Safety, Tolerability, and Pharmacokinetics of Valemetostat Tablets and the Effect of Food on Valemetostat Pharmacokinetics in Healthy Subjects: Two Phase 1 Studies

Abstract Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog‐2 (EZH2) and EZH1. In a first‐in‐human phase‐1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non‐Hodgkin lymphoma. Subsequently, a film‐coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200‐mg), the relative bioavailability between capsules and tablets, and the effect of food (high‐fat or low‐fat meals) on the PK of valemetostat tablets. In the ascending‐dose study, valemetostat maximum plasma concentration (C max ) and area under the concentration–time curve (AUC) increased dose‐proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200‐mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%‐60% lower C max , 30%‐50% lower AUC, and a median T max delay of 2.5‐3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment‐emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect.