Stealth BioTherapeutics : Investor Presentation August 2020.

Targeting the powerhouse of the cell

to treat rare genetic and age-related diseases

August 2020

Our forward-looking statements and disclaimers

This presentation and various remarks we make during this presentation contain forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding Stealth BioTherapeutics' plans, strategies and expectations for its preclinical and clinical advancement of its drug development programs including elamipretide, SBT-20,SBT-272,SBT-259 and SBT-550; the potential benefits of Stealth BioTherapeutics' product candidates; its key milestones for 2020; its plans regarding future data presentations; and its financial guidance regarding the period in which it will have capital available to fund its operations. The words "anticipate," "expect," "hope," "plan," "potential," "possible," "will," "believe," "estimate," "intend," "may," "predict," "project," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make as a result of known and unknown risks, uncertainties and other important factors, including: our ability to obtain additional funding; the ability to successfully demonstrate the efficacy and safety of Stealth BioTherapeutics' product candidates and future product candidates; the preclinical and clinical results for Stealth BioTherapeutics' product candidates, which may not support further development and marketing approval; the potential advantages of Stealth BioTherapeutics' product candidates; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, which may affect the initiation, timing and progress of preclinical studies and clinical trials of Stealth BioTherapeutics product candidates; Stealth BioTherapeutics' ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Stealth BioTherapeutics' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in the Stealth BioTherapeutics' Annual Report on Form 20-F for the year ended December 31, 2019 filed with the Securities and Exchange Commission on April 1, 2020 and any future filings with the Securities and Exchange Commission. Any forward-looking statements contained in this presentation and various remarks we make during this presentation speak only as of the date hereof, and Stealth BioTherapeutics' expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

2 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Pioneering mitochondrial medicine

Platform potential	Improved organ function	Patient-focused
rare and common diseases	with long-term therapy	targeting unmet needs

Barth,	Geographic
Duchenne,
	atrophy,
Becker,
	LHON
Friedreich's
ALS, MSA

Elamipretide:	ReCLAIM (dry AMD)	Across rare and common
rare cardiomyopathies, geographic	Geographic atrophy growth rate	patient populations
atrophy, LHON	measured by FAF and OCT
Pipeline (SBT-272,SBT-550):	less than expected by published natural history

neurology

3 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Our pipeline

Category Product Candidate

Elamipretide

Elamipretide

SBT-272

SBT-259

SBT-550

Indication

Geographic atrophy

Friedreich's ataxia

Leber's hereditary optic neuropathy

Barth syndrome

Duchenne, other rare

cardiomyopathies Amyotrophic lateral sclerosis/multiple system atrophy Charcot-Marie-Tooth T2/other

Leigh's

syndrome/other

Discovery

Preclinical

Phase 1

Phase 2

Phase 3

>75% enrolled

Phase 2/3 completed

Planning

ongoing ongoing*

*in healthy volunteers

ongoing

ongoing

Next

Milestone

Complete

enrollment YE

2020

P2 to commence

H2 2020

P3 initiation 2021+

2020 regulatory

interactions

Protocol

submission 2021

Complete Phase 1

trial

Progress to clinical

trials

Preclinical

studies

4 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Over 10 decades of drug development expertise

Reenie McCarthy, Chief Executive Officer

Brian Blakey, PharmD, Chief Business Officer

Jim Carr, PharmD, Chief Clinical Development Officer

Marty Redmon, PhD, Executive VP, Discovery,

Development and Technical Operations

Rob Weiskopf, Chief Financial Officer

5 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Elamipretide mechanism

6

Mitochondria: essential for human life, complicit in disease and aging

fuel	enable	form	drive
organ function	neurotransmission	plaques, deposits	fibrosis

produce energy	maintain calcium	impair	produce
ATP	equilibrium	mitophagy	toxic ROS

7 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

CardiolipinElamiperoxidretide aggregatestion- finalandcommonstabilizes diseasecardiolipinpathway

Normal mitochondria

Diseased mitochondria

ATP (energy)

Cardiolipin

Oxidative stress/free radicals

ROS

Protein importation

Super-complex formation

Fission, fusion, mitophagy

Cardiolipin

Cristae

Electron transport chain (ETC) complexes

e Electrons

Reactive oxygen species (ROS)

8 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

CardiolipinElamiperoxidretide aggregatestion- finalandcommonstabilizes diseasecardiolipinpathway

Normal mitochondria

Diseased mitochondria

Cardiolipin

ROS

Elamipretide(ELAM) associates with

Fission, fusion, mitophagy

cardiolipin(CL) in a 1ELAM: 2CL molar ratio, improving mitochondrial structure and function across numerous disease models

Cardiolipin

Cristae

Electron transport chain (ETC) complexes

e Electrons

Reactive oxygen species (ROS)

9 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Elamipretide normalizes mitochondrial morphology

