Fulcrum Therapeutics (FULC) Leerink’s Global Healthcare Conference 2025 summary

Key clinical milestones and data readouts

• Two important Phase 1b clinical readouts for pociredir in sickle cell disease are expected: the 12mg cohort mid-year and the 20mg cohort by year-end, each with approximately 10 patients.

• The study focuses on safety and pociredir’s ability to increase fetal hemoglobin (HbF) levels, with a mid-single-digit percent increase considered clinically meaningful.

• Enrollment is progressing well, with 15 sites activated and potential for up to 20; over-enrollment in the 12mg cohort is possible due to high interest.

• Dose escalation to 20mg is contingent on DSMB review after the eighth patient in the 12mg cohort completes four weeks of dosing.

• Open-label extension is not currently available but is being considered for future studies, especially for patients in the 20mg cohort.

Mechanism of action and differentiation

• Pociredir inhibits the EED subunit of the PRC2 complex, leading to upregulation of HBG and increased fetal hemoglobin expression.

• Differentiation from other HbF inducers includes targeting histone methylation (EED inhibition) versus DNA methylation or transcription factor degradation.

• Other agents in development target different mechanisms, such as hydroxyurea (stress erythropoiesis), DNMT1 inhibitors, and transcription factor degraders.

Regulatory and patient population updates

• A clinical hold in early 2023 was resolved by redefining the patient population to include those with more severe disease or prior therapy failure, without requiring new preclinical or clinical studies.

• Inclusion criteria now focus on patients with frequent acute events or end-organ disease, and those who failed or are intolerant to hydroxyurea.

• FDA feedback suggests broader inclusion criteria and longer dosing may be considered if Pioneer study data demonstrate clear benefit.