Fulcrum Therapeutics (FULC) Status Update summary

Study Overview and Objectives

• PIONEER is a Phase 1b, open-label, dose-escalation study evaluating pociredir in adults with severe sickle cell disease (SCD).

• The goal is to develop a once-daily oral HbF inducer with robust efficacy, pan-cellular induction, and favorable tolerability.

• Key endpoints include safety, HbF induction, hemolysis, anemia, and incidence of vaso-occlusive crises (VOC).

Patient Demographics and Baseline Characteristics

• 12 patients in the 20 mg cohort, mean age 32.3 years, 58% male, with severe SCD.

• Baseline mean HbF was 7.1%, and patients reported a mean of 2.4 VOCs over 6 months or 6.7 over 12 months.

Efficacy Results and Clinical Impact

• 20 mg dose showed a 9.9% mean absolute increase in HbF at week 6, with mean HbF rising from 7.1% to 16.9%.

• 58% of patients achieved HbF ≥20%, and all had at least a 6.5% absolute HbF increase.

• Over 3.75-fold mean induction of HbF at 12 weeks in the 20 mg cohort, compared to 2.4-fold in the 12 mg cohort.

• Proportion of F-cells rose from 31% to 58% at week 6, indicating pan-cellular HbF induction.

• 67% of patients reported no VOCs during the treatment period, with only 5 VOCs observed versus 16 expected.