Fulcrum Therapeutics, Inc. · NASDAQ:FULC
Fulcrum Therapeutics — Investor Presentation (January 2026)
28 slides from Fulcrum Therapeutics's investor presentation, Jan 12, 2026
Slide 1: Fulcrum Therapeutics
8 Fulcrum Therapeutics yelNasdaq FULC January 2026
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: Potential best-in-class oral HbF inducer for SCD
Potential best-in class oral HbF inducer for SCD Robust, rapid, and clinically meaningful pan-cellular increases in HbF with early evidence of improvements in hemolysis, anemia, and VOCs Fast Track and Orphan Drug Designations Composition of matter and method of use coverage through 2040 Phase 1b PI
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 Castration Resistant Prostate Cancer DBA: Diamond Bl
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: 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 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SCD Unmet Need Remains High Despite Recent Therapeutic Advances 2019 Approval of Adakveo and Oxbryta 2024 Oxbryta withdrawn from WW Market due to safety concerns 2023 Approval of Casgevy and Lyfgenia gene therapies 2024-Today Limited uptake of gene therapies due to complexities,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 Att
Slide 9: Pociredir has the Potential to Fill a Significant Treatment Gap for SCD
Pociredir has the Potential to Fill a Significant Treatment Gap for SCD Anti-Polymerization Adhes. & Inflam. Modulator Gene Therapy Upstream / Targets Range of Disease Manifestations Downstream/Targets Subsets of Disease Manifestations Convenient / Easy to Administer Inconvenient / Challenges to Adm
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. Data from Fulcrum analysis of Picnic Health real-world dataset, n=673; ≥2 years ; mean HbF 8.6% - Data presented at
Slide 11: 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 Pociredir Is a Potent and Selective EED Binder Decrea
Slide 12: Pociredir Translates Consistently from Preclinical Models to Healthy Volunteers to Patients
Pociredir Translates Consistently from Preclinical Models to Healthy Volunteers to Patients 12 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 c
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. 1 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: 20 mg Cohort Patient Disposition (Data Cut: Nov 11, 2025)
20 mg Cohort Patient Disposition (Data Cut: Nov 11, 2025) Disposition and all subsequent data as of Nov 11, 2025, data cut 1. Grade 5 SAE determined by the investigator unrelated to treatment following complications from VOC reported on Day 1 of study. Patient excluded from the PD Analysis Set 2. Ad
Slide 16: 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 17: 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 18: Pociredir 20 mg Building on Robust Increases in Fetal Hemoglobin (HbF)
PIONEER: Pociredir 20 mg Building on the Robust and Clinically Relevant Increases in Fetal Hemoglobin (HbF) Mean Absolute %HbF Mean Absolute %HbF Change from Baseline 12 mg cohort 3b analysis & figures includes data from all patients enrolled (n=16) regardless of transfusions during treatment period
Slide 19: Clinically Relevant HbF Induction in all Patients at 20 mg
PIONEER: Clinically Relevant HbF Induction in all Patients at 20 mg *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 th
Slide 20: Demonstrated Progression Towards Pan-Cellular Induction
PIONEER: 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 transfusions during treatment period; In p
Slide 21: Reductions in Anemia
PIONEER: 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 12 mg cohort 3b analysis & figure includes data from all patients enrolled (n=
Slide 22: Consistent Reductions in Markers of Hemolysis
PIONEER: 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 often with RBC destruction 12 mg cohort 3b analysis & figure includes data from a
Slide 23: Consistent Improvements in Red Blood Cell Morphology and Erythropoiesis
PIONEER: 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 Decreased RDW-CV indicates a mor
Slide 24: 20 mg Continues to Demonstrate Encouraging VOC Trends in this Severe SCD Population
PIONEER: 20 mg Continues to Demonstrate Encouraging VOC Trends in this 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
Slide 25: PIONEER 12 mg and 20 mg Safety Data to Date
PIONEER 12 mg and 20 mg Safety Data to Date: Generally Well-tolerated with No Serious Treatment-related Adverse Events * AEs in table are treatment-emergent AEs. 1. Safety Analysis Set 2. One discontinuation due to death (Grade 5 SAE). Death determined by the investigator unrelated to treatment foll
Slide 26: Pociredir 20 mg Generally Well-tolerated with No Serious Treatment-related Adverse Events
PIONEER: Pociredir 20 mg Generally Well-tolerated with No Serious Treatment-related Adverse Events *AEs in table are treatment-emergent AEs. AEs could be reported multiple times as individual symptoms during an event such as a VOC. 1. Safety Analysis Set 2. One discontinuation due to death (Grade 5
Slide 27: Initial 20 mg cohort data raises the bar on Pociredir's Best-in-Class Potential
PIONEER: Initial 20 mg cohort data raises the bar on Pociredir’s Best-in-Class Potential 2.4-fold induction of HbF at Week 12 in 16 patients 5.6% mean absolute increase in HbF at Week 6 / 8.6% at Week 12 Demonstrated pan-cellularity and improvements in anemia and hemolysis Encouraging trends in VOC
Slide 28: Fulcrum is Positioned to Establish Pociredir as a Potential Best-in-Class Treatment for SCD
Fulcrum is Positioned to Establish Pociredir as a Potential Best-in-Class Treatment for SCD 1. Cash balance is preliminary, unaudited and based on management estimates. Q1 2026 PIONEER Data Complete 20mg cohort and share updated results H1 2026 Regulatory Alignment End-of-Phase meeting with FDA; see
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