Targeting the powerhouse of the cell · sclerosis/multiple system atrophy/other: SBT-259. Neuropathy: Charcot-Marie-Tooth T2/other. SBT-550: ... optical coherence tomography) Objective

Targeting the powerhouse of the cellto treat rare genetic and age-related diseases

January 2020

© 2019 Stealth BioTherapeutics. C O N F I D E N T I A L2

This presentation and various remarks we make during this presentation contain forward-looking statements within the meaning of The Private Securities Litigation ReformAct of 1995. Such forward-looking statements include those regarding Stealth BioTherapeutics’ plans, strategies and expectations for its preclinical and clinical advancementof its drug development programs including elamipretide, SBT-20, SBT-272, SBT-259 and SBT-550; the potential benefits of Stealth BioTherapeutics’ product candidates; its keymilestones 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 areintended 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 eventscould differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make as a result of known and unknown risks, uncertaintiesand 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 furtherdevelopment and marketing approval; the potential advantages of Stealth BioTherapeutics’ product candidates; the content and timing of decisions made by the U.S. FDA, theEMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, which may affect the initiation, timing and progress ofpreclinical studies and clinical trials of Stealth BioTherapeutics product candidates; Stealth BioTherapeutics’ ability to obtain and maintain requisite regulatory approvals and toenroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Stealth BioTherapeutics’ ability to obtain, maintain andenforce patent and other intellectual property protection for any product candidates it is developing; and general economic and market conditions. These and other risks aredescribed 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, 2018 filedwith the Securities and Exchange Commission on April 4, 2019 and any future filings with the Securities and Exchange Commission. Any forward-looking statements containedin this presentation and various remarks we make during this presentation speak only as of the date hereof, and Stealth BioTherapeutics’ expressly disclaims any obligation toupdate any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

Our forward-looking statements


Our patient-centric mission

Leading mitochondrial

medicine

Orphan diseases:Barth, LHON (clinical)

FDRA, ALS, CMT (preclinical)Age-related diseases:

dry AMD

Significant unmet need

Life-limiting cardiomyopathy: ~150 US Barth patients; potential for

Friedreich’s ataxia (FDRA)Visual impairment:

~10m US AMD + ~10k LHON patientsOrphan neurodegeneration

Orphan peripheral neuropathy

First in class therapies

Fast track: Barth, LHON, AMD w/GA

Orphan drug: Barth, LHON

No US approved therapies

Multi-asset platform

Experiencedteam

>10 decades drug development experienceDedicated to improving

the lives of patients

Pipeline-in-a-product100+ pipeline compounds

Mito targeting platform>600 patents issued + pending


Our pipeline

Targeting diseases in which mitochondrial dysfunction leads to measurable impairment in end organ function

Product Category Disease Preclinical Phase 1 Phase 2 Phase 3 FDA

Elamipretide

Cardiology Barth syndrome

Ophthalmic Geographic atrophy

Ophthalmic Leber’s hereditary optic neuropathy

Cardiology Friedreich’s ataxia

SBT-272 NeurologyAmyotrophic lateral

sclerosis/multiple system atrophy/other

SBT-259 Neuropathy Charcot-Marie-Tooth T2/other

SBT-550 Neurology Leigh’s syndrome/other

Phase 2/3 completed Q1 meeting

P3 protocol submitted; trial

initiation post-2020

~50% enrolled

developing protocol

ongoingongoing

ongoing

Finances & lessons learned


lead investor; financed through 2017

Feb 2019 IPO; net proceeds $76.9m

$30m in connection with Oct 2019 option

$50m cash at Dec 31, 2019 runway through 2020:• Barth regulatory interactions +

anticipated NDA filing• SBT-272 safety trial + preclinical studies• Geographic atrophy (GA) enrollment

Lessons learned from primary mitochondrial myopathy (PMM) P3

PMM is characterized by impaired skeletal muscle function, leading to exercise intolerance +fatigue across a highly heterogeneous + genetically diverse patient population.

