Fulcrum Therapeutics : Corporation Overview Presentation

Regulating Gene Expression to Treat the Root Cause of Disease

May 2020

Disclaimer & 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 timing of availability of clinical trial data and the Company's ability to fund its operations with cash on hand . All statements, other than statements of historical facts, contained in this presentation, 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; replicate in later clinical trials positive results found in preclinical studies and early-stage clinical trials of losmapimod and its other product candidates; advance the development of its product candidates under the timelines it anticipates in current and future clinical trials; 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 presentation 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.

This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data and estimates. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. Neither Fulcrum nor its affiliates, advisors or representatives makes any representation as to the accuracy or completeness of that data or undertakes to update such data after the date of this presentation.

FULCRUM THERAPEUTICS

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Fulcrum Overview

Clinical stage biopharmaceutical company using systematic approach to identify small molecules able to rebalance gene expression

Gene

Expression

Gene

Expression

• ~7,000 genetically defined diseases today
• We are building on decades of research highlighting gene expression role in disease
• High-throughputproduct engine designed to rapidly identify and validate drug targets that can modulate gene expression - and treat disease at its root cause
• Focus on small molecules as therapeutic modality

Our vision is to treat genetically defined diseases by addressing their root cause

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Demonstrated Systematic Target and Therapeutic Discovery Potential

Targeting genetically defined rare disease

Proprietary drug	Highly-efficient and	Multiple Ongoing	IND-enabling studies
discovery platform	Phase 2 studies in	complete for select	Research & Discovery
patient-driven
based on systematic	Facioscapulohumeral	hemoglobinopathies	Collaboration with
discovery &
and rapid therapeutic	Muscular Dystrophy	(Sickle Cell Disease	Acceleron
development process
discovery	(FSHD)	and β-thalassemia)

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Highly Efficient, Patient-Driven Product Engine

Patient-derived, relevant models

Proprietary annotated compound library

Customized CRISPR guide libraries

Genetic regulatory pathways

Genomic databases

Previously

unknown pathway relationships steer target identification

Drug target

identification and candidate development

FulcrumSeek

Proprietary database

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Significant Opportunity to Address a Wide Spectrum of Genetically Defined Diseases at Their Root Cause

The ability to up or down regulate gene expression has potential applications in the treatment of many diseases

Gain of Function		Loss of Function

Repeat Expansion

Ortholog / Paralog

•FSHD - DUX4

• Alpha-Synucleinopathies- SNCA
• Tauopathies - MAPT`
• Noonan Syndrome - PTPN11`
• Noonan Syndrome - SOS1`
• Early onset AD - APP`
• Frontotemporal Dementia - FUS`
• Parkinson's - LRRK2`

•Spinocerebellar Ataxia - CACNA1A

`

• Tubular Aggregate Myopathy - STIM1`
• Hypocalcemia - CASR`
• Centronuclear Myopathy - DNM2`
• Paroxysmal extreme pain disorder - SCN11A`
• Charcot-Marie-Tooth- PMP-22`

• Prader-Willi- SNORD116
• Angelman Syndrome - UBE3A
• Familial Dilated Cardiomyopathy - LMNA
• Emery-DreifussMD - LMNA
• Frontotemporal Dementia - GRN
• Familial Isolated Arrhythmogenic Ventricular

Dysplasia - DSP

•Williams Syndrome - ELN

•Sotos Syndrome - NSD1

•Tuberous Sclerosis Complex - TSC2

•Frontotemporal Dementia - VCP

•Rett Syndrome - MECP2

•WAGRO Syndrome - BDNF

•Bethlem Myopathy - COL6A1

• GLUT1 Deficiency - SLC2A1

•Fragile X Syndrome - FMR1

•Friedreich Ataxia -FXN

• Myotonic Dystrophy 1 - DMPK
• Myotonic Dystrophy 2 - CNBP
• ALS - C9orf72

• Huntington's Disease - HTT

• Frontotemporal Dementia - C9orf72
• Spinocerebellar Ataxia 2 - ATXN2
• Spinocerebellar Ataxia 7 - ATXN7
• Spinocerebellar Ataxia 17 - TBP
• Spinocerebellar Ataxia 10 - ATXN10

