EXPErimental medicine Route To Success in Amyotrophic Lateral Sclerosis (EXPERTS-ALS)

Central proposal The proposal is the creation of a UK multi-centre platform for the prioritisation of a growing pool of candidate pre-clinical drugs into Phase III trials for those living with amyotrophic lateral sclerosis (ALS, also known as motor neuron disease, MND). This EXPErimental Route To Success in ALS (EXPERTS-ALS) will also generate a bioresource linked to a range of nested research for the discovery and development of novel biomarkers to further innovate trials and build UK capacity in ALS. Background A major rate-limiting step in therapeutic advancement for ALS is the capacity to deliver Phase III randomised controlled trials at pace for a growing pool of drugs. Using the current outcome measures of survival or function, Phase III trials in ALS necessitate large (300-600 participants), lengthy (12-18 months), and so costly (£10s of millions) studies. This model has a more than 99% failure rate to date, with concern that the choice of candidates has been based on inadequate evidence of likely clinical benefit. Through multiple cohort studies, blood neurofilament light chain (NfL) level has been established as an objective correlate of the individual rate of disability progression in ALS. This underpins a rationale for considering significantly lowered NfL levels by a drug intervention as a likely surrogate marker of future clinical benefit, and the basis for building greater confidence in definitive Phase III study investment. Aims, Objectives & Methods The EXPERTS-ALS programme consists of three workstreams: Workstream 1: IMP identification. This will identify and prioritise compounds to be tested. Workstream 2: Drug Prioritisation Platform. This is a Bayesian Phase II open label, randomised platform, using blood NfL levels as a surrogate outcome for biological efficacy alongside other exploratory endpoints. Workstream 3: Nested biomarker development studies. Using the deeply-phenotyped participants alongside a bioresource of biosamples and other data, this will harness the expertise of the NIHR Biomedical Research Centres and UK Dementia Research Institute network to define the molecular and network-level changes associated with drug administration, including understanding individual ‘responders’ and ‘non-responders’. Timelines We will set up the drug administration platform and bioresource infrastructure within the first year of the award. We will commence participant recruitment from Year 2 and by the end of the award will have evaluated 6-9 drugs, with bioresource-nested science being undertaken in parallel. We will seek funding from major MND charities and industry to create a sustainable pipeline of screening beyond. Impact and dissemination EXPERTS-ALS will mark a major shift in the efficiency of candidate drug screening, filling a gap between discovery science and the successful Phase III initiatives e.g. the UK’s MND-SMART and wider European TRICALS consortium. More of those diagnosed with ALS will have access to one or more active drugs during their lifetime. This programme will harness and develop skills and expertise across centres and clinical research networks and lead to an increase in capacity for Experimental Medicine and therapeutic trials research in ALS. We will take an innovative approach to communication guided by close partnership with our PPIE co-applicants and the major MND charities, involving frequent widely accessible online content alongside traditional approaches to dissemination.