Targeting the powerhouse of the cell - Jefferies Group · marketing approval; the potential...

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

November 2019

© 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 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 and SBT-272; the potential benefits of Stealth BioTherapeutics’ product candidates; its key milestones for

2019; 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’ prospectus dated February 14, 2019 filed with the Securities and Exchange

Commission 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.

Our forward-looking statements


Our patient-centric mission

Leading mitochondrial

medicine

Orphan diseases:PMM, Barth, LHON

Age-related diseases:Phase 2b dry AMD

Significant unmet need

Life-limiting myopathy + fatigue: ~40k US PMM + Barth patients

Visual impairment:~10m US AMD + LHON patients

First in class therapies

Fast track: PMM, Barth, LHON, AMD w/GA

Orphan drug: PMM, 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

Indication Preclinical Phase 1 Phase 2 Phase 3 Next Milestone

Elamipretide

Primary mitochondrial myopathy

Phase 3 clinical data January 2020

Barth syndromeFDA meetings early 2020 to discuss OLE data and NDA submission

Leber’s hereditary optic neuropathy

Submission of P3 protocol year-end 2019

Geographic atrophy in dAMD Completion of enrollment targeted early 2020

SBT-272

Rare neurodegenerative diseases

Initiation of Phase 1 clinical trial year-end 2019

Targeting Platform

Delivering cargoes to mitochondria

Animal studies initiating 2020

Late-stage programs target rare disease indications; platform potential for age-related diseases

Finances

History

• Lead investor Morningside Venture financed the company prior to 2018

• 2018 financing round raised $50m in convertible debentures from new investors (converted to common in IPO)

• February 2019 IPO raised net proceeds of $76.9m

• $53.2m cash and cash equivalents at June 30

Partnering for Success

• October 2019 announced potential partnership with ALXN, with option exercisable post-P3 PMM data

• Stealth retains 50% of US market for elamipretide, and all pipeline compounds

• Positions elamipretide for successful launch – anticipate faster ramp to peak year sales and deeper penetration

• $30m payments associated with ALXN option, with additional payments on option exercise and near-term milestones post-P3 PMM data

Over 10 decades of drug development expertise

Reenie McCarthy, Chief Executive Officer

Mark Bamberger, PhD, Chief Scientific Officer

Brian Blakey, PharmD, Chief Business Officer

Jim Carr, PharmD, Chief Clinical Development Officer


Rob Weiskopf, Chief Financial Officer

7

Mechanism

ROS

8 © 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

Cristae-mediated mitochondrial power grid


Huang et al., Nature Biotechnology 2018

Fusion Event

Dr. Dylan Burnette (@mag2art), Vanderbilt Univ.

Distributes energy (ATP) efficiently throughout cell. Dysfunctional mitochondria (high ROS) leave the network and are tagged for degradation (mitophagy)


Elamipretide normalizes mitochondrial morphology, protects the cristae “power grid”

Mouse model of diabetic retinopathy

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

Networked Cristae = YellowOrphaned Cristae = Red

Normoxic


Disease


Disease + Elamipretide



Elamipretide - safety and tolerability

Exposure

~900 subjects systemically,

~53 subjects topical ophthalmic drops

Durationof exposure

>2 years in PMM + LHON, >1 year in Barth,

6 mos. in dry AMD

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

13

Primary Mitochondrial Myopathy


How our PMM program has evolved

Preclinical

Cell lines/animal models of Complex I deficiency/

inhibition, mtDNA depletion, Complex IV assembly factor,

Leigh’s related, POLG, MELAS related

Naturalhistory

RePOWER pre-trial registry: 18m median

6MWT decline in 12 mos., fatigue remains

unchanged.

MDA, 2019, UMDF 2019

Earlyclinical

MMPOWER Phase 1/2:established dose + identified

6MWT + enrichment strategy.MPOWER Phase 2:

SC + identified PMMSA Total Fatigue + enrichment strategy.

Karaa, Neurology, 2018; UMDF 2017

Current & next steps

Phase 3 data Jan. 2020.>90% of P3 patients

opting into OLE.Extensive FDA interactions.

Open-label durability

24 subjects on therapy >2 years. Continued

improvement in patient reported outcome

assessments; maintenance of 6MWT performance.

