Stoke Therapeutics
Transcript of Stoke Therapeutics
Stoke TherapeuticsNovember 2020Nasdaq: STOK
© Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
Disclaimer
2 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
This presentation has been prepared by Stoke Therapeutics, Inc. (“Stoke” or “our”) for informational purposes only and not for any other purpose. Nothing contained in this presentation is, orshould be construed as, a recommendation, promise or representation by the presenter or Stoke or any officer, director, employee, agent or advisor of Stoke. This presentation does not purport tobe all-inclusive or to contain all of the information you may desire. Information provided in this presentation speaks only as of the date hereof. Stoke assumes no obligation to publicly update anyinformation or forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments, subsequent events, orcircumstances after the date hereof, or to reflect the occurrence of unanticipated events.
This presentation contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to:preclinical data and study results regarding OPA1, future operating results, financial position and liquidity, the direct and indirect impact of COVID-19 on our business, financial condition andoperations, including on our expenses, supply chain, strategic partners, research and development costs, clinical trials and employees; our expectation about timing and execution of anticipatedmilestones, responses to regulatory authorities, expected nomination of future product candidates and timing thereof, our ability to complete lead optimization of ASOs for ADOA, the timing andresults of ADOA preclinical studies, our ability to develop ASOs treat the underlying causes of ADOA, our ability to advance OPA1 as our next preclinical target, and our ability to use study data toadvance the development of STK-001; the ability of STK-001 to treat the underlying causes of Dravet syndrome; and the ability of TANGO to design medicines to increase protein production andthe expected benefits thereof. These forward-looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,”“may,” “might,” “plan,” “potential,” “possible,” “will,” “would,” and other words and terms of similar meaning. These forward-looking statements involve risks and uncertainties, as well asassumptions, which, if they do not fully materialize or prove incorrect, could cause our results to differ materially from those expressed or implied by such forward-looking statements. Thesestatements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop, obtain regulatory approvalfor and commercialize STK-001, OPA1 and future product candidates; the timing and results of preclinical studies and clinical trials; the risk that positive results in a clinical trial may not bereplicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; risks associated with clinical trials, including our ability to adequatelymanage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or furtherstudies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; failure to protect and enforce our intellectual property, and otherproprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives; risks relating to technology failures or breaches; our dependence oncollaborators and other third parties for the development, regulatory approval, and commercialization of products and other aspects of our business, which are outside of our full control; risksassociated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; risks associated with current and potential future healthcarereforms; risks relating to attracting and retaining key personnel; failure to comply with legal and regulatory requirements; risks relating to access to capital and credit markets; environmental risks;risks relating to the use of social media for our business; and the other risks and uncertainties that are described in the Risk Factors section of our most recent annual or quarterly report and inother reports we have filed with the U.S. Securities and Exchange Commission. These statements are based on our current beliefs and expectations and speak only as of the date of thispresentation. We do not undertake any obligation to publicly update any forward-looking statements.
By attending or receiving this presentation you acknowledge that you are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date suchstatements are made; you will be solely responsible for your own assessment of the market and our market position; and that you will conduct your own analysis and be solely responsible forforming your own view of the potential future performance of Stoke.
Stoke Therapeutics
Amplifying Science to Transform the Experience of Life
Stoke is making a new generation of RNA-based genetic medicines that upregulate protein expression to restore human health.
3 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Foundational Elements of Stoke
4 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Experienced Leaders in Innovation
Differentiated Platform with Broad
Applicability
Strong Financial Position to Support
Growth
Focused Development
Program
to transform the experience of life.
Amplifying Science
5 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
TANGO Restores Protein Levels by Stoking Output From Healthy Genes
• Stoke’s ASOs bind to specific stretches of pre-mRNA to reduce non-productive mRNA and increase productive mRNA
• The increased levels of productive mRNA from the functional copy of the gene result in increased protein production
• For haploinsufficiences, TANGO restores the target protein to near-normal levels
TANGO: An RNA-Based Genetic Medicine Platform for Protein Upregulation
6 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Targeted Augmentation of Nuclear Gene Output
• Addresses underlying cause of disease
• Applicable to most loss-of-function mutations
• Applies equally to small or large gene targets
• Gene and tissue specific
• Controllable dose and duration
• Can address wide array of diseases
• Simple and scalable manufacturing
TANGO
Stoke uses RNA science to restore
missing proteins by increasing – or stoking –
protein output from healthy genes.
Transformative Potential of TANGO Technology for Gene Upregulation
7 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Source: Lim, K.H., Han, Z., Jeon, H.Y. et al. Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression. Nat Commun 11, 3501 (2020).
