Fulcrum Therapeutics Conference Call Summary Company Overview - **Company**: Fulcrum Therapeutics (NasdaqGM: FULC) - **Focus**: Development of treatments for sickle cell disease, particularly through fetal hemoglobin induction Key Industry Insights - **Sickle Cell Disease**: A debilitating condition affecting over 7 million individuals globally, with around 100,000 cases in the U.S. [13] - **Unmet Need**: Patients face significant health challenges, including painful vaso-occlusive crises (VOCs), chronic anemia, and reduced life expectancy by over 20 years compared to the general population [14] Core Drug Insights - **Drug**: Pociredir - **Mechanism**: Inhibits EED subunit of PRC2, leading to increased fetal hemoglobin (HbF) levels by reducing BCL11A activity [17][18] - **Clinical Data**: - **20 mg Cohort**: Showed a 9.9% mean absolute increase in HbF at week six, exceeding the 12 mg cohort's results [10][11] - **Efficacy**: 58% of patients achieved HbF levels greater than or equal to 20% [10][47] - **Induction**: 3.75-fold increase in HbF induction observed [11][47] - **Safety**: Generally well tolerated with no discontinuations due to adverse events [43][46] Patient Population and Study Design - **Study Population**: 13 patients enrolled, predominantly with severe genotypes, ages 18 to 65 [25] - **Adherence**: 97% adherence rate documented using an AiCure app [28] - **Endpoints**: Focused on safety, tolerability, HbF induction, hemolysis, and anemia [26] Clinical Outcomes - **HbF Induction**: Absolute increase of 16.9% HbF at day 42, compared to 16.2% at 12 weeks for the 20 mg cohort [31] - **VOCs**: Only five VOCs observed in four patients during the treatment period, with 67% of patients reporting no VOCs [42] - **Hemolysis Markers**: Significant reductions in lactate dehydrogenase (LDH) and indirect bilirubin levels, indicating improved hemolysis [37] Future Directions - **Next Steps**: Completion of the 20 mg cohort and preparation for an end-of-phase meeting with the FDA planned for early 2026 [55] - **Open Label Extension Study**: Expected to begin enrolling patients in the first half of next year [55] - **Registrational Study**: Plans to initiate a registrational study in the second half of next year, pending regulatory feedback [55] Additional Insights - **Potential for Cure**: Discussion on the possibility of achieving functional cures for some patients through high levels of HbF induction [58][59] - **Market Expansion**: Consideration of expanding the patient population to include those with less severe symptoms, as the disease progresses even without acute pain [94] Conclusion - Fulcrum Therapeutics is making significant strides in the treatment of sickle cell disease with promising data from the Pociredir trials, indicating potential for transformative patient outcomes and a pathway towards regulatory approval.

Core Viewpoint - Fulcrum Therapeutics is set to present new clinical data from the Phase 1b PIONEER trial of pociredir for sickle cell disease (SCD) at an investor event on December 7, 2025, which will also be shared at the 67th American Society of Hematology Annual Meeting [1][3]. Company Overview - Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on developing small molecules aimed at improving the lives of patients with genetically defined rare diseases, particularly in areas with high unmet medical needs [6]. - The company's lead clinical program, pociredir, is designed to increase fetal hemoglobin expression for the treatment of sickle cell disease [6][8]. Clinical Trial Information - The upcoming event will provide initial clinical data from the 20 mg dose cohort and full data from the 12 mg dose cohort of the Phase 1b PIONEER trial of pociredir in SCD [3]. - Pociredir has shown proof-of-concept in initial data from the PIONEER trial, achieving absolute levels of fetal hemoglobin increases that may benefit patients [8]. - The drug has been generally well-tolerated in patients with SCD during the trial, with no treatment-related serious adverse events reported over three months of exposure [8]. Expert Involvement - The event will feature insights from Dr. Sheinei Alan, Director of the Inova Adult Sickle Cell Program, and Dr. Martin Steinberg, a prominent hematologist specializing in sickle cell disease [2][4][5]. - Dr. Alan leads multiple clinical trials and has contributed to the development of national guidelines for sickle cell care, while Dr. Steinberg has extensive research experience and has published over 450 articles on sickle cell disease [4][5]. Disease Context - Sickle cell disease is a genetic disorder caused by a mutation in the HBB gene, leading to inefficient oxygen transport and the formation of sickle-shaped red blood cells, which can cause various serious health complications [9].