Pipeline Programs

• Sickle Cell Disease - HBG1/2
• Beta-thalassemia- HBG1/2

•Duchenne Muscular Dystrophy - UTRN

• Hemoglobin H Disease(alpha-thalassemia)
  - HBM, HBZ

•Becker Muscular Dystrophy - UTRN

• Marfan Syndrome - FBN2
• Familial Thoracic Aortic Aneurysm & Aortic

Dissection - FBN2

• CongenitalFiber-Type Disproportion

Myopathy - MYl7

• Spinal Muscular Atrophy - SMN2

• Hypertrophic Cardiomyopathy - MYH6

Discovery Screening Programs

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Fulcrum Rare Disease Pipeline

DISCOVERY PRECLINICAL

PHASE 1

PHASE 2

PHASE 3

STATUS

PROGRAM (PRODUCT CANDIDATE)

FSHD (losmapimod)

Sickle Cell Disease (FTX-6058)

β-Thalassemia(FTX-6058)

DISCOVERY SCREENING

Duchenne Muscular Dystrophy

Friedreich Ataxia Myotonic Dystrophy 1 α-Synucleinopathies Undisclosed Neurological Disease Undisclosed Pulmonary Disease (Acceleron) Additional screens & FulcrumSeek planned for 2020

Completed Ph 2 enrollment

Submit IND in 2H 2020

Submit IND in 2H 2020

Target ID / Validation

Target ID / Validation

Target ID / Validation

Target ID / Validation

Target ID / Validation

Target ID / Validation

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Pulmonary Research & Discovery Collaboration

Fulcrum eligible to receive >$400M in milestone payments + upfront and R&D reimbursement

• Fulcrum receives $10M upfront payment & Acceleron to reimburse all relevant research expenses
• Fulcrum eligible to receive:

Financial	−R&D and commercial milestones up to $295M for first product commercialized
Terms
−Up to $143.5M in additional milestones for all subsequent products commercialized
	−Tiered royalty payments on net sales ranging from mid-single to low double-digits

Transaction Overview

• Research collaboration & license agreement to identify therapeutic targets and small molecules that modulate pathways associated with a targeted pulmonary indication
• • Fulcrum to utilize its proprietary product engine to identify therapeutic targets that control the expression of genes known to impact pathways relevant to the targeted pulmonary disease
  • Acceleron responsible for all development & commercialization activities for any potential therapeutics identified

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Hope For People Living With FSHD

"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."

"You know how many years it took to get out of that? That's a scary feeling."

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Understanding FSHD

Devastating disease characterized by progressive muscular degeneration

Front Side Back

• Skeletal muscle replaced by fat
• Begins with facial weakness that makes communication difficult and smiling challenging
• Impairs movement of shoulders and arms
• Eventually affects legs and mobility, leading to loss of independence
• Patients report chronic pain, anxiety and depression
• Approximately 2/3 of cases are familial- inherited and 1/3 of cases are sporadic

FULCRUM THERAPEUTICS

*Based on recent estimates of prevalence of 1 / 20,000 and 1 / 8,333 and U.S. population of 320 million

Company data

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Market Opportunity & Competitive Landscape

Progressive disease with significant unmet need

• No approved therapies
• No other industry sponsored programs in clinical development

• Second most common muscular dystrophy

Estimated US FSHD Population*

16,000-38,000

Affects all ethnic groups with similar incidence and prevalence worldwide

FULCRUM THERAPEUTICS

*Based on recent estimates of prevalence of 1 / 20,000 and 1 / 8,333 and U.S. population of 320 million

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DUX4 is The Root Cause of FSHD

FULCRUM THERAPEUTICS

24 SEPTEMBER 2010 VOL 329 SCIENCE

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FSHD: The Fulcrum Product Engine At Work

