Fulcrum Therapeutics (FULC) investor relations material

Key clinical results

• 20 mg dose of pociredir resulted in a mean absolute increase in fetal hemoglobin (HbF) of 9.9% at week six, with mean HbF rising from 7.1% to 16.9%.

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

• Over 3.75-fold mean induction of HbF was observed at 12 weeks in the 20 mg cohort, surpassing the 12 mg cohort.

• 67% of patients reported no vaso-occlusive crises (VOCs) during treatment, with only 5 VOCs observed versus 16 expected.

• Significant improvements were seen in anemia, hemolysis markers (28–37% reductions in LDH, indirect bilirubin), and total hemoglobin, with a mean increase of 0.8 g/dL.

Patient population and study design

• PIONEER is a Phase 1b, open-label, dose-escalation study in adults with severe sickle cell disease, enrolling 12–13 patients in the 20 mg cohort, ages 18–65, not on hydroxyurea.

• Baseline mean HbF was 7.1%, with patients reporting a mean of 2.4 VOCs over 6 months.

• Primary endpoints were safety and PK; secondary endpoints included HbF induction, hemolysis, anemia, and VOC incidence.

• Adherence was high at 97%, and the cohort included patients from Nigeria for the first time.

• All 12 patients in the 20 mg cohort completed 6 weeks; 6 reached 12 weeks as of data cutoff.

Mechanism and clinical significance

• Pociredir increases HbF by inhibiting PRC2, reducing BCL11A activity, and has a clean off-target profile.

• Pan-cellular HbF induction was observed, with F-cells rising from 31% to 58% at week 6.

• Even small increases in HbF are clinically meaningful, with real-world data showing a jump in VOC-free rates from 12% to 60% as HbF rises from 0% to 5%.

• The agent achieved HbF levels about twice those seen with hydroxyurea, with greater hemoglobin increases.