Fulcrum Therapeutics : Corporate Presentation - April 2026

Published: 2026-04-27 09:20:17 ET FULC

Published on 04/27/2026 at 09:20 am EDT

FULC April 2026

Unlocking the Power of Small Molecules to Change the Course of Genetically Defined Rare Diseases

Strategic Focus

Developing oral small molecules designed to modify gene expression in rare disease with a focus on benign hematology

Pociredir

Potential best-in class oral HbF inducer for SCD

- Robust, rapid, and clinically relevant 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 PIONEER completed in Q1 2026

Update on next trial design in Q2 2026 following receipt of End-of-Phase meeting minutes

Initiate a potential registration-enabling trial in 2H 2026

Pipeline Sustainability & Capital Strength

Advancing discovery programs focused on benign hematological diseases to provide long-term pipeline sustainability

$333.3 million of cash as of March 31, 2026

Cash runway into 2029

Fully funded to support anticipated Pociredir registrational milestones

3 HbF: Fetal hemoglobin; VOC: Vaso-occlusive crisis

F UL CRUM T HE RA P E UT I CS

Indication

Asset / Mechanism of Action

Preclinical

Phase 1

Phase 2

Phase 3

Clinical Programs

Sickle Cell Disease

Pociredir (HbF Induction)

Discovery Programs

Sickle Cell Disease

Castration Resistant Prostate Cancer

Novel HbF Inducers

f o r S i c k l e C e l l D i s e a s e

Fast Track Designation Orphan Drug Designation

F UL CRUM T HE RA P E UT I CS

Global Impact

Sub-Saharan Africa

~6M3

~120K1

individuals

Europe + UK

~55K2

individuals

~7.7 million3 worldwide

individuals

SCD is driven by abnormal, sickle-shaped RBCs with a shortened lifespan that rupture and block blood vessels causing extreme pain for the patient

Disease

Debilitating Symptoms

Painful VOCs contribute to >75% of SCD-related hospitalizations4

Acute manifestations also include stroke, pulmonary hypertension, priapism, leg ulcers, and splenic sequestration

Chronic anemia and hemolysis result in end-organ damage

Patients with SCD face a substantial reduction in life expectancy (>20 years), with a mortality rate up to 9X higher than the general population5

Yao Fu et al. ASH 2023 (poster #3900)

EMA, Piel et al., 2013, Inusa et al. 2019

GBD 2021, Piel et al.,2013, Makani et al. 2013

Shah, et.al. 2019

GBD 2021, CDC

RBC, red blood cell; SCD, sickle cell disease

20 mg Cohort: Robust HbF Induction with Improvements in Markers of Hemolysis and Anemia

F UL CRUM T HE RA P E UT I CS

12.2% mean absolute HbF increase from a baseline of 7.1% to 19.3% at Week 12

58% of patients (7/12) reached ≥20% HbF at Week 12

Progression toward pan-cellularity and improvements in markers of hemolysis and anemia (>1 g/dL Hb increase)

Continued encouraging trends in VOC reduction over 12 weeks

Continued evidence of pociredir being generally well-tolerated at 20 mg

20 mg cohort data as of Dec 23, 2025 Data Cut.

F UL CRUM T HE RA P E UT I CS

2019

Approval of Adakveo and Oxbryta

2023

Recent additions of therapeutic options to the hydroxyurea standard of care have not satisfied the significant unmet need in SCD patients

Adakveo fails confirmatory

VOC study and withdrawn

from EU Market

Approval of Casgevy and Lyfgenia gene therapies

Oxbryta withdrawn from WW Market

due to safety concerns

Limited uptake of gene therapies due to complexities, cost, and access

Attrition of late-stage pipeline candidates

Current Reality for SCD Patients

High VOC burden persists Access barriers for gene therapies

Lack of broadly effective, durable oral therapies

Significant racial and socioeconomic disparities remain

Pociredir has the Potential to Fill a Significant Treatment Gap for SCD

Gene Therapy

Pociredir

Oral HbF Inducer

Hydroxyurea

Convenient / Easy to Administer

Anti-Polymerization

F UL CRUM T HE RA P E UT I CS

Downstream/Targets Subsets of Disease Manifestations

Upstream / Targets Range of Disease Manifestations

Adhes. & Inflam.

