Fulcrum Therapeutics, Inc. · NASDAQ:FULC
Fulcrum Therapeutics — Technical Presentation (December 2025)
31 slides from Fulcrum Therapeutics's technical presentation, Dec 8, 2025
Slide 1: Pociredir PIONEER Study: 20 mg Cohort ASH Data Release
Pociredir PIONEER Study: 20 mg Cohort ASH Data Release December 7, 2025
Slide 2: Disclaimer and Notice
Disclaimer and Notice This presentation contains “forward-looking statements” of Fulcrum Therapeutics, Inc. (Fulcrum or Fulcrum Therapeutics) within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including express or implied stat
Slide 3: Today's Guest Speakers
Today’s Guest Speakers Drs. Alan and Steinberg are practicing physicians and paid Investigators in Fulcrum Therapeutics’ PIONEER Study. The views and opinions expressed by Drs. Alan and Steinberg are their own and do not necessarily reflect those of Fulcrum Therapeutics. Sheinei Alan, M.D., Ph.D. Di
Slide 4: Agenda for Investor Call
Agenda for Investor Call Introduction Alex C. Sapir, President & CEO Sickle Cell Disease (SCD) and the Potential of a Once Daily Oral HbF-Inducer Iain Fraser MBChB, D.Phil, SVP Early Clinical Development PIONEER Study Overview and 20 mg Pociredir Cohort Data Update Sheinei Alan, M.D., Ph.D., Directo
Slide 5: Initial 20 mg cohort data raises the bar on Pociredir's Best-in-Class Potential
Initial 20 mg cohort data raises the bar on Pociredir’s Best-in-Class Potential 20 mg cohort data as of Nov 11, 2025 Data Cut. 6 of 12 patients in the PD Analysis Set completed treatment period as of data cut Pan-cellular HbF induction Robust and rapid increase in HbF Improved anemia and hemolysis M
Slide 6: Agenda for Investor Call
Agenda for Investor Call Introduction Alex C. Sapir, President & CEO Sickle Cell Disease (SCD) and the Potential of a Once Daily Oral HbF-Inducer Iain Fraser MBChB, D.Phil, SVP Early Clinical Development PIONEER Study Overview and 20 mg Pociredir Cohort Data Update Sheinei Alan, M.D., Ph.D., Directo
Slide 7: Sickle Cell Disease Is a Debilitating Disease With High Unmet Need
Sickle Cell Disease Is a Debilitating Disease With High Unmet Need Sickle Cell Disease (SCD) is driven by abnormal, sickle-shaped RBCs with a shortened lifespan that rupture and block blood vessels causing extreme pain for the patient Painful Vaso-Occlusive Crises (VOCs) contribute to >75% of SCD-re
Slide 8: Higher HbF Levels Result in Reduced Symptomology in People Living With Sickle Cell Disease
Higher HbF Levels Result in Reduced Symptomology in People Living With Sickle Cell Disease Reduced hemolysis Reduced anemia Fewer recurring events HbF, fetal hemoglobin; VOC, vaso-occlusive crisis. 1. Peter Bruun-Rasmussen. ASH 2024 (poster #1124). 2. Data from Fulcrum analysis of Picnic Health real
Slide 9: Targeting EED Results in HbF Increases
Targeting EED Results in HbF Increases EED inhibition targets known modulators of HbF, including BCL11A and MYB1 Pociredir is a potent EED binder1 Highly selective Clean off-target profile Robust target engagement observed at doses as low as 2 mg EED, embryonic ectoderm; HbF, fetal hemoglobin; mRNA,
Slide 10: Previously Disclosed Data Highlights Pociredir's Potential as an HbF Inducer in SCD
Previously Disclosed Data Highlights Pociredir’s Potential as an HbF Inducer in SCD 1. n=6 per cohort 2. n=16 12mg cohort 3b. Previously-conducted incomplete 12 mg cohort due to U.S. FDA full clinical hold for pociredir on February 23, 2023, which was lifted August 23, 2023. Safety data collection c
Slide 11: Agenda for Investor Call
