Post by Drug Hunter

The EZH2 inhibitor tazemetostat (Tazverik®) is being voluntarily withdrawn, roughly six years after its first approval, after secondary hematologic malignancy concerns emerged in a confirmatory trial. Tazemetostat was the first FDA-approved EZH2 inhibitor, targeting the catalytic subunit of PRC2, a chromatin-regulating complex that deposits repressive H3K27 methylation marks. PRC2 activity is functionally counterbalanced by SWI/SNF chromatin remodeling, and dysregulation of this balance has been implicated across multiple cancers. The drug became the first FDA-approved systemic therapy specifically for epithelioid sarcoma despite achieving a modest 15% overall response rate in its registration-enabling Ph. 2 cohort. Stronger responses were later observed in follicular lymphoma, particularly in patients with EZH2-mutant disease, leading to an expanded accelerated approval in 2020. However, in the Ph. 3 SYMPHONY-1 confirmatory trial in follicular lymphoma, secondary hematologic malignancies were reported, leading Ipsen to withdraw tazemetostat from all indications in its markets. Full Ph. 3 data have not yet been disclosed. The secondary hematologic malignancies seen with tazemetostat appears to have already influenced the FDA’s cautious approach towards other PRC2-targeting drug candidates: on June 1, Fulcrum Therapeutics announced the discontinuation of their PRC2 inhibitor pociredir (FTX-6058), stating in their press release that the “FDA raised concerns regarding the potential malignancy risk associated with pociredir’s inhibition of the PRC2 complex, given the experience with Tazverik." It appears the regulatory path forward for future PRC2 inhibitors, especially in chronic, non-oncology indications, could become substantially more difficult.