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

Cunniffe, Nick
Vuong, Khue Anh
Ainslie, Debbie
Baker, David
Beveridge, Judy
Bickley, Sorrel
Camilleri, Patrick
Craner, Matthew
Fitzgerald, Denise
de la Fuente, Alerie G
Giovannoni, Gavin
Gray, Emma
Hazlehurst, Lorraine
Kapoor, Raj
Kaur, Ranjit
Kozlowski, David
Lumicisi, Brooke
Mahad, Don
Neumann, Björn
Palmer, Alan
Peruzzotti-Jametti, Luca
Pluchino, Stefano
Robertson, Jennifer
Rothaul, Alan
Shellard, Lyndsey
Smith, Kenneth J
Wilkins, Alastair
Williams, Anna
Coles, Alasdair

¹Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK,
²Multiple Sclerosis Society, London, UK,
³Research Network, Multiple Sclerosis Society, London, UK,
⁴Blizard Institute, Queen Mary University of London, London, UK,
⁵Independent consultant, Stevenage, UK,
⁶Department of Neurology, University of Oxford, Oxford, UK,
⁷Wellcome-Wolfson Institute for Experimental Medicine, Queen’s Univeristy, Belfast, UK,
⁸Faculty of Brain Sciences, Queen Square Institute of Neurology, University College London, London, UK,
⁹Centre for Clinical Brain Sciences, Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK,
¹⁰University of Reading, Reading, Berkshire, UK,
¹¹Independent consultant, Woodstock, Oxfordshire, UK,
¹²Department of Neuroinflammation, Queen Square Institute of Neurology, University College London, London, UK,
¹³Department of Neurology, University of Bristol, Bristol, UK,
¹⁴MS Centre, Centre for regenerative medicine, University of Edinburgh, Edinburgh, UK,

Correspondence to Dr Nick Cunniffe, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK; e-mail; [email protected]

Received June 16, 2020; revision received September 08, 2020; Accepted October 13, 2020; previously published online November 12, 2020

Journal of Neurology, Neurosurgery, & Psychiatry 92(3):p 295-302, March 2021. | DOI: 10.1136/jnnp-2020-324286

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.