Focus on organ systems with consistently high metabolic demand

Subjective, effort-dependent endpoints (6MWT and fatigue PRO assessed in PMM) may be more susceptible to hope bias

More objective biomarker endpoints include echocardiograms measuring heart function (Barth), retinal imaging measuring GA progression (GA) and neurofilament light chain (NfL) measuring axonal damage (SBT-272)

Although muscle (assessed in PMM) uses significant energy when active, energy use is correlated with effort-dependent activity levels

Heart (Barth), eye (dry AMD) and brain (SBT-272) have consistently high metabolic demand

Importance of objective endpoints

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

7

Elamipretide mechanism & development

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

maintain calcium equilibrium

impairmitophagy

produce energyATP

enableneurotransmission

fuelorgan function

formplaques, deposits

drivefibrosis

produce toxic ROS

old or dysfunctional mitochondria© 2019 Stealth BioTherapeutics. C O N F I D E N T I A L8

ROS

9 © 2019 Stealth BioTherapeutics. C O N F I D E N T I A L

Cardiolipin peroxidation – a final common disease pathway

ATP (energy)

Oxidative stress/free radicals

Super-complex formation

Protein importation

Fission, fusion, mitophagy

Normal mitochondria Diseased mitochondria

Cardiolipin

Cardiolipin

Cristae

Electron transport chain (ETC) complexes

Electrons

Reactive oxygen species (ROS)

e


Elamipretide normalizes mitochondrial morphology

Mouse model of diabetic retinopathy

Szeto HH, Birk AV. Clin Pharmacol Ther. 2014 Szeto, Birk, Am J Physiol 2014

Normoxic Disease Disease + Elamipretide

Wang et al., PNAS 2019

Elamipretide Improves Complex I and IV activity in the Failing Human Heart

N = 9 N = 13N = 10 N = 18

‡ p

Clinical development considerations - organ systems most dependent on ATP

1, Hultman, et al. J. Physiol. 1983: 2, Stanley, et al. Physiol Rev. 2005: 3, Soltoff, et al. Ann. Rev. Physiol. 1986: 4, Okawa, et al. Curr Biol. 2008: 5, Lei, et al. PNAS. 2003: 6, Befroy, et al. Diabetes.

ATP

Gene

ratio

n in

Mam

mal

ian

Tiss

ues

(µm

ol/g

/min

)

84.0

30.0 27.0*

13.0 12.1 9.4

0102030405060708090

Target organs are affected by ↓ ATP and ↑ ROS

Muscle1(activity)

Heart2 Kidney3 Eye4 Brain5 Muscle6(rest)

ATP Turnover in Mammalian Tissue

*Range 18-36 umoL/min*g (rate fluctuates as a function of kidney anatomy, blood pressure, and fed/fasted state)


Clinical development considerations – target organ & endpoint selection


Organ system

Endpoints Subjective (6MWT, fatigue) Objective (echocardiogram)Objective (fundus

autofluorescence, optical coherence tomography)

Objective (neurofilament light chain)

Metabolic demandLow at rest, high at maximal

exertion. Variability may introduce effort bias.

High; utilizes ~6kg ATP daily High; most metabolically challenged organ.High; among the most

metabolically active organs.

DataEarly signals but PMM P3 did not

show benefit due to placebo effect.

Barth data suggests reverse remodeling. Trends

observed in early HFpEFtrials.

Signals in early trials in dry AMD (P1), Fuchs corneal

dystrophy (P2) and trends in LHON (P2).

Encouraging preclinical signals in amyotrophic lateral sclerosis (ALS)

w/SBT-272.

Next steps n/a May inform other rare indications.GA (P2) ongoing; LHON (P3)

protocol submitted.SBT-272 P1 ongoing;

preclinical work ongoing.


Elamipretide - safety and tolerability

Exposure

~900 subjects systemically,

~53 subjects topical ophthalmic drops

Durationof exposure

>2 years(systemic and topical)

Injection sitereactions

Eosinophil increase (mild/moderate + no associated signs/symptoms), URI, increased blood IgE (no associated

signs/symptoms), dizziness, headache, UTI + viral gastroenteritis

Side effects in >5% exposed subjects

Transient mild to moderate ISRs in majority of subjects

receiving elamipretide by SC administration

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

15

Elamipretide for Barth Syndrome


Barth development program

Preclinical

Barth 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

Naturalhistory

Comparison of published natural history data for 10

subjects matching Phase 2/3 trial inclusion criteria shows

de minimis 6MWT improvement over 2 years (7.4m) versus 36-week OLE

data (95.9m, p=0.017 [T-test])

Derived from Hornby et al., Orphanet (2016; 2019)

Clinical

No changes in 6MWT or BTHSA-Total Fatigue

during 12-week treatment in Phase 2/3

crossover trial. Responders observed in pre-specified sub-group. Trends toward improved

cardiac function.MDA, 2019, UMDF, 2019

Current & next steps

FDA meeting Q1 2020 to inform

regulatory path forward.

