Slide 1: Pociredir Pioneer Study: 12 mg Cohort Data Release
Pociredir Pioneer Study: 12 mg Cohort Data Release July 29, 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 Smith are practicing physicians and paid Investigators in Fulcrum Therapeutics’ Pioneer Study. The views and opinions expressed by Drs. Alan and Smith are their own and do not necessarily reflect those of Fulcrum Therapeutics. Sheinei Alan, M.D. Director, Inova A
Slide 4: Agenda for Investor Call
Agenda for Investor Call Introduction Alex 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 12 mg Pociredir Cohort Data Update Sheinei Alan, M.D., Director, Inova A
Slide 5: Pociredir's Best-in-Class Potential as a once daily oral therapy for SCD
Evidence of pan-cellularity shown by a mean 67% F-Cells at 12 weeks 8.6% mean absolute increase in Fetal Hemoglobin (HbF) at 12 weeks 0.9 g/dL mean increase in hemoglobin (Hb) with an improvement in all key markers of hemolysis Encouraging trends in VOC reduction over 12 weeks Pociredir, Once-Daily
Slide 6: Agenda for Investor Call
Agenda for Investor Call Introduction Alex 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 12mg Pociredir Cohort Data Update Sheinei Alan, M.D., Director, Inova Ad
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 SCD
Abolition of VOCs 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. Unpublished data from Fulcrum
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: Evidence Generated to Date Highlights Pociredir's Potential as an HbF Inducer in SCD
Evidence Generated to Date Highlights Pociredir’s Potential as an HbF Inducer in SCD Previously Disclosed Fulcrum Data 1. N=6 per cohort 2. 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
Slide 11: Agenda for Investor Call
Agenda for Investor Call Introduction Alex 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 12 mg Pociredir Cohort Data Update Sheinei Alan, M.D., Director, Inova A
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. a The incomplete prior 12 mg cohort (3a) conducted prior to study hold not included in this analysis HbF, fetal hemoglobin; HU, hydroxyurea; Q
Slide 13: 12 mg Cohort Patient Disposition as of June 26th Data Cut
12 mg Cohort Patient Disposition as of June 26th Data Cut No patients discontinued study or treatment early. High adherence (98%) to treatment schedule1 Safety Data presented includes all 12 mg data as of June 26th data cut Efficacy Data from the 12 mg cohort treatment period for all 16 patients wil
Slide 14: 12 mg Cohort Baseline Demographics and Characteristics
12 mg Cohort Baseline Demographics and Characteristics Pociredir 12 mg; N=16 % or mean (SD) Sex, % Male 44% Age, Years 34.3 (12.25) Country US 62.5% South Africa 37.5% Genotype Hb SS 87.5% Hb Sβ0 12.5% Baseline HbF (%) 7.6% (4.7) Baseline Hb (g/dL) 7.8 (1.8) Baseline VOCs Reporting over 6 months (N=
Slide 15: Dose-Related Pociredir Exposure PK in Patients
Dose-Related Pociredir Exposure PK 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) Plasma PK C
Slide 16: Pociredir 12 mg: Robust Increases in Fetal Hemoglobin (HbF)
Pociredir 12 mg: Achieved Robust and Clinically Relevant increases in Fetal Hemoglobin (HbF) Mean Absolute %HbF Mean Absolute %HbF Change from Baseline Pociredir increased %HbF from 7.6% to 16.2% Pociredir increased %HbF 8.6% by 12 weeks Analysis & Figure includes data from all patients enrolled (n=
Slide 17: Pociredir 12 mg: Increased HbF in all Patients
Pociredir 12 mg: Increased HbF in all Patients Baseline %HbF and Change from Baseline %HbF at Week 12 Patient 13 and Patient 16 received multiple transfusions over the 12-week treatment period. Transfusions will increase total hemoglobin (HbA) leading to an iatrogenic reduction in %HbF. Subsequent s
Slide 18: Pociredir 12 mg: Meaningful Thresholds of %HbF Reached
