Our Take
The FDA rejected Fulcrum's mechanistic argument that its PRC2 inhibitor posed lower cancer risk than Ipsen's withdrawn drug, treating all PRC2 inhibition as equivalent malignancy liability regardless of which subunit the drug targets.
Why it matters
Sickle cell drug development has now lost two major candidates in months (Oxbryta and pociredir), signaling that mechanistic selectivity may not shield oral PRC2 inhibitors from serious side effects. Pipeline momentum is shifting to alternative targets like cereblon modulators.
Do this week
Regulatory teams: audit your PRC2 inhibitor programs now and model the FDA's position that target selectivity does not offset class-level risk before advancing Phase II trials.
Fulcrum terminates pociredir following FDA malignancy concerns
Fulcrum Therapeutics announced May 28 it is stopping development of pociredir, its lead candidate for sickle cell disease, after the FDA raised heightened concerns about cancer risk at an end-of-phase meeting. The agency's stance was triggered by secondary blood cancers observed in patients treated with Ipsen's Tazverik (tazemetostat), another PRC2 inhibitor that Ipsen withdrew from the market in March 2024.
Pociredir targets EED, a component of the polycomb repressive complex 2 (PRC2), while Tazverik targets EZH2, a different PRC2 subunit. Fulcrum had argued to the FDA that these mechanistic differences meant pociredir carried lower malignancy risk than Tazverik. The agency rejected that argument, concluding that any drug blocking the PRC2 complex carries equivalent cancer liability "regardless of the specific subunit engaged," according to Fulcrum's statement.
Pociredir had shown clinical promise. In February 2024, interim Phase Ib data (PIONEER trial, 12 patients) reported a mean absolute increase in fetal hemoglobin (HbF) of 12.2 percentage points at 12 weeks, rising from baseline 7.1% to 19.3%. Seven of 12 patients (58%) achieved HbF levels of 20% or higher. Zero vaso-occlusive crises were reported in 58% of treated patients during the treatment period. No treatment-related serious adverse events had been observed with pociredir to date.
Fulcrum CEO Alex C. Sapir said the company had "no path forward" with pociredir and announced a comprehensive strategic review, including potential merger, acquisition, or sale of assets. The company also began cost reduction efforts to preserve capital. Fulcrum held $333.3 million in cash and marketable securities at end of Q1 2024, with runway extending into 2029 (per company filing).
Markets reacted sharply. Fulcrum shares fell 51% on May 28, closing at $3.13 from $6.42 the prior day.
Class-level regulatory skepticism narrows SCD drug options
The FDA's rejection of Fulcrum's selectivity argument represents a significant setback for the broader strategy of targeting PRC2 inhibition in sickle cell disease. The agency treated the entire PRC2 complex as a malignancy liability zone, regardless of which subunit a drug engages. That posture closes pociredir as a regulatory path and potentially constrains future PRC2-targeted programs.
Pociredir's termination compounds recent losses. Pfizer withdrew Oxbryta (voxelotor) from the market in 2024 after clinical trial deaths and vaso-occlusive crises were reported, despite the drug acting through a different mechanism (hemoglobin oxygen affinity).
Vijay Sankaran, MD, PhD, a pediatrics professor at Boston Children's Hospital, told GEN that preclinical work on pociredir "might not have revealed the full range of potential effects" because much of it relied on cell models. Vivien Sheehan, MD, PhD, director of translational sickle cell research at Emory University, characterized Fulcrum's interim data as "reasonable, although not game changing." She noted that "more efficacious drugs in the pipeline may have also influenced the decision."
Sheehan expressed greater enthusiasm for BMS-986470, a cereblon E3 ligase modulator in Phase I/II trials, which targets different transcription factors (ZBTB7A and WIZ) and aims to induce fetal hemoglobin through a mechanistically distinct route. Preclinical work by BMS researchers showed BMS-986470 generated robust gamma-globin induction predicted to ameliorate SCD pathology (per 2024 BMS research).
What regulators and developers should track
The FDA's PRC2 class-level stance does not foreclose HbF induction as a therapeutic target. Instead, it filters the pathway: oral PRC2 inhibitors face higher bar for malignancy risk mitigation across the entire complex. Alternative mechanisms for raising fetal hemoglobin (cereblon modulators, other transcription factor modulators) remain available for development.
For Fulcrum, the financial pressure is real. The company had projected pociredir would achieve peak sales of $1.5 billion by 2038 with a 2029 launch (per Bank of America Securities estimate). Loss of that asset, combined with cash burn, creates urgency around the announced strategic review. Merger or acquisition scenarios are likely to unfold within the next 18 months.
The broader lesson: mechanistic selectivity does not automatically override class-level safety signals in the FDA's eyes. Regulatory strategy must account for the possibility that a safety concern tied to a protein target or pathway will be treated as a class effect, limiting individualized risk-benefit arguments.