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.

Pociredir 20mg Cohort Data Highlights - The 20 mg cohort data raises the bar on Pociredir's best-in-class potential for treating sickle cell disease[14, 17] - At Week 6, the 20 mg cohort (n=12) showed a 99% mean absolute increase in HbF[17] - 58% of patients (7/12) in the 20 mg cohort achieved ≥20% HbF at their latest study visit[17] - In the 20 mg cohort, the six patients who completed the 12-week treatment period achieved >375-fold induction of HbF[17] Clinical Improvements - The study observed a 28% reduction in Lactate Dehydrogenase (LDH) and a 37% reduction in indirect bilirubin, indicating consistent reductions in markers of hemolysis with the 20 mg dose[71, 72] - There was a 31% reduction in Mean Absolute Reticulocyte Count (ARC) and a 22% reduction in Mean Red Cell Distribution Width (RDW-CV) with the 20 mg dose, indicating consistent improvements in red blood cell morphology and erythropoiesis[75] - Mean hemoglobin increased from 73 g/dL to 81 g/dL in the 20 mg cohort[81] - 67% of patients (8/12) reported no vaso-occlusive crises (VOCs) during the 12-week treatment period[86] Safety and Tolerability - Pociredir at 20 mg was generally well-tolerated, with 23% of patients (3/13) reporting treatment-related adverse events[90] - There were no serious treatment-related adverse events in the 20 mg cohort[90]

Core Insights - Fulcrum Therapeutics reported positive initial results from the 20 mg dose cohort of the Phase 1b PIONEER trial for pociredir in sickle cell disease, showing a clear dose-response and clinically meaningful increases in fetal hemoglobin (HbF) levels [1][2][4] Trial Design and Data Overview - The PIONEER trial is a Phase 1b open-label dose-escalation study evaluating pociredir's safety and efficacy in adult patients with severe sickle cell disease, with the 20 mg cohort consisting of 12 adults [3][13] - As of the November 11, 2025 data cutoff, all 12 patients completed the Week 6 visit, and 6 patients reached the Week 12 visit [3] Efficacy Data - At Week 6, the mean absolute HbF increased by 9.9% in the 20 mg cohort, with 58% of patients achieving HbF levels ≥20% [4][10] - A >3.75-fold mean induction of HbF was observed at Week 12 in the 20 mg cohort compared to a 2.4-fold induction in the 12 mg cohort [4][5] - The proportion of F-cells increased from 31% at baseline to 58% at Week 6, indicating early progression toward pan-cellular HbF induction [10] Safety Profile - Pociredir was generally well-tolerated, with no treatment-related serious adverse events reported as of the November 11, 2025 data cutoff [1][11] - The safety profile observed in the 20 mg cohort remained consistent with previously reported safety data from the 12 mg cohort [10][11] Future Plans - Fulcrum plans to host an investor event on December 7, 2025, to discuss the results from the PIONEER trial [1][7] - Updated results from the trial are expected to be reported in Q1 2026 [3]

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].

Core Points - U.S. stock futures are lower, with Dow futures down approximately 200 points [1] - Helmerich and Payne Inc reported a fourth-quarter loss of 1 cent per share, with quarterly sales of $1.012 billion, exceeding analyst expectations of $973.678 million [1] - Helmerich and Payne shares fell 7% to $25.69 in pre-market trading [1] Company Movements - Alpha Technology Group Ltd shares decreased by 19% to $17.50 after a significant surge of 132% on Monday [4] - Invivyd Inc shares fell 13.4% to $2.46 following the announcement of a $125 million public offering [4] - Nice Ltd shares dropped 7.3% to $112.00 after a 9% decline on the previous day [4] - H World Group Ltd shares fell 6.7% to $41.95 despite reporting better-than-expected third-quarter results [4] - Fulcrum Therapeutics Inc shares decreased by 6.6% to $9.01 after a 12% gain on Monday [4] - Rocket Pharmaceuticals Inc shares declined 6% to $2.86 [4] - OBOOK Holdings Inc shares fell 5.6% to $7.53 [4] - Iperionx Ltd shares decreased by 5% to $33.00 [4] - Home Depot Inc shares slipped 2% to $351.01 after reporting worse-than-expected third-quarter adjusted EPS and lowering FY25 adjusted EPS outlook [4]

