June 2022 - Investor Relations
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June 2022
Disclaimer and Notice This presentation contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the development status of the Company’s product candidates, the potential advantages and therapeutic potential of the Company’s product candidates planned meetings with regulatory agencies and availability of clinical trial data. All statements, other than statements of historical facts, contained in this press release, including statements regarding the Company’s strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrum’s ability to obtain and maintain necessary approvals from the FDA and other regulatory authorities; continue to advance its product candidates in clinical trials; initiate and enroll clinical trials on the timeline expected or at all; correctly estimate the potential patient population and/or market for the Company’s product candidates; replicate in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of losmapimod and its other product candidates; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties and other important factors, in the Company’s most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent the Company’s views as of the date hereof and should not be relied upon as representing the Company’s views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Company’s views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. FULCRUM THERAPEUTICS 2
Our Mission is to Treat Root Cause of Rare Genetic Diseases
We aim to
Deliver disease-modifying therapies that improve the lives
of people with rare genetic diseases
Three Clinical-Stage Programs
FSHD: Phase 3; positioned to be first-to-market
with a disease-modifying therapy
Sickle cell disease: Phase 1b patient study; potential first
oral functional cure
Non-SCD hemoglobinopathies: Phase 1b ready
FulcrumSeekTM
Product engine to systematically identify high-value, de-risked
targets at speed and scale for rare genetic diseases
FULCRUM THERAPEUTICS 3
FulcrumSeekTM Systematically Identifies High-value,
De-risked Therapeutic Targets for Rare Genetic Diseases
Toolbox of Disease Relevant Cell
Models Interrogated with Highly Insights Harvested from Rich Disease-Modifying Targets
Curated Perturbagens Data Readouts and Value-Unlocking Datasets
Small Molecules Targets with specificity
Transcriptomic
Readout and selectivity
CRISPR
Comprehensive data set that
significantly accelerates
Computational development
RNAi
Biology &
High-content Analytics
Imaging
Disease-Relevant
Cell Models
FULCRUM THERAPEUTICS 4
Pipeline of Potentially Disease-modifying Therapies
DISCOVERY PRECLINICAL EARLY CLINICAL MID-CLINICAL LATE CLINICAL RIGHTS
Losmapimod FSHD
(p38 Inhibition)
FTX-6058 Sickle Cell Disease
(Oral HbF Inducer)
Non-SCD Hemoglobinopathies
Blood Disorder
Neurologic Disorder
Muscle Disorder
Cardiomyopathies
FULCRUM THERAPEUTICS
Next IND by end of 1Q 2023 5
2021 Achievements Position Us for Transformative 2022
2021 Achievements 2022 Milestones
✓ Reported positive Phase 2b data ✓ Provide 1Q update on plans
Losmapimod
FSHD ✓ Met with FDA on plan for Phase 3 for Phase 3 trial
▪ Initiate Phase 3 trial in 2Q
✓ Reported positive Phase 1 HV data ▪ Report initial data from Phase 1b
✓ Initiated Phase 1b SCD trial SCD trial at EHA 2022 Congress
FTX-6058
Sickle Cell ✓ Completed 3-month preclinical toxicology ▪ Open next dosing cohort in Phase
Disease & Other ✓ Initiated chronic toxicology studies 1b SCD trial in 2Q
Hemoglobinopathies
✓ Submitted IND for non-SCD ▪ Initiate Phase 1b trial in non-SCD
hemoglobinopathies hemoglobinopathies in 2H
✓ Enhanced to dramatically accelerate ▪ Nominate next development
FulcrumSeek™ pace of discovery candidate for early 2023 IND
✓ Continued to advance collaborations
FULCRUM THERAPEUTICS 6
Poised for Substantial Growth in 2022 and Beyond
3 potentially
Multiple clinical
disease-modifying Next IND by end Cash runway
milestones in
clinical-stage of 1Q 2023 into 2024
2022
programs
FULCRUM THERAPEUTICS 7
Losmapimod for
Facioscapulohumeral
Muscular Dystrophy
(FSHD)
8
FSHD is Second Most Common Muscular Dystrophy
The Disease Robust global opportunity for
Rare, genetic disorder in which disease modifying therapy
skeletal muscle is replaced by fat Fat
infiltrates
Caused by aberrant expression muscle
of DUX4 gene Estimated US FSHD
Population*
2/3 of cases are hereditary 16,000-38,000
Symptoms
▪ Progressive weakening of muscles
▪ Significantly impaired upper and lower function Estimated Global
▪ Increasing difficulties with activities of daily living, FSHD Population*
leading to loss of independence 300,000-780,000
▪ Many become dependent on wheelchairs
▪ Chronic pain, fatigue, anxiety, and depression
FULCRUM THERAPEUTICS *Deenen, JCW, et al. Neurology. 2014; Preston, MK et al. GeneReviews – FSHD. 2020 9
Urgent Need for Therapy to Slow or Stop Disease Progression
No approved treatments; losmapimod only program in clinical development
Physicians highlight therapy to slow
disease progression as most important
need in FSHD
Top attributes patients want in a therapy:
▪ Slow disease progression
▪ Improve mobility
▪ Preserve upper extremity function
▪ Safety and tolerability “They told me that I was probably going to die
from muscular dystrophy at 30 years old—that
I would probably roll over and suffocate myself
in my sleep.”