Normoxic	Disease	Disease + Elamipretide
Normoxic	Disease	Disease + Elamipretide

Mouse model of diabetic retinopathy

10 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

Szeto, Birk, Am J Physiol 2014

Szeto HH, Birk AV. Clin Pharmacol Ther. 2014

Elamipretide restores healthy mitochondrial function

• ATP production

Healthy elderly patients (n=40) with muscle mitochondrial dysfunction

MOTION P2 trial

• Oxidative stress/free radicals

Increased mitochondrial ROS in

cardiomyopathy fibroblasts

• Protein transcription/importation

Improvements observed in protein importation observed in BTHS, FRDA and HF models; may explain differential signals in mtDNA vs nDNA mutations in PMM P3 trial

p=0.055*

Plac

Elam

*after exclusion of 1 outlier	Machiraju et al., Frontiers Cardiovascular Medicine 2019
Conley et al., HFSA 2016

11 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

Elamipretide improves frataxin expression in FDRA patient-derived lymphoblasts (GM15850)

Zhao, Sci Rep, 2017

Elamipretide safety

12

Elamipretide - safety and tolerability

Exposure	Duration	Side effects	Injection site
	of exposure	in >5% exposed subjects	reactions

~900 subjects	>2 years	Eosinophil increase (mild/moderate +	Transient mild to moderate
systemically,	(systemic and topical)	no associated signs/symptoms), URI,	ISRs in majority of subjects
~53 subjects topical		increased blood IgE (no associated	receiving elamipretide by SC
ophthalmic drops		signs/symptoms), dizziness,	administration
		headache, UTI + viral gastroenteritis

IgE - immunoglobin E; ISR - injection site reaction; SC - subcutaneous; URI - upper respiratory tract infection; UTI - urinary tract infection

13 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Ophthalmic indications

14

Dry AMD development program

Route of	Preclinical	Natural	Clinical	Current &
administration	models	history	data	next steps

2021

1 mg/kg SC elamipretide	Improved mitochondrial	High risk drusen +	Phase 1 ReCLAIM trial showed	ReCLAIM-2 Phase 2b
reaches retina in higher	function and vision in	intermediate geographic	improvement in visual function	trial of SC elamipretide
concentrations than 1.0%	animal models.	atrophy (GA) patients lose	in patients with GA and drusen	in patients with GA
topical ophthalmic drops +	Improvements in dry	up to 5 letters of visual	and apparent slowing of GA	ongoing; data 2021.
is more quickly efficacious.	AMD donor eyes.	acuity every	progression after 6 mos. once	IVT development
		6-12 months.	daily SC elamipretide.	ongoing.
Stealth, data on file; Alam,	Cousins, Retina Today,	Holkamp, Angiogenesis,	Angiogenesis, 2019,
Dis. Mod. Mech. 2015	2016, Angiogenesis, 2017,	2018; Ladd, data on file.	ARVO, 2019, ASRS 2019
	Kapphahn, ARVO, 2017

15 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Preclinical reversal of AMD pathophysiology & improvement of vision

Normal Diet

Hi Fat + Vehicle

Hi Fat + Elamipretide

Hi Fat + Vehicle

Hi Fat + Elamipretide

Oxidative stress

Flavoprotein

Fluorescent green

Cell integrity

RPE nuclei blue

Cytoskeleton red

		300			#818090-1 (Normal diet) Right eye, Steps 1-9	300
Vision		200										200
(uV))	100									(uV))	100
pattern electrogram	2(Result	0									1 (Result	0
Chan	-100									Chan	-100
		-200										-200
		-300										-300
		-100	0	100	200	300	400	500

Step 1 (Time (ms))

#945945-2 (HFC diet) Left eye, Steps 1-9

Chan 1 (Result (uV))

-100

0

100

200

300

400

500

Step 1 (Time (ms))

300

200

100

0

-100

-200

-300

-100

0

100

200

300

400

500

Step 1 (Time (ms))

• *

Deposits

Electron microscopy

16	S. Cousins, Duke Eye Center, Angiogenesis, Exudative, and Degeneration, February 2016, Miami, FL
© 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

ReCLAIM Phase 1 high-risk drusen and geographic atrophy

Screening		BL	W1	W4	W8	W12	W16	W20	W24		W28: Washout

		>5 letters						Endpoints
	High-risk drusen	low luminance						Primary Endpoint: Safety
		deficit
									Adverse event attributed to drug
	BCVA ≥ 55	n=21						Exploratory Endpoints: Efficacy
						Low luminance visual acuity (LLVA)
	letters			Elamipretide 40 mg (s.c.)
							Best corrected visual acuity (BCVA)
						Once daily		Low luminance reading acuity (LLRA)
		>5 letters						Low Luminance Questionnaire (LLQ)
				No placebo control
	Noncentral GA				NEI Visual Function Questionnaire (VFQ)
	low luminance						Dark adaptation (DA)
		deficit
							Drusen volume
		n=19						Fundus hyperautofluorescence
	BCVA ≥ 55 letters						Cone light sensitivity (microperimetry)

Stealth Biotherapeutics [data on file].

