Valemetostat (DS-3201): A Comprehensive Monograph on a First-in-Class Dual EZH1/EZH2 Inhibitor for Hematologic Malignancies

Executive Summary

Valemetostat, marketed under the brand name Ezharmia®, represents a significant advancement in the field of epigenetic therapy for cancer. It is a first-in-class, orally bioavailable, small molecule that functions as a dual inhibitor of the histone lysine methyltransferases Enhancer of Zeste Homolog 1 (EZH1) and Enhancer of Zeste Homolog 2 (EZH2).[1] These enzymes are the catalytic subunits of the Polycomb Repressive Complex 2 (PRC2), which plays a critical role in gene silencing. The dual-inhibition strategy is a key therapeutic innovation designed to overcome the compensatory activity of EZH1, a known mechanism of resistance that can limit the efficacy of selective EZH2 inhibitors.[2]

Developed by Daiichi Sankyo, Valemetostat has achieved landmark regulatory approvals from Japan's Pharmaceuticals and Medical Devices Agency (PMDA). In September 2022, it received its initial approval for the treatment of patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATL), a rare and aggressive hematologic malignancy with a high unmet medical need, particularly in Japan.[2] This was followed by an expanded approval in June 2024 for the treatment of adult patients with R/R peripheral T-cell lymphoma (PTCL), a heterogeneous group of aggressive non-Hodgkin lymphomas.[6]