• Disease modeled using patient- derived myotubes
• Targets identified using proprietary probe library
• Compounds identified that reduced DUX4 expression
• Fulcrum product engine identified p38α (MAPK) as key regulator of DUX4 expression
• p38α (MAPK) validated using genomic and chemogenomic tools across multiple cells

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Aberrant DUX4 Activity is Correlated with Weak Muscle Function in FSHD Patients

Aberrant DUX4 activity correlated with muscle pathology

(1-10)	10
Score	8
Pathology	6

Mean	4
2
	0
			None	Low - Medium	High

DUX4 Activity

	Aberrant DUX4 activity	Increased MRI fat fraction
observed as abnormal MRI	is correlated with loss of
						function and disability
Relative DUX4 RNA Seq Values
STIR+ MRI		Normal MRI

STIR+ MRI and skeletal muscle death is associated with increased fat fraction

FULCRUM THERAPEUTICS

Wang L et al, 2018; Mul K et al, Neurology 2017; Janssen B et al, 2014

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Reduction In DUX4 May Provide Functional Benefit in FSHD Patients

Relationship between DUX4 expression and FSHD disease presentation

Relationship between DUX4 expression and FSHD disease presentation

Asymptomatic	Asymptomatic	Asymptomatic
Healthy	Healthy	Healthy
FSHD	FSHD	FSHD

DUX4	DUX4	DUX4
low	moderate	high

Healthy	Asymptomatic	Symptomatic
		DUX4 reduction

FULCRUM THERAPEUTICS

Peter Jones; Fulcrum Therapeutics FSHD KOL Breakfast Forum	15

Higher Aberrant DUX4 Activity Resulted in Greater Functional Impairment and Increased Weakness

Relationship observed between DUX4 target gene expression and murine FSHD phenotype

Genotype	Tamoxifen	DUX4-fl	Phenotype
Dose	expression
ACTA1-MCM/+	High	No	Control
ACTA1-MCM;FLExD/+	None	Yes	Mild
ACTA1-MCM;FLExD/+	Low	Yes	Moderate
ACTA1-MCM;FLExD/+	High	Yes	Severe

(DUX4 target gene)

Reduction in DUX4 expression

correlated to improved muscle function

Ex-vivo force contractility

In-vivo treadmill performance

Some recovery of function observed after single TMX dose

FULCRUM THERAPEUTICS

Jones, TI. bioRxiv. 2018.

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Losmapimod Selection & License Process

Evaluation of clinical

p38α/β inhibitors

Fulcrum Profiling

Public Information

Toxicology Data

Human Safety Data

Human PK/PD Data

Stage of Development

Losmapimod selected as the development candidate

• Over 3,500 subjects dosed, including chronic dosing
• Extensive safety and tolerability
• Worldwide, exclusive license to losmapimod obtained from GSK in February 2019
• US Patents: 10342786 and 10537560
• Expiration: 2038

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Losmapimod Reduced DUX4 in vitroand in vivo

Reduced DUX4 protein and DUX4-	Losmapimod suppressed DUX4
driven gene expression in vitro	expression in a xenograft model of FSHD

Range of concentrations observed in phase 1 study at 15 mg BID dose

(~30-100 ng/mL or 75-265 nM)

Terminal plasma concentration = 23 nM

FULCRUM THERAPEUTICS

*Oliva et al., 2019

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Losmapimod Prevented Muscle Death in vitroand in vivo

Apoptosis markers reduced	Losmapimod (6 mpk b.i.d.) increased
relative human cell content, consistent
	with decreased muscle cell death

Range of concentrations observed in phase 1 study at 15 mg BID dose

(~30-100 ng/mL or 75-265 nM)

Terminal plasma concentration = 23 nM

Company data

FULCRUM THERAPEUTICS

*Oliva et al., JPET, 2019

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Integrated Development Strategy

Natural history &

preparatory studies

Phase 1

Phase 2 Open Label Study

Phase 2b (ReDUX4)

24 or 48 weeks dosing with

interim analysis

• Disease progression
• Clinical endpoints
• Target engagement
• Muscle penetration in FSHD
• Molecular endpoint in muscle biopsy

