma Holdings of America, Amylyx, Rapa Therapeutics, nQ Medical, Transposon Therapeutics, Muscular Dystrophy Association, ALS One, ALS Association, Tambourine, and ALS Finding A Cure; advisory board fees from Biogen, Clene Nanomedicine, Janssen, MT Pharma of America, MT Pharma Holdings of America, Regeneron, RRD International, Biogen; speaker fees from Projects in Knowledge; travel reimbursement from Muscular Dystrophy Association Travel reimbursement for presenting at a conference outside the submitted work; and unpaid roles on the advisory boards for the non-profits Everything ALS and ALS One. Dr Bowser reported receiving consultant fees from Iron Horse Diagnostics Inc, Mitsubishi Tanabe Pharma America, AcuraStem, Alector, and RRD International and being cofounder of Iron Horse Diagnostics Inc and nVector Inc (companies involved in diagnostics and gene therapy related to ALS and other neurologic diseases) outside the submitted work. Dr Brown reported receiving consultant fees from APIC and Sanofi; having equity in Amylyx and ARNA Therapeutics; and being a scientific cofounder and consultant for ApicBio outside the submitted work. Dr Glass reported receiving research support from ALS Association, Muscular Dystrophy Association, National Institute on Aging, and National Institute of Neurological Disorders and Stroke and consulting fees from Biogen, Regeneron, Nura Bio, Orthoganal outside the submitted work. Dr Maragakis reported receiving grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Department of Defense, and Healey Center; personal fees from Amylyx, Apellis, Eledon, Nura Bio, Orion, Cytokinetics, Braintrust Bio, and Massachusetts General Hospital; and being a site principal investigator for the following clinical trial sponsors: Biogen/Idec, Medicinova, Anelixis, Apellis, Orion, and Helixmith. Dr Miller reported receiving consulting/advisory board fees from Ionis Pharmaceuticals, Biogen, Cytokinetics, UCB, Disarm Therapeutics, Bioio, Regeneron, and Denali; having a licensing agreement with C2N and Ionis Pharmaceuticals; and having a patent for methods to detect miRNA issued Washington University. Dr Rothstein reported receiving grants from Expansion Therapeutics, Calico, Fralin Biomedical Research Institute, Answer ALS, and TEDCO (Maryland Technology Development Corporation) outside the submitted work; having a patent for Chmp7 antisense pending; receiving nonfinancial support from Ionis Pharmaceuticals; Calico, Biogen, and IBM Watson; research grant support from the National Institute of Neurological Disorders and Stroke, National Institute on Aging, Department of Defense, the Chan Zuckerberg Initiative, Microsoft, the ALS Association, the Muscular Dystrophy Association, Target ALS, F Prime, ALS Finding A Cure, Answer ALS, Robert Packard Center for ALS Research, GlaxoSmithKline, Travelers Insurance, American Airlines, Caterpillar, and the National Football League; and personal consulting fees from Expansion Therapeutics and Team Gleason. Dr Cudkowicz reported receiving consulting fees from Transposon, Biogen, Regeneron, Immunity Pharma, Quralis, RRD International, Lilly, Locustwalk, Servier, and Cytokinetics; grants from Wave, UCB, Biohaven, Clene Nanomedicine, Prilenia, and Seelos; and board member fees from Praxis. No other disclosures were reported.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.