Open-label

Improvement from Phase 2/3 baseline on multiple pre-specified endpoints

(cardiac function, 6MWT, BTHSA-Total Fatigue, Muscle Strength, PGI

Symptoms) in 8 patients at week 36 of OLE.

MDA, 2019, UMDF 2019

2020

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

20202020

Barth is a fatal genetic disease with no approved therapies

~111diagnosed

90% reportcardiomyopathic

symptoms

85%mortality by age 5

© 2019 Stealth BioTherapeutics. C O N F I D E N T I A L17Barth Syndrome Foundation Voice of the Patient Report, 2019; PFDD Conference, 2018

“When he was 3 weeks old, he suddenly was dead, and we reanimated him on the carpet on our own. Two days later, we found out that he had had a stroke because of his LVNC heart.”

-BTHS caregiver

“On April 23rd in 2000, I suffered my first cardiac arrest at age 11, and I had my first defibrillator implanted. On April 17th, 2018, I suffered my eighth cardiac arrest and was saved by the shock of my fourth defibrillator.”

-BTHS affected individual

“He worries too much about things a 9-year-old should not worry about. He asks me every night to listen to his heart. Sometimes he says he doesn't want to die. We went for a trip to Italy this year and had to toss a coin in a fountain and make a wish. His brother wished for getting all the Transformer toys. He wished for a cure to Barth.”

-BTHS caregiver

Reduction in cardiac fibrosis observed preclinically

Ventricle Barth’s positivesaline treatment

Ventricle Barth’s positiveelamipretide treatment

Red indicates fibrosis

Data from first cohort of preclinical mouse KD model (n=5); not significant across cohort of 40 due to sex differences.

Pu, et. al., BSF Poster Presentation 2016© 2019 Stealth BioTherapeutics. C O N F I D E N T I A L18

Longer therapy improved multiple endpoints

* preliminary analysis, pending official outputs; p-values represent a t-test for matched pairs, comparing mean at baseline to mean at Week 36 in TAZPOWER.

TAZPOWER Open Label Extension (OLE) Week 36


TAZPOWER: patient and caregiver perception of change

0 10 20 30 40 50 60 70 80 90 100

Incontinence

Sleep Quality

Sweating

Headaches

Depression

Healing from Sickness

Fogginess

Muscle Pain

Healing From Wounds

Heat Tolerance

Appetite

Muscle Strength

Stamina/Endurance

Fatigue/Energy Levels

Percent of Patients

Functional Improvement

0 10 20 30 40 50 60 70 80 90 100

Independence

Work/School

Quality of Life

Physical Activities

Daily Life Activities

Percent of Patients

Daily Life Improvement

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


Changes correlate across most endpoints

21

Spearman Correlation Coefficient

Parameter (change) Change p value

6MWT 0.43 0.29

Muscle Strength by HHD (newtons) 0.81 0.01

SWAY Balance Score -0.05 0.91

5XSST (seconds) -0.76 0.03

BTHS-SA Total Fatigue Score -0.40 0.32

CGIS Q1 -0.38 0.35

PGIS Q1 -0.46 0.26

PROMIS Fatigue T-Score -0.17 0.69

Data on file. Stealth BioTherapeutics.

Correlation of Change in Stroke Volume with Changes in Functional & PRO Assessments at OLE W36 (N=8)


https://bendavia.egnyte.com/app/index.do#storage/files/1/Shared/Medical%20Affairs/MedVal%20Collaboration/Barth%20Program/Slides/Barth%20presentation%202019-04-29/Barth%20presentation%20annotated%20references

22

LV End-DiastolicVolume (mL) z-score %

LV End-SystolicVolume (mL) z-score %

LV EjectionFraction (%)

Normal males 102-235 78-81 55-73

TAZPOWERbaseline values

60 38th 20 17th 66

54

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

11/12 subjects with improved volumes screening/BL to end-of-treatment (through week 36 OLE)

