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

Abstract

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 ( C max ), time to reach C max ( T max ), 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 . Electronic supplementary material The online version of this article (10.1007/s13318-020-00652-2) contains supplementary material, which is available to authorized users.

A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis

“…Taken together, these results do not support the notion that RIPK1 inhibition alone at the level achieved in this study could translate into transformative improvement of UC. 27–29 …”

“…Taken together, these results do not support the notion that RIPK1 inhibition alone at the level achieved in this study could translate into transformative improvement of UC. [27][28][29] Other limitations to the study include the relatively small sample size and that baseline information regarding disease severity, including Montreal classification, was not collected. The impact of disease heterogeneity between treatment groups may have affected outcomes.…”

Necroptosis in Pulmonary Diseases: A New Therapeutic Target

“…GSK2982772 is a RIPK1 inhibitor. The first-in-human study showed that single and repeat doses of GSK2982772 were generally safe and well-tolerated in healthy adult volunteers, which support progression into Phase II clinical trials (Weisel et al, 2017;Tompson et al, 2021). The phase 2a clinical trials showed a certain therapeutic effect on active plaque psoriasis, and other phase 2a clinical trials in moderate to severe psoriasis are currently underway (Weisel et al, 2020).…”

Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using DiffCORE Technology

“…GSK2982772 is considered a Biopharmaceutics Classification System (BCS) class 2 drug substance characterized by high passive permeability (human Peff [effective permeability] > 2 × 10 -4 cm/s), and low solubility (0.1 mg/mL) (9,10). Despite the low solubility, when GSK2982772 is administered either as standard immediate-release (IR) tablets or powder in capsules, there is no evidence of dissolution rate-limiting absorption up to a dose of 240 mg (11). Median time to maximum concentration (T max ) is approximately 2 h post-dose (8).…”