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

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

doi:10.1136/jnnp-2020-324286

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

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

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	295-302
Number of pages	8
Journal	Journal of Neurology, Neurosurgery and Psychiatry
Volume	92
Issue number	3
DOIs	https://doi.org/10.1136/jnnp-2020-324286
Publication status	Published - 01 Mar 2021

Bibliographical note

Funding Information:
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.

Publisher Copyright:
©

Keywords

Animals
Drug Evaluation
Drug Repositioning
Humans
Multiple Sclerosis, Chronic Progressive/drug therapy

ASJC Scopus subject areas

Surgery
Clinical Neurology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cunniffe, N., Vuong, K. A., Ainslie, D., Baker, D., Beveridge, J., Bickley, S., Camilleri, P., Craner, M., Fitzgerald, D., de la Fuente, A. G., Giovannoni, G., Gray, E., Hazlehurst, L., Kapoor, R., Kaur, R., Kozlowski, D., Lumicisi, B., Mahad, D., Neumann, B., ... Coles, A. (2021). Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry, 92(3), 295-302. https://doi.org/10.1136/jnnp-2020-324286

@article{9258936db40d42faa3e12db3047dfe56,

title = "Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis",

abstract = "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.",

keywords = "Animals, Drug Evaluation, Drug Repositioning, Humans, Multiple Sclerosis, Chronic Progressive/drug therapy",

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

note = "Funding Information: 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 {\textquoteright}5five per mille{\textquoteright} public funding, by the Isaac Newton Trust RG 97440 and the Addenbrooke{\textquoteright}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. Publisher Copyright: {\textcopyright} ",

year = "2021",

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doi = "10.1136/jnnp-2020-324286",

language = "English",

volume = "92",

pages = "295--302",

journal = "Journal of Neurology, Neurosurgery and Psychiatry",

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Cunniffe, N, Vuong, KA, Ainslie, D, Baker, D, Beveridge, J, Bickley, S, Camilleri, P, Craner, M, Fitzgerald, D, de la Fuente, AG, Giovannoni, G, Gray, E, Hazlehurst, L, Kapoor, R, Kaur, R, Kozlowski, D, Lumicisi, B, Mahad, D, Neumann, B, Palmer, A, Peruzzotti-Jametti, L, Pluchino, S, Robertson, J, Rothaul, A, Shellard, L, Smith, KJ, Wilkins, A, Williams, A & Coles, A 2021, 'Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis', Journal of Neurology, Neurosurgery and Psychiatry, vol. 92, no. 3, pp. 295-302. https://doi.org/10.1136/jnnp-2020-324286

TY - JOUR

T1 - Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis

AU - Cunniffe, Nick

AU - Vuong, Khue Anh

AU - Ainslie, Debbie

AU - Baker, David

AU - Beveridge, Judy

AU - Bickley, Sorrel

AU - Camilleri, Patrick

AU - Craner, Matthew

AU - Fitzgerald, Denise

AU - de la Fuente, Alerie G

AU - Giovannoni, Gavin

AU - Gray, Emma

AU - Hazlehurst, Lorraine

AU - Kapoor, Raj

AU - Kaur, Ranjit

AU - Kozlowski, David

AU - Lumicisi, Brooke

AU - Mahad, Don

AU - Neumann, Björn

AU - Palmer, Alan

AU - Peruzzotti-Jametti, Luca

AU - Pluchino, Stefano

AU - Robertson, Jennifer

AU - Rothaul, Alan

AU - Shellard, Lyndsey

AU - Smith, Kenneth J

AU - Wilkins, Alastair

AU - Williams, Anna

AU - Coles, Alasdair

N1 - Funding Information: 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. Publisher Copyright: ©

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

AB - 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.

KW - Animals

KW - Drug Evaluation

KW - Drug Repositioning

KW - Humans

KW - Multiple Sclerosis, Chronic Progressive/drug therapy

U2 - 10.1136/jnnp-2020-324286

DO - 10.1136/jnnp-2020-324286

M3 - Article

C2 - 33184094

AN - SCOPUS:85096528360

SN - 0022-3050

VL - 92

SP - 295

EP - 302

JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

IS - 3

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this