23

25.93

27.63 27.80

25.85

26.88

30.79 30.83

33.66

20

22

24

26

28

30

32

34

36

38

40

Screening V1 Pre-dose TP1 V5 Week 12 Visit6 Pre-dose TP2 Visit 10 W12 Visit 11B OLE W12 Visit 12 OLE W24 Visit 13 OLE W36

Average Left Ventricular End-Systolic Volume (mL)

66.70

69.94 68.73 70.13

69.13

79.36

77.89

85.44

50

55

60

65

70

75

80

85

90

95

100

Screening V1 Pre-dose TP1 V5 Week 12 Visit6 Pre-dose TP2 Visit 10 W12 Visit 11B OLE W12 Visit 12 OLE W24 Visit 13 OLE W36

Average Left Ventricular End-Diastolic Volume (mL)

n=12 n=12 n=12 n=12 n=12 n=12 n=10 n=8 n=12 n=12 n=12 n=12 n=12 n=12 n=10 n=8


Sustained improvementscreening/BL to end-of-treatment (through week 72 OLE)

24

25.93

27.63 27.80

25.85

26.88

30.79 30.83

33.66 33.9933.60

20

22

24

26

28

30

32

34

36

38

40

Screening V1 Pre-dose TP1 V5 Week 12 Visit6 Pre-doseTP2

Visit 10 W12 Visit 11B OLEW12

Visit 12 OLEW24

Visit 13 OLEW36

Visit 14 OLEW48

Visit 15 OLEW72

Average Left Ventricular End-Systolic Volume (mL)

66.70

69.94 68.73 70.13

69.13

79.36

77.89

85.44

86.9086.16

50

55

60

65

70

75

80

85

90

95

100

Screening V1 Pre-doseTP1

V5 Week 12 Visit6 Pre-doseTP2

Visit 10 W12 Visit 11B OLEW12

Visit 12 OLEW24

Visit 13 OLEW36

Visit 14 OLEW48

Visit 15 OLEW72

Average Left Ventricular End-Diastolic Volume (mL)

n=12 n=12 n=12 n=12 n=12 n=12 n=10 n=8 n=8 n=7 n=12 n=12 n=12 n=12 n=12 n=12 n=10 n=8 n=8 n=7

25Data on file. Stealth BioTherapeutics.

28

29

30

31

32

33

34

35

36

Baseline OLE Week 12 OLE Week 24 OLE Week 36

Average Indexed Stroke Volume

p < 0.05*

* Average of estimated slopes via linear regression

Evidence of cardiac remodeling


n=8 in OLE at week 36

https://bendavia.egnyte.com/app/index.do#storage/files/1/Shared/Medical%20Affairs/MedVal%20Collaboration/Barth%20Program/Slides/Barth%20presentation%202019-04-29/Barth%20presentation%20annotated%20references


Reflective of trends observed in other cardiac indications

26

Observations following 6 months of elamipretide therapy:

• Patient improved from markedly ill to borderline ill. • Patient discharged from NICU.• Cardiac function (measured by bi-weekly echocardiogram) improved and has remained relatively stable (as of November 30, 2018). • Pharmacokinetic studies indicate drug exposure comparable to other elamipretide clinical trials. • Elamipretide appeared to be well-tolerated with no obvious associated side effects.• In December 2018, patient expired due to complications following surgical procedure.

^ Stealth BT data on file; Bjornsson, H. et.al., AEPC Cardiology, 2019.

Parasternal short axis view of the left ventricle in end-diastole at week 1 (A) and week 20 (B) of treatment.

Senger’s syndrome – compassionate use protocol for 3 mos. old infant in neonatal intensive care

• Autosomal recessive mitochondrial disorder characterized by early onset hypertrophic cardiomyopathy, congenital cataracts and hypotonia.

• Average published survival for children presenting at this age is 4.2 months.

