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

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. Herve 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.