Pociredir 12 mg: Meaningful Thresholds of %HbF Reached %HbF Threshold Achieved after 12 Weeks of Treatment Analysis & Figure includes data from all patients enrolled (n=16) regardless of transfusions during treatment period Excluding patients with multiple transfusions (patients 13 and 16) yields: H
Slide 19: Pociredir 12 mg: F-cell Data Consistent with Pan-Cellular Induction
Pan-Cellular Range1 Pociredir 12 mg: F-cell Data Consistent with Pan-Cellular Induction 1. Dai et.al., 2017; Quinn et. al., 2021 F-Cell assay utilized - fluorescent-based flow cytometry assay Analysis & Figure includes available data from all patients enrolled (n=16) regardless of transfusions durin
Slide 20: Pociredir 12 mg: Reductions in Hemolysis
Pociredir 12 mg: Reductions in 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 often with red blood cell destruction Analysis & Figure includes data from all patients enrolle
Slide 21: Pociredir 12 mg: Improved Red Blood Cell Morphology and Erythropoiesis
Pociredir 12 mg: Improved 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 Decreased RDW-CV indicates a more uniform
Slide 22: Pociredir 12 mg: Reductions in Anemia
Pociredir 12 mg: Reductions in Anemia Mean Hemoglobin Mean Change from Baseline Hemoglobin Increases in hemoglobin are historically associated with improvements in fatigue, decreased risk of stroke, and improved overall survival1 Analysis & Figure includes data from all patients enrolled (n=16) rega
Slide 23: Encouraging VOC Trends in this Severe SCD Population
Encouraging VOC Trends in this Severe SCD Population 1 Expected VOCs derived from Reported Baseline VOCs – ((2.83 VOCs / 26 weeks)*6 patients) + ((5.20 / 52 weeks)*10 patients)) * 12 weeks 2.Additional 3 VOCs observed in Safety Follow-up period as of June 26th data cut Eight of 16 patients (50%) rep
Slide 24: 12 mg Pociredir: Generally Well-tolerated with No Serious Treatment-related Adverse Events
12 mg Pociredir: Generally Well-tolerated with No Serious Treatment-related Adverse Events 2 AEs (preferred terms) could be reported multiple times as individual symptoms during an event such as a VOC. Event Patients n=16 (%) All Adverse Events (AE) Regardless of Causality 15 (94) Treatment-related
Slide 25: Pociredir's Best-in-Class Potential Informed by 12 mg Cohort Results
Evidence of pan-cellularity as shown by a mean 67% F-Cells at 12 weeks 8.6% mean absolute increase in Fetal Hemoglobin (HbF) at 12 weeks 0.9 g/dL mean increase in hemoglobin (Hb) with an improvement in all key markers of hemolysis Encouraging trends in VOC reduction over 12 weeks Pociredir, once-dai
Slide 26: Agenda for Investor Call
Agenda for Investor Call Introduction Alex 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 12 mg Pociredir Cohort Data Update Sheinei Alan, M.D., Director, Inova A
Slide 27: Expert Perspective on HbF Induction and Clinical Benefit in SCD Patients
Expert Perspective on HbF Induction and Clinical Benefit in SCD Patients Wally Smith, M.D. Director, VCU Adult Sickle Cell Program & Professor School of Medicine at Virginia Commonwealth University
Slide 28: Q&A
4 8 Ful Pieneer Fy Flea Q&A
Slide 29: Strong 12 mg Data Driving Continued Pociredir Development
Strong 12 mg Data Driving Continued Pociredir Development Key Next Steps Continued 20 mg dose cohort enrollment N=6 enrolled as of July 25th - 1 discontinued1 20 mg data release expected by the end of 2025 End of Phase 1 meeting with FDA anticipated in early 2026 to discuss initiation of next study
Slide 30: Pociredir's Best-in-Class Potential Summary
Evidence of pan-cellularity shown by a mean 67% F-Cells at 12 weeks 8.6% mean absolute increase in Fetal Hemoglobin (HbF) at 12 weeks 0.9 g/dL mean increase in hemoglobin (Hb) with an improvement in all key markers of hemolysis Encouraging trends in VOC reduction over 12 weeks Pociredir, Once-Daily
Slide 31: We thank the patients and their caregivers who participated in Pioneer
We thank the patients and their caregivers who participated in Pioneer, and our investigators and their teams