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Efficacy and Safety of Temelimab, an Antibody Antagonist of the Human Endogenous Retrovirus Type-W env Protein, in Participants with Relapsing Remitting Multiple Sclerosis: A Double-Blind, Randomised, Placebo-Controlled Phase 2b Clinical Trial

130 Pages Posted: 17 May 2019

See all articles by Hans-Peter Hartung

Hans-Peter Hartung

Heinrich Heine University Dusseldorf - Department of Neurology; Heinrich Heine University Dusseldorf - Center for Neurology and Neuropsychiatry LVR Klinikum

Tobias Derfuss

University of Basel - University Hospital Basel

Bruce Cree

University of California, San Francisco (UCSF) - UCSF Weill Institute for Neurosciences

Maria Pia Sormani

Department of Health Sciences (DISSAL); Ospedale Policlinico San Martino

Krzysztof Selmaj

Medical University of Lodz

Jon Stutters

University College London - Institute of Neurology

Ferran Prados

University College London - Institute of Neurology; Open University of Catalunya (UOC) (Open University of Catalonia)

David MacManus

University College London - Institute of Neurology

Hans-Martin Schneble

Servier International Research Institute (IRIS)

Hervé Porchet

GeNeuro SA; University of Pretoria

Robert Glanzman

GeNeuro SA

Estelle Lambert

Servier International Research Institute (IRIS)

Gordon Francis

GeNeuro SA

Francois Curtin

GeNeuro SA; University of Geneva

Frederik Barkhof

VU University Amsterdam - Amsterdam Neuroscience; University College London - Institute of Neurology; University College London

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Abstract

Background:  The envelope protein encoded by pathogenic Human Endogenous Retrovirus type-W (pHERV W-env) has been involved in the pathophysiology of MS. In pre-clinical studies pHERV-W-env directly activated microglia and inhibited remyelination; both mechanisms contribute to MS-related CNS damage. Temelimab (GNbAC1) is a humanised, IgG4-kappa monoclonal antibody that targets pHERV-W-env, neutralising its effects in preclinical models. The aim of this Phase 2 study was to evaluate efficacy and safety of three doses of temelimab in participants with relapsing-remitting MS.

Methods:  A 24-week randomised, double-blind, placebo-controlled Period 1 was followed by a 24 week randomised, dose-controlled Period 2 (NCT02782858). Placebo-treated subjects from Period 1 were re-randomised to one of the active treatment arms for Period 2. Six injections were repeated in both periods. Primary endpoint was the cumulative number of Gd-enhancing T1 lesions in monthly brain MRIs from week 12 to 24. Secondary and exploratory endpoints were: hypointense T1 lesion number/volume, T2 lesion number/volume, change in brain volume, change in magnetisation transfer ratio (MTR), clinical relapse, and disability at weeks 24 and 48.

Findings:  270 participants were randomised. The primary endpoint was not met at week 24 (comparison ratio 0.90 (95% CI=0.49-1.64) highest dose vs placebo). 247 participants (91.5% of original cohort) entered Period 2; 236 (87.4%) completed week 48 evaluations. A dose-related decrease of brain atrophy and positive effects on T1 hypointense lesion number and MTR in the 18 mg/kg group were observed at week 48. No safety issue emerged.

Interpretation:  This is the first clinical efficacy study of temelimab, a specific anti-HERV-directed therapy. No benefit was seen on inflammatory measures at week 24; however, week 48 data suggests dose-dependent effects of temelimab on 3 neurodegeneration measures: brain atrophy, MTR and T1 hypointense lesions. Temelimab has further development potential as a neuroprotective treatment that specifically blocks deleterious CNS effects of pHERV-W-env in MS.

Clinical Trial Number: EudraCT Number 2015-004059-29.

Funding Statement: GeNeuro SA funded TOTZKE & DREHER SCIENTFIC SA, Geneva, Switzerland to assist with drafting a first version of the final manuscript from an outline and material prepared by RG, FC, HPH and editorial comments from all authors during the process. No honoraria, grants, or other form of payment were provided to investigators, with the exception of funding needed to do the study.

