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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02302404.

Keywords: GSK2982772; RIPK1; anti-inflammatory agents; pharmacodynamics; pharmacokinetics; safety.

© 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

Figures

Figure 1

Study design. In Part A, subjects in Cohorts 1 and 2 were randomized 1:1:1:1 to 1 of 4 treatment sequences. During each period of Part A, 6 of 8 subjects in Cohorts 1 and 2 received the assigned dose level of GSK2982772 and 2 subjects received placebo, except for Cohort 2 during Period 4 (fed state) where all subjects received GSK2982772 with a high‐fat meal. In Part B, subjects received the assigned dose of GSK2982772 for 14 days of continuous treatment. Cohorts at the next higher dose level began once the preceding dose was deemed safe. In Part C, subjects were randomized to receive either GSK2982772 20‐mg capsules or tablets. BID, twice daily; Pbo, placebo; QD, once daily

Figure 2

Part A. Mean blood GSK2982772 concentration‐time plots by treatment, semi‐logarithmic scale. The dotted line represents lower limit of quantitation of 0.2 ng/mL

Figure 3

Part B. Mean plasma GSK2982772 concentration‐time plots by treatment. The dotted line represents lower limit of quantitation of 0.2 ng/mL

Figure 4

Adjusted mean (95% CI) of TEAR1 percent target engagement for Part A (A) and for Part B on Day 1 (B, left panel) and Day 14 (B, right panel)

Figure 5

Concentration‐response plot of TEAR1 target engagement

Figure 6

Adjusted mean (95% CI) of MIP‐1α % inhibition on Day 14

Figure 7

Concentration‐response plot of MIP‐1α target engagement