Modulator

Inconvenient / Challenges to Administer

Percent Observing Zero VOC/Year by %HbF1

Observed

Model Prediction

Each 1% increase in %HbF…

Percentage of Patients With Zero VOC per Year (%)

100

…is associated with a 4%-8% reduction in VOCs2

F UL CRUM T HE RA P E UT I CS

Raising HbF levels also results in:

Reduced hemolysis

Reduced anemia

Fewer recurring events

0 10 20 30 40

Imputed %HbF

HbF level

% of Patients reporting zero VOCs

(Model Prediction)

15%

89%

20%

94%

25%

97%

Data from Fulcrum analysis of Picnic Health real-world dataset, n=673; ≥2 years ; mean HbF 8.6% - Alan et al., 20th Annual Sickle Cell & Thalassaemia Conference. Br J Haematol, 207: S5-S135. 2025

Peter Bruun-Rasmussen. ASH 2024 (poster #1124).

Pociredir Is a Potent and Selective EED Binder

Decreased expression of HbF repressors and regulators

Elevated expression of HbF mRNA and protein

F UL CRUM T HE RA P E UT I CS

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, messenger RNA; PRC2, polycomb repressive complex 2.

1. Stuart B, et.al., Hemasphere 2022

Pre-Clinical: Pociredir HbF Induction in

Healthy and SCD CD34+ Donor Cells

Healthy

Sickle Cell Trait Sickle Cell Disease

2-3 Fold Induction

Control

Pociredir (FTX-6058)

8 - 25% absolute increase in %HbF

Consistent 2-3 fold induction across both healthy subject and SCD CD34+ donor-derived cells

Phase 1b: Mean % Change from Baseline

%HbF in SCD Patients

20mg [Cohort 4] 12mg [Cohort 3b] 12mg [Cohort 3a]

6mg [Cohort 1]

End of Treatment

2 4 6 8 10 12 13

Study Visit (Weeks)

Time- and Dose-related HbF induction in previous PIONEER Cohorts2

Cohorts 1-3a conducted in all-comer adult SCD population with no requirement for disease severity

HbF (% of total Hb)

Mean Fold Change from Baseline %HbF

(Mean +/- SE)

Phase 1: Gamma Globin (HBG) Induction in

Healthy Volunteers

Time- and Dose-related HBG mRNA Induction in Healthy Volunteer Multiple Ascending Dose Cohorts1

F UL CRUM T HE RA P E UT I CS

n=6 per cohort

20 mg cohort PD Analysis Set n=12. 12mg cohort 3b 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 with data cut of March 3, 2023. 12mg cohort 3a n=1 at Day 42, 6mg cohort n=5 at Day 84, 2 mg cohort n=1 at Day 84.

Study Design (Open Label, Dose Escalation, ≈10 Patients per Cohort)

12-Week Treatment Period (QD Capsule)

Cohort 1 6 mg (n=10)

F UL CRUM T HE RA P E UT I CS

4-Week Screening Period

Cohort 2 2 mg (n=2) Cohort 3a 12 mg (n=4) Cohort 3b 12 mg (n=16)1 Cohort 4 20 mg (n=13)

Completed under previous protocol with a less

severe, all-comer SCD patient population

Completed

4-Week Follow-Up Period

Select Inclusion Criteria

Key Study Endpoints

SCD Patients 18-65 years

Discontinued HU for ≥60 days

Severe SCD as defined by ≥4 VOCs over 12 months or ≥2 VOCs over 6 monthsa

Primary

Safety and tolerability assessments

PK parameters

Secondary

HbF induction

Hemolysis

Anemia

Exploratory

Globin gene expression

% F-cells

Incidence of VOCs

Additional criteria apply. For more information, please see https://www.clinicaltrials.gov/study/NCT05169580. HU, hydroxyurea; QD, once daily; PK, Pharmacokinetic; F-Cells, Cells expressing HbF

13 Adapted from Alan S, et al. J Sick Cell Dis. 2025;2(Suppl 1)

Patients Enrolled

N= 13

Patients Completing 12-week Treatment Period

N= 12

Completed Treatment Period + 4-week Follow-up

N= 7

Completed Treatment Period + 4-week Follow-up Ongoing

N= 5

F UL CRUM T HE RA P E UT I CS

One previously disclosed patient discontinuation on Day 1 due to unrelated Grade 5 SAE1

Continued high adherence (97%) to treatment schedule in the 20 mg cohort2

Pharmacodynamic (PD) Analysis Set presented today is through Week 12 of treatment; Safety Data Set includes all 20 mg data as of December 23, 2025 data cut

Disposition and all subsequent data as of Dec 23, 2025, data cut

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

Adherence measured via AiCure®, an artificial intelligence data collection tool providing real-time feedback and data collection to measure and improve study drug adherence. Dosing interruptions on study not included in AiCure adherence analysis

F UL CRUM T HE RA P E UT I CS

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

62.5%

58.3%

South Africa

37.5%

8.3%

Nigeria

33.3%

Genotype

Hb SS

87.5%

83.3%

Hb Sβ0

12.5%

8.3%

Hb Sβ+

8.3%

Baseline HbF (%)