FULCRUM THERAPEUTICS 10
Trinity Qualitative Research, June-July 2021; N=20 HCPs and N=30 patientsLosmapimod: Potential First-to-Market Therapy for FSHD
FulcrumSeekTM identified losmapimod as optimal drug candidate
to treat root cause of FSHD
▪ Highly selective p38α/β MAPK inhibitor
▪ Reduced DUX4 expression in preclinical studies
▪ Aberrant expression DUX4 gene is known root cause of FSHD
▪ Generally well-tolerated, with clinical experience in >3,600 people
FULCRUM THERAPEUTICS 11REACH: A Phase 3 Trial of Losmapimod in FSHD
Aligned with regulators on key aspects of trial design; plan to initiate REACH in 2Q 2022
Study ~230 subjects with FSHD1 and FSHD2, 18-65 years old, enriched for
Population progression as measured by RWS
Baseline Assessment 7-Day Safety
& Randomization Follow-Up
48-Week Placebo-Controlled Treatment Period
28-day Placebo tablet twice per day (N=115)
Study Screening
Design Period Losmapimod tablet 15 mg twice per day (N=115)
Baseline Week
Day 1 48
Primary Secondary Healthcare Utilization
Study RWS quantification of total relative ▪ MFI ▪ Healthcare utilization questionnaire
Endpoints surface area with 500g wrist weight ▪ Neuro-QoL Upper Extremity ▪ EQ-5D questionnaire
in dominant arm ▪ PGIC
▪ Safety and tolerability
FULCRUM THERAPEUTICS 12REACH Trial Design Leverages Learnings from ReDUX4
What we know from ReDUX4 REACH Phase 3 Trial Design
Losmapimod demonstrated measurable
impact on disease progression at 48 weeks 48-week treatment duration
of treatment
Reachable Workspace (RWS) is a reliable
and quantifiable measure of function and RWS is primary endpoint
disease progression
Muscle Fat Infiltration (MFI) is a sensitive
measure of muscle health most susceptible MFI is secondary endpoint
to disease pathology
Patient-reported outcomes are effective Patient-reported outcomes (PGIC and
measure of disease progression in FSHD Neuro-QoL) are secondary endpoints
FULCRUM THERAPEUTICS 13ReDUX4 Showed Benefits on Endpoints for REACH
Function Muscle Health Quality of Life Safety and
Preserved or improved Decreased MFI as Patients reported Tolerability
muscle function as measured by MRI feeling better as Clinical experience
measured by RWS measured by PGIC in ~3,600 people
ReDUX4 enrolled 80 people with FSHD in a randomized, double-blind,
placebo-controlled Phase 2b trial with a 48-week treatment period
14Losmapimod Showed Significant Improvement in RWS
Total Surface Area
500g Weight at 48 Weeks
Non-Dominant p=0.05
Shoulder Abductors Placebo (n=31)
Losmapimod (n=29)
Worsening Improvement
Reachable Workspace (RWS) is:
• Quantitative measure of upper Dominant p=0.01
Shoulder Abductors
extremity range of motion and function
• Objectively measured -0.10 -0.05 0.00 0.05
• Highly correlated with ability to perform
activities of daily living and maintain Change in total relative surface area
independence
FULCRUM THERAPEUTICS 15
Data from ReDUX4 trialLosmapimod Decreased Muscle Fat Infiltration
Losmapimod slowed fat infiltration in Losmapimod preserved health
muscles already affected by disease of normal-appearing muscles
0.3
0.8 p=0.01
0.2
Change from BL (%)
Change from BL (%)
0.6
(48 weeks)
(48 weeks)
Worsening
0.1
0.4
0.0
Improvement
Worsening
0.2 -0.1
