FDA’s post-Tazverik safety stance ends Fulcrum’s sickle cell ambitions

Fulcrum Therapeutics, Inc. (Nasdaq: FULC) announced the discontinuation of its PRC2 inhibitor pociredir program for sickle cell disease following FDA feedback indicating no viable regulatory path forward. The program has been discontinued as a consequence, with Fulcrum stating it will carry out a review of strategic alternatives, including a potential merger, acquisition, or business combination.

According to Fulcrum, the FDA cited the unexpectedly high incidence of secondary hematologic malignancies found to be associated with Tazverik (tazemetostat), another PRC2 inhibitor developed by Ipsen for follicular lympoma and sarcoma. Those findings led Ipsen to voluntarily withdraw Tazverik from the market in March 2026. Fulcrum noted that pociredir’s inhibition of the PRC2 complex targeted a different subunit – EED instead of EZ2. However, the FDA concluded that pharmacological disruption of the PRC2 complex carries a comparable malignancy risk regardless of the subunit targeted. Combined with previously disclosed preclinical malignancy findings for pociredir, the agency indicated there was no viable regulatory pathway for further development.

Pociredir is an investigational oral small-molecule inhibitor of EED, a structural component of the PRC2 complex responsible for epigenetic silencing of fetal hemoglobin gene expression. By inhibiting EED, pociredir disrupts PRC2 activity, de-repressing fetal globin genes and increasing fetal hemoglobin levels in red blood cells — a validated therapeutic strategy for sickle cell disease.

In the PIONEER Phase Ib clinical trial, pociredir demonstrated dose-dependent increases in fetal hemoglobin, pan-cellular fetal hemoglobin induction, and improvements in markers of hemolysis and anemia across the 12 mg and 20 mg dose cohorts, with no treatment-related serious adverse events reported at up to three months of exposure. The drug had received both Fast Track and Orphan Drug Designation from the FDA for the treatment of sickle cell disease.

Pociredir was discovered internally at Fulcrum Therapeutics using the company’s proprietary gene regulatory network discovery platform, which identifies small molecules capable of modulating gene expression to address genetically defined diseases. Fulcrum reported USD 333.3 million in cash as of March 31, 2026, and indicated it has initiated efforts to reduce operating expenses. No timeline for the strategic review was provided.

Implications for PRC2 inhibition

The FDA’s position could have implications beyond Fulcrum. Multiple companies are developing therapies that target the polycomb repressive complex 2 (PRC2), either through direct inhibition of EZH2, the complex’s catalytic subunit, or through alternative approaches targeting EED, a scaffolding component required for PRC2 function. The agency’s apparent conclusion that malignancy risk may extend across the PRC2 complex rather than being confined to a single subunit raises questions for developers pursuing related mechanisms.

Among the most visible programs is Oric Pharmaceuticals’ rinzimetostat (ORIC-944), an EED-targeting PRC2 inhibitor in clinical development for metastatic castration-resistant prostate cancer. ORIC has previously emphasized the mechanistic distinction between EED inhibition and EZH2 inhibition, arguing that EED-directed approaches may offer advantages over first-generation EZH2 inhibitors.

Other companies have also advanced PRC2-directed programs into the clinic, including Novartis with the EED inhibitor MAK683 and Ascentage Pharma with APG-5918, another EED-targeting molecule. Both programs were developed on the premise that disrupting PRC2 through EED could provide a differentiated safety and efficacy profile relative to EZH2 inhibition. MAK683 is not under active development currently, while Ascentage’s APG-5918 is in ongoing early-phase trials for solid tumors or lymphomas.