Declaration of Interests: Frederick Barkhoff: Board membership: Brain, Neurology, Radiology, Eur Radiology, Multiple Sclerosis Journal Consultancy: Bayer-Schering Pharma (SC), Biogen Idec, Teva, Merck Serono, Novartis, Jansen Research (Consultancy, data-analysis center), IXICO Ltd. (Consultancy, safety reads), Geneuro (Consultancy, data-analysis), Roche (Advisory Board, Consultancy, Data-analysis center, DSMB, all personal fee); Genzyme-Sanofi (Consultancy, DSMB), Apitope Ltd (Consultancy, personal fee and money paid to institution) Grants/grants pending: AMYPAD (IMI), EuroPOND (H2020), UK MS Society, Dutch MS Society, PICTURE (IMDI-NWO), NIHR UCLH Biomedical Research Centre (BRC), ECTRIMS-MAGNIMS (money paid to institution) Honoraria: for consultancy above Payment for development of educational presentations including service on speakers' Bureaus: Biogen-IDEC (personal fee and money paid to institution) Payment for development of educational presentations including service on speakers' Bureaus: IXICO (personal fee) Bruce Cree: Dr. Cree reports personal fees from GeNeuro during the conduct of the study; personal fees from: Abbvie, Akili, Alexion, Biogen, EMD Serono, Novartis, and Sanofi Genzyme, outside the submitted work. Francois Curtin: Francois Curtin is an employee and shareholder of Geneuro. Tobias Derfuss: reports fees other from GeNeuro, during the conduct of the study; grants and other from Novartis, grants and other from Biogen, other from Roche, other from Merck, other from Sanofi Genzyme, other from MedDay, other from Celgene, other from Mitsubishi Pharma, other from Actelion, outside the submitted work. Gordon Francis:G. Francis has nothing to disclose. Robert Glanzman: reports that he was a paid consultant for GeNeuro S.A. during the conduct of the study and outside the submitted work. Hans-Peter Hartung: reports personal fees from Bayer Healthcare, Biogen, Celgene Receptos, EMD Serono, GeNeuro, Greenwich Biosciences, MedDay, Merck, MedImmune, Novartis, Roche, Sanofi Genzyme, Teva, TG Therapeutics. Estelle Lambert: reports personal fees from Institut de Recherches Internationales de Servier I.R.I.S, outside the submitted work. David McManus: has nothing to disclose. Hervé Porchet: reports personal fees from GeNeuro SA. Ferran Prados: reports grants from Non-clinical Guarantors of Brain Fellowship, outside the submitted work. Hans-Martin Schneble: reports personal fees from Institut de Recherches Internationales de Servier I.R.I.S., outside the submitted work. Krzysztof Selmaj: reports personal fees from Biogen, Celgene Corporation, Genzyme, Merck, Novartis, Ono Pharma, Roche, Synthon, and Teva. Maria Pia Sormani: reports personal fees from GeNeuro, during the conduct of the study; personal fees from Biogen, TEVA, Novartis, Roche, Sanofi Genzyme, Merck, MedDay, outside the submitted work. Jonathan Stutters: has nothing to disclose.

Ethics Approval Statement:  The local Independent Ethics Committees reviewed and approved the protocol. The study was conducted in accordance with Good Clinical Practice and the European Medicines Agency’s Guideline on Clinical Investigation of Medicinal Products for the Treatment of MS. Participants provided informed consent before beginning any protocol-driven activities.

Keywords: Multiple sclerosis; HERV-directed temelimab; phase 2 trial; neuroprotection

Suggested Citation

Hartung, Hans-Peter and Derfuss, Tobias and Cree, Bruce and Sormani, Maria Pia and Selmaj, Krzysztof and Stutters, Jon and Prados, Ferran and MacManus, David and Schneble, Hans-Martin and Porchet, Hervé and Glanzman, Robert and Lambert, Estelle and Francis, Gordon and Curtin, Francois and Barkhof, Frederik, Efficacy and Safety of Temelimab, an Antibody Antagonist of the Human Endogenous Retrovirus Type-W env Protein, in Participants with Relapsing Remitting Multiple Sclerosis: A Double-Blind, Randomised, Placebo-Controlled Phase 2b Clinical Trial (May 14, 2019). Available at SSRN: https://ssrn.com/abstract=3388820

Hans-Peter Hartung (Contact Author)

Heinrich Heine University Dusseldorf - Department of Neurology ( email )

Germany

Heinrich Heine University Dusseldorf - Center for Neurology and Neuropsychiatry LVR Klinikum ( email )

Germany

Tobias Derfuss

University of Basel - University Hospital Basel

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

Bruce Cree

University of California, San Francisco (UCSF) - UCSF Weill Institute for Neurosciences

505 Parnassus Ave
San Francisco, CA 94143
United States

Maria Pia Sormani

Department of Health Sciences (DISSAL)

Italy

Ospedale Policlinico San Martino

Genoa
Italy

Krzysztof Selmaj

Medical University of Lodz

Lodz
Poland

Jon Stutters

University College London - Institute of Neurology

Queen Square
London WC1N 3BG
United Kingdom

Ferran Prados

University College London - Institute of Neurology

Queen Square
London WC1N 3BG
United Kingdom

Open University of Catalunya (UOC) (Open University of Catalonia)

Tibidabo Av. 39-43
08035 Barcelona, Barcelona 08035
Spain

David MacManus

University College London - Institute of Neurology

Queen Square
London WC1N 3BG
United Kingdom

Hans-Martin Schneble

Servier International Research Institute (IRIS)

France

Hervé Porchet

GeNeuro SA

Switzerland

University of Pretoria

Physical Address Economic and Management Sciences
Pretoria, Gauteng 0002
South Africa

Robert Glanzman

GeNeuro SA

Switzerland

Estelle Lambert

Servier International Research Institute (IRIS)

France

Gordon Francis

GeNeuro SA

Switzerland

Francois Curtin

GeNeuro SA

Switzerland

University of Geneva

102 Bd Carl-Vogt
Genève, CH - 1205
Switzerland

Frederik Barkhof

VU University Amsterdam - Amsterdam Neuroscience

Amsterdam
Netherlands

University College London - Institute of Neurology

Queen Square
London WC1N 3BG
United Kingdom

University College London

Gower Street
London, WC1E 6BT
United Kingdom

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