Endpoints and biomarkers in amyotrophic lateral sclerosis clinical trials

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with limited therapeutic options. Clinical trials play a crucial role in evaluating potential treatments, and selecting appropriate endpoints and biomarkers is essential for their success. This review examines the current status and challenges of endpoints and biomarkers in ALS clinical trials, focusing on their utility in efficacy assessment and regulatory decision–making. Traditionally, ALS clinical trials have relied on survival and functional measures, particularly the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS–R). However, concerns regarding its variability and the absence of a standardized international approach have prompted efforts toward global harmonization and the development of alternative assessment methods. Concurrently, the role of biomarkers in ALS trials has expanded. Neurofilament light chain (NfL) has emerged as a key biomarker applicable across different disease stages. It has potential applications as a susceptibility/risk biomarker in high–risk populations, a prognostic biomarker in early–stage ALS, and a pharmacodynamic biomarker for evaluating treatment response in clinical trials. The recent accelerated approval of tofersen, an antisense oligonucleotide targeting SOD1 mutations, was primarily based on NfL reduction as a surrogate marker of therapeutic efficacy. However, whether NfL qualifies as a “reasonably likely surrogate endpoint” remains under debate, as its predictive validity for clinical benefit may vary depending on the stage of intervention. As regulatory agencies, including the FDA, continue to refine their frameworks for biomarker qualification, ongoing discussions continue regarding the formal recognition of NfL as a biomarker in ALS. This review highlights the need for further research and regulatory clarity to optimize biomarker–driven ALS clinical trials, with implications for both therapeutic development and broader neurodegenerative disease research.