17 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

Phase 1 improvement in low luminance visual acuity

Drusen: Mean Change in LLVA n=19			Quiescent Neovascular Non-Study
			Eyes: Mean Change in LLVA

p=0.006

GA: Mean Change in LLVA n=15

Mean:+6.1 letters p=0.0012

n=14

p=0.025

18 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Phase 1 improvement in visual acuity

Drusen: Mean Change in BCVA n=19			Quiescent Neovascular Non-Study
					Eyes: Mean Change in BCVA
	p=0.025

GA: Mean Change in BCVA n=15

p=0.003

19 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Phase 1 improvement in low light reading acuity

Drusen: Mean Change in Low-Luminance Smallest Line Read Correctly

p=0.0001

3-line gain

GA: Mean Change in Low-Luminance Smallest Line Read Correctly

p=0.017

5-line gain

20 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Phase 1 geographic atrophy growth rate trails natural history

Elamipretide may be slowing disease progression at 6 months

10 Studies	0.91mm2
	5 Studies

0.50 mm2

0.19 mm

0.14 mm

5 Studies

0.18 mm

0.13 mm^^

Other Studies2

X Stealth Study

1. 6 Month change in GA Area by OCT is 0.45 mm2
2. Fleckenstein, Ophthalmology. 2018 Mar;125(3):369-390, "Filly", Mac. Soc. Feb. 2018; "Chroma" and "Spectri", JAMA Opth. Jun. 2018; "Proxima A", Angiogenesis 2018 (all assuming linear growth)

21 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

ReCLAIM 2B for geographic atrophy currently enrolling

Screening

GA area ≥0.05mm2/
<10.16 mm2
BCVA ≥ 55 letters	n=180
>5 letters low
luminance deficit

Inclusion criteria mimic Phase 1 ReCLAIM GA cohort (BCVA ≥ 55 letters, >5 letters low luminance deficit)

Projecting full enrollment H2 2020

BL	W4	W8	W12	W24	W36	W48		W52: Washout

Elamipretide 40 mg SC or placebo once daily, 2:1 randomization

Efficacy endpoints

Low luminance visual acuity (LLVA)

Low luminance reading acuity (LLRA)

Best corrected visual acuity (BCVA)

Geographic atrophy by fundus autofluorescence (FA)

Geographic atrophy by optical coherence tomography (OCT)

NEI Visual Function Questionnaire (VFQ)

Low Luminance Questionnaire (LLQ)

Conversion to choroidal neovascularization (wet AMD)

22 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Friedreich's ataxia development program

Nonclinical	Natural	Clinical
Data	history	plan

Elamipretide improves frataxin	Friedreich Ataxia Collaborative
expression in FRDA patient-	Clinical Research Network has
derived lymphoblasts	assessed visual acuity in >500
(GM15850)	patients longitudinally over 5+
	years.

Zhao, et al., Scientific Reports, 2017.

23 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Phase 2 68-weekopen-label clinical study at CHOP to assess safety and efficacy and inform P2/3 endpoint selection.

Vision loss and cardiomyopathy in Friedreich's ataxia - an unmet need

Pressing unmet need

"Without vision you have nothing - isolation from the world is complete."

- FRDA Voice of the Patient Report

most experience

visual dysfunction

>90% develop

cardiomyopathic symptoms

37.5

average age of death

Natural history

Mean Change in Overall Vision Acuity from BL

	0	1	2	3	4	5	6
	6.00
	4.00	1.13
	2.00
	0.00	0
Change	-2.00	-1.38
-4.00
-6.00	-3.98
Mean				-7.36
-8.00
	-10.00					-10.97
	-12.00
					-12.58
	-14.00
					-13.33
	-16.00			Years from Baseline

Total Cohort Age <16 @ BL Age 16-40 @ BL Age >40 @ BL

Collaborative Clinical Research Network FRDA natural history cohort; n=~900, >500 with 5+ years longitudinal data

Nonclinical data

Control

FRDA

FRDA + Elam

Elamipretide improves mitochondrial morphology in FRDA patient-derived lymphoblasts (GM15850)

Hanson, et.al., World J Cardiol., Jan. 2019; FRDA Voice of the Patient Report, 2017.

Zhao, et al., Scientific Reports, 2017.

24 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Phase 2 study commencing H2 2020*

Screening

BL W1 W4	W16	W36	W52	W68		Optional 36-week extension

		Genetically		n=10
		confirmed FRDA
	Primarily visually		Primarily affected by
	compromised:
	Visual acuity worse		cardiac dysfunction:
	•	Ejection fraction
	than 20/40
	Impaired contrast:		<50% and
	•	Visual acuity of
	•	high contrast
		20/25-20/40
		visual acuity of
		20/50-20/800, or
	•	hand motion
		vision

* Protocol being finalized and subject to IRB approval

Elamipretide 40 mg (s.c.)

