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

Debra Tompson,Rennan Pan,Mark Whitaker,Litza Mckenzie,Geoffrey Johnson,Kathy Abbott-Banner,Vanessa Zann,Teresa Fuller,Marcy Powell,Simon Hawkins

doi:10.1007/s11095-021-03124-7

Abstract

PurposeGSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology.MethodsPart A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR-18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120–960 mg) in different prandial states.ResultsPharmacokinetic profiles for all MR formulations and doses tested in the fasted and fed states were consistent with QD dosing.ConclusionsThe DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018).

Highlights

GSK2982772 is a highly selective, receptor-interacting protein-1 kinase (RIPK1) inhibitor being developed for the treatment of plaque psoriasis and other immunemediated inflammatory diseases
In order to reduce the possibility of food effects with high-fat meals, the current study evaluated MR formulations utilizing GSK proprietary DiffCORETM technology, which has previously shown robustness against food effects (e.g., Lamictal XR) [16]
Single doses of GSK2982772 DiffCORE MR and entericcoated formulations were generally well tolerated in healthy subjects

Summary

Introduction

GSK2982772 is a highly selective, receptor-interacting protein-1 kinase (RIPK1) inhibitor being developed for the treatment of plaque psoriasis and other immunemediated inflammatory diseases. RIPK1 has dual roles as a kinase and a scaffolding protein Through both functions, it acts as a key mediator of cell death and inflammation downstream of numerous pathways and signaling receptors, including the tumor necrosis factor (TNF) family of cytokines [1, 2]. RIPK1 facilitates TNF-mediated classical apoptosis and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκβ) signaling through its scaffolding function [2, 5, 6]. Inhibitors of RIPK1 activity are being investigated in diseases linked to TNF activation, including plaque psoriasis and other inflammatory diseases [1, 7, 8]

Methods

Results

Discussion

Conclusion