Reflective of trends observed in early studies in other cardiac indications


-20

-15

-10

-5

0

5

10

15

20∆ EDV (ml)

ControlMTP-131

-10-8-6-4-202468

10∆ ESV (ml)

ControlMTP-131

-10-8-6-4-202468

10∆ EF (%)

ControlMTP-131

-12

-9

-6

-3

0

3

6

9

12∆ SV (ml)

ControlMTP-131

-1.0-0.8-0.6-0.4-0.20.00.20.40.60.81.0

∆ CO (L/min) ControlMTP-131

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

0.3

0.4∆ CI (L/min/m2)

ControlMTP-131

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5∆ Sep E/e

ControlMTP-131

'

-30

-25

-20

-15

-10

-5

0

5∆ LAV (ml)

ControlMTP-131

Δ in end diastolic volume (ml) n=26

Δ in end systolic volume (ml) n=26

Δ in ejection fraction (%) n=26

Δ in stroke volume (ml) n=26

Δ in cardiac output (L/min) n=26

Δ in cardiac index (L/min/m2) n=26

Δ in septal E/è n=45

Δ in left atrial volume (ml)

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

• 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

Left atrial enlargement common in HFpEF

Cardiac output is reduced in HFpEF

Stroke volume is reduced in HFpEF

Ejection fraction is normal in HFpEF

Systolic volumes are reduced in HFpEF

Diastolic volumes are reduced in HFpEF

Fang, Curr Opin Card, Feb 2014; Nanayakkara, et.al., JAHA, Sep. 2017; Obokata, Circulation, Feb. 2017

Elevated in HFpEF, particularly during stress

Graphs reflect assessment of raw data conducted by Dr. Hani Sabbah, Henry Ford Institute, for Stealth BT.

Cardiac function during maximum stress favored elamipretide across numerous endpoints


Additional orphan cardiomyopathic indications of interest

28

• 1/50,000 live births• Nearly all FRDA patients develop cardiomyopathy due to mitochondrial

proliferation, loss of contractile proteins leading to myocardial fibrosis with left ventricular wall thickening

• Characterized by concentric or asymmetric hypertrophy and less commonly dilated cardiomyopathy

• Highly effective advocacy group with demonstrated success in rapidly enrolling clinical trials

• Proposed clinical trial:• 14 FDRA subjects with evidence of left ventricular hypertrophy by

echocardiography & normal ejection fraction• 6:1 randomization; 1 year duration• Assess change from baseline in left ventricular volume index, stroke

volume, diastolic function (E/e’, LAVI, E/A ratio), mFARS, contrast sensitivity

Cardiomyopathy is a leading cause of early death across many rare diseasese.g. Freidreich’s ataxia (FDRA), Duchenne’s muscular dystrophy, familial dilated cardiomyopathy, Leigh’s syndrome

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

Zhao, Sci Rep, 2017

Friedreich’s ataxia (FDRA)

Hanson, et.al., World J Cardiol., Jan. 2019

29

Elamipretide for Geographic Atrophy


Dry AMD development program

Formulation

Improved mitochondrial function and vision in

animal models. Improvements in dry

AMD donor eyes.

Cousins, Retina Today, 2016, Angiogenesis, 2017,

Kapphahn, ARVO, 2017

Naturalhistory

High risk drusen + intermediate geographic

atrophy (GA) patients lose up to 5 letter of visual

acuity every 6-12 months.

Holkamp, Angiogenesis, 2018; Ladd, data on file.

Earlyclinical

Phase 1 ReCLAIM trial showed improvement in visual function in patients with GA and drusen

and apparent slowing of GA progression after 6 mos. once

daily SC elamipretide. Angiogenesis, 2019,

ARVO, 2019, ASRS 2019


ReCLAIM-2 Phase 2b trial of SC elamipretide

in patients with GA ongoing; data 2021.

Topical ophthalmic drop trial under

consideration.

2021

Preclinical

1 mg/kg SC elamipretide reaches retina in higher

concentrations than 1.0% topical ophthalmic drops + is more quickly efficacious.

Stealth, data on file; Alam, Dis. Mod. Mech. 2015

2021

Hi Fat +Vehicle

Normal Diet

Hi Fat +Elamipretide

Oxidative stress

Flavoprotein Fluorescent green

S. Cousins, Duke Eye Center, Angiogenesis, Exudative, and Degeneration, February 2016, Miami, FL

Cell integrity

RPE nuclei blueCytoskeleton red

Preclinical reversal of AMD pathophysiology & improvement of vision


-100 0 100 200 300 400 500-300

-200

-100

0

100

200

300#818090-1 (Normal diet) Right eye, Steps 1-9

Chan

2 (R

esul

t (uV

))

