Tobias Derfuss1, François Curtin2, Claudia Guebelin1, Claire Bridel3, Maria Rasenack1, Alain Matthey4, Renaud Du Pasquier5, Myriam Schluep5, Jules Desmeules4, Alois B Lang6, Hervé Perron6, Raphael Faucard6, Hervé Porchet7, Hans-Peter Hartung8, Ludwig Kappos1, Patrice H Lalive9. 1. Neurology Department, Basel University Hospital, Switzerland. 2. GeNeuro SA, Switzerland fc@geneuro.com. 3. Department of Clinical Neurosciences, Geneva University Hospital, Switzerland. 4. Pharmacology and Toxicology Division, Geneva University Hospital, Switzerland. 5. Neurology Department, Lausanne University Hospital, Switzerland. 6. GeNeuro SA, Switzerland. 7. GeNeuro SA, Switzerland/Pharmacology Department, University of Pretoria, South Africa. 8. Neurology Department, Heinrich Heine University, Germany. 9. Department of Clinical Neurosciences, Geneva University Hospital, Switzerland/Department of Genetic and Laboratory Medicine, Geneva University Hospital, Switzerland/Department of Pathology and Immunology, University of Geneva, Switzerland.
Abstract
BACKGROUND:GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. OBJECTIVE: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. METHODS:Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. RESULTS: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. CONCLUSION: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.
RCT Entities:
BACKGROUND:GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. OBJECTIVE: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MSpatients. The primary objective was to assess GNbAC1 safety in MSpatients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. METHODS: Ten MSpatients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. RESULTS: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. CONCLUSION: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MSpatients over a six-month treatment period.
Authors: Maria Zimmermann; Nicholas S R Sanderson; Maria Rasenack; Patrice H Lalive; Alois B Lang; Francois Curtin; Raija L P Lindberg; Ludwig Kappos; Tobias Derfuss Journal: Neurol Neuroimmunol Neuroinflamm Date: 2015-08-20