Core Insights - Fulcrum Therapeutics is set to present new clinical data from the Phase 1b PIONEER trial of pociredir for sickle cell disease at the upcoming ASH Annual Meeting [1][2] - The company will also showcase preclinical data on its calmodulin pathway modulator program aimed at treating bone marrow failure syndromes [1] Presentation Details - The presentation titled "Pociredir, a novel oral once-daily fetal hemoglobin inducer: Results from the Phase 1b PIONEER study in adult participants with severe sickle cell disease and hydroxyurea intolerance or unresponsiveness" will occur on December 6, 2025, from 5:30 – 7:30 PM ET [2] - Another presentation titled "First-in-class small molecule calmodulin pathway modulators attenuate excess p53 activity and correct erythropoietic defects in models of diamond-blackfan anemia" will also take place on the same date and time [2] - Pociredir's poster has been selected for inclusion in the Poster Walk on Novel and Emerging Therapeutics in Erythrocyte and Iron Disorders on December 7, 2025 [2] Investor Event - Fulcrum will host a live and webcast investor event on December 7, 2025, at 7:00 AM ET in Orlando, featuring company leadership and medical experts [4] - The event will be accessible via the Investor Relations section of Fulcrum's website, with a recording available afterward [4] Company Overview - Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on developing small molecules for genetically defined rare diseases [5] - The lead clinical program, pociredir, aims to increase fetal hemoglobin expression for treating sickle cell disease [5][7] - Pociredir has received FDA Fast Track designation and Orphan Drug Designation for sickle cell disease treatment [7] About Pociredir - Pociredir is an investigational oral small-molecule inhibitor of EED, leading to downregulation of fetal globin repressors and increased fetal hemoglobin levels [6][7] - Initial data from the PIONEER Phase 1b trial indicated proof-of-concept with well-tolerated results and no treatment-related serious adverse events reported [7] About Sickle Cell Disease - Sickle cell disease is a genetic disorder caused by a mutation in the HBB gene, leading to inefficient oxygen transport and sickle-shaped red blood cells [8] - Patients typically experience severe clinical consequences, including anemia, pain, infections, and reduced life expectancy [8]

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]

Financial Data and Key Metrics Changes - Research and development expenses for Q3 2025 were $14.3 million, a slight decrease from $14.6 million in Q3 2024, primarily due to reduced employee compensation costs and discontinued programs [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] Business Line Data and Key Metrics Changes - The pociredir program for sickle cell disease showed promising results, with 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 ASH conference [6][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 100,000 U.S. patients meet the inclusion-exclusion criteria defined in the PIONEER trial [34] Company Strategy and Development Direction - The company aims to position pociredir as a best-in-class once-daily oral therapy for sickle cell disease, with plans to engage the FDA for an end-of-Phase I meeting in Q1 2026 [8][9] - The company is also advancing programs for bone marrow failure syndromes and plans to submit an IND for these conditions in Q4 2025 [9] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the upcoming data readout at the ASH conference and the potential for pociredir to provide a differentiated therapeutic option for sickle cell disease [8][13] - The company is focused on getting pociredir to market quickly to address the unmet needs of patients following the withdrawal of other treatment options [35][36] Other Important Information - The company has completed enrollment in the 20-milligram dose cohort and expects to present data from this cohort at the ASH conference [6][9] - The open-label extension study for pociredir was initiated to allow patients to continue treatment after the PIONEER trial [22][24] Q&A Session Summary Question: How are you internally thinking about what is a win here and whether ways to measure if there's a dose response? - Management believes they have already achieved a win with the 12-milligram cohort, showing robust increases in fetal hemoglobin and a trend toward reduced vaso-occlusive crises [16] Question: Can you provide insight into the baseline level of HbF for the patients in the first half of the 20 mg cohort? - The initial patients enrolled in the 20 mg cohort trended lower than the overall mean, but the exact numbers will be revealed at the data disclosure [29][32] Question: What do you need to see from the 20 mg dose cohort for it to be the go-forward Phase III dose? - Management will look for efficacy endpoints indicating improvement, favorable tolerability, and adherence to the study drug [44] Question: What is the FDA's expectation regarding safety data? - The FDA has not provided specific numerical criteria but expects ongoing favorable safety and tolerability data to be contextualized with the potential benefits of the therapy [75] Question: When will the final PIONEER data set be available? - The full data set is expected to be shared in the first quarter of next year [56]

Financial Data and Key Metrics Changes - Research and development expenses for Q3 2025 were $14.3 million, a slight decrease from $14.6 million in Q3 2024, primarily due to reduced employee compensation costs and discontinued programs [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, with a dose-dependent increase in fetal hemoglobin and a reduction in vaso-occlusive crises [4][8] - Enrollment in the 20-milligram dose cohort was completed, with data to be presented at the upcoming ASH conference [5][6] - 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 [3] - The company estimates that about 20% of the U.S. sickle cell population meets the inclusion-exclusion criteria for the Phase 1B Pioneer trial [30] 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 [5][21] - 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] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the encouraging results from the FTX-6058 program and the potential to provide differentiated therapeutic options for sickle cell disease patients [8][12] - The company is focused on expediting the drug's market entry to address the unmet needs of patients, especially following the withdrawal of other treatment options [31] Other Important Information - The company presented preclinical data for FTX-6274, an oral EED inhibitor, showing efficacy in prostate cancer models, indicating potential expansion beyond hematology programs [9] Q&A Session Summary Question: Insights on baseline characteristics of the 20 mg cohort - Management noted that the baseline characteristics of the 20 mg cohort are similar to previous cohorts, and they are analyzing the data to determine the dose response [14][15] Question: Interest in the open-label extension study - The decision to initiate the open-label extension study was influenced by patient and investigator feedback, allowing continued treatment for patients post-trial [20][21] Question: Addressable market assumptions - The company estimates that about 20% of the 100,000 U.S. patients with sickle cell disease meet the trial criteria, and they aim to expand treatment access [30][31] Question: Safety follow-up requirements from the FDA - The FDA has not specified numerical criteria for safety follow-up, but ongoing favorable safety profiles will be crucial for future discussions [64] Question: Future clinical plans beyond Phase 1B - The next study design will depend on discussions with regulators and may include a registrational trial focused on VOC reduction as a primary endpoint [65][66]