p=0.16
0.0 -0.2
Placebo Losmapimod Placebo Losmapimod
(n=29) (n=24) (n=29) (n=24)
FULCRUM THERAPEUTICS 16
Data from ReDUX4 trialLosmapimod-treated Patients Reported Feeling Better
Four times as many losmapimod- 20% fewer losmapimod-treated
treated patients felt better vs placebo patients felt worse vs placebo
30 3: Minimally improved
40 7: Very much worse
2: Much improved 35 6: Much worse
25 1: Very much improved 5: Minimally worse
30 4: No change
20
% Patients
% Patients
25
15 20
15
10
10
5
5
0 0
Placebo Losmapimod Placebo Losmapimod
(n=31) (n=29) (n=31) (n=29)
48 Weeks 48 Weeks
Patients’ Global Impression of Change (PGIC)
FULCRUM THERAPEUTICS 17
Data from ReDUX4 trialExtensive Safety and Tolerability Data
▪ Majority of treatment-emergent adverse events (TEAEs)
were mild or moderate
▪ No TEAE led to treatment discontinuation or study withdrawal
▪ No significant changes in vital signs, laboratory studies, or electrocardiogram were observed
▪ Majority of TEAEs assessed as unlikely related or not related to study drug
▪ Most common AEs: fall, procedural pain, back pain, and headache
▪ Majority of AEs resolved with continued dosing
▪ Observed safety and tolerability data are consistent with prior losmapimod experience
in >3,600 clinical study participants
Losmapimod has been generally well-tolerated with no serious treatment-related adverse events
18
Data from ReDUX4 trial.FTX-6058 for Sickle
Cell Disease & Other
Hemoglobinopathies
19Sickle Cell Disease: Debilitating Disease with High Unmet Need
The Disease Global Impact
Genetic disorder caused by mutation in
Hemoglobin-Beta (HBB) gene ~50K
Results in abnormal sickle-shaped red blood ~100K EU
U.S. individuals
cells that block blood vessels or rupture cells
individuals
Millions more worldwide
Debilitating Symptoms
▪ Vaso-occlusive crises (VOCs) Treatment Options
▪ Other complications, including Current therapies are highly invasive and/or do not address
stroke, neuropathy, and acute broad symptomatology
chest syndrome ▪ Current SOC offers limited benefit and is only effective
▪ Anemia / hemolysis in a subset of patients
▪ Morbidity and mortality ▪ Newly approved therapies address only a subset of SCD
symptomatology (i.e., anemia or VOCs)
FULCRUM THERAPEUTICS SCT: Stem Cell Transplant; CDC; WHO; UpToDate. 20Significant Unmet Need Remains
HbS Polymerization
Hydroxyurea P-Selectin Inhibitors BCL11A gene editing
Inhibitors
Current Standard of Care Increasing Total Hemoglobin Leukocyte Binding to P-selectin Increasing Fetal Hemoglobin
Potential to ameliorate Potential for a cure
Addresses anemia Reduces VOCs
disease pathology
Does not address broad Does not address broad Highly invasive
Non-responders
disease pathology disease pathology
Does not improve IV administration Unknown durability
Waning efficacy
outcomes
Safety and tolerability
issues Barriers to access
FULCRUM THERAPEUTICS 21Human Genetics Demonstrate that Only Elevated Fetal
Hemoglobin (HbF) Addresses All SCD Symptoms
▪ HbF is typically silenced at birth and Hemoglobin-Beta gene turns on to produce red
blood cells
▪ Subset of people with SCD have additional mutations that cause a condition known as
hereditary persistence of fetal hemoglobin (HPFH)
