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.

Financial Data and Key Metrics Changes - Research and development expenses for Q3 2025 were $14.3 million, a decrease from $14.6 million in Q3 2024, primarily due to reduced employee compensation costs and decreased costs associated with a discontinued program [10] - General administrative expenses decreased to $7.6 million in Q3 2025 from $8.4 million in Q3 2024, mainly due to lower professional services costs [10] - The net loss for Q3 2025 was $19.6 million, compared to a net loss of $21.7 million in Q3 2024 [11] - Cash, cash equivalents, and marketable securities at the end of Q3 2025 totaled $200.6 million, down from $241 million at the end of 2024, primarily due to cash used for operating activities [11] - The company expects its existing cash resources to fund operations into 2028, allowing for substantial progress in clinical development [11] Business Line Data and Key Metrics Changes - The lead program, FTX-6058, for sickle cell disease showed promising results, including a dose-dependent increase in fetal hemoglobin and a reduction in vaso-occlusive crises [5][8] - Enrollment in the 20-milligram dose cohort was completed with 12 evaluable patients, and data will be presented at the upcoming ASH conference [6][7] - The company is also advancing programs for bone marrow failure syndromes and plans to submit an IND for these conditions in Q4 2025 [9] Market Data and Key Metrics Changes - Approximately 100,000 people in the U.S. and 7.7 million worldwide suffer from sickle cell disease, indicating a significant market need for effective treatments [4] - The company estimates that about 20% of the U.S. sickle cell disease population meets the inclusion-exclusion criteria for the Phase 1B Pioneer trial [35] Company Strategy and Development Direction - The company aims to position FTX-6058 as a best-in-class once-daily oral therapy for sickle cell disease, with plans for an open-label extension trial to evaluate long-term safety and efficacy [6][8] - The strategy includes engaging with the FDA for an end-of-Phase 1 meeting in Q1 2026 to discuss the next stages of clinical development [8] - The company is focused on expediting the drug's market entry to address the unmet needs of sickle cell disease patients globally [36] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the encouraging results from the 12-milligram cohort and the upcoming data readout at the ASH conference [12][13] - The management team highlighted the importance of generating additional safety data through the open-label extension study, which is expected to inform future discussions with the FDA [24][75] Other Important Information - The company has seen a high adherence rate of over 90% among patients in the study, indicating strong patient engagement with the treatment regimen [7] - The management team emphasized the need for a comprehensive approach to evaluating the drug's efficacy, considering multiple parameters such as fetal hemoglobin levels and reduction in vaso-occlusive crises [52] Q&A Session Summary Question: How does the company define a win in the context of the trial results? - Management believes they have already achieved a win with the 12-milligram cohort, showing robust increases in fetal hemoglobin and a favorable safety profile [16] Question: What are the expectations for the 20 mg dose cohort? - Management anticipates that the 20 mg cohort will outperform the 12 mg cohort based on previous healthy volunteer data [18] Question: What is the addressable market following the withdrawal of a competitor's product? - The company estimates that about 20% of the 100,000 U.S. patients with sickle cell disease currently meet the trial criteria, with plans to discuss potential market expansion with the FDA [35] Question: What metrics will be important for defining the activity of FTX-6058? - Management indicated that the totality of data, including fetal hemoglobin levels, pan-cellularity, and reduction in markers of hemolysis, will be crucial for evaluating the drug's efficacy [52] Question: What is the timeline for the final Pioneer data set? - The full data set is expected to be available in the first quarter of the following year [56]