A Single-Blind Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients with Stroke (S52.005)

OBJECTIVE: Primary: examine safety and tolerability of GSK249320. Secondary: examine immunogenicity, pharmacokinetics, biomarkers, neurophysiology, and motor function. BACKGROUND: Restorative therapies improve stroke outcome with a wide time window. After stroke, levels of the axon outgrowth inhibition molecule myelin-associated glycoprotein (MAG) increase. Blockade of MAG promotes axon growth. GSK249320 is a humanized IgG1 monoclonal antibody against MAG that has a disabled Fc region to prevent toxicity, crosses BBB, neutralizes MAG-mediated inhibition, promotes axon growth, and reduces oligodendrocyte death. DESIGN/METHODS: Patients with mild-moderate stroke and a weak arm, leg, or both were randomized to IV GSK249320 (1, 5, or 15 mg/kg per infusion, in escalating cohorts) vs. placebo. Infusion 1 was 24-72 hr post-stroke; Infusion 2, 9±1 days later. RESULTS: Baseline (n=42) features across treatment groups were similar, with median NIHSS scores of 6-7.5, infarct volume 16-35 cc, and time to first dose 46-55 hr. No safety concerns were found based on adverse events, exam, vital signs, EKG, nerve conduction tests, brain imaging, motor testing, and laboratory studies. Two of the 25 subjects dosed with GSK249320 developed transient anti-drug antibodies. The PK profile was as expected. Serum levels of the biomarker S100β did not differ between groups. Global outcome measures were similar across groups. Modality-specific endpoints were consistently measured in the first days post-stroke, and while not powered for efficacy, one (gait velocity) showed a trend towards improvement with GSK249320 vs. placebo. CONCLUSIONS: GSK249320 was generally well tolerated. No major safety issues were identified in this first study of a monoclonal antibody to modulate brain repair after stroke. Restorative therapies have the potential to be accessed by many stroke patients and so complement reperfusion and rehabilitation therapies. Future studies might further explore the efficacy of GSK249320 as a restorative therapy for stroke. Supported by: GlaxoSmithKline. Disclosure: Dr. Cramer has received personal compensation for activities with GlaxoSmithKline, Inc., Pfizer Inc, and Microtransponder. Dr. Abila has received personal compensation for activities with GlaxoSmithKline as an employee. Dr. Scott has received personal compensation for activities with GlaxoSmithKline as an employee. Dr. Simeoni has receied personal compensation for activities with GlaxoSmithKline as an employee. Dr. Enney has received personal compensation for activities with GlaxoSmithKline, Inc. as an employee. Dr. Cramer has received personal compensation for activities with GlaxoSmithKline, Inc., Pfizer Inc, and Microtransponder.