MDA, 2019, UMDF 2019

20202020

PMM in our patients’ words: trapped, precarious, failure, broken

“Precariousness. I live/function on a tightrope held up by other people” – F – age 36

“[A] picture of a broken person; physically, mentally and emotionally” - F- age 57

“I feel like my life is just me stuck on a roller coaster I can’t escape from. The hills are OK, the valleys – not so much. Trapped on a ride I can’t escape from, which is mildly terrifying” – F – age 38

PMM Adult Patient Journey Report, CAP July 2018; Neuromuscular Neurologists and Primary Mitochondrial Myopathy Report, CAP A ugust 2018

“I feel like I am not living a full life and I am a

failure to myself, family and friends due to this disease” – F – age 29


~40,000diagnosed

Review of Truvan database

95% reportmyopathic symptoms

Zolkipli-Cunningham, et. al.,https://doi.org/10.1371/journal.pone.0197513,

~10X healthyhealthcare resource utilization

Cohen, B. et. al., Orphanet, 2018

Well-resourced to reduce diagnostic journey, expedite and enhance patient access

PMM Adult Patient Journey Report, CAP July 2018; Neuromuscular Neurologists and Primary Mitochondrial Myopathy Report, CAP A ugust 2018

Onset

Evaluation

Neuro-muscular specialist referral

Diagnosis

Life with PMM

10+ specialists seen

9-16 years diagnostic journey

No approved therapies (anti-seizure drugs, pain medications, vitamins for symptoms)

Often adult-onset

~3k initial neuromuscular neurologist targets

Convert OLE, treatment IND and registry patients by removing insurance

barriers

1

Treat additionaldiagnosedpatients,

facilitating compliance and

persistency

2

Identify additional patientsby expediting journey to diagnosis

3

Life cycle management:pediatric and

newborn screening

4

Life cycle management:new orphan indications

5

Patients contextualize impact of fatigue and exercise intolerance on daily life

Source: Annual Report, Frost & Sullivan analysis 2018

Participant in MMPOWER, MMPOWER-2 & MMPOWER-OLE

Mid-dose cohort of MMPOWER MMPOWER-2

Open-label extension


MMPOWER and MMPOWER-2 informed MMPOWER-3 design

MMPOWER Phase 1/2 Randomized Controlled Trial36 subjects, 5-days, 9 active:3 placebo at 0.02, 0.20, 0.50 mg/kg/day IV

Karaa, Neurology, 2018

MMPOWER-2 Phase 2 Randomized Controlled Crossover Trial30 subjects, 28-days active, 28-days placebo, 28-day washout, 40 mg SC

Forest plot depicts primary and secondary endpoints (primary = 6MWT); Mean – Least Squared Mean Change; CI – confidence interval, representing the range of the values within which there is 95% certainty the true value lies (2.5% low and high tails excluded)

^Post-hoc sequence effect among subjects walking <450M at baseline (p=0.047 6MWT; p=0.0063 3TUG), triggered post-hoc TP1 analysis.

6MWT and PMMSA Total Fatigue are part of Phase 3 primary endpoint family


Enrichment for 6MWT, which may be expected to decline absent intervention

MMPOWER Phase 1/2 Randomized Controlled Trial36 subjects, 5-days, 9 active:3 placebo at 0.02, 0.20, 0.50

mg/kg/day IV

Karaa, Neurology, 2018

MMPOWER-2 Phase 2 Randomized Controlled Crossover Trial

30 subjects, 28-days active, 28-days placebo, 28-day washout, 40 mg SC

Patients more compromised at baseline (<450m) improved more on 6MWT; natural history predicts 6MWT decline


* Adjusted post hoc for gender + baseline differences; unadjusted p=0.053** R-squared of adjusted model=0.42; R-squared of primary analysis model=0.18.

Δ in 6MWT Distance at Day 5 – Heterogeneous Slope Model*

• 21 “low walkers” (<450m at baseline)• ~24m mean improvement on

elamipretide

• 9 “high walkers” (>450m at baseline)• ~8.5m mean improvement on

elamipretide 300

325

350

375

Baseline 6 Month 12 Month

Dis

tan

ce W

alke

d 6

MW

T (m

eter

s)

Natural Hx(n=25)

RePOWER 6MWT baseline to 12 mos re-assessment

Fatigue primary shows durable response in OLE

Total Fatigue Endpoint – MMPOWER-2 Total Fatigue Endpoint – OLE at 12 mos.

