Fulcrum Therapeutics is set to release new clinical trial data by mid-2024 for pociredir (FTX-6058), their innovative oral therapy candidate for sickle cell disease (SCD). The data will come from the ongoing PIONEER Phase 1b trial's third-highest dosing group, with results from the highest dose group expected by year-end.
The PIONEER trial (NCT05169580) continues to recruit participants across multiple U.S. sites and one in South Africa, with additional sites preparing to open in both the U.S. and Nigeria. The expansion demonstrates the growing scope of this potentially transformative therapy's development program.
Novel Mechanism Targeting Fetal Hemoglobin Production
Pociredir represents a unique therapeutic approach to SCD treatment. The oral small molecule is designed to inhibit the embryonic ectoderm development (EED) protein, a component of the polycomb repressive complex 2 (PRC2). This inhibition aims to reactivate the production of fetal hemoglobin (HbF), which is naturally switched off in infancy.
The strategy addresses the fundamental cause of SCD, where mutations in adult hemoglobin lead to sickle-shaped red blood cells that obstruct blood vessels and cause painful vaso-occlusive crises (VOCs). Fetal hemoglobin is more effective at carrying oxygen than its adult counterpart, making its reactivation a promising therapeutic strategy.
Early Trial Results Show Promise
The Phase 1b trial has enrolled patients aged 18-65 years, evaluating four different daily oral doses: 6 mg (Cohort 1), 2 mg (Cohort 2), 12 mg (Cohort 3), and 20 mg (Cohort 4). Initial data has been encouraging, demonstrating:
- Dose-dependent increases in HbF levels
- Improvements in biomarkers of red blood cell destruction and anemia
- Good tolerability with no serious treatment-related adverse events in 16 participants
Trial Progress Following FDA Hold Resolution
The trial experienced a temporary FDA clinical hold in 2023 due to concerns about PRC2 inhibition and potential blood cancer risks. Following the implementation of stricter inclusion criteria, the hold was lifted, and enrollment resumed with a focus on patients with severe SCD who:
- Have documented history of VOCs and other SCD complications
- Are ineligible for or have failed to respond to hydroxyurea
- Have not responded to or tolerated at least one of: Adakveo, Oxbryta, or Endari
The FDA has granted pociredir both fast track and orphan drug designations, potentially expediting its development and approval process.
Market Positioning and Future Outlook
Fulcrum positions pociredir as a potential best-in-class therapy for SCD, citing its demonstrated proof-of-concept and unique mechanism of action. While other HbF inducers are in development, pociredir's oral administration and promising early results suggest it could address significant unmet needs in the SCD treatment landscape.
The company views 2025 as a potentially transformational year for the program, with upcoming data readouts from higher-dose cohorts expected to provide crucial insights into the therapy's efficacy and safety profile.