▪ In these people, the fetal globin gene stays on and produces elevated levels of HbF,
leading to reduced or no symptoms
HbF induction provides a direct path to addressing
all aspects of disease symptomatology
FULCRUM THERAPEUTICS 22Increasing HbF is Only Mechanism Shown to Broadly
Improve Outcomes in SCD
Typical SCD Patient SCD Patient with HPFH
Stroke
2 – 3 Fold
Pulmonary Hypertension Induction
Acute Chest Syndrome (ACS)
30% Asymptomatic Reduced hemolysis
Nephropathy presentation
Reduced anemia
Reduced VOCs
10 – 30% 20%
Osteonecrosis Reduced Fewer Recurring Events
recurring
events
Ulcer / Pain SCD Patient 10%
Baseline HbF Progressively
5-10% reduced
mortality
HbF Level
FULCRUM THERAPEUTICS VOCs: Vaso-occlusive crisis; Powars, DR. Blood. 1984; Platt, OS. NEJM. 1994; Akinsheye, I. Blood. 2011. 23Increases in HbF Protein can Provide Broad Clinical Benefit
Numerous Published Analyses Demonstrate Increased HbF Levels are Associated with
the Clinical Benefit of Increased HbF Improved Clinical Outcomes
15
5 1 3 – 7% Increase
Average %HbF
15
Mortality in HbF
6 10
Hospital Admissions resulted in lower
ACS Events event occurrence*
Stroke/Cerebrovascular
8 Retinopathy 5
Transfusion
15 Priapism
9
0
Patients With SCD Patients Without SCD
Event Occurrence Event Occurrence
Mortality Hospital Admit ACS Stroke
Retinopathy Transfusion Priapism
Sources: Systematic Literature Review of publications from 1980 to 2021. Adeodu, et al. Mediterr J Hematol Infect Dis. 2017; Duan, et al. Am J Ophthalmol. 2019; Curtis, et al.
FULCRUM THERAPEUTICS
PLoS One. 2016; Odenheimer, et al. Am J Hum Genet. 1987; Shurafa, et al. Am J Hematol. 1982. * Data represents observational studies of SCD patients, each line represents 24
a separate analysis over the study duration.FTX-6058: Oral HbF Inducer with Potential to Provide a
Functional Cure
FulcrumSeek identified EED as a
therapeutic target for SCD
▪ Once-daily treatment
▪ Potent and Highly Selective
EED
▪ Clean Off-target Profile
FTX-6058
▪ Composition of Matter Patent
Expires 2040
▪ Induced HBG mRNA and HbF
Internal Medicinal Chemistry Led to FTX-6058, protein preclinically
a Potent and Selective EED Inhibitor
FULCRUM THERAPEUTICS 25FTX-6058 Potently Downregulates Key HbF Repressors, Including
BCL11A and MYB, in Preclinical Studies
Gene Expression Profiles in Erythroid Cultures Derived from CD34+ Cells
FTX-6058
2
Log2 Fold Change
HbF Inducers
Pomalidomide
G9Ai 0
Hydroxyurea
-2
DNMT1i
MYB
LRF
BCL11A
KLF1
Fetal Globin Repressors
FULCRUM THERAPEUTICS Representative RNASeq mRNA expression from one healthy CD34+ donor. 26Consistent 2 – 3 Fold HbF Induction with Strong Correlation
Between mRNA and Protein in Preclinical Studies
Extensive Preclinical Validation Healthy CD34+ Cells SCD Townes Mouse
%HBG mRNA %HBG mRNA
3 3
Fold Change
Fold Change
HUDEP-2 Cells (Human)
2 2
1 1
Healthy CD34+ Cells (Human) 0 0
Pre- Post- Pre- Post-
Treatment Treatment Treatment Treatment
SCD CD34+ Cells (Human)
%HbF Protein %HbF Protein
3 3
Fold Change
Fold Change
Wild-type Mouse* 2
2
1 1
0 0
SCD Townes Mouse
Pre- Post- Pre- Post-
Treatment Treatment Treatment Treatment
