Abstract
ObjectiveTo develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.DesignSystematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.ResultsWe identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation.ConclusionsWe demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.
Highlights
Multiple sclerosis (MS) is estimated to affect more than 2.5 million people globally and is the commonest non-traumatic cause of acquired disability for young adults in the industrialised world [1,2]
We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action
After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation
Summary
Multiple sclerosis (MS) is estimated to affect more than 2.5 million people globally and is the commonest non-traumatic cause of acquired disability for young adults in the industrialised world [1,2]. It is an autoimmune disorder that has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression (SP) [3]. The failure to develop clinically effective neuroprotective drugs for SPMS likely reflects a combination of factors including the limited predictive value of existing animal models [5,6], and challenging trial design issues such as patient and disease heterogeneity, selection of relevant outcomes and biomarkers, and trial duration [7]. By exploiting existing trial and regulatory data on clinical safety and efficacy, “drug rescue” (evaluating drugs at advanced stage of development but abandoned before approval) and “repurposing” (evaluating drugs already approved for other conditions), offer the potential to reduce both the cost and time to achieve licensed approval status [10]
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