Open Label Extension

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Ongoing Natural History and Preparatory Studies in

FSHD

Planned total enrollment of 362 subjects across 4 studies, with sites in the US and Europe

Important opportunity to profile biomarkers and clinical endpoints in FSHD:

• Root cause of disease muscle biopsy endpoint (DUX4 driven gene expression)
• MRI health biomarkers (lean muscle volume, fat fraction)
• Mobility endpoint (FSHD Optimized Timed Up and Go - FSHD TUG)
• Arm function endpoint (Reachable Work Space - RWS)
• FSHD Quality of Life/Activities of Daily Living (QOL/ADLs) - (Patient Reported Outcomes - PROs)
• In-personand internet based surveys (direct patient input into Phase 2b Protocol)

FULCRUM THERAPEUTICS

Sponsored by NIH and company

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Phase 1 Confirmed Safety and Selection of 15 mg Dose

Losmapimod was safe and well tolerated in FSHD patients

Achieved clinically relevant, dose-dependent concentrations in muscle

Exposures in plasma and muscle were concentrations that showed efficacy in pre-clinical evaluations in multiple labs

15 mg PO BID dose showed sustained and robust target inhibition

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Phase 2b ReDUX4 Trial (n=80)

Randomized, double-blind,placebo-controlled,multi-site international

15 mg twice per day for 24 or 48* weeks

• Primary endpoint:
• • DUX4 driven gene expression in skeletal muscle needle biopsy at 16 or 36 weeks*, as measured byqRT-PCR in a panel of DUX4-regulated gene transcripts
• Secondary endpoints:
• • Safety and tolerability
  • PK in blood
  • Losmapimod concentration in skeletal muscle biopsies
  • Target engagement in blood and in skeletal muscle biopsies
  • MRI Lean Muscle Volume & MRI Fat Fraction

• Exploratory endpoints:
• • RWS
  • FSHD-TUG
  • Muscle Function Measure (MFM)
  • Muscle Strength (Dynamometry)
  • PROs
  • 12 patients completed Week 24 and have enrolled into open label extension
  • Interim analysis data expected Q3 2020
  • Topline data expected Q1 2021

* Protocol amendment to accommodate COVID-19 impact (extend trial to 48 weeks and allow 2nd' biopsy to occur at either 16 or 36 weeks)

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Exploratory FSHD Endpoints

Reachable Workspace Functional Test

Measures proximal arm and shoulder function

Quadrant	Progression Rate
(weighted)	(% annualized)
Quadrant 1	-7.20
Quadrant 2	+1.40
Quadrant 3	-8.09
Quadrant 4	-0.76
Total	-1.82

• Capable of detecting slowly progressive proximal arm/shoulder function changes
• Greater % decline with 500gm weights
• The upper quadrants (1&3) of FSHD patients with abnormal RWS demonstrate greater annual declines

Skeletal Muscle Fat Content by MRI

Fat replacement in

skeletal muscle in

FSHD patients vs. controls

*p<0.05,

**p<0.0001

T2-value- a measure of extent/severity of tissue pathology, used to measure the relative level of muscle pathology

Muscle fat content- % of fat within a muscle, used to monitor muscle degradation

• T2-valueand fat fraction both worsen over time in FSHD
• Worsening of fat fraction already seen by 6 months
• Fat fraction progression is higher in muscles with higher T2

FULCRUM THERAPEUTICS

Hatch et. al., 2019, Neuromuscular Disorders

Prof. John Vissing Poster at World Muscle Society Congress, Mendoza, 2018

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Comprehensive Evaluation of Efficacy

Original

Protocol Design

12 of 80 enrolled

subjects completed Week 24 and were rolled into OLE

Amended

Protocol Design

Remaining ~68

enrolled subjects

that did not complete

Week 24 remain

active in 48-week

placebo-controlled

trial followed by OLE

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Amended Protocol Provides Opportunity for Additional Clinical Evaluations

Day 1 & Week 16 or 36: Muscle Biopsy (MBx)

DUX4-driven gene expression in skeletal muscle needle biopsy

Visit 1, Week 12, Week 48: MRI

Lean skeletal muscle volume; skeletal muscle fat fraction

Day 1, Weeks 4, 12, 16, 24, 36, 48: Clinical assessments

PK; safety; Reachable Work Space; FSHD-Timed Up & GO, Muscle function measures, dynamometry and Patient Reported Outcomes

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Hemoglobinopathies:

Sickle Cell Disease & Beta-Thalassemia

"The world doesn't see us.

