Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis

Abstract

ObjectiveTo 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).MethodsWe 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.ResultsFrom 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.ConclusionsWe report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.

MS can be considered a primary progressive disease in all cases, but some patients have superimposed relapses – Commentary

“…Processes downstream the inflammatory demyelinating injury, however, evidently play an important role for the neuro-axonal damage and loss, and resulting disability accrual. 9 Where does this leave the discussion about disease progression affecting all people with MS? Although definitions vary, we agree with Cross and Naismith that BMS does exist.…”

“…Processes downstream the inflammatory demyelinating injury, however, evidently play an important role for the neuro-axonal damage and loss, and resulting disability accrual. 9…”

Metabolic Control of Smoldering Neuroinflammation

“…Therapeutically attractive targets have emerged, with preliminary in vitro and in vivo testing of compounds proving to be promising. Within this framework, two routes to therapeutic relevance have emerged, targeted therapies using small molecules and compounds ( 175 ) and non-targeted therapies. In regard to the latter, the use of dietary intervention (e.g., through the ketogenic diet and/or exercise) may hold the most direct and clinically translatable therapeutic approach towards reprogramming myeloid metabolism from harmful to helpful ( 176 ).…”

Stem Cell Therapies for Progressive Multiple Sclerosis

“…Here, DMTs work to prevent acute inflammatory insults by limiting infiltration of activated T cells, B cells, and macrophages into the CNS where they contribute to the initial demyelinating insult that eventually leads to axonal loss and neurological disability (Mallucci et al, 2015). However, with increasing age and the subsequent transition of patients into the progressive phase of the disease, conventional DMTs no longer have a clear rationale of use nor provide obvious clinical benefits (Cunniffe et al, 2021). In fact, the progressive form of MS differs from RRMS in that it is a distinct neurodegenerative process shaped by persistent inflammation behind a closed blood-brain barrier (BBB) involving mostly activated microglia/macrophages, and only partially T and B cells.…”

“…A recent combined systematic approach has reviewed existing evidence of human safety, BBB penetrance, demonstrable efficacy, and mechanistic targeting of licensed drugs for repurposing in PMS (Cunniffe et al, 2021). By focusing on processes and mechanisms of action that are specifically relevant to the pathogenesis of progression, four treatments were recommended for immediate testing in PMS: (R)-α-lipoic acid, metformin, the combination treatment of both (R)-α-lipoic acid and metformin, and niacin.…”