Progress, development, and challenges in amyotrophic lateral sclerosis clinical trials

ABSTRACTIntroduction Amyotrophic Lateral Sclerosis (ALS) brings unique challenges to a clinical trial setting, due in part to relatively low disease prevalence coupled with a poor prognosis, in addition to the complexities linked to disease heterogeneity. As critical understanding of the disease develops, particularly in relation to clinical phenotype and the mechanisms of disease progression, so too new concepts evolve in relation to clinical trials, including the advent of precision therapy, targeted to subgroups of ALS patients.Areas covered Individualized, or precision medicine in ALS recognizes the heterogeneous nature of the disease and utilizes information such as the clinical phenotype of the disease, clinical biomarkers, and genotyping to promote a tailored approach to treatment. Separate to these considerations, the present review will discuss clinical trial design and how this can be improved to better match patient and investigator needs in ALS clinical trials.Expert opinion Precision therapy will promote a more focused treatment approach, with the goal of improving clinical outcomes for ALS patients. An increased community awareness of ALS, coupled with significant industry and philanthropic funding for ALS research, is accelerating this process.KEYWORDS: Amyotrophic lateral sclerosisbiomarkersclinical trialsdiagnostic criteriagenotypemagnetic resonance imagingmotor neuron disease Article highlights ALS is a heterogeneous disease, with key challenges in relation to clinical trials, heightened by diagnostic delay and an overall poor prognosis of the disease.Precision therapy aims to improve outcomes by targeting a treatment approach toward ALS subcategories, rather than treating the disease as one entityThe recently established Gold Coast criteria, developed in 2020, simplify the diagnosis of ALS. A more definitive early diagnosis will inevitably facilitate patient recruitment and inclusion into clinical trials, in addition to providing more diagnostic certainty for patients and treating physiciansIn terms of trial design, the use of master protocols will greatly increase the efficiency of clinical trials by using a common system for patient selection, logistics, templates, and data management systems.Biomarkers may facilitate clinical trial management by providing outcome measures of target engagement and thereby efficacy. In addition to the physiological assessment of cortical function through techniques such as transcranial magnetic stimulation, newer structural approaches such as magnetic resonance spectroscopy (1H-MRS) may provide further detailed longitudinal data in ALS patients, with further translational potential as a clinical biomarkerDeclaration of interestThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia (1132524, 1095127, 1060992). M Kiernan is supported by an NHMRC Practitioner Fellowship (1156093).