Serum pharmacokinetics and cerebrospinal fluid concentration analysis of the new IgG4 monoclonal antibody GNbAC1 to treat multiple sclerosis: A Phase 1 study

Abstract

GNbAC1 is a humanized IgG4 monoclonal antibody antagonist of Mulitple Sclerosis Retrovirus Envelope (MSRV-Env), a protein that could play a critical role in multiple sclerosis. This randomized placebocontrolled dose-escalation study evaluated the safety and pharmacokinetics of GNbAC1 in 21 healthy volunteers after single intravenous infusion at doses of 6, 18 and 36 mg/kg. Lumbar punctures were performed at days 2, 15 or 29 to measure GNbAC1 concentrations in cerebrospinal fluid (CSF). GNbAC1 was well tolerated. Serum data show a dose-linear pharmacokinetics. A mean CSF/serum ratio of 0.12% was observed at Day 2, increasing to 0.39% at Day 15 and 0.42% at Day 29. Linear regression analysis shows a relationship between GNbAC1 CSF/serum ratio and albumin CSF/serum ratio and a relationship at the limit of statistical significance with the timing of CSF sampling.

A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody

“…GNbAC1 was assessed for the first time in humans in a phase I trial in 33 healthy subjects up to a dose of 6 mg/kg . Another phase I study, in which single doses of GNbAC1 of 6, 18 and 36 mg/kg were tested in 21 healthy male subjects, confirmed the pharmacokinetic data observed at the lower dose . The pharmacokinetic variables are in line with those usually observed with similar monoclonal antibodies.…”

“…So far three clinical trials have been performed and completed with GNbAC1: two were pharmacology studies in healthy volunteers and one was a clinical study in patients with MS . Currently a phase IIb clinical trial is underway in ~260 patients with MS …”

“…The geometric mean elimination half‐life was estimated to be between 21 and 26 days across all dose levels up to 36 mg/kg. Geometric mean residence time values by dose were calculated to a range from 29 to 36 days . The median time to maximal concentration (t max ) is observed at times ranging from 2 to 4 hours.…”

“…The median time to maximal concentration (t max ) is observed at times ranging from 2 to 4 hours. GNbAC1 exposure increases with increasing doses in a dose‐proportional manner for the ratios of the means, for the peak concentration and the areas under the curve . When repeated doses of GNbAC1 are administered, the accumulation factor is estimated to be ~2‐fold …”

Human Endogenous Retroviruses in Neurological Diseases

“…Together, these data argue that pathogenic HERV-W Env protein (formerly MSRV-Env) is a potential therapeutic target in MS, and that the neutralizing humanized antibody GNbAC1 therefore warrants development; indeed, several early-phase trials have now been completed [73,[75][76][77]. A Phase IIb multicenter clinical trial including 260 relapsing-remitting MS (RRMS) patients in 12 European countries is ongoing with this humanized IgG4 antibody.…”