Improving clinical trial outcomes in amyotrophic lateral sclerosis

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. The identification of pathogenic targets in amyotrophic lateral sclerosis means that effective therapies are increasingly likely. In this Review, Kiernan et al. discuss advances towards therapy and the innovations needed in clinical trials to facilitate the translation into treatments for patients. 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 respon