171: Effect of Mild to Moderate Hepatic Impairment on Valemetostat Pharmacokinetics: An Open-Label, Phase 1 Study

Statement of Purpose: Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog 2 (EZH2) and EZH1 under investigation for the treatment of various cancers, including non-Hodgkin lymphomas and solid tumors. Due to the critical role of cytochrome P450-mediated metabolism in facilitating valemetostat elimination, and the large contribution of plasma protein binding on valemetostat clearance, investigation is warranted to assess changes in valemetostat pharmacokinetics (PK) in the setting of hepatic impairment (HI). This study evaluated the PK of valemetostat in subjects with or without HI to inform future dosing recommendations.

Description of Methods & Materials: This open-label, Phase 1, single-dose study (NCT04276662) enrolled healthy subjects with mild or moderate HI, as defined by National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria, and subjects with normal hepatic function (HF) matched by body weight, age and sex to both HI groups. All subjects received a single 50-mg dose of valemetostat, and valemetostat PK profiles were compared between groups using an analysis of variance model.

Data & Results: Overall, 24 subjects were enrolled with mild HI (n=8), moderate HI (n=8), or normal HF (n=8). All groups were similar in age, sex, race, weight and BMI at screening. Mean baseline serum albumin was 39.1, 34.3, and 42.9 g/L in subjects with mild HI, moderate HI and normal HF, respectively, and α1-acid glycoprotein was 15.8, 11.4 and 16.6 μmol/L. Total valemetostat peak concentration (C_max) and exposure extrapolated to infinity (AUC_inf) decreased by 29% and 23%, respectively, for subjects with mild HI, and by 29% and 35% for those with moderate HI, compared with the normal HF cohort. Unbound valemetostat C_max and AUC_inf decreased by 29% and 19%, respectively, in subjects with mild HI compared with normal HF, but increased by 19% and 25% for those with moderate HI. The mean unbound fraction (fu) of valemetostat was higher in the moderate HI cohort (range 0.0600–0.0813) vs mild HI (0.0373–0.0535) and normal HF (0.0365–0.0433). The mean (SD) AUC_inf of the metabolite-to-parent ratio (MPR) between total oxidized metabolite CALZ-1809a and valemetostat decreased from 0.645 (0.124) for normal HF to 0.516 (0.162) for mild HI and 0.503 (0.176) for moderate HI. The half-life was comparable among all groups for total and unbound valemetostat and CALZ-1809a. The 50-mg valemetostat dose showed acceptable safety and tolerability in all subjects, with no drug-related treatment-emergent adverse events reported.

Interpretation, Conclusion or Significance: Changes in valemetostat exposure in subjects with mild and moderate HI were not considered clinically meaningful. Currently, no dosing adjustments are recommended for cancer patients with HI. While the decrease in MPR in subjects with HI suggests a reduction in valemetostat metabolism to CALZ-1809a, total valemetostat exposure decreased in moderate HI. The higher fu in the moderate HI cohort was due to lower baseline serum albumin and α1-acid-glycoprotein levels (vs normal HF), which are both bound by valemetostat. This increased valemetostat clearance, ultimately reducing total valemetostat exposure.

Disclosures: MT, TS, YL, MA report employment by and equity ownership in Daiichi Sankyo. TC reports former employment by Daiichi Sankyo. TM reports equity ownership in Daiichi Sankyo and employment by Orlando Clinical Research Center SO reports no conflict. GA reports no conflict.