Agenda for Investor Call Introduction Alex C. Sapir, President & CEO Sickle Cell Disease (SCD) and the Potential of a Once Daily Oral HbF-Inducer Iain Fraser MBChB, D.Phil, SVP Early Clinical Development PIONEER Study Overview and 20 mg Pociredir Cohort Data Update Sheinei Alan, M.D., Ph.D., Directo
Slide 12: PIONEER: A Phase 1B Study in Patients With SCD
PIONEER: A Phase 1B Study in Patients With SCD1 Additional criteria apply. For more information, please see https://www.clinicaltrials.gov/study/NCT05169580. HbF, fetal hemoglobin; HU, hydroxyurea; QD, once daily; SCD, sickle cell disease; VOC, vaso-occlusive crisis; PK, Pharmacokinetic; F-Cells, Ce
Slide 13: 20 mg Cohort Patient Disposition (Data Cut: Nov 11, 2025)
20 mg Cohort Patient Disposition (Data Cut: Nov 11, 2025) 20 mg Pharmacodynamic (PD) Analysis Set includes n=12 patients. 6 of 12 patients (50%) have reached 12 weeks and 12 of 12 patients (100%) had reached at least 6 weeks as of data cut. Safety Analysis Set to be presented includes all 12 mg (n=1
Slide 14: PIONEER Baseline Demographics and Characteristics – PD Analysis Set
PIONEER Baseline Demographics and Characteristics – PD Analysis Set 1. n=12 PD Analysis Set Pociredir 12 mg; n=16 % or mean (SD) Pociredir 20 mg; n=121 % or mean (SD) Sex, % Male 44% 17% Age, Years 34.3 (12.25) 32.3 (6.98) Country US 62.5% 58.3% South Africa 37.5% 8.3% Nigeria 0% 33.3% Genotype Hb S
Slide 15: Dose-Dependent Pociredir PK Exposure in Sickle Cell Disease Patients
Dose-Dependent Pociredir PK Exposure in Sickle Cell Disease Patients Dose (PIONEER Study) Number of Patients Mean Cmax ng/mL (%CV) Median Tmax hrs (range) Mean AUC0-4h ng·hr/mL (%CV) 6 mg (Day 1) 9 18.1 (20.9) 2.0 (2.0-4.0) 45.2 (24.7) 12 mg (Day 1) 16 38.5 (38.9) 3.0 (2.0-4.0) 94.8 (45.4) 20 mg (Da
Slide 16: Pociredir 20 mg: Robust and Clinically Relevant Increases in Fetal Hemoglobin (HbF)
Pociredir 20 mg: Building on the Robust and Clinically Relevant increases in Fetal Hemoglobin (HbF) Mean Absolute %HbF Mean Absolute %HbF Change from Baseline 20 mg Pociredir increased %HbF from 7.1% to 16.9% at Week 6 20 mg Pociredir increased %HbF by 9.9% at Week 6 12 mg cohort 3b analysis & figur
Slide 17: Pociredir 20 mg: Clinically Relevant HbF Induction in all Patients
Pociredir 20 mg: Clinically Relevant HbF Induction in all Patients *Patients yet to complete Day 84 treatment visit. Latest visit indicated and Change from Baseline %HbF from latest study visit included. 1. In progress 20 mg cohort PD Analysis Set (n=12). No patients received transfusions during the
Slide 18: Pociredir 20 mg: Demonstration of Dose-Response
Pociredir 20 mg: Demonstration of Dose-Response Mean fold change from baseline calculated by taking the mean of individual patients’ fold change from baseline at each timepoint. 1. In progress 20 mg cohort PD Analysis Set (n=12). Figure & analysis includes n=6 patients who completed 12 weeks as of d
Slide 19: Pociredir 20 mg: F-cell Data Demonstrated Progression Towards Pan-Cellular Induction
Pan-Cellular Range1 Pociredir 20 mg: F-cell Data Demonstrated Progression Towards Pan-Cellular Induction 1. Dai et.al., 2017; Quinn et. al., 2021 F-Cell assay utilized - fluorescent-based flow cytometry assay 12mg cohort 3b analysis & figure includes available data from all patients regardless of tr
Slide 20: Pociredir 20 mg: Consistent Reductions in Markers of Hemolysis
Pociredir 20 mg: Consistent reductions in Markers of Hemolysis Mean Indirect Bilirubin Mean Lactate Dehydrogenase (LDH) LDH is an intracellular enzyme released into the blood in response to cell damage Indirect bilirubin rises with red blood cell destruction 12 mg cohort 3b analysis & figure include