Step 1 (Time (ms))-100 0 100 200 300 400 500

-300

-200

-100

0

100

200

300#945945-2 (HFC diet) Left eye, Steps 1-9

Chan

1 (R

esul

t (uV

))

Step 1 (Time (ms))

B wave (Synapse and Bipolar)

A wave(Outer segment)

Normal Diet HFD Diet Vehicle

-100 0 100 200 300 400 500-300

-200

-100

0

100

200

300

Cha

n 1

(Res

ult (

uV))

Step 1 (Time (ms))

#787562-2 (MTP-131 Tx) Left eye, Steps 1-9

HFD Diet Elamipretide

Vision (pattern electroretinogram)

Improvement in low luminance visual acuity

p=0.006

p=0.025

Mean:+6.1 lettersp=0.0012n=14

Quiescent neovascular AMD non-study eyes

GA: Mean change in LLVA

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

GA: Mean Change in LLVA


p=0.003

Improvement in visual acuity

Quiescent neovascular AMD non-study eyes

GA: Mean change in LLVA

Quiescent Neovascular Non-Study Eyes: Mean Change in BCVA

GA: Mean Change in BCVA

Drusen: Mean Change in BCVAp=0.025


Improvement in low light reading acuity

p=0.0001

p=0.017

3-line gain

5-line gain

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

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

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


Geographic atrophy growth rate trails natural history

10 Studies5 Studies 5 Studies0.91mm

2

0.50 mm2

0.14 mm

0.19 mm 0.18 mm

0.13 mm^^

Other Studies2 X Stealth Study

1 6 Month change in GA Area by OCT is 0.45 mm22 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)

Elamipretide may be slowing disease progression at 6 months


ReCLAIM 2B for geographic atrophy currently enrolling

Screening W52: WashoutBL W4 W8 W12 W24 W36 W48

GA area ≥0.05mm2/5 letters low luminance deficit

n=180

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)

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

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

Projecting full enrollment early 2020, data H1 2021


37

SBT-272 for neurodegenerative indications


SBT-272 development program

Preclinical signals

Improved survival in male cohort of ALS

SOD-1 model; correlated reduction of

neurofilament light chain (NfL)

Keefe, et.al., NEALS 2019

Earlyclinical

P1 single-ascending dose trial ongoing in healthy

volunteers; data H1 2020

Improved ADME characteristics

orally bioavailablemitochondrial uptake (>6X)^

Cmax (~3X) in rat brain^

AUC (>25X) in rat brain^

Stealth, data on file

^ in each case relative to elamipretide; Cmax = greater maximum concentration; AUC = area under the drug concentration-time curve

SBT-272 – improved ADME characteristics


1

10

100

1000

10000

0 4 8

Conc

. (ng

/mL o

r ng/

g)

Time (h)

SBT-272-04PlasmaSBT-272-04BrainSBT-31 Plasma

SBT-31 BrainElam Brain

272-Plasma

272-Brain

• Mitochondria-targeted small molecule

• Orally bioavailable

• >6X higher mitochondrial update relative to elamipretide

• ~3X higher Cmax and >25X higher AUC in brain relative to elamipretide

Elam Plasma

SBT-272: potential neuronal protective therapeutic agent

Neurofilament light chain (NfL) biomarker

A biomarker of axonal dysfunction, NfL is robustly elevated in many neurological and degenerative conditions including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Parkinson’s, Huntingtons’ and Alzheimers, with increasing evidence showing correlation between NfL plasma concentrations and morbidity across various diseases.

Improved survival correlates with NfL in ALS SOD-1 model


SBT-272 has also demonstrated neuroprotective benefit in a murine stroke model (p=0.006)(measuring respiratory control ratio in brain mitochondria post ischemia reperfusion).

Pearson r 0.8NfL Δ p

SBT-272: next steps

Preclinical development Clinical development


SOD-1 (copper zinc superoxide dismutase 1) model: treatment with SBT-272 demonstrated survival (p

42

Elamipretide for Leber’s hereditary optic neuropathy


LHON development program

Formulation Naturalhistory

For patients >12 mos. post vision-loss, visual field and acuity are not

expected to improve over 2 yr. period.

Lam, JAMA Ophthamology, 2014

Earlyclinical

ReSIGHT Phase 2 did not show improvement in BCVA

after 48-weeks of elamipretide 0.1% topical

ophthalmic drops. Improvement in visual field

and visual quality of life.