FULCRUM THERAPEUTICS *Assessment based on embryonic ortholog in wild-type mouse; Note: Representative mRNA and protein data from one healthy CD34+ donor 27HbF Induction Comparable to Gene Editing in Preclinical Studies
FTX-6058 HbF Induction in Healthy HbF Induction with BCL11A Gene Editing
and SCD CD34+ Donors (CTX001) in Healthy CD34+ Donors1
of total hemoglobin)
45 Healthy 45
Sickle Cell Trait
40
40 40
Sickle Cell Disease
(% of total(%hemoglobin)
(% of total hemoglobin)
35 35
Fetal Hemoglobin
Fetal Hemoglobin
30
30 30
2 – 3 Fold
25 Induction 25
3-Fold
20
20 20
Induction
Fetal Hemoglobin
15 15
10
10 10
5 5
00 0
Control
Control FTX-6058
FTX-6058 Control Edited
▪ FTX-6058 achieved HbF levels (25 – 35% HbF) associated ▪ Robust preclinical HbF induction with CTX001 has translated
with asymptomatic disease to the clinic, achieving “curative” HbF levels
FULCRUM THERAPEUTICS 1Vertex / CRISPR Therapeutics Company Data and Frangoul, H. NEJM. 2020; Powars, DR. Blood. 1984; Platt, OS. NEJM. 1994; Akinsheye, I. Blood. 2011. 28HbF Fold Induction in CD34+ Assay has Reliably Translated
to the Clinic
Preclinical HbF SCD Clinical HbF Time to Maximal HbF
Mechanism / Asset
Fold Induction1 Fold Induction2 Induction
BCL11A gene editing ~3 ~103 ~5 months
DNMT1i 1.5 – 2 2 – 2.54 >2 months7
Hydroxyurea 1.1 – 1.2 ~1.75 Up to 6 months
PDE9i No ChangeTime Course of Erythropoiesis Influenced Phase 1 and 1b Trial Designs
CD34+ Human Red Blood Cell
Erythroblast Reticulocyte
Stem Cell (HSC) (RBCs)
1 – 5 days ~7 days ~5 days
Cell Type & ~120 days (HVs)
Time at Each Stage ~30 days (SCD)
Newly formed reticulocytes require
~14 days to enter circulation
Target Engagement
Relative HBG mRNA Expression
Chronology of
F-Reticulocyte
Pharmacodynamic
Measures F-Cell
HbF Protein
Time (days)
Anticipated HbF
FTX-6058 Phase 1 Healthy Volunteer Study (14 Day Duration) induction
FTX-6058
Clinical Trial(s)
FTX-6058 Phase 1b in SCD 1 Month 3 Month
FULCRUM THERAPEUTICS 30Robust Target Engagement Demonstrates Proof-of-Mechanism
Mean Reduction (%) of H3K27me3 Levels
Change in H3K27me3 from Baseline
Treatment Period Placebo
2mg
% Change in H3K27me3 from BL
00 6mg ▪ Robust target engagement in
10mg
Phase 1 trial observed at doses
(Normalized Total H3)
Placebo
(Normalized to Total H3)
20mg
2mg FTX-6058
30mg as low as 2mg
6mg FTX-6058
-50
-50
pHBG mRNA Induction Exceeds Thresholds Predicted
to Provide Life-Changing Benefits to SCD Patients
HBG mRNA Induction is both Time- and Dose-dependent in MAD Cohorts
2mg
Treatment Period 6mg
10
10
10mg
HBG mRNA Fold Induction
20mg
▪
Demonstrated proof-of-biology in
(Normalized to HBB)
HBG Fold Induction
(Normalized to HBB)
30mg
pIncreases in F-Reticulocytes Provide Earliest Indication that
HbF Protein Production is Starting
F-reticulocytes do not Predict HbF Fold Induction, but Demonstrate Translation of HBG to HbF
88 2mg
Treatment Period
6mg
F Reticulcyte Fold Increase (%RBCs)
10mg
F-Reticulocyte Fold Increase
66
20mg Mean 1.7 – 3.9 fold increase
▪
30mg
in F-reticulocytes observed in Phase 1
trial at safety follow-up (SFU) visit at
(%RBCs)
44 pFTX-6058 has been Generally Well-Tolerated in Healthy
Volunteers in Phase 1 Trial
MAD
▪ No SAEs reported to date Placebo FTX-6058
▪ No discontinuation due to TEAE TEAEs N =10
2mg
N=6
6mg
N=6
10mg
N=6
20 mg
N=6
30 mg