Once daily

No placebo control

May be extended to 2-year duration to assess durability of any observed response

Safety Endpoints

Adverse event attributed to drug

Ophthalmic Efficacy Endpoints

High contrast visual acuity or low vision alternative

Low contrast visual acuity

Low luminance visual acuity (LLVA)

Optical coherence tomography

Visual function questionnaire

Cardiac Efficacy Endpoints

Ejection fraction by cardiac MRI

Left ventricular volume index

Stroke volume

Fibrosis

Strain

Exploratory Efficacy Endpoints

MFARS, FA ADL, FA functional disability scale

REDENLAB speech assessments

PGIC/CGIC

25 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

LHON development program

Route of	Preclinical	Natural	Clinical	Open-label	Current &
administration	Models	history	data	data	next steps

2021+

1.0% topical ophthalmic	Improved mitochondrial	For patients >12 mos.	ReSIGHT Phase 2 did not
drops reach the retina in	function in murine-derived	post vision-loss, visual	show improvement in BCVA
therapeutic concentrations	retinal ganglion cell (RGC)	field and acuity are not	after 48-weeks of
+ demonstrate efficacy.	line. Improved RGC survival +	expected to improve	elamipretide 0.1% topical
Higher concentrations	visual outcomes in murine	over 2 yr. period.	ophthalmic drops.
reach retina via SC	acute traumatic optic		Improvement in visual field
delivery.	neuropathy model.		and visual quality of life.
Stealth, data on file; Alam,	Chen 2017; Pelaez, Tse	Lam, JAMA	ARVO, 2019, EUNOS, 2019,
Dis. Mod. Mech. 2015	(ongoing)	Ophthamology, 2014	UMDF, 2019.

Improvements from P2	Phase 3 protocol
baseline in visual acuity,	submitted to FDA
visual field, color, contrast +	year-end 2019.
visual quality of life	Phase 3 initiation
observed at week 28.	post-2020.

ARVO, 2019, EUNOS, 2019,

UMDF 2019

26 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Early improvement in central visual field; long-term improvement across endpoints

Double-masked,fellow-eye control trial	Open-label extension (at 6 months)

In double-masked,fellow-eye control trial, improvements observed in Humphrey's visual field (p<0.02), particularly in the central visual field (p<0.0001) which is most impaired in

LHON

Central Field Analysis (post-hoc)

central field

mid-peripheral outer peripheral

Visual Field OLE

p=0.025

Contrast OLE

p=0.005

BCVA OLE

p=0.051

Color OLE

Raw values averaged between eyes; blue = double masked portion of trial, green = OLE; n=12

27 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Phase 3 protocol pending FDA feedback; initiation post-2020

Screening

BL

W4

W8

W12

W24

W36

W48

W60

W78

W82 follow-up

•	Ages ≥15
•	LHON with DNA mutations

Elamipretide 40 mg SC or placebo once daily, 2:1 randomization

Primary efficacy analysis to be conducted in patients with mt.11778G>A mutation

mt.11778G>A, mt.3460G>A, or

mt.14484T>C

• Loss of vision in study eye

within 0-2 years of screening

• ≥50 microns RNFL in study eye

• ≥40 microns GCL in study eye

n=~160

n=~120 with mt.11778G>A

mutation (primary analysis group)

Efficacy endpoints

Central visual field

Full visual field

NEI Visual Function Questionnaire (VFQ)

Best corrected visual acuity (BCVA)

Color discrimination

Contrast sensitivity

Exploratory endpoints

Neurofilament light chain (NfL) Retinal nerve fiber layer by optical

coherence tomography (OCT)

Retinal ganglion cell thickness by OCT

EQ-5D-5L Questionnaire Efficacy in non-study eye

28 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Rare cardiomyopathies

Barth; potential for DMD

29

Metabolic cardiomyopathies

Failing heart: an engine out of fuel		Progressive remodeling		Significant US unmet need

Normal heartHypertrophic heart

Small left chamber &

thickened muscle with or

without fibrosis

Low stroke volume Exercise intolerance

Arrythmias, sudden

cardiac death

Dilated heart

Large left chamber with

thin walls

Poor contraction &

reduced ejection fraction

Exercise intolerance

Arrythmias, sudden

cardiac death, blood clots,

edema, heart failure

Barth <200

FRDA 1:50,000

DMD 1:5,000

HFpEF >3m*

• Pipeline partnering potential

BSF Voice of the Patient Report, 2019; Hanson, et.al., World J Cardiol., Jan. 2019; Payne, R.M., Prog. Pediatr. Cardiol., 2011; Giugliano, GR et al., Tex Heart Inst J, 2007; Machiraju et al., Front Cardiovasc Med 2019; Vasan et al., JACC: Cardiovascular Imaging 2018.

