Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One re...

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Bibliographic Details
Published in:Muscle & nerve 2020-08, Vol.62 (2), p.156-166
Main Authors: Goyal, Namita A., Berry, James D., Windebank, Anthony, Staff, Nathan P., Maragakis, Nicholas J., Berg, Leonard H., Genge, Angela, Miller, Robert, Baloh, Robert H., Kern, Ralph, Gothelf, Yael, Lebovits, Chaim, Cudkowicz, Merit
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Biomarkers
Clinical trials
disease heterogeneity
Drug development
enrichment strategies
Heterogeneity
Invited Review
Invited Reviews
Neurodegenerative diseases
outcome measures
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Summary:Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.
ISSN:0148-639X
1097-4598
1097-4598
DOI:10.1002/mus.26801