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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.

Introduction/Aims: An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone. Methods: This global, open‐label, phase 3 study evaluated the long‐term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105‐mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone. Results: The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment‐emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty‐six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug. Discussion: This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified. [ABSTRACT FROM AUTHOR]