ARVO, 2019, EUNOS, 2019, UMDF, 2019.


Phase 3 protocol submitted to FDA

year-end 2019. Phase 3 initiation

post-2020.

2020

1.0% topical ophthalmic drops reach the retina in

therapeutic concentrations + demonstrate efficacy.Higher concentrations

reach retina via SC delivery.

Stealth, data on file; Alam, Dis. Mod. Mech. 2015

Preclinical

Improved mitochondrial function in murine-derived retinal ganglion cell (RGC)

line. Improved RGC survival + visual outcomes in murine

acute traumatic optic neuropathy model.

Chen 2017; Pelaez, Tse(ongoing)

Open-label

Improvements from P2 baseline in visual acuity,

visual field, color, contrast + visual quality of life

observed at week 28.

ARVO, 2019, EUNOS, 2019, UMDF 2019

20202021+

Endpoints favored elamipretide

^ post hoc analysis of change from baseline (all subjects) did not meet primary endpoint of change in BCVA averaged over week 20 to 52

Endpoint Mean (CI) P-valueBCVA (letters) 0.6 (-0.9, 2.1) 0.4370Humphrey Visual Field (mean deviation) 0.8 (0.1, 1.4) 0.0173Color Discrimination 0.2 (0.0, 0.4) 0.0826Retinal Nerve Fiber Layer Thickness 1.9 (-3.3, 7.0) 0.4390Retinal Ganglion Cell Layer Thickness 1.6 (-0.5, 3.7) 0.1274VFQ - Composite^ 6.0 (2.1, 9.9) 0.0063

Summary of Treatment Effect - Entire DM Period (Intent-to-Treat)Treatment Effect Rescaled to a Common Standard Error Unit of 1

-3 -2 -1 0 1 2 3 4 5 6

Favors treatmentFavors control

Patients with G11778A mutation (~4% likelihood of spontaneous visual improvement, typically in first year) >1 and

Improvement in central visual field

Central Field Analysis (post-hoc)

central fieldmid-peripheral

outer peripheral

HVF Pattern Elam Δ from BaselinePlacebo Δ from

Baseline Treatment Effect p-value

Central 1.8 0.0 1.8 (1.0, 2.7)

OLE catch-up in placebo-treated fellow-eye

Visual Field OLE

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

BCVA OLE Color OLEContrast OLE

p=0.025 p=0.051 p=0.005 p=0.005



Phase 3 protocol pending FDA feedback; initiation post-2020

47

Screening W82 follow-upBL W4 W8 W12 W24 W36 W48

n=~160

n=~120 with mt.11778G>A mutation (primary analysis group)

Efficacy endpointsCentral visual field

Full visual fieldNEI Visual Function Questionnaire (VFQ)

Best corrected visual acuity (BCVA)Color discrimination Contrast sensitivity

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

W60 W78

Exploratory endpointsNeurofilament light chain (NfL)

Retinal nerve fiber layer by optical coherence tomography (OCT)

Retinal ganglion cell thickness by OCTEQ-5D-5L QuestionnaireEfficacy in non-study eye

• Ages ≥15• LHON with DNA mutations

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

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

48

Pipeline

Pipeline compounds

^ in each case relative to elamipretide; Cmax = greater maximum concentration; AUC = area under the drug concentration-time curve

100+ proprietary

differentiated compounds

multiple families


SBT-259 mitochondrial uptake in peripheral tissue (>3X)^

under assessment for peripheral neuropathy

under assessment for CMT

SBT-550 may protect cells from

ferroptosis, a form of cell death implicated in several

neurodegenerative diseases

Wu, et.al., J Mol Neurosci., Oct 2018

SBT-259 for rare peripheral neuropathiesCompounds in SBT-259 family have demonstrated benefit in animal models; SBT-259 studies ongoing

SBT-259 is being evaluated in a murine model of Charcot-Marie-Tooth (CMT) Type 2 disease, a rare inherited neurological disorder affecting peripheral nerves. Data expected H2 2020.

SBT-20, a precursor to the SBT-259 family of compounds, demonstrated protective effect on murine intraepidermal nerve fiber density after repeated (3 weekly 10 mg/kg) administration of oxalplatin, a chemotherapeutic agent (naive mouse (a), vehicle (b), treated (c)); p=0.006). Toyoma, ACS Chem Neurosci, 2019.

