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Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T‐cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure–response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150–200 mg), and six safety endpoints in patients with non‐Hodgkin lymphoma (n = 102, 150–300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment‐emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184–887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter‐individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL. [ABSTRACT FROM AUTHOR]

Valemetostat is an EZH2/1 inhibitor that has been approved in Japan for the treatment of patients with relapsed/refractory adult T‐cell leukemia/lymphoma, based mainly on results from a single‐arm phase II trial. It is currently under investigation worldwide for the treatment of other non‐Hodgkin lymphomas (NHLs), including peripheral T‐cell lymphoma, and for solid tumors. Semi‐mechanistic population pharmacokinetic modeling of total and unbound valemetostat and an analysis of the platelet time course during treatment with valemetostat were conducted using data from five clinical trials (two in patients with NHL and three in healthy volunteers). Pharmacokinetic data, including 3162 total/1871 unbound valemetostat observations from 102 patients and 72 healthy volunteers, were described by a three‐compartment model with sequential zero‐/first‐order absorption and saturable binding in the central compartment. Alpha‐1‐acid glycoprotein (AAG) was the most influential covariate for total valemetostat exposure, yet had little impact on unbound exposure, meaning no dose adjustment was warranted based on AAG levels. The longitudinal platelet data from 101 patients (2313 observations) were adequately described by a modified Friberg model with two proliferation compartments, which characterized unique spontaneous recovery of platelet counts without dose modifications. A model‐based simulation quantitatively assessed the proposed dose‐adjustment guidance in case of platelet count decreased by comparing the probability of treatment discontinuation due to platelet count decreased with or without the dose adjustment. In summary, the models described observed total and unbound valemetostat concentrations and a unique time course of platelets during treatment, which can justify the clinical dose and provide dose‐adjustment guidance. [ABSTRACT FROM AUTHOR]

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 (Cmax) 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 Cmax, 30%‐50% lower AUC, and a median Tmax 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. [ABSTRACT FROM AUTHOR]