Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS

Abstract

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.

Keywords: amyotrophic lateral sclerosis; biomarkers; clinical trials; disease heterogeneity; enrichment strategies; outcome measures.

Figure 1

Sources of heterogeneity in amyotrophic lateral sclerosis clinical trials. MOA, mode of action

Figure 2

Use of prognostic models to assess the effects of heterogeneity and guide appropriate trial designs. ALS, amyotrophic lateral sclerosis; ALSFRS‐R, ALS Functional Rating Scale‐Revised; BMI, body mass index; fALS, familial ALS; FVC, forced vital capacity; MUNE, motor unit number estimation; MUNIX, motor unit number index; sALS, sporadic ALS; SOD1, superoxide dismutase 1; SVC, slow vital capacity; TMS, transcranial magnetic stimulation