A Systematic Approach to Identify Neuroprotective Interventions for Motor Neuron Disease

Background Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Objectives Here we detail a systematic, structured, and unbiased evidence-based approach to guide selection of drugs for clinical evaluation in the Motor Neuron Disease – Systematic Multi-arm Adaptive Randomised Trial (MND-SMART, [clinicaltrials.gov][1] registration number: [NCT04302870][2]), an adaptive platform trial. Methods We conducted a two-stage systematic review and meta-analysis to identify potential neuroprotective interventions. In stage one, we identified drugs from the clinical literature tested in at least one study in MND or in two or more cognate diseases with potential shared pivotal pathways (Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, or multiple sclerosis). We scored and ranked 66 drugs thus identified using a predefined framework evaluating safety, efficacy, study size and quality of studies. In stage two, we conducted a systematic review of the MND preclinical literature describing efficacy of these drugs in animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies; 17 of these drugs were reported to improve survival in at least one preclinical study. An expert panel then shortlisted and ranked 22 drugs considering stage one and stage two findings, mechanistic plausibility, safety and tolerability, findings from previous clinical trials in MND, and feasibility for use in clinical trials. Results Based on this process, the panel selected memantine and trazodone for testing in MND-SMART. Discussion For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human induced pluripotent stem cells. STRENGTHS AND LIMITATIONS OF THIS STUDY ### Competing Interest Statement In the last 3 years, J. Chataway has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche. ### Clinical Protocols ### Funding Statement For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. MND-SMART is funded by grants from MND Scotland, My Name'5 Doddie Foundation (DOD/14/15) and specific donations to the Euan MacDonald Centre. The Chandran lab is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. E.E is a clinical academic fellow jointly funded by MND Scotland (MNDS) and the Chief Scientist Office (CSO) (217ARF R45951). A.R.M. was a Lady Edith Wolfson Clinical Fellow, jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). A.Salzinger is funded by Marie Sklodowska-Curie actions Innovative Training Network (ITN). B.T.S is funded by Rowling fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are available in the Supplementary material. [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04302870&atom=%2Fmedrxiv%2Fearly%2F2022%2F04%2F22%2F2022.04.13.22273823.atom