Slide 21: Pociredir 20 mg: Consistent Improvements in Red Blood Cell Morphology and Erythropoiesis
Pociredir 20 mg: Consistent Improvements in Red Blood Cell Morphology and Erythropoiesis Mean Absolute Reticulocyte Count (ARC) Mean Red Cell Distribution Width (RDW-CV) Reductions in reticulocytes accompanied by increases in hemoglobin indicate reduced stress erythropoiesis Normalization of RDW-CV
Slide 22: Pociredir 20 mg: Reduction in Anemia
Pociredir 20 mg: Reduction in Anemia Mean Hemoglobin Mean Change from Baseline Hemoglobin Increases in hemoglobin are associated with improvements in fatigue, decreased risk of stroke, and improved overall survival1 12 mg cohort 3b analysis & figure includes data from all patients enrolled (n=16) re
Slide 23: Pociredir 20 mg: Encouraging VOC Trends in a Severe SCD Population
Pociredir 20 mg: Encouraging VOC Trends in a Severe SCD Population 1. Expected VOCs derived from reported baseline VOCs for the PD Analysis Set – ((2.40 VOCs / 26 weeks)*5 patients) + ((6.71 / 52 weeks)*7 patients)) * 12 weeks 2. Nov 11, 2025 data cut includes 82% (59 of 72) of the post-baseline stu
Slide 24: Pociredir 20 mg: Generally Well-tolerated with No Serious Treatment-related Adverse Events
Pociredir 20 mg: Generally Well-tolerated with No Serious Treatment-related Adverse Events AE > 10% of Patients (n) with event* Treatment-related AEs Preferred term n (%) Highest Grade Preferred term # of AEs Grade VOC 5 (38) 3 Reticulocytopenia (ARC) 1 3 Pain (back, extremity) 2 (15) 2 Insomnia 1 1
Slide 25: PIONEER 12mg and 20mg Safety Data to Date
* AEs in table are treatment-emergent AEs. a. Safety Analysis Set b. One discontinuation due to death (Grade 5 SAE). Death determined by the investigator unrelated to treatment following complications from VOC reported on Day 1 of study. Previously undisclosed hospital admissions for VOC on Days -7
Slide 26: Initial 20 mg cohort data raises the bar on Pociredir's Best-in-Class Potential
Initial 20 mg cohort data raises the bar on Pociredir’s Best-in-Class Potential 20 mg cohort data as of Nov 11, 2025 Data Cut. 6 of 12 patients in the PD Analysis Set completed treatment period as of data cut 2.4-fold induction of HbF at Week 12 in 16 patients 5.6% mean absolute increase in HbF at W
Slide 27: Agenda for Investor Call
Agenda for Investor Call Introduction Alex C. Sapir, President & CEO Sickle Cell Disease (SCD) and the Potential of a Once Daily Oral HbF-Inducer Iain Fraser MBChB, D.Phil, SVP Early Clinical Development PIONEER Study Overview and 20 mg Pociredir Cohort Data Update Sheinei Alan, M.D., Ph.D., Directo
Slide 28: Expert Perspective on HbF Induction and Clinical Benefit in SCD Patients
Expert Perspective on HbF Induction and Clinical Benefit in SCD Patients Martin H. Steinberg, M.D. Professor of Medicine, Pediatrics, Pathology and Laboratory Medicine at Boston University Chobanian & Avedisian School of Medicine
Slide 29: 20 mg cohort advancing Pociredir to next program milestones
20 mg cohort advancing Pociredir to next program milestones Key Next Steps Complete 20 mg Cohort and share updated results in Q1 2026 Prepare for End of Phase 1 meeting with FDA anticipated in H1 2026 Begin enrolling PIONEER patients in Open Label Extension (OLE) study in H1 2026 Continue finalizing
Slide 30: Q&A
4 8 Ful Pieneer Fy Flea Q&A
Slide 31: We thank the patients, caregivers, investigators and their staff
We thank the patients, caregivers, investigators and their staff who participated in PIONEER
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