Total of 4 questions, each score 1= not at all to 4 = severe (score range 4-16)


Total of 4 questions, each score 1= not at all to 4 = severe (score range 4-16)

MMPOWER-3 – Total Fatigue and 6MWT primary endpoint family

Screening W28: Follow-upBL W4 W12 W24 Open-label extension

Elamipretide 40 mg SC or placebo once daily, 1:1 randomization, n=218 n=161 out of 166 Part 1 completers*

Part 2Part 1

• Family of primary endpoints: 6MWT, PMMSA Total Fatigue

Either at p≤0.025 or both at p≤0.05

Enriched for 6MWT by excluding “high walkers”

Powered at 90% confidence for p≤0.025 on 6MWT with 30-meter improvement

• Secondary endpoints: NeuroQoL short form fatigue, Patient & Clinician Global Impression Scale of Change, PMMSA Most Bothersome Symptom

Stratified by classes of genetic mutations

Median baseline 330m vs. 385m in MMPOWER-2

Pre-trial registry n>400

Direct enrollment

≥16 - ≤80 years genetically confirmed PMD

expert panel consensus of PMM

walking >100 and <450 meters at screening and baseline visits

*as of 9/30/2019


28 sites in U.S., Canada, Denmark, Hungary, Italy, Germany and U.K.

22

Barth Syndrome


How our Barth program has evolved

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.

MDA, 2019, UMDF, 2019


Ongoing virtual match natural history and patient

as own control.FDA meetings Q4 2019 +

Q1 2020 to inform regulatory path forward.

Open-label

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

(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

95% reportmyopathic symptoms

85%mortality by age 5


Barth Syndrome Foundation Voice of the Patient Report, 2019; PFDD Conference, 2018

“Walking more than 2 blocks leaves my legs unbearably tired.”

-BTHS affected individual

“I must make impossible choices every day…to conserve energy.”


“To get rid of fatigue is essentially to fix my personal problems. That’s my ideal treatment.”


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


Improvements unexpected relative to natural history

Comparison of Wk 36 OLE data to published natural history data collected by the Johns Hopkins team from 2014-2016

Hornby et al., (2019)© 2019 Stealth BioTherapeutics. C O N F I D E N T I A L26

Improvements in clinician global impression of symptomsduring open-label extension

Clinician Global Impression of Symptoms (all ages)

Date Completed:______________________

1. Overall, how severe are the patient’s Barth Syndrome symptoms today?

No Symptoms

Mild Symptoms

Moderate Symptoms

Severe Symptoms

Very Severe Symptoms

0

1

2

3

4

3 out of 8 patients graded at “0” –showing no symptoms of Barth syndrome –

at OLE week 36

P=0.017

27Data 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

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

Changes correlate across most endpoints

28

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

29

Dry Age-Related Macular Degeneration


How our AMD program has evolved

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 low-light

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 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

Improvement in visual function in GAFDA aligned on LLVA as primary efficacy endpoint

p=0.025

GA: Mean change in LLVAMean Change in LLVA


Low luminance visual acuity (LLVA) Best corrected visual acuity (BCVA) Low luminance (LL) reading acuity

Mean Change in BCVA Mean Change in LL Smallest Line Read

p=0.017

5-line gain

p=0.003

Potential slowing of progression in GA


Geographic atrophy growth rate trails natural history

Other Studies1 X Stealth Study

^ 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)^^ 6 Month change in GA Area by OCT is 0.45 mm2

ReCLAIM 2B for geographic atrophy currently enrolling

Screening W52: WashoutBL W4 W8 W12 W24 W36 W48

GA area ≥0.05mm2/<10.16 mm2

BCVA ≥ 55 letters

>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


34

Leber’s Hereditary Optic Neuropathy


How our LHON program has evolved

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 to be submitted to FDA

year-end 2019. Phase 3 initiation 2020.

2020

1.0% topical ophthalmic drops reach the retina in

therapeutic concentrations + demonstrate efficacy.

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

20202020

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-value

BCVA (letters) 0.6 (-0.9, 2.1) 0.4370

Humphrey Visual Field (mean deviation) 0.8 (0.1, 1.4) 0.0173

Color Discrimination 0.2 (0.0, 0.4) 0.0826

Retinal Nerve Fiber Layer Thickness 1.9 (-3.3, 7.0) 0.4390

Retinal Ganglion Cell Layer Thickness 1.6 (-0.5, 3.7) 0.1274

VFQ - 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 <10 years post-diagnosis.


