Fulcrum Therapeutics, Inc. · NASDAQ:FULC

Fulcrum Therapeutics — Technical Presentation (June 2024)

16 slides from Fulcrum Therapeutics's technical presentation, Jun 14, 2024

  1. Slide 1: TTT)

    TTT) NI: i fa: ai E STREAMED” . m o g A, om *

  2. Slide 2: Interim Results of a Phase 1b Study (PIONEER) of an Oral HbF Inducer, Pociredir, in Sickle Cell Disease

    Interim Results of a Phase 1b Study (PIONEER) of an Oral HbF Inducer, Pociredir, in Sickle Cell Disease Kenneth Rivlin, MD, PhD1; Jae Ahn, PhD2; William Engelman, MD2; Billy Stuart, PhD2; Caterina Minniti, MD3 1. New York City Health & Hospitals / Jacobi 2. Fulcrum Therapeutics 3. Albert Einstein Co

  3. Slide 3: Increasing Fetal Hemoglobin (HbF) is an Established Mechanism to Broadly Improve Outcomes in SCD

    Increasing Fetal Hemoglobin (HbF) is an Established Mechanism to Broadly Improve Outcomes in SCD SCD Patient SCD Patient with High Fetal Hemoglobin (HbF) RBC sickling VOCs Anemia Hemolysis Stroke 30% Asymptomatic Pulmonary Hypertension presentation Reduced hemolysis Acute Chest Syndrome (ACS) (e.g.,

  4. Slide 4: Targeting the EED subunit of PRC2 Increases HbF

    Targeting the EED subunit of PRC2 Increases HbF Pociredir Inhibits the PRC2 Complex and Induces HbF expression EED H3K27me3 HBG mRNA Pociredir HbF Protein  Highly Selective Pociredir  Clean Off-target Profile  Residual H3K27me3 remains (20 – 30%) HbF: Fetal hemoglobin protein; HBG: Gamma globin g

  5. Slide 5: Phase 1b Clinical Trial in SCD Participants

    Phase 1b Clinical Trial in SCD Participants Study Population Study Design (dose escalation with 10 patients per cohort) • Participants with SCD • Aged 18 – 65 yr (inclusive) Screening Period • Open Label 4 Weeks • d/c’ed HU ≥60 days (Day -28 to D -1) Treatment Period (once daily capsule) 12 Weeks (D

  6. Slide 6: Phase 1b Clinical Trial in SCD Participants

    Phase 1b Clinical Trial in SCD Participants Study Endpoints Primary Endpoints • Safety and tolerability assessments • PK parameters Secondary Endpoints • Measurement of the effect of increased fetal hemoglobin on hemolysis and anemia biomarkers: • % HbF (HPLC) • Absolute reticulocyte count • Total h

  7. Slide 7: Initial Pociredir Data Demonstrates Dose-dependent Increases in HbF in SCD Participants

    Initial Pociredir Data Demonstrates Dose-dependent Increases in HbF in SCD Participants Absolute %HbF Change from Baseline 12 2mg FTX-6058 Change from Baseline 10 6mg FTX-6058 Absolute %HbF Mean (+/- SE) 8 12mg FTX-6058 6 4 • Peak increases in HbF have yet to be 2 determined, especially the peak inc

  8. Slide 8: Pociredir Appears to Have a Dose Dependent, Clinically Relevant and Consistent Increase in HbF

    Pociredir Appears to Have a Dose Dependent, Clinically Relevant and Consistent Increase in HbF 2mg 6mg 12mg 25 25 25 Subject 11 Subject 1 Subject 13 20 Subject 12** 20 Subject 2 20 Subject 14* %HbF (HPLC) Subject 3 Subject 15* 15 15 15 Subject 7* 10 10 Subject 8 10 Subject 9* 5 5 5 Subject 10* 0 0 0

  9. Slide 9: Pociredir Appears to Have a Dose Dependent, Clinically Relevant and Consistent Increase in Total Hemoglobin

    Pociredir Appears to Have a Dose Dependent, Clinically Relevant and Consistent Increase in Total Hemoglobin 6mg 12mg 11.0 11.0 10.5 10.5 Hemoglobin (g/dL) Hemoglobin (g/dL) 10.0 Subject 7* 10.0 9.5 9.5 Demonstrates Subject 8 9.0 9.0 Improvement Subject 13 8.5 8.5 in Anemia 8.0 8.0 Subject 14* 7.5 7.

  10. Slide 10: Hematological Effects of Pociredir

    Hematological Effects of Pociredir Safety Safety Follow-up Follow-up 12 400 2mg Pociredir 2mg Pociredir Absolute Reticulocytes Absolute Neutrophils 10 6mg Pociredir 6mg Pociredir 300 Mean (+/- SE) Mean (+/- SE) 8 12mg Pociredir (x10E3/uL) 12mg Pociredir (x10E3/uL) 6 200 4 100 2 0 0 0 14 28 42 56 70

  11. Slide 11: Hematological Effects of Pociredir

    Hematological Effects of Pociredir Safety Safety Follow-up Follow-up 800 20 2mg Pociredir 2mg Pociredir 6mg Pociredir 6mg Pociredir 600 15 Absolute WBC Mean (+/- SE) Mean (+/- SE) 12mg Pociredir 12mg Pociredir (x10E3/uL) (x10E3/uL) Platelets 400 10 200 5 0 0 0 14 28 42 56 70 84 98 112 0 14 28 42 56

  12. Slide 12: Pociredir Was Generally Well-tolerated with No Serious Treatment-related Adverse Events

    Pociredir Was Generally Well-tolerated with No Serious Treatment-related Adverse Events (Pioneer Ph1b – Open Label)​ Pociredir 23 Treatment Emergent Adverse Events (TEAEs) in 10/16 Number of Patients with:​ (n=16)​ (62.5%) patients n (%)​ • 8/23 treatment-related TEAEs in 5/16 (31.3%) patients: Any

  13. Slide 13: Background on Resolved Clinical Hold

    Background on Resolved Clinical Hold • Clinical hold initiated on 23-Feb-2023 to allow for further evaluation of a potential safety signal observed in preclinical studies. • FDA requested an updated study population in which the potential benefit balances the potential risk. • Previous experience wi

  14. Slide 14: Site Activation Status

    Site Activation Status Active Sites:  University of Miami  Augusta University  University of North Carolina, Chapel Hill  Jacobi Medical Center (Bronx, NY)  Lynn Health Sciences Institute  Virginia Commonwealth University On-boarding Sites:  US Sites  University of California Los Angeles  U

  15. Slide 15: Study Conclusions

    Study Conclusions Preliminary data from the PIONEER study shows that pociredir: • Has the potential to increase HbF to levels associated with significant clinical benefits in patients with SCD • Short term data reveal no safety signal • Additional data will be generated to further define the benefit

  16. Slide 16: Thank You

    Thank You Advocacy Information Advocacy@fulcrumtx.com www.clinicaltrials.gov NCT05169580 Clinical Trial Information ClinicalTrials@fulcrumtx.com General Information https://www.pioneerscdstudy.com/ Info@fulcrumtx.com

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