Safety, pharmacokinetics, and pharmacodynamics of escalating repeat doses of GSK249320 in patients with stroke.

ABSTRACT

BACKGROUND AND PURPOSE: Restorative therapies have the potential to improve function and reduce disability after stroke with a wide therapeutic window. The current study evaluated GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule myelin-associated glycoprotein and also protects oligodendrocytes. METHODS: Patients with mild-moderate stroke were randomized to intravenous GSK249320 (1, 5, or 15 mg/kg per infusion, in escalating cohorts of 8-9 subjects) versus placebo (n=17). Infusion 1 was 24 to 72 hours after stroke; infusion 2 was 9 ± 1 days later. The primary objective evaluated safety and tolerability, and the secondary objectives evaluated immunogenicity, pharmacokinetics, biomarkers, neurophysiology, and motor function. RESULTS: Baseline (n=42) characteristics were similar across treatment groups. No safety concerns were found based on adverse events, examination, vital signs, ECG, nerve conduction tests, brain imaging, motor function testing, and laboratory studies. Two of the 25 subjects dosed with GSK249320 developed transient antidrug antibodies after infusion 1. The pharmacokinetics profile was as expected for an IgG1 type monoclonal antibody. Serum levels of the biomarker S100ß did not differ between groups. Global outcome measures were similar across groups. Modality-specific end points could be consistently measured in the first few days after stroke, and one of these, gait velocity, demonstrated a trend toward improvement with GSK249320 compared with placebo. CONCLUSIONS: GSK249320 was generally well tolerated. No major safety issues were identified in this first study of a monoclonal antibody to modulate the neurobiology of brain repair after stroke. Future studies might explore the efficacy of GSK249320 as a restorative therapy for stroke. Clinical Trial Registration- URL http//www.clinicaltrials.gov. Unique Identifier NCT00833989.