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  • Review Article
  • Published:

Improving clinical trial outcomes in amyotrophic lateral sclerosis

Nature Reviews Neurology volume 17, pages 104–118 (2021)Cite this article

Subjects

Abstract

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s — a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.

Key points

  • The development of effective treatments for amyotrophic lateral sclerosis (ALS) has been limited by a lack of comprehensive understanding of the biological processes that trigger the disease and promote progression.

  • Causative genetic mutations have been identified, many of which are linked to RNA function and metabolism.

  • Disease heterogeneity suggests that a precision medicine paradigm incorporating extensive phenotypic and genotypic information will be required to realize effective therapy and improve the outcomes for individual patients with ALS.

  • The repurposing of drugs with established safety profiles from their use in other human diseases is a new approach to therapeutic discovery in ALS.

  • Enhanced clinical trial designs, including multi-arm, multi-stage platform trials, that incorporate biomarkers of treatment responses will accelerate drug discovery and increase trial participation.

  • Improved patient stratification and patient-reported outcome measures, including home assessments, will improve the reliability and sensitivity of trial endpoints.

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Fig. 1: The pathophysiology of ALS.
Fig. 2: Model of precision medicine for ALS.
Fig. 3: MAMS adaptive platform trial design.

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Acknowledgements

This manuscript was prepared by members of ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases and funded by the National Health and Medical Research Council of Australia Program Grant (#1132524), a Dementia Research Team Grant (#1095127) and a Partnership Project (1153439). M.C.K. is supported by an NHMRC Practitioner Fellowship (1156093). J.M.S. receives funding from ALS Finding a Cure Foundation. A.A.-C. is supported through the United Kingdom Medical Research Council (MR/R024804/1) under the aegis of JPND (www.jpnd.eu), the Motor Neurone Disease Association, and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. P.W. is employed by Wicks Digital Health, which has received funding from Ada Health, AstraZeneca, Baillie Gifford, Bold Health, Camoni, Compass Pathways, Coronna, EIT, Happify, HealthUnlocked, Inbeeo, Kheiron Medical, Sano Genetics, Self Care Catalysts, The Learning Corp, The Wellcome Trust, VeraSci and Woebot. M.R.T. is supported by the Motor Neurone Disease Association.

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Authors and Affiliations

  1. Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia

    Matthew C. Kiernan & William Huynh

  2. Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

    Matthew C. Kiernan & William Huynh

  3. Sydney Medical School Westmead, University of Sydney, Sydney, New South Wales, Australia

    Steve Vucic

  4. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Kevin Talbot, Thanuja Dharmadasa & Martin R. Turner

  5. Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK

    Christopher J. McDermott

  6. NIHR Sheffield Biomedical Research Centre, Sheffield, UK

    Christopher J. McDermott

  7. Academic Neurology Unit, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    Orla Hardiman

  8. National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland

    Orla Hardiman

  9. Department of Neurology, Barrow Neurological Institute, University of Arizona College of Medicine Phoenix, Creighton University, Phoenix, AZ, USA

    Jeremy M. Shefner

  10. King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, London, UK

    Ammar Al-Chalabi

  11. Massachusetts General Hospital, Boston, MA, USA

    Merit Cudkowicz

  12. Harvard Medical School, Boston, MA, USA

    Merit Cudkowicz

  13. Neurosciences Department, Barwon Health District, Melbourne, Victoria, Australia

    Paul Talman

  14. Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands

    Leonard H. Van den Berg

  15. Wicks Digital Health, Lichfield, United Kingdom

    Paul Wicks

  16. The Motor Neurone Disease Association of New Zealand, Auckland, New Zealand

    Claire Reilly

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Contributions

M.C.K. researched data for the article. M.C.K. and S.V. made substantial contributions to discussion of the content. M.C.K., S.V., K.T., C.J.M., O.H., J.M.S., A.A.-C. and M.R.T. contributed to the writing of the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to Matthew C. Kiernan.

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Nature Reviews Neurology thanks M. de Carvalho, C. Lunetta, S. Petri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

ALS Therapy Development Institute: www.als.net

ANSWER ALS: www.answerals.org

PatientsLikeMe: www.patientslikeme.com

TARGET ALS: www.targetals.org

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Kiernan, M.C., Vucic, S., Talbot, K. et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol 17, 104–118 (2021). https://doi.org/10.1038/s41582-020-00434-z

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