Rare peripheral neuropathiesFamily development & optimization

• Mitochondria-targeted peptides• Administered by injection; potential proprietary

approach to ameliorate ISRs• Resistant to enzymatic degradation• Increased (~5X) exposure in peripheral tissues

0.1

1

10

100

1000

10000

0 4 8 12 16

Conc

. (ng

/mL o

r ng/

g)

Time (h)

SBT-20PlasmaSBT-20HeartSBT-259PlasmaSBT-259Heart


SBT-550 for neurodegenerative diseasesCell assays suggest mechanistic benefit in Friedreich’s ataxia, potential for other indications

In FRDA, a monogenic mitochondrial disease, reduced synthesis of frataxin renders cells differentially susceptible to ferroptosis, a form of iron dependent programmed cell death.• Preliminary studies suggest that the SBT-550 family of compounds protect primary FDRA

patient cells from ferroptosis. • Compounds are orally bioavailable.• The ferroptosis pathway is an emerging therapeutic target in additional

neurodegenerative diseases, including Huntington’s disease and Parkinson’s disease.• Additional characterization ongoing; candidate nomination to IND-enabling studies

targeted in 2020.

frataxin

Maximal Cell Survival % of Control

Incubation time SBT-548 SBT-550

24 hours 102.3 103.2

48 hours 91.22 99.75

72 hours 91.22 98.32

120

100

80

60

40

200

3 4 5Cel

l via

bilit

y, %

of c

ontr

ol

SBT 548SBT-550

72h incubation

log [pM]

Stealth BT, data on file. Cotticelli, et.al., J Pharmacol Exp Ther., Apr 2019© 2019 Stealth BioTherapeutics. C O N F I D E N T I A L51

Carrier program

Delivering therapeutic cargoes to the mitochondria

Mitochondrial-targeted ‘carrier’Active vs. Inactive

LinkerStable vs. Labile

In progress: small molecules (e.g. scavengers, CoQ10 analogs, iron chelators)

In progress: proteins (e.g., frataxin, tafazzin)

Future: oligonucleotides (e.g., DNA / siRNA / miRNA)

POC with doxorubicin, idebenone, tempo, iron chelators, glutathione analogs, nanoparticles (PLGA)


53

Be mighty…our patients are waiting

272 Phase 1 Initiation, year-end 2019

Geographic atrophy complete enrollment, early 2020

Barth FDA interactions early 2020

Barth NDA submission mid-2020

Geographic atrophy datamid-2021

Slide Number 1Slide Number 2Slide Number 3Slide Number 4Slide Number 5Over 10 decades of drug development expertise�Elamipretide mechanism & developmentSlide Number 8Cardiolipin peroxidation – a ﬁnal common disease pathwaySlide Number 10Slide Number 11Clinical development considerations - organ systems most dependent on ATPClinical development considerations – target organ & endpoint selectionSlide Number 14Elamipretide for Barth SyndromeSlide Number 16Barth is a fatal genetic disease with no approved therapiesSlide Number 18Slide Number 19Slide Number 20Changes correlate across most endpointsBaseline cardiac dysfunction – low volume due to hypertrophic cardiomyopathy11/12 subjects with improved volumes �screening/BL to end-of-treatment (through week 36 OLE)Sustained improvement�screening/BL to end-of-treatment (through week 72 OLE)Evidence of cardiac remodelingReflective of trends observed in other cardiac indicationsReflective of trends observed in early studies in other cardiac indicationsAdditional orphan cardiomyopathic indications of interestElamipretide for Geographic AtrophySlide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36SBT-272 for neurodegenerative indicationsSlide Number 38Slide Number 39Slide Number 40Slide Number 41Elamipretide for Leber’s hereditary optic neuropathySlide Number 43Slide Number 44Slide Number 45Slide Number 46Phase 3 protocol pending FDA feedback; initiation post-2020PipelineSlide Number 49Slide Number 50Slide Number 51Slide Number 52Slide Number 53

Documents

Targeting the powerhouse of the cell · sclerosis/multiple system atrophy/other: SBT-259. Neuropathy: Charcot-Marie-Tooth T2/other. SBT-550: ... optical coherence tomography) Objective