7.6% (4.7)

7.1% (4.4)

Baseline Hb (g/dL)

7.8 (1.8)

7.3 (1.2)

Baseline VOCs

Reporting over 6 months

2.83 (N=6)

2.40 (N=5)

Reporting over 12 months

5.20 (N=10)

6.71 (N=7)

1. n=12 PD Analysis Set

F UL CRUM T HE RA P E UT I CS

Plasma PK Comparison between cohorts in PIONEER Study

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)

18.1 (20.9)

2.0 (2.0-4.0)

45.2 (24.7)

12 mg (Day 1)

38.5 (38.9)

3.0 (2.0-4.0)

94.8 (45.4)

20 mg (Day 1)

69.4 (54.7)

3.0 (1.0-4.0)

168.0 (58.0)

Consistent with previously reported healthy volunteer data, dose-dependent increases in Cmax and AUC observed across the 6 mg, 12 mg, and 20 mg cohorts

Data as of Dec 23, 2025 Data Cut

Mean Absolute %HbF

Mean Absolute %HbF Change from Baseline

19.3%

16.2%

12mg Cohort

20mg Cohort

End of Treatment

F UL CRUM T HE RA P E UT I CS

Absolute %HbF

(Mean +/- SE)

0 2 4 6 8 10 12 13 16

Study Visit (Weeks)

End of Treatment

12.2%

8.6%

12mg Cohort

20mg Cohort

(Mean +/- SE)

0 2 4 6 8 10 12 13 16

20 mg Pociredir increased %HbF from 7.1% to 19.3% at Week 12

20 mg Pociredir increased %HbF by 12.2% at Week 12

12 mg cohort 3b analysis & figures includes data from all patients enrolled (n=16) regardless of transfusions during treatment period 20 mg cohort n=12. No patients received transfusions during the treatment period.

Data as of Dec 23, 2025 Data Cut

Baseline %HbF and Change from Baseline %HbF at Week 12

Change from Baseline %HbF at Baseline %HbF

F UL CRUM T HE RA P E UT I CS

Patient 11

Patient 10

Patient 12

Patient 9

Patient 8

Patient 1

Patient 7

Patient 6

Patient 13

Patient 3

Patient 4

Patient 5

Week 12

20% HbF

7 of 12 patients (58%) achieved a ≥20% absolute level of %HbF at their latest study visit

All patients in the 20 mg cohort achieved at least a 6.5% absolute increase in HbF (or greater)1

1. No patients received transfusions during the treatment period.

Mean %F-Cells

Pan-Cellular Range1

12mg Cohort

20mg Cohort

100

F UL CRUM T HE RA P E UT I CS

(Mean +/- SE)

End of Treatment

Data as of Dec 23, 2025 Data Cut

20 mg Week 12 sample size reflects missing data from two patients with higher F-cell levels at prior visits

0 2 4 6 8 10 12 13 16

F-Cells are red blood cells that contain HbF, which increases their resistance to sickling and hemolysis. A higher proportion of F-cells is associated with improved red blood cell health.1

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;

20 mg cohort PD Analysis Set (n=12). Analysis includes data through visits with complete laboratory data. No patients received transfusions during the treatment period. Sample size varies across timepoints due to sample availability. 12 mg n=12 at Day 84. 20 mg n=10 at Day 84.

Data as of Dec 23, 2025 Data Cut

Mean Lactate Dehydrogenase (LDH)

Mean Indirect Bilirubin

700

F UL CRUM T HE RA P E UT I CS

600

LDH (IU/L)

SE)

500

(Mean +/-

400

300

200

100

12mg Cohort 20mg Cohort

End of Treatment

28% Reduction

34% reduction

Healthy Normal

Indirect Bilirubin (µmol/L)

(Mean +/- SE)

12mg Cohort

20mg Cohort

End of Treatment

40% Reduction

37% Reduction

Healthy Normal

0 2 4 6 8 10 12 13 16

Study Visit (Weeks)

0 2 4 6 8 10 12 13 16

Study Visit (Weeks)

LDH is an intracellular enzyme released into the blood in response to cell damage

Indirect bilirubin increases with red blood cell destruction

12 mg cohort 3b analysis & figure includes data from all patients enrolled (n=16) regardless of transfusions during treatment period

20 mg cohort PD Analysis Set (n=12). Analysis includes data through visits with complete laboratory data. No patients received transfusions during the treatment period.

Disclaimer

Fulcrum Therapeutics Inc. published this content on April 27, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on April 27, 2026 at 13:19 UTC.