Financial Performance - Collaboration revenue for the three months ended September 30, 2025, was $0, compared to $80,000,000 for the same period in 2024, indicating a significant drop[19] - Net loss for the three months ended September 30, 2025, was $19,595,000, compared to a net loss of $21,696,000 for the same period in 2024, showing an improvement of about 9.7%[19] - For the nine months ended September 30, 2025, the company reported a net loss of $54.546 million compared to a net income of $6.843 million in the same period of 2024[25] - The net loss for the nine months ended September 30, 2025, was $54.5 million, compared to a net income of $6.8 million for the same period in 2024, primarily due to $80.0 million of collaboration revenue recognized in 2024[101] - The company has incurred significant operating losses since inception and expects to continue incurring losses over the next several years[156] Assets and Liabilities - Total current assets decreased from $249,923,000 as of December 31, 2024, to $205,863,000 as of September 30, 2025, a decline of approximately 17.7%[16] - Cash and cash equivalents decreased from $58,212,000 as of December 31, 2024, to $47,078,000 as of September 30, 2025, a decrease of approximately 19.1%[16] - Total liabilities decreased from $17,684,000 as of December 31, 2024, to $16,492,000 as of September 30, 2025, a reduction of about 6.7%[16] - Stockholders' equity decreased from $243,034,000 as of December 31, 2024, to $198,366,000 as of September 30, 2025, a decline of approximately 18.4%[16] - As of September 30, 2025, total cash equivalents and marketable securities amounted to $200,404,000, a decrease from $241,021,000 as of December 31, 2024[43][44] Operating Expenses - Total operating expenses for the nine months ended September 30, 2025, were $62,076,000, down from $82,468,000 in the same period of 2024, representing a reduction of approximately 24.7%[19] - General and administrative expenses for the nine months ended September 30, 2025, were $21,389,000, down from $28,732,000 in the same period of 2024, a decrease of approximately 25.6%[19] - The company recorded total operating expenses of $21,858,000 for the three months ended September 30, 2025, down from $25,126,000 in the same period of 2024[94] - Total operating expenses decreased by $20.4 million from $82.5 million in the nine months ended September 30, 2024 to $62.1 million in the same period in 2025[127] Research and Development - Research and development expenses for the three months ended September 30, 2025, were $14,296,000, slightly down from $14,639,000 in the same period of 2024[19] - Research and development expenses fell by $11.0 million from $51.7 million in the nine months ended September 30, 2024 to $40.7 million in the same period in 2025, mainly due to decreased external research and employee compensation costs[131] - External research and development expenses for pociredir were $5.4 million for the three months ended September 30, 2025, compared to $2.2 million in the same period in 2024[113] Cash Flow - Net cash used in operating activities was $43.267 million for the nine months ended September 30, 2025, a significant decrease from $14.543 million provided in the same period of 2024[25] - The company expects its cash and marketable securities to be sufficient to fund operating expenses for at least 12 months from the date of the financial statements[32] - The company had $200.6 million in cash, cash equivalents, and marketable securities as of September 30, 2025, which is expected to fund operations into 2028[104] Stock and Equity - Weighted-average common shares outstanding, basic, increased from 62,409,000 for the three months ended September 30, 2024, to 62,597,000 for the same period in 2025[19] - The company has reserved 28,952,871 shares of common stock for future issuance as of September 30, 2025, an increase from 26,673,185 shares as of December 31, 2024[52] - The total number of outstanding stock options increased to 11,870,785 with a weighted average exercise price of $6.57[61] Collaboration Agreements - The Company entered into a collaboration and license agreement with Sanofi in May 2024, which included an upfront payment of $80.0 million, but was terminated in April 2025[69][70] - The Company recognized no revenue associated with the Sanofi Agreement during the nine months ended September 30, 2025[74] - Collaboration revenue dropped by $80.0 million from $80.0 million in the nine months ended September 30, 2024 to $0 in the same period in 2025, due to the termination of the Sanofi collaboration agreement[128] Clinical Development and Risks - The successful development of product candidates remains uncertain, with no revenue expected from product sales for several years[105] - The company is still in the early stages of product development and has not completed development of any product candidates[156] - The company may face limitations on utilizing its net operating losses and research and development tax credit carryforwards due to an ownership change deemed to have occurred on September 12, 2024[176] - The company is subject to risks related to the lengthy and expensive clinical drug development process, which may not yield successful outcomes[184] - The company may need to conduct additional clinical trials or testing if initial results are not positive, which could delay marketing approvals[189] Market and Competition - Competition in the pharmaceutical industry is substantial, with major companies potentially developing products more successfully or rapidly[212] - Recent FDA approvals for competitive products, such as CASGEVY and LYFGENIA, could impact the company's market position[214] - The company may need to price its products at a significant premium over generic alternatives, affecting market acceptance and sales[214]