Robust Target Identification Process Utilizing Proprietary Bioinformatics
• Approximately 50% of human genes contain a TANGO signature
• Cross-referencing with genetic disease databases identifies approximately 2,900 monogenic diseases amenable to TANGO
• Enables rapid and systematic identification of clinically relevant targets
RNA sequencing and in silico discovery datasets
Proprietary bioinformatics analysis
Universe of non-productive splicing events
Genetic disease databases
TANGO amenability assessment
TANGO targets
Cell and tissue validation
Hit identification
Candidate evaluationand prioritization
Source: Stoke data
Target identification process
8 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
TANGO is Applicable to a Broad Range of Targets
9 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Genetic epilepsy – haploinsufficiency
- 30 60 120 30 60 1200
20
40
60
80
% n
on-p
rodu
ctiv
e ev
ent
- 30 60 120 30 60 1200
1
2
3
4
Fold
of S
ynG
AP p
rote
in
- 30 60 120 30 60 1200
1
2
3
4
5Fo
ld o
f SYN
GAP
1 m
RNA
SYNGAP1non-productive event productive mRNA protein
NT ASOnM
NT ASOnM
NT ASOnM
Pathway target – wild type
- 5 20 80 5 20 800
1
2
3
Fold
of C
D274
mRN
A
- 5 20 80 5 20 800
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20
30
% n
on-p
rodu
ctiv
e ev
ent
- 5 20 80 5 20 800.0
0.5
1.0
1.5
2.0
Fold
of P
D-L
1 pr
otei
n
NT ASOnM
NT ASOnM
NT ASOnM
CD274 (PD-L1)non-productive event productive mRNA protein
0 20 40 60 80 1000123456789
Fold
upr
egul
atio
n
R2 = 0.94p = 0.03
% non-productive event
Correlation between event abundance (+CHX) & upregulation
SCN1ASYNGAP1
CD274PCCA
NT: non-targeting ASO control, all experiments n = 3, in vitro
Liver target – autosomal recessive
PCCAnon-productive event productive mRNA protein
NT ASOnM
NT ASOnM
NT ASOnM- 1 5 25 1 5 25
0
5
10
15
% n
on-p
rodu
ctiv
e ev
ent
- 1 5 25 1 5 250
1
2
3
Fold
of P
CCA
mRN
A
- 1 5 25 1 5 250.0
0.5
1.0
1.5
2.0
Fold
of P
CCA
mRN
A
Dravet Syndrome: A Severe, Progressive Genetic Epilepsy
10 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
85%
1 out of
16,000 babies are born with Dravet syndrome
20%
Note: 1 Sudden Unexpected Death in Epilepsy Sources: 2018 Health Advances Report; Djémié et al., Molecular Genetics & Genomic Medicine 2016; Lagae et al., Developmental Medicine & Child Neurology 2017; Nabboutet al., Orphanet Journal of Rare Diseases 2013
of children and adolescents with Dravet die before adulthood, due to SUDEP1, prolonged seizures, seizure-related accidents or infections
~35,000
Seizures are not adequately controlled in
90% of people with Dravet
of cases caused by a haploinsufficiency of the SCN1A gene 50%
NaV1.1 protein expression
results in
people affected in the U.S., Canada, Japan, Germany, France and the UK
Up to
Dravet syndrome is not concentrated in a particular geographic area or ethnic group.
Non-Seizure Comorbidities of Dravet Syndrome Are Not Addressed by Current Therapies
11 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Dravet is Not Limited to Seizures:More than 90% of patients suffer from at least one non-seizure comorbidity, including:
• Intellectual disability• Developmental delays• Movement and balance issues• Language and speech disturbances• Growth defects• Sleep abnormalities• Chronic infections• Disruptions of the autonomic nervous
system• Mood disorders
High Incidence of Premature Death:Up to 20% of children and adolescents die before adulthood, due to:
• SUDEP
• Prolonged seizures
• Seizure-related accidents
• Infections
Sources: Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravetsyndrome Han et. al., Science Translational Medicine 2020; Shmuely et al Epilepsy & Behavior 2016
STK-001 Increases Scn1a mRNA and NaV1.1 Protein in Wild-type Mice
12 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
Decrease in non-productive Scn1a mRNA
Increase in productive Scn1a mRNA
C o n t r o l 0 . 3 1 . 0 3 . 0 1 00
1 0
2 0
3 0
4 0
5 0
D o s e ( u g / m o u s e )
% N
MD
ex
on
in
clu
sio
n
C o n t r o l 0 . 3 1 . 0 3 . 0 1 00
2
4
6
8
1 0
D o s e ( u g / m o u s e )
Fo
ld c
ha
ng
e
Perc
ent n
on-p
rodu
ctiv
e m
RNA
Source: Stoke data
Increase of NaV1.1 protein
C o n t r o l 0 . 3 1 . 0 3 . 0 1 00
2
4
6
8
1 0
D o s e ( u g / m o u s e )
Fo
ld c
ha
ng
e (
Na
v 1
.1)
Fold
chan
ge
Fold
chan
ge
13 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
STK-001 Restores NaV1.1 to Near Normal Levels for >3 Months in Dravet Syndrome Mice
Note: Nav1.1 protein quantification based on standard curve obtained from untreated wild-type mouse brain as a reference control Source: Stoke data; University of Michigan (in-life study)
In preclinical studies, STK-001 exhibits long-lasting exposure, suggesting the potential for a favorable dosing regimen of as few as two to three administrations per year