Fulcrum Therapeutics reported new Phase 1b data for its oral EED inhibitor, pociredir, in sickle cell disease, showing dose-dependent, clinically meaningful increases in fetal hemoglobin with pan-cellular induction, improvements in hemolysis markers, higher total hemoglobin, and encouraging trends in fewer vaso-occlusive crises after 12 weeks at 12 mg. The company has completed enrollment in the 20 mg cohort, with data expected by year-end, is opening an extension study to assess durability and safety, and is entering Q4 with $200.6 million in cash and runway into 2028. Additional data are slated for presentation at the ASH annual meeting in December.
The signal is larger than one company’s update. If sustained and safe, an oral HbF inducer that drives pan-cellular expression challenges the emerging narrative that disease modification in sickle cell will be dominated by one-time gene therapies. The central strategic question now is whether regulators and payers will accept HbF as a reasonably likely surrogate for outcomes in SCD—particularly after recent retrenchments around surrogate-based approvals in hematology—or demand hard reductions in VOCs and healthcare utilization before granting broad access.
For patients and HCPs, the near-term relevance is practical. Gene editing and lentiviral gene addition promise functional cures but carry intensive conditioning, infrastructure bottlenecks, and seven-figure price tags. An oral, once-daily option—if it reproducibly raises HbF across erythroid cells and reduces crises—could scale across community settings and Medicaid-heavy populations, potentially as monotherapy or layered onto hydroxyurea. Adherence in Fulcrum’s 20 mg cohort has reportedly exceeded 90% to date, but long-term persistence will decide real-world effectiveness and payer contracting. Safety remains the gating factor: EED inhibition is an epigenetic mechanism that will face heightened scrutiny for off-target and oncogenic risks, making the open-label extension and multi-year pharmacovigilance pivotal to credibility.
For payers, HbF-linked outcomes could enable value frameworks that avoid the binary bet of curative therapies. Fulcrum’s presented real-world analyses correlating HbF levels with VOC reductions aim to backstop a surrogate-driven regulatory path and to underwrite outcomes-based contracts. But the bar has moved. After the withdrawal of certain SCD biologics and pressure to confirm clinical benefit beyond lab markers, it is unlikely that hemoglobin or HbF alone will sustain a label or reimbursement without convincing VOC and utilization data. Expect step therapy debates: if oral HbF induction proves robust, plans may push patients to try it before authorizing gene therapies, reshaping uptake curves for recently launched cell and gene treatments.
Competitionally, the SCD landscape is fragmenting into high-intensity, high-cost one-time interventions and chronic oral agents that modulate hemolysis or HbF. Pociredir’s pan-cellular induction directly echoes the mechanism underpinning BCL11A-targeted gene edits, offering a pharmacologic route to a similar biology. If Fulcrum can pair a clean safety profile with VOC reductions in larger, longer studies, it could catalyze renewed investment in epigenetic small molecules after prior regulatory setbacks in the class. With runway into 2028 and a broadened pipeline (including a planned IND for bone marrow failure syndromes), the company has time to pursue pivotal development, though partnering for global execution and ex-US access remains a logical lever.
The next inflection arrives at ASH and with the 20 mg readout: will the magnitude and distribution of HbF induction translate into tangible crisis reduction and healthcare savings sufficient to shift treatment sequencing—and, if so, do payers start to make oral HbF induction the gatekeeper before gene therapy?
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