N=6
▪ All TEAEs possibly related to FTX-6058 Diarrhoea (Loose Stool)b 1 (10%) 0 0 0 0 0
Dry Mouth 0 1 (17%) 0 0 0 0
were Grade 1 or 2 per CTCAE criteria
Abnormal Stool 0 0 0 1 (17%) 0 0
and resolved
Diarrhoea 1 (10%) 0 0 0 0 0
▪ Grade 3 and 4 TEAEs both unrelated Neutrophil Count Decrease 0 0 0 1 (17%) 0 0
to FTX-6058 Headache 0 0 0 1 (17%) 0 0
b Did not meet the WHO definition of diarrhea per protocol
Food Effect SAD
FTX-6058 Placebo FTX-6058 Blinded
20mgc Treatment-Emergent 2mg 4mg 10mg 20mg 30mg 40mg 60mg
TEAEs N = 10 Adverse Events (TEAEs) N = 14 N=3 N=3 N=5 N=5 N=5 N=5 N=5
Nausea 1 Eosinophilia Count Increased 1 (7%) 0 0 0 0 0 0 0
Leukopenia 0 0 0 0 1 (20%) 0 0 0
Headache 0 0 0 0 0 0 0 1 (20%)
FULCRUM THERAPEUTICS 34Ongoing Phase 1b Clinical Trial
Study
Population
Subjects with SCD, Age 18 – 65, on or off hydroxyurea
8-Week Treatment Extension
Cohort 1 (6mg)
Study
Design Cohort 2 (TBD)
Cohort 3 (TBD)
4-Week Treatment Period
Primary Secondary Exploratory
Study ▪ Safety and tolerability ▪ %HbF protein by HPLC ▪ Target engagement
Endpoints ▪ Pharmacokinetic measurements ▪ %F-cells by flow cytometry ▪ Incidence of VOCs
▪ Biomarkers of hemolysis
▪ QOL measures
FULCRUM THERAPEUTICS 35FTX-6058 Mechanism of HbF Induction Also Potentially Disease
Modifying for Non-SCD Hemoglobinopathies
The Disease(s) Global Impact
Hemoglobin-Beta (HBB) gene mutation
leading to ineffective erythropoiesis,
hemolysis and chronic anemia
~3K ~20K
Fetal hemoglobin (HbF) is a validated U.S. EU individuals
genetic modifier of non-SCD individuals
hemoglobinopathies (e.g. β-Thalassemia,
HbE/β-Thalassemia)
~40K newborns worldwide each year
Disease Burden
▪ Frequent blood transfusions Treatment Options
▪ Pulmonary hypertension Frequent blood transfusions impact patient QoL, and iron chelation
▪ Venous thromboembolism therapy is often necessary to address iron overload
▪ Heart failure ▪ Intravenous erythroid maturation agents lack robust efficacy
▪ Liver disease
▪ Significant morbidity and mortality ▪ Stem cell transplants and gene therapy are potentially curative, but
are burdensome, inherently risky, and costly
FULCRUM THERAPEUTICS 36Multiple Anticipated Value-Driving Milestones
Cash runway into 2024; $195.1M as of 3/31/2021
2022 2023
1Q 2Q 3Q 4Q
Losmapimod Announced Ph3 REACH Phase 3 Trial
FSHD Trial Design Initiate Trial 2Q 2022
Phase 1b SCD Trial SCD Phase 2/3 Trial Initiation
FTX-6058 Initial Data at 2022 EHA Congress Anticipated in Early 2023
Sickle Cell
Disease & Other
Hemoglobinopathies Non-SCD Hemoglobinopathies Trial
Initiate Trial 2H 2022
Next IND
Nominate
Advancing New Targets DC in 2022
by end of
1Q 2023
FulcrumSeek™ Ongoing
BMS Collaboration
FULCRUM THERAPEUTICS 37Our Mission and Our Purpose FULCRUM THERAPEUTICS 38
Appendix
39FTX-6058 Demonstrates Robust Relationship Between BCL11A
Downregulation and Fetal Hemoglobin Induction in Erythroid Cells
EEDi Modulation of BCL11A and HBG1/2 mRNA Translates to Robust HbF Protein Induction
BCL11A mRNA HBG1/2 mRNA HbF Protein
4 25
1
FTX-6058 Concentration (nM) 20
HBG1/2 mRNA
3
%HbF (HPLC)
0
BCL11A mRNA
log2(FC)
10 100 15
log2(FC)
-1 2
HBG1 10
-2 1 HBG2 5
-3
0 0
10 100 10 100
-4 FTX-6058 Concentration (nM) FTX-6058 Concentration (nM)
