Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective: To 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. Design: Systematic 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. Results: We 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. Conclusions: We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders

Selection process for publications & interventions.

<p>Selection process for publications & interventions.</p

Short-listed interventions ranked by overall drug scores.

<p>* Amiloride added to the shortlist at committee review based on awareness of relevant but unpublished data. Scores for amiloride were then calculated following publication of this data.</p><p>Short-listed interventions ranked by overall drug scores.</p

Effect of shortlisted interventions on neurobehavioural and pathological outcomes in EAE.

<p>Symbols represent the point estimates of efficacy for interventions. Symbol sizes represent the log₁₀ of the number of animals contributing to that comparison. The vertical line represents the line of no effect.</p

Candidate interventions excluded during short-listing.

<p>MOA = mechanism of action</p><p>Candidate interventions excluded during short-listing.</p

Scoring method for evaluation of study quality.

<p>Following systematic review, study quality was evaluated according to previously published criteria (CAMARADES, Delphi, and GRADE—see text). A maximum of 24 points were available by the sum of these individual score</p><p>Scoring method for evaluation of study quality.</p

Eligibility criteria for publications included in systematic review.

<p>Data on efficacy was defined as (the) “reporting of change in clinical status (relapse frequency, disability progression, behavioural symptoms) or changes in biomarkers of clinical status (magnetic resonance imaging (MRI), blood, cerebral spinal fluid (CSF))”.</p