A phase I, first-in-human single ascending dose study of the MEK inhibitor WX-554 given to healthy male subjects.

Abstract

e13666 Background: WX-554 is a small molecule inhibitor targeting mitogen-activated protein kinase kinase (MEK1 and MEK2). The Ras/Raf/MEK/ERK pathway is one of the major signal transduction pathways that cells use to control proliferation and survival. WX-554, originally developed by UCB, is one of several MEK inhibitors currently in development. The study is designed to deliver reliable PK and PD data to guide rational drug dose and therapeutic regimen. WX-554 is being administered as a single dose i.v. to healthy volunteers and with the aim of delivering the benchmark dose(s) for a subsequent oral study, ideally in the same healthy volunteer population. Methods: Treatment groups will consist of 5 subjects each. The targeted number of evaluable subjects is 25. The planned single doses of WX-554 will be in the range 0.05 mg/kg to 5.0 mg/kg in accordance with the adaptive Verweij approach. Dose escalation will continue until maximum pERK inhibition is observed provided that no dose limiting toxicity (DLT) occurs. Plasma levels of WX-554 will be determined at various intervals after dosing. pERK and TNF alpha inhibition in PBMCs will be assessed. Results: The first two cohorts have been successfully completed and show excellent target inhibition with no worrisome drug-related side-effects. Conclusions: Dose-escalation will therefore continue. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration WILEX