Fulcrum Therapeutics, Inc. · NASDAQ:FULC
Fulcrum Therapeutics — Investor Presentation (August 2025)
30 slides from Fulcrum Therapeutics's investor presentation, Aug 28, 2025
Slide 1: Fulcrum Therapeutics
8 Fulcrum Therapeutics yelNasdaq FULC August 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: Unlocking the Power of Small Molecules to Change the Course of Genetically Defined Rare Diseases
Developing oral small molecules designed to modify gene expression in rare diseases with a focus on benign hematology Potential best-in class oral small molecule HbF inducer for SCD Demonstrated robust and rapid increase in HbF & Hb, and decreases in VOCs, hemolysis and anemia Fast Track and Orphan
Slide 4: Small Molecule Pipeline Across Multiple Rare Diseases
Small Molecule Pipeline Across Multiple Rare Diseases Indication Asset / Mechanism of Action Preclinical Phase 1 Phase 2 Phase 3 Clinical Programs Sickle Cell Disease Pociredir (HbF Induction) Discovery Programs DBA & Other BMFS Novel HbF Inducers Fibrotic Disorders Undisclosed Program DBA: Diamond
Slide 5: Pociredir for Sickle Cell Disease
Pociredir for Sickle Cell Disease Fast Track Designation Orphan Drug Designation
Slide 6: Sickle Cell Disease: Debilitating Disease with High Unmet Need
Sickle Cell Disease: Debilitating Disease with High Unmet Need 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 VOCs contribute to >75% of SCD-related hospitalizations4 Acute manifestations also
Slide 7: Addressing the Significant Unmet Need in SCD via HbF Induction
PIONEER 12 mg Cohort 3b: Addressing the Significant Unmet Need in SCD via HbF Induction Evidence of pan-cellularity as shown by a mean 67% F-Cells at 12 weeks 8.6% mean absolute increase in HbF at 12 weeks 0.9 g/dL mean increase in Hb with an improvement in all key markers of hemolysis Encouraging t
Slide 8: SCD Unmet Need Remains High Despite Recent Therapeutic Advances
SCD Unmet Need Remains High Despite Recent Therapeutic Advances 2019 Approval of Adakveo and Oxbryta 2024 Oxbryta withdrawn from WW Market due to safety concerns 2023 Approval of Casgevy and Lyfgenia gene therapies 2024-Today Limited uptake of gene therapies due to complexities, cost, and access Cur
Slide 9: HbF Inducers Competitive Landscape in SCD
HbF Inducers Competitive Landscape in SCD HbS Polymerization Inhibitors Oxbryta® – Pfizer (withdrawn) Osivelotor (GBT-601) – Pfizer (partial FDA clinical hold) PK Activators Mitapivat (AG-348) – Agios Etavopivat (FT-4202) – Novo Nordisk Tebapivat (AG-946) – Agios Current Standard of Care Gene Therap
Slide 10: Higher HbF Levels Result in Reduced Symptomology in People Living With SCD
Higher HbF Levels Result in Reduced Symptomology in People Living With SCD Reduced hemolysis Reduced anemia Fewer recurring events 1. Peter Bruun-Rasmussen. ASH 2024 (poster #1124). 2. Unpublished data from Fulcrum analysis of Picnic Health real-world dataset, n=673; ≥2 years ; mean HbF 8.6% - Data
Slide 11: Pociredir Targets EED Resulting in HbF Increases
Pociredir Targets EED Resulting in HbF Increases EED: Embryonic Ectoderm; HbF: Fetal hemoglobin; HBG: Gamma globin gene (encodes mRNA for fetal hemoglobin) Pociredir is a Potent and Selective EED Binder pociredir EED H3K27me3 HBG mRNA HbF Protein pociredir Identified Targets that Regulate HbF Identi
Slide 12: 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 Pre-Clinical: Pociredir HbF Induction in Healthy and SCD CD34+ Donor Cells 8 – 25% absolute increase in %HbF Consistent 2-3 fold induction across both healthy subj
Slide 13: A Phase 1b Study in Patients With SCD
PIONEER: A Phase 1b Study in Patients With SCD 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 HU, hydroxyurea; QD, once daily; PK, Pharm
Slide 14: PIONEER Phase 1b Clinical Trial Sites
Active Sites United States UT Houston (PI: Idowu) Queens Hospital Cancer Center (PI: Ferman) University of North Carolina (PI: Little) Jacobi Medical Center (PI: Rivlin) Lynn Health Sciences Institute (PI: Griffin) Virginia Commonwealth University (PI: Smith) Boston Medical Center (PI: Wilks) Univer
