A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.
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.


CONCLUSIONS
The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.
Neurology Department, Basel University Hospital, Switzerland.
Tobias
T
Derfuss
GeNeuro SA, Switzerland fc@geneuro.com.
François
F
Curtin
Neurology Department, Basel University Hospital, Switzerland.
Claudia
C
Guebelin
Department of Clinical Neurosciences, Geneva University Hospital, Switzerland.
Claire
C
Bridel
Neurology Department, Basel University Hospital, Switzerland.
Maria
M
Rasenack
Pharmacology and Toxicology Division, Geneva University Hospital, Switzerland.
Alain
A
Matthey
Neurology Department, Lausanne University Hospital, Switzerland.
Renaud
R
Du Pasquier
Neurology Department, Lausanne University Hospital, Switzerland.
Myriam
M
Schluep
Pharmacology and Toxicology Division, Geneva University Hospital, Switzerland.
Jules
J
Desmeules
GeNeuro SA, Switzerland.
Alois B
AB
Lang
GeNeuro SA, Switzerland.
Hervé
H
Perron
GeNeuro SA, Switzerland.
Raphael
R
Faucard
GeNeuro SA, Switzerland/Pharmacology Department, University of Pretoria, South Africa.
Hervé
H
Porchet
Neurology Department, Heinrich Heine University, Germany.
Hans-Peter
HP
Hartung
Neurology Department, Basel University Hospital, Switzerland.
Ludwig
L
Kappos
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.
Patrice H
PH
Lalive
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D004311:Double-Blind Method; D020077:Endogenous Retroviruses; D005260:Female; D015686:Gene Products, env / Q000037:antagonists & inhibitors*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology* / Q000821:virology; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000032:analysis
D061067:Antibodies, Monoclonal, Humanized; D015686:Gene Products, env; D012367:RNA, Viral; C581064:temelimab
Multiple sclerosis; clinical trial; endogenous retrovirus; human endogenous retrovirus type W family; monoclonal antibody; multiple sclerosis-associated retrovirus