30 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Elamipretide-mediated improvements in cardiac function

Heart failure	Barth syndrome (BTHS)

Dystrophies (DMD, BMD)

Elamipretide improves respiration in failing

human heart tissue (ischemic, non- ischemic, acquired and congenital)

Change:Elamipretide treated		‡
from Untreated
Percent	N = 9 N = 10	N = 13 N = 18

‡ p<0.005 Untreated vs Treated

Stauffer, ESC HF, 2017, Chatfield, JACC Basic Translational Sc, 2019

31 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Elamipretide improves respiration in Barth

human IPS derived cardiomyocytes

‡

Barth + vehicle

Barth + elamipretide

Wild type + vehicle

Wild type + elamipretide

Pu, et. al., BSF Poster Presentation 2016

Elamipretide improves respiration in failing Becker MD heart tissue

Stauffer, et al., unpublished, 2020.

Barth development program

Our Barth development initiative was prompted by requests from advocacy (Barth Syndrome Foundation) and KOLs.

Preclinical	Clinical	Open-label	Natural history	Current &
models	data	data	comparative control	next steps

BTHS derived

cardiomyocytes +

lymphoblastoid cells; TAZ KD mouse model; lipid bi- layer modeling systems; DCMA fibroblasts

Pu, BSF, 2016; Vernon, ongoing; Mitchell, 2019; Allen, 2019, pub. pend., Machiraju, 2019

2020

No changes in 6MWT or	Improvement from Phase	SPIBA-001 observational	Rare pediatric
BTHSA-Total Fatigue	2/3 baseline on multiple	study established the	designation
during 12-week	pre-specified endpoints	effectiveness of	awarded.
treatment in TAZPOWER	(cardiac function, 6MWT,	elamipretide compared to	FDA interactions
Phase 2/3 crossover trial.	BTHSA-Total Fatigue,	natural history control with
to inform
Responders observed in	Muscle Strength, PGI	statistically significant
regulatory path
pre-specifiedsub-group.	Symptoms) in 8 patients at	improvement on 6MWT
forward.
Trends toward improved	week 36 of OLE.	(p=0.0005) primary
cardiac function.	MDA, 2019, UMDF 2019	endpoint and other
MDA, 2019, UMDF, 2019	secondary endpoints.

32 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

TAZPOWER: longer therapy during OLE improved multiple endpoints

	6MWT (n=8)			BTHS-SA fatigue (n=8) Muscle strength (n=8)
	500				478 479 489				9														200
						points)15-(3fatigueoffeelingWorst														188 187
	480							7.95
minutes6inwalkedMeters													8										Newtons	180							175
	460
																7.38
	440														7														160
	420																5.88			6.25
														6								140
	400																								132
	382
	380
														5														120
	360
	340														4														100
	320
														3														80
	300
	BL	W36 W48 Wk				BL W36 W48	Wk			BL W36 W48 Wk
					OLE OLE 72							OLE OLE	72							OLE OLE 72
									OLE												OLE										OLE

SWAY balance (n=8)

8584

83

80

76

75

71

70

65

BL W36	W48	Wk 72
OLE	OLE	OLE

Seconds

5X SST (n=8)

14

13 12.9

12

11.3 11.4

1110.8

10

BL W36 W48 Wk

OLE OLE 72

OLE

CGI Symptoms (n=8)		PGI Symptoms (n=8)
2.0												2.0
												1.75
														1.50
1.5	1.38									1.5
									1.25
														1.13
1.0												1.0
		0.75
						0.63
0.5									0.50			0.5
											0.0
0.0
										BL W36 W48 W72
BL W36	W48	W72
			OLE	OLE	OLE					OLE OLE OLE

BL:Wk 36 OLE	BL:Wk 36 OLE	BL:Wk 36 OLE	BL:Wk 36 OLE
p=0.02	p=0.03	p=0.02	p=0.20
BL:Wk 72 OLE	BL:Wk 72 OLE	BL:Wk 72 OLE	BL:Wk 72 OLE
p=0.01	p=0.07	p=0.008	p=0.01

33 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

BL:Wk 36 OLE p=0.22

BL:Wk 72 OLE p=0.10

BL:Wk 36 OLE	BL:Wk 36 OLE
p=0.10	p=0.05
BL:Wk 72 OLE	BL:Wk 72 OLE
p=0.0006	p=0.10

TAZPOWER: patient and caregiver perception of change

Fatigue/Energy Levels Stamina/Endurance Muscle Strength Appetite Heat Tolerance

Healing From Wounds Muscle Pain Fogginess Healing from Sickness Depression Headaches Sweating Sleep Quality Incontinence

Functional Improvement			Improvements reported by participating subjects (and/or
								their caregivers) (n=10 represented subjects)

																			Daily Life Activities				Daily Life Improvement
																			Physical Activities
																			Quality of Life
																			Work/School
																			Independence
0	10	20	30	40	50	60	70	80	90	100	0	10	20	30	40	50	60	70	80	90	100
							Percent of Patients															Percent of Patients

34 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

SPIBA-001 natural history comparative control study

Week 36 OLE compared to prognostically matched natural history controls (NHC)

Primary endpoint		Secondary endpoints

6MWT	from baseline		Muscle strength by
	90	81.26			HHD	from baseline
	80			45	42.75
minutes	60				40
			35
	70
6	50				30
walkedin			Newtons	25
40
				20
	30
Meters				15
20				10
	10		0.59		5		1.03
	0			0
	Elamipretide	Natural history		Elamipretide	Natural
			control				history control