Slide 15: Utilizing AI App from AiCure to Increase Study Drug Adherence
Utilizing Artificial Intelligence App from AiCure to Increase Study Drug Adherence Improves Study Drug Adherence Robust Data Collection Real-Time Feedback to Clinical Trial Sites
Slide 16: 3b Baseline Demographics and Characteristics
12 mg Cohort 3b 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
Slide 17: 3b: Achieved Robust and Clinically Relevant Increases in HbF
PIONEER 12 mg Cohort 3b: Achieved Robust and Clinically Relevant increases in 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=16) and dat
Slide 18: 3b Demonstrated Dose Response
PIONEER: 12 mg Cohort 3b Demonstrated Dose Response 12mg cohort 3b includes data from all patients enrolled (n=16). 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 continued wi
Slide 19: 3b: Increased HbF in all Patients
PIONEER 12 mg Cohort 3b: 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 increase total hemoglobin (HbA) leading to an iatrogenic reduction in %HbF. Additiona
Slide 20: 3b: Meaningful Thresholds of %HbF Reached
PIONEER 12 mg Cohort 3b: 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) y
Slide 21: PIONEER 3b: F-cell Data Consistent with Pan-Cellular Induction
Pan-Cellular Range1 PIONEER 12 mg Cohort 3b: F-cell Data Consistent with Pan-Cellular Induction F-Cell assay utilized - fluorescent-based flow cytometry assay Analysis & Figure includes data from all patients enrolled (n=16) and data with transfusion patients (pts 13 and 16) removed (N=14). Sample s
Slide 22: 3b: Reductions in Anemia
PIONEER 12 mg Cohort 3b: 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=
Slide 23: 3b: Reductions in Hemolysis
PIONEER 12 mg Cohort 3b: 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 RBC destruction Analysis & Figure includes data from all patients enrolled (
Slide 24: 3b: Improvements in RBC Morphology and Erythropoiesis
PIONEER 12 mg Cohort 3b: Improvements in RBC 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 unif
Slide 25: 3b: Encouraging VOC Trends in this Severe SCD Population
PIONEER 12 mg Cohort 3b: 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
Slide 26: Ph1b Cohorts 1-3a – Pociredir Was Generally Well-tolerated
PIONEER Ph1b Cohorts 1-3a – Pociredir Was Generally Well-tolerated with No Serious Treatment-Related AEs in the All-Comer SCD Population TEAE: Treatment-emergent Adverse Event; SAE: Serious adverse event # All mild in severity, non-serious and resolved while patient remained on study drug Cohorts 1-
Slide 27: Ph1b 3b – Pociredir was Generally Well-tolerated in the Severe SCD Population
PIONEER Ph1b 12 mg Cohort 3b – Pociredir was Generally Well-tolerated with No Serious Treatment-related AEs in the Severe SCD Population Event Patients n=16 (%) All AEs Regardless of Causality 15 (94) Treatment-related AEs 3 (19) Grade ≥ 3 AEs 7 (44) Grade ≥ 3 Treatment-related AEs 0 (0) SAEs 5 (31)
Slide 28: Pociredir Achieves Target Product Profile and Addresses Unmet Need in SCD
PIONEER Ph1b 12 mg Cohort 3b – Pociredir Achieves Target Product Profile and Addresses Unmet Need in Sickle Cell Disease Key Next Steps 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 hemo
Slide 29: Strong 3b Data Driving Continued Pociredir Development
Strong 12 mg Cohort 3b Data Driving Continued Pociredir Development Key Next Steps Continued 20 mg dose cohort enrollment N=6 enrolled as of July 25, 2025 - 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
Slide 30: Well-Positioned for Transformational Year in 2025
Well-Positioned for Transformational Year in 2025 Pociredir: Best-in-class potential Oral small molecule HbF inducer with proof-of-concept Robust and rapid increase in HbF & Hb, and decreases in vaso-occlusive crises, hemolysis and anemia in cohort 3b Potential to be broadly protective of SCD sympto
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