▪ FTX-6058 treatment results in dose-dependent BCL11A downregulation, and subsequent HBG1/2 upregulation and HbF induction
▪ Observe 2 – 3 fold HbF protein induction when BCL11A expression is reduced >50%
▪ Continue to establish relationship between MYB downregulation and HBG mRNA / HbF protein induction
FULCRUM THERAPEUTICS Representative RNASeq mRNA expression from one healthy CD34+ donor 40In Vitro BCL11A Downregulation Observed with EED
Inhibition Translates In Vivo
CD34+ Cell Derived
Wild-Type Mouse Townes SCD Mouse
Erythroid Culture
150 150 ✱✱ 400
✱✱ HBG1
BCL11A
BCL11A mRNA
BCL11A mRNA
300
(%Vehicle)
(%Vehicle)
100 100
(%DMSO)
mRNA
200
50 50
100
0 0 0
DMSO 100nM FTX-EEDi Vehicle 10mg/kg FTX-6058 Day 0 Day 7 Day 14 Day 21
▪ Observe consistent ~50% reduction in BCL11A across in vitro and in vivo studies
▪ In WT and Townes mouse, achieve ~50% reduction in BCL11A by day 5 – 7 of FTX-6058 treatment
▪ Durable BCL11A reduction achieved in Townes mouse model translates to robust 2 – 3 fold HBG1 induction
FULCRUM THERAPEUTICS FTX-EEDi is structurally and pharmacologically similar EED inhibitor to FTX-6058. Representative mRNA expression from one healthy CD34+ donor. 41
WT mouse whole blood mRNA, 5-days of 10mg/kg. Townes whole blood mRNA at 5mg/kg FTX-EEDiFTX-6058 Clinical Results Achieve Induction Thresholds
Predicted to Provide Life-Changing Benefits to SCD Patients
Strong Correlation Between mRNA
and Protein in Healthy CD34+ Cells
Clinical Data is Predictive of Meaningful HbF Induction
%HBG mRNA
HBG mRNA
3
Fold Change
2 10
8
Fold Change
1
6
0
Pre- Post- 4
Treatment Treatment 2-3 Fold HbF induction
predicted to provide
2 meaningful clinical
benefits in SCD
%HbF Protein
0
Placebo 6mg 10mg 20mg
3
Fold Change
2 FTX-6058
1
Anticipate similar HbF protein induction to translate in individuals with SCD
0
Pre- Post-
Treatment Treatment
FULCRUM THERAPEUTICS Powars, DR. Blood. 1984; Platt, OS. NEJM. 1994; Akinsheye, I. Blood. 2011. 42Phase 1 Healthy Volunteer Trial Established Proof-of-Biology
and Proof-of-Mechanism
Phase 1 Design and Endpoints Overview of Phase 1 SAD / MAD Cohorts
SAD MAD Cohorts
Cohorts Dose (mg) (QD, 14d)
Primary ▪ Safety and tolerability Cohort 1 2 Cohort 1
Cohort 2 4
6 Cohort 2
▪ Pharmacokinetic measurements
Cohort 3 10 Cohort 3
Secondary (bioavailability and half-life
measurements) Cohort 4 20 Cohort 4 SCD Cohort (6 mg)
Cohort 5 30 Cohort 5
▪ Target engagement
Cohort 6 40
▪ HBG (fetal hemoglobin) mRNA Cohort 7 60
Exploratory
▪ F-reticulocytes (i.e., reticulocytes
containing HbF protein)
Completed cohorts
Each MAD cohort has 8 subjects (6 on study drug and 2 on placebo)
FULCRUM THERAPEUTICS 43FTX-6058 PK Profiles Demonstrated Dose Proportionality
in SAD and MAD Cohorts in Healthy Volunteers
Plasma FTX-6058 Pharmacokinetics from MAD Cohorts
Day 1 Day 14
Mean FTX-6058 Plasma Concentration (ng/ml)
Mean FTX-6058 Plasma Concentration (ng/ml)
Scheduled Time (hr) Scheduled Time (hr)
▪ Dose-proportional pharmacokinetics demonstrated across both SAD and MAD cohorts
▪ Mean half-life was approximately 6-7 hours in the MAD cohorts, and supports QD dosing
▪ No food effect observed with FTX-6058
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