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

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.

Comparison of the Pharmacokinetics of RIPK1 Inhibitor GSK2982772 in Healthy Western and Japanese Subjects.

BACKGROUND AND OBJECTIVES: GSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2). METHODS: Both studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A (N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects (N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 (N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day. RESULTS: GSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC(0-7)) of 120 and 240 mg, and (AUC(0-24)) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects. CONCLUSIONS: The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov .

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers.

GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open-label relative bioavailability study comparing 20-mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24-hour period for the 60-mg and 120-mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.