Fulcrum Therapeutics : Corporate Presentation January 2025

Published: 2025-01-13 07:35:06 ET FULC

FULC

January 13, 2025

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

Strategic Focus

3 HbF: Fetal hemoglobin

Pociredir

Discovery &

Cash Position

F U L C R U M T H E R A P E U T I C S

Small Molecule Pipeline Across Multiple Rare Diseases

Indication

Asset / MOA

Preclinical

Phase 1

Phase 2

Phase 3

Collaborator

Clinical Programs

Sickle Cell Disease

Pociredir (HbF Induction)

Discovery Programs

DBA & Inherited

Aplastic Anemias

Novel HbF Inducers

Fibrotic Disorders

Cardiomyopathies

DBA: Diamond-Blackfan anemia

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

Sickle Cell Disease: Debilitating Disease with High Unmet Need

F U L C R U M T H E R A P E U T I C S

The Disease

Debilitating Symptoms

Global Impact

~100K

U.S. individuals

4.4 million worldwide

6 VOC: Vaso-occlusive crisis; CDC; WHO; UpToDate.

F U L C R U M T

Competitive Landscape in SCD

Hydroxyurea

Current Standard of Care

HbF Inducers

Pociredir - Fulcrum Therapeutics

BMS-986470 - Bristol Myers Squibb

ITU-512 - Novartis

Ndec (decitabine + tetrahydrouridine) - Novo Nordisk / EpiDestiny

H E R A

SCD Treatment

P E U T I C S

Adakveo® - Novartis

Selectin Inhibitors

Anti-Polymerization

Inclacumab - Pfizer

Gene Therapy

Lyfgenia® - Bluebird Bio

Casgevy® - Vertex Pharmaceuticals

HbS: Sickle hemoglobin. PK: Pyruvate kinase.BEAM-101- Beam Therapeutics

EDIT-301 - Editas Medicine (ceased development)

HbS Polymerization Inhibitors

Oxbryta® - Pfizer (withdrawn) Osivelotor (GBT-601) - Pfizer

PK Activators

Mitapivat (AG-348) - Agios

Etavopivat (FT-4202) - Novo Nordisk

Tebapivat (AG-946) - Agios

F U L C R U M T H E R A P E U T I C S

Best-in-class Potential of Pociredir to Address Significant Unmet Need for People Living With SCD

Addresses underlying

Ability to reduce VOC /

Safety & Tolerability

Ability to be

disease pathology

impact survival

administered orally

HbF Inducers

PK Activators

HbS Polymerization

Inhibitors

Selectin Inhibitors

Higher HbF Levels Result in Reduced Symptomology in People Living with Sickle Cell Disease

F U L C R U M T H E

Typical SCD Patient

Stroke

Pulmonary hypertension Acute Chest Syndrome (ACS)

SCD Patient with High HbF Levels

30%

Asymptomatic

presentation

Reduced hemolysis

R A P E U T I C S

Nephropathy

Osteonecrosis

Ulcer / pain

SCD Baseline

HbF 5-10%

20%

Reduced

Reduced anemia

recurring

Reduced VOCs

events

10%

Progressively

Fewer recurring events

reduced

mortality

HbF Level

By Raising HbF Levels, Pociredir Provides the Potential to Ameliorate Disease Pathology

VOC: Vaso-occlusive crisis; Powars, DR. Blood. 1984; Platt, OS. NEJM. 1994; Akinsheye, I. Blood. 2011.

Even Modest Increases in HbF Reduce Mortality and Symptom Severity

Each 1% increase in HbF is associated with

a 4%-8% reduction in VOCs1

Analysis

IRR (95% CI)

Interpretation

F U L

Cooperative Study of SCD (CSSCD)

Analysis 1: Baseline

0.94 (0.92 -

1% increase in HbF is associated

HbF Approach

R U

N=1395

0.97)

with 6% reduction in VOC rate

N=1395

T H E

Analysis 2: Equal

R A

observation time

0.96 (0.94 -

1% increase in HbF is associated

P E

approach

0.98)

with 4% reduction in VOC rate

N=1367

U T I

N=3056

C S

Analysis 3: All

0.95 (0.94 -

1% increase in HbF is associated

observation approach

N=1367

0.97)

with 5% reduction in VOC rate

N=3056

Multicenter Study on Hydroxyurea (MSH) (N= 299)

HbF analysis:

0.92 (0.89 -

1% increase in HbF is associated

Post-randomization

0.96)

with 8% reduction in VOC rate

VOC

HbF levels > mid-to-high 20% results in near

abolition of VOCs2

100

withpatientsyearper 50 ofPercentVOCzero 25

Imputed HbF (%)

Probability of observing zero VOC/year by HbF

Blue line = model prediction; Black line = observed

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

Unpublished data from Fulcrum analysis of Picnic Health real-world dataset, n = 673; ≥ 2 years old ; Mean HbF = 8.6%

Targeting EED Results in HbF Increases

F U L

CRISPR + Compound Screening Engine

Experimentally screened candidate targets

Computational Data Mining

Identified EED as a Novel Drug Target of

Polycomb Repressor Complex 2

Identified Targets

PRC2

Allosteric

Activation

that Regulate HbF

H3K27me3

C R U M T H E R A P E

Computationally mined candidate targets

H3K27me3 Propagation

HBG mRNA HbF Protein

U T I C S

Pociredir is a Potent and Selective EED Binder

EED

H3K27me3

pociredir

HBG mRNA

HbF Protein

Reduced H3K27me3 Propagation

pociredir

Highly Selective

Clean Off-target Profile

Composition of Matter Patent Expires 2040

11 EED: Embryonic Ectoderm; HbF: Fetal hemoglobin; HBG: Gamma globin gene (encodes mRNA for fetal hemoglobin)

Disclaimer

Fulcrum Therapeutics Inc. published this content on January 13, 2025, and is solely responsible for the information contained herein. Distributed by Public, unedited and unaltered, on January 13, 2025 at 12:34:13.145.