5XSST from

baseline

0

	-0.002
-0.5
Seconds					Elamipretide

-1
				Natural history
					control
-1.5
-2
-2.3
-2.5

	SWAY balance	from
	baseline
8	7.35
7
6
5
4
3
2			0.89
1
0	Elamipretide	Natural history
			control

Multi-domain

responder index

score

4
3
3
2
1	0.6
0
Elamipretide	Natural history
	control

p=0.0005

Week 48 OLE: Elam 93.08, NHC 0.88, p=0.0006

Week 72 OLE: 115.28 (29.50); p=0.0002

p=0.0002

Week 48 OLE: Elam 49.92, NHC 1.97, p=0.0004

Week 72 OLE: 58.17 (14.58); p=0.0001

p<0.05

Week 48 OLE: Elam -2.76, NHC -0.004, p=0.04

Week 72 OLE:-3.3 (1.18); p=0.006

p=0.13

Week 48 OLE: Elam 8.69, NHC

1.11, p=0.12

Week 72 OLE: 11.98 (5.14);

p=0.02

p=0.0001

Week 48 OLE: Elam LSM 3.1, NHC 0.7, p=0.0001

Week 72 OLE:

35 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Increased left ventricular volumes

SPIBA-201 patients under-perfused at BL				3D LV Stroke Volume (Indexed)
mean BL CI = 2.3L/min/m2 (~3,300 L/day)
40.00
		Double-blindcross-over		Open-label extension
		38.00
		36.00								35.33	35.31
5.0 L	Healthy teenager	34.00						33.38		34.46
	~4.13L/min/m2
	(6,000-7,500 L/day )	32.00							32.46
		28.69	30.49
	Congestive heart failure	30.00
3.0 L
	~2.3L/min/m2	28.00						28.48
					28.17	28.52
	Cardiogenic shock
	26.00
	<2.2L/min/m2	24.00
		22.00						Slope of ∆ BL to Week 72 OLE p<0.0001
CO = cardiac output, the amount of blood pumped each minute (SV X HR)	20.00	Baseline	V5 Wk12	V6 Pre-	V10 Wk12 OLE Wk12	OLE Wk24	OLE Wk36 OLE Wk48 OLE Wk72
CI = cardiac index (CO indexed to body surface area)	Screening
					dose
EF = % of blood in left ventricle ejected with each contraction (EF = SV/EDV)
HR = heart rate		Indexed LVEDV slope of ∆ BL to Week 72 OLE p<0.0001
		Indexed LVESV slope of ∆ BL to Week 72 OLE p=0.0002

36 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Morantz, Am. Fam. Phys., 2003; Cattermole, Phys. Reps., 2017; Carsson et al., J Cardiovasc Magn Reson. 2012; Klabunde, Card. Phys. Conc., 2012.

Stroke volume may predict clinical benefit

Associated with improved exercise capacity	May lead to improved outcomes

• Major determinant of peak exercise capacity
• Correlations (resting SV & 6MWT) strengthening with long-term OLE therapy (OLE Week 72 r=0.52)
• Durable improvements in 6MWT, strength, balance, 5XSST (TAZPOWER
  OLE) unexpected in the natural history (SPIBA-001)(slide 21)
• No increased effort/hope bias (Borg scale)
• Characterized by patients as meaningful (PPC video protocol)(slide 20)

ACC Poster Presentation, 2020; Berliner et al Eur J Cardiothorac Surg. 2019; Lele et al., 1995; McCurdy, K., Letter to FDA, 5/26/2020.

.

37 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

• SV =key component of cardiac output and EF
• • all forms of HF are associated with deteriorating SV and CO
  • EF has been well-correlated with survival
• Natural history predicts decline in SV, particularly at age ≥12-years and particularly preceding death or transplant:
• • SPIBA-001NH controls (n=12) -4.8mL vs. TAZPOWER OLE week 72
    +1.92mL, ∆ 6.72 mL, p=0.002),
• TAZPOWER safety profile (no deaths, transplants or cardiac events) in ≥12- year-patients over >72-weeks compares to 9% death in 12-19-year-olds and 27% death in ≥20-year-old US patients (12% of all transplants in 12-19-year- olds, 4% of all transplants in in ≥20-year-old US patients).

• Division of Rare Disease and Medical Genetics recommends collecting additional controlled clinical data prior NDA submission to support an evaluation of efficacy

38 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Next steps

Next steps

• NDA: Company believes existing data may meet requirements for NDA
• Additional controlled data:
• • Trial designs: One potential design which FDA has suggested is a randomized withdrawal from drug for the patients remaining in open-label extension. Alternatively, new patients could be recruited, potentially including pediatric patients.
  • Pre-NDA: After discussions with patient advocacy and KOLs, and based on prior experience, Company does not believe it would be feasible or practicable to conduct an additional trial prior to NDA submission, due to ultra-rare nature of disease, prior utilization of ~10% of patient population, COVID-19 concerns.
  • Phase 4 Commitment: Company acknowledges FDA's perspective that additional controlled data would better inform efficacy. Company hopes to engage FDA regarding prospective trial designs which could commence during NDA review and be conducted as part of a post-marketing commitment.

