Objective To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS).
Methods We long-listed licensed drugs with evidence of human safety, blood–brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review.
Results From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine.
Conclusions We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.
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Contributors NC and AC accept full responsibility for the work and conduct of the study, had access to the data and controlled the decision to publish. Study concept and design: all authors. Members of treatment selection group responsible for analysis or interpretation of data: all authors. Drafting of manuscript: NC, KAV and AC. Critical revision of the manuscript: all authors.
Funding JB received expense payments from Novartis for speaking as patient representative during Siponimod licensing. AC receives funding from the Medical Research Council (MRC) and MS Society UK. DF is funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and has a project with Sangamo. AGdlF has been supported by the European Committee for Treatment and Research in MS (ECTRIMS) postdoctoral fellowship during this period. GG declares current research funding from Merck KGa (CLAD-B study), Roche (ORATORIO-HAND study) and Takeda (SIZOMUS Study). DM received funding previously from Biogen, MedDay and SanofiGenzyme. BN received funding from the Cambridge Centre for Myelin Repair, funded by MS Society UK. SP declares current funding from Italian and US Multiple Sclerosis Societies. LP-J has been supported by a senior research fellowship FISM—Fondazione Italiana Sclerosi Multipla—cod. 2017/B/5 and financed or co financed with the ‘5five per mille' public funding, by the Isaac Newton Trust RG 97440 and the Addenbrooke’s Charitable Trust RG 97519. KJS declares current funding from Fondation Leducq, Multiple Sclerosis Society, Rosetrees Trust. AW received a research grant from Sanofy (2018). AW declares funding from MS Society UK, Roche, MRC and Lifearc.
Competing interests DB received compensation for consultancy activity from Canbex Therapeutics, Japan Tobacco, Lundbeck, InMune Bio, Merck, Novartis, and Roche in the past 3 years. AC received honoraria and travel support from Genzyme (a Sanofi company) prior to 2017. MC has received honoraria for educational events and/or consultancy from Biogen, Merck, Roche, AbbVie and Novartis. GG has received compensation for serving as a consultant in relation to multiple sclerosis drug development from AbbVie, Actelion, Atara Bio, Biogen, Celgene, EMD Serono, Japanese Tobacco, Sanofi-Genzyme, Genentech, GlaxoSmithKline, GW Pharma, Merck KGa, Novartis, Roche and Teva. LH holds a small number of GSK shares as part of her renumeration when she was an employee, which she left 4 years ago. DM received consultancy fees from Biogen, MedDay and SanofiGenzyme and Novartis. BN holds a patent regarding the treatment of demyelinating diseases including metformin: WO2019/206419 A1, Treatment for demyelinating disease. SP is cofounder, CSO and shareholder (>5%) of CITC Ltd and iSTEM Therapeutics, and cofounder and non-executive director at Asitia Therapeutics. LP-J is Head of Research at iSTEM Therapeutics. AW receives research support from Roche not associated with drug development or use.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All authors had access to the data in this study and had responsibility for the decision to submit for publication. All data relevant to the study are included in the article or uploaded as supplementary information. Information recorded in the drug CVs is available from the MS Society and can be requested via email: email@example.com.
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