Fulcrum Therapeutics (FULC) investor relations material

Key clinical data and feedback

• PIONEER study showed robust and rapid induction of fetal hemoglobin (HbF), with average increases from 7.1% to 19.3%, and all key hemolysis markers trending positively.

• Early data indicated a reduction in vaso-occlusive crises (VOCs), with only six observed versus 16 expected over 12 weeks, and seven of 12 patients had no VOCs during treatment.

• All patients saw HbF increases, with 60% reaching at least 20% HbF; even those with lower increases experienced clinically meaningful benefits.

• Safety profile was favorable, with most adverse events manageable and only one notable case of cytopenia linked to a viral infection, not the drug.

• Physician and patient community feedback has been highly positive, with increased interest in future studies.

Study design and regulatory strategy

• Next steps include a pivotal registrational study of 200–300 patients, targeting a more severe sickle cell population, with an interim HbF analysis at six months for potential accelerated approval.

• Powering assumptions for the study are conservative, factoring in higher baseline VOC rates and dropout rates to ensure robust results.

• Plans to engage with the EMA mid-year, aiming for harmonized regulatory guidance with the FDA to streamline global development.

• Anticipates a broad label post-approval, not limited by strict VOC entry criteria, based on precedent from other sickle cell therapies.

Patient population and response variability

• Geographic and genetic factors, such as the Central African Republic (Bantu) haplotype, may influence HbF response; future studies may stratify by geography.

• Post hoc analyses are ongoing to better understand response variability, especially in patients with low baseline HbF or those receiving transfusions.