© 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

Duchenne's cardiomyopathy - an unmet need

Pressing unmet need

"Now that we have drugs to hopefully help the skeletal muscle in our boys, are their hearts built to last?"

- Leading patient advocate, in discussion with FDA

>90% develop

cardiomyopathic symptoms

cardiomyopathy

primary cause of premature death

Clinical trial planning - discussing protocol with KOLs, FDA interactions anticipated H2 2020

Subject demographics:

• Evidence of left ventricular hypertrophy by echocardiography/cardiac MRI
• • Prior to severe fibrosis and dilation (i.e. pre-pubescent through mid-teens)
• Normal ejection fraction
• n = ~100+

Duration:

6-monthrun-in followed by randomization of responders to 1-year randomized withdrawal trial

Endpoints:

• left ventricular volume index
• stroke volume
• diastolic function (E/e', LAVI, E/A ratio)
• diaphragm function (MED scale, ultrasound)
• myocardial fibrosis
• global longitudinal strain

Payne, R.M., Prog. Pediatr. Cardiol., 2011; Giugliano, GR et al., Tex Heart Inst J, 2007; Machiraju et al., Front Cardiovasc Med 2019.

39.

Beyond rare - pipeline partnering potential

Heart failure with preserved ejection fraction (HFpEF)

a disease in which the heart is not relaxing properly, leading to low cardiac volumes & reduced perfusion, particularly during maximum stress

P2, 1-month elamipretide or placebo, n=46, assessed function during stress and at rest

Cardiac function during maximum stress favored elamipretide across numerous endpoints

			in end diastolic				in end systolic
20		volume (ml) n=26	10		volume (ml) n=26
15					Control			8						Control
				Elam								Elam
10							6
										4
5
										2
0
										0
-5											-2
-10											-4
										-6
-15
										-8
-20
										-10

	in ejection		in stroke volume		in cardiac output		in cardiac index
10	fraction (%) n=26	12	(ml) n=26	1.0	(L/min) n=26	0.4	(L/min/m2) n=26
Control	Control	Control	Control
8		0.8
9	Elam	Elam	0.3
6	Elam	Elam
	6		0.6		0.2
4			0.4
	3			0.1
2			0.2
0		0		0.0		0.0
-2		-3		-0.2		-0.1
-4			-0.4
	-6			-0.2
-6			-0.6
	-9			-0.3
-8			-0.8
-10		-12		-1.0		-0.4

in septal E/è

n=45

0.5

0.0

-0.5

-1.0

-1.5

-2.0

Control

-2.5Elam

in left atrial volume (ml)

5
0
-5
-10
-15
-20
-25	Control
-30	Elam

Diastolic volumes are	Systolic volumes are
reduced in HFpEF	reduced in HFpEF

Ejection fraction is	Stroke volume is	Cardiac output is	Elevated in HFpEF,
normal in HFpEF	reduced in HFpEF	reduced in HFpEF	particularly during
Graphs reflect assessment of raw data conducted by Dr. Hani Sabbah, Henry Ford Institute, for Stealth BT.	stress

Left atrial enlargement common in HFpEF

• Did not hit primary endpoint for change in E/E' at rest.
• Trends toward improvement E/E' and global longitudinal strain during maximal exertion
• Trends toward improvement across multiple echocardiographic parameters

40 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L	Fang, Curr Opin Card, Feb 2014; Nanayakkara, et.al., JAHA, Sep. 2017; Obokata, Circulation, Feb. 2017

Rare neurological diseases

41

MMPOWER-3 stratified by genetic mutations; ~25% nDNA mutations

MMPOWER-3

Prespecified stratification and subgroup analysis included based upon FDA feedback and to de-risk potential heterogeneity introduced by basket trial design

	MMPOWER-3 Stratification	All Subjects
	(N=218)
	Mitochondrial DNA (mDNA) Mutation	~75%
	Nuclear DNA (nDNA) Mutation	~25%

↑ >22% POLG and replisome related disorders

42 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

All mtDNA maintenance proteins are encoded by nucleargenes

• Cardiolipin mediates importation of nuclear proteins via the translocase outer membrane complex
• mtDNA typically spatially arranged into nucleoids, tethered to the IMM by cardiolipin
• Replisome defects usually lead to stalling at the replication fork and deletion/depletion of mtDNA over time
• Knockout of major components (POLG and Twinkle) are embryonic lethal
• • Rapid loss of mtDNA
  • Preclinical models often over-express a mutant version as a

viable strategy that is compatible with life.