Improvement in central visual field

Central Field Analysis (post-hoc)

central fieldmid-peripheral

outer peripheral

HVF PatternElam Δ from

BaselinePlacebo Δ from

BaselineTreatment Effect p-value

Central 1.8 0.0 1.8 (1.0, 2.7) <0.0001

Mid-peripheral 1.4 1.6 -0.1 (-0.9, 0.6) 0.6965

Outer peripheral

1.6 1.2 0.4 (-0.3, 1.1) 0.2329


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


39

Pipeline

Discovery 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 272 orally bioavailable

mitochondrial uptake (>6X)^

Cmax (~3X) in rat brain^

AUC (>25X) in rat brain^

2019 Phase 1 trial initiation

under assessment for ALS, MSA


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

under assessment for peripheral neuropathy

under assessment for CMT

SBT 550 may function as electron

donor, facilitating Complex 1 by-pass

under assessment for Friedrich’s ataxia

SBT-272


1

10

100

1000

10000

0 4 8

Co

nc.

(n

g/m

L o

r n

g/g

)

Time (h)

SBT-272-04Plasma

SBT-272-04Brain

SBT-31 Plasma

SBT-31 Brain

272-Plasma

272-Brain

• Mitochondria-targeted small molecule• Orally bioavailable• >6X higher mitochondrial update*• ~3X higher Cmax, >25X higher AUC in brain*

*in each case relative to elamipretide

SBT-272: potential neuronal protective therapeutic agentPipeline compound, orally bioavailable, >6X higher mitochondrial update, ~3X higher Cmax, >25X higher AUC in brain*

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<0.05Improved survival p<0.02n=10 in each of high dose cohort and vehicle

SBT-272: next steps

Preclinical development Clinical development


SOD-1 (copper zinc superoxide dismutase 1) model: treatment with SBT-272 demonstrated survival (p<0.05) and functional (p<0.05) benefit in male mice.

TDP-43 (transitive response DNA/RNA-binding protein 43 kDa) model: data expected H1 2020.

ALS

Multiple system atrophy

Data expected H2 2020.l

Single ascending dose Phase 1 clinical trial • commencing year-end 2019• data expected H1 2020• assessing safety, tolerability, plasma PK

Chronic tox and preclinical development ongoing H1 2020

Multiple ascending dose Phase 1 clinical trial • target commencing H2 2020• assessing safety, tolerability, plasma and

CNS PK and bioavailability

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 (naiive 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

Co

nc.

(n

g/m

L o

r n

g/g

)

Time (h)

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

SBT-550 for Friedrich’s ataxiaCell assays suggest mechanistic benefit; may enable Complex 1 by-pass

In Friedrich’s ataxia (FA), a genetic mitochondrial disease, reduced synthesis of fratazin, a mitochondrial iron chaperon protein, silences Complex 1 of the electron transport chain.

• Preliminary studies suggest that the SBT-550 family of compounds may facilitate a Complex 1 by-pass to improve oxidative phosphorylation via Complex 3 of the electron transport chain.

• Preliminary in vitro studies in primary fibroblast cells from FA patients stressed by eliminating the glutathione defense mechanism (typically leading to cell death) show dose-dependent improvements in cell viability (survival) with SBT-550 family compounds

• 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

20

03 4 5C

ell v

iab

ility

, %

of

cont

rol

SBT 548

SBT-550

72h incubation

log [pM]

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

In progress: oligonucleotides, e.g., DNA / siRNA / miRNA

POC with doxorubicin, idebenone,

tempo, iron chelators, glutathione

analogs, nanoparticles (PLGA)


47

Be mighty…our patients are waiting

ReCLAIM-2b First Patient Enrolled, March 2019

MMPOWER-3 Complete Enrollment, April 2019

Barth and LHON FDA Interactions, Q2 2019

272 Phase 1 Initiation, year-end 2019

MMPOWER-3 data, January 2020

ReCLAIM-2b complete enrollment, early 2020

Barth FDA interactions early 2020

AXLN co-promote option, Q4 2019

Targeting the powerhouse of the cell - Jefferies Group · marketing approval; the potential...

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