We have an invisible

disability."

FULCRUM THERAPEUTICS		27

Hemoglobinopathies: The Fulcrum Product Engine At Work

Approach validated by extensive research in human genetics

Root cause associated with mutation(s) in, or deletion of, the HBBgene that codes for the β-subunit of adult hemoglobin

Research supports efforts to induce expression of fetal hemoglobin (HbF) to compensate for the mutated adult β-globin gene in SCD and β-thalassemia

Novel HemoglobinopathiesTarget /

Novel Chemical Entity:

• Potent, efficacious and selective
• Optimizeddrug-like properties for oral QD dosing
• Novel IP

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HbF Mitigates Mortality and Morbidity Risks Associated with Sickle Cell Disease

SCD Patient

SCD Patient with High HbF

RBC sickling

VOCs

Hemolysis

Acute

Chest

Syndrome

Osteonecrosis

Stroke

Pulmonary

Hypertension

Nephropathy

Ulcer / Pain

Pancellular
HbF	30%		Asymptomatic
Expression
	presentation
and
Induction				Increased F-cells*
	20%		Reduced	Reduced VOCs
			recurring
			events	Reduced hemolysis

(VOCs, ACS,

Hospitalization)

10%

Reduced mortality

HbF Level

FULCRUM THERAPEUTICS

*F-cells - fetal hemoglobin expressing cells	29

Meaningful Increases in Percent of Fetal Hemoglobin in CD34+ Cells

• In preclinical studiesFTX-6058 showed a pancellular increase in HbF levels to ~30% total hemoglobin
• Results indicate thatFTX-6058 could play a role in reducing risk of crises in people living with sickle cell disease

Hemoglobin quantification: CD34+ cells differentiated and treated for 7 days

Quantification of % fetal hemoglobin in

differentiated primary CD34+cells

	50	Mass Spec	HPLC	FPLC
Hemoglobin		(HBG1/2)	(HbF)	(HbF)
40	33.4%
		28.5%	28.1%
30
20	11.7%	14.5% 14.5%
Fetal	13.0%14.5%
	6.1%
10
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Superior Induction of Human Fetal Hemoglobin mRNA and Protein Versus SOC in Townes SCD Mice

Target Engagement

HBG1mRNA levels

Fetal hemoglobin protein levels

Monocyte TE

150

MFI

Control/MFIMarker Vehicleof%as

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SCD Mice

Townes mouse model:

Hydroxyurea was administered once daily at 100 mg/kg for 28 days;**p<0.01; ***p<0.001

FTX-6058 was administered twice per day at 5 mg/kg for 28 days

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Opportunity for Continued Rapid Progress in 2020

Cash runway into 3Q2021

Losmapimod

FSHD

FTX-6058

Sickle Cell Disease

& β-Thalassemia

Product Engine

2020

Q1		Q2		Q3		Q4

Phase 2b

Interim analysis data in 3Q 2020

Topline data on primary endpoint in 1Q 2021

Phase 2 Open Label Study

IND-Enabling	IND Filing
Studies Complete

Screens in 6 New Diseases

Acceleron Research & Discovery Collaboration

FULCRUM THERAPEUTICS	Developmental	32
Regulatory	Expected Data Readout

Summary

▪Strategy and platform that support rapid progress and opportunities to target major areas of unmet need in healthcare

▪Unmatched experience in understanding and targeting the root cause of genetically defined diseases

▪Expertise and resources in place to advance multiple promising therapies

▪Progress provides strong validation of platform

fulcrumtx.com

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