PMM ∆ From Baseline in 6MWT in nuclear subgroup

Subgroup: Nuclear DNA Mutation

•

nDNA patients on placebo did not improve on 6MWT functional assessment - possibly suggesting

from		35	Elamipretide 40 mg			16.4 (-18.5, 51.2)
	30				•
	Placebo				p = 0.35
of Change	(meters)
25
20
Squares Mean (SE)	Baseline in 6MWT
15						16.0
10
5
							•
Least		0						-0.4
	-5
		0	4	8	12	16	20	24
					Weeks

limited mitochondrial reserve capacity

mtDNA patients on placebo did improve on 6MWT functional assessment (particularly patients with

MELAS)

• "Hope bias"
• Possibly suggests increased mitochondrial reserve capacity (heteroplasmy?)

Most nDNA patients had POLG-related or other replisome disorders - i.e. defects in nuclear genes encoding for proteins important for mtDNA replication

• Mechanistically, cardiolipin's role in protein importation and replisome activity may help explain this finding

43 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

Nuclear subgroup findings (per protocol)

Subgroup: Nuclear DNA Mutation - per protocol

	in		35	Elamipretide 40 mg
	Baseline		30
		Placebo					27.8
		25
	from
Improvement		20						24.1 (-0.1, 48.3)
Squares Mean (SE) of Change	6MWT (meters)
15						p = 0.05
10
5						3.7
0
-5
	Least		-10
		0	4	8	12	16	20	24
						Weeks

• Subjects with nDNA mutations walked about 30m farther at the end of the study
• • Most of these subjects had mutations associated with the mtDNA Replisome
  • POLG and Twinkle made up about 50% of the nDNA cohort

44 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

Pipeline compounds

100+	SBT-272	SBT-259	SBT-550
proprietary	Clinical stage (Phase 1)	↑ mitochondrial uptake in	550 series may protect cells
differentiated	↑ mitochondrial uptake (>6X)^	peripheral tissue (>3X)^	from ferroptosis, a form of
	cell death implicated in
compounds	Cmax (~3X), AUC (>25X) in rat brain^	under assessment for
several neurodegenerative
multiple families	↑ survival in male cohort of ALS SOD-1	peripheral neuropathy	diseases
under assessment for CMT
	model; correlated NfL reduction

• in each case relative to elamipretide; Cmax = greater maximum concentration; AUC = area under the drug concentration-time curve; NfL = neurofilament light chain Stealth BT data on file; Keefe et al., NEALS 2019; Wu, et.al., J Mol Neurosci., Oct 2018

46 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

SBT-272: potential neuronal protective therapeutic agent

Improved blood-brain-barrier penetration	Improved survival correlates with NfL in ALS SOD-1 model

	120							SBT-0272		Pearson r 0.8
								NfL	p<0.05
	100							Elamipretide	Improved survival p<0.02
tissues										n=10 in each of high dose
80										cohort and vehicle
ng/g	60
Compound,
40
	20
	0
	0	4	8	12	16	20	24	28	32	36
					Time, h

• Mitochondria-targeted small molecule	• Survival correlated with improvement in NfL, a biomarker of axonal
dysfunction which is elevated in ALS, MSA, Parkinson's, Huntingtons' and
• >6X higher mitochondrial update relative to elamipretide
Alzheimers, with increasing evidence showing correlation between NfL
• ~3X higher Cmax and >25X higher AUC in brain relative to	plasma concentrations and morbidity across various diseases.
elamipretide	• SBT-272 has also demonstrated neuroprotective benefit in a murine stroke
• Phase 1 single ascending dose ongoing; data H2 2020 (safety,	model (p=0.006)(measuring respiratory control ratio in brain mitochondria
post ischemia reperfusion).
tolerability, plasma PK)
• Preclinical studies ongoing in TDP-43 ALS and proteinopathy models
Stealth BT data on file; showing brain accumulation in Sprague Dawley after 5mg/kg
SBT-272 or elamipretide (n=4 per time-point).	ALS=amyotrophic lateral sclerosis; MSA=multiple system atrophy; SOD-1=copper zinc
47 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L	superoxide dismutase 1; TDP-43=(transitive response DNA/RNA-binding protein 43 kDa
	Keefe, et al. NEALS 2019

At a glance

Leading	Significant	First in class	Multi-asset	Experienced
mitochondrial	unmet need	therapies	platform	team
medicine

Orphan diseases:	Life-limiting cardiomyopathy: <200	Fast track:	Pipeline-in-a-product	>10 decades drug
Barth, LHON (clinical)	US Barth patients; potential for	Barth, LHON, AMD w/GA	100+ pipeline compounds	development experience
FRDA, ALS, CMT (preclinical)	Friedreich's ataxia (FRDA)	Orphan drug:	Mito targeting platform	Dedicated to improving
Age-related diseases:	Visual impairment:	Barth, LHON	>600 patents issued + pending	the lives of patients
dry AMD	~10m US AMD + ~10k LHON patients	No US approved therapies
	Orphan neurodegeneration
	Orphan peripheral neuropathy

48 © 2020 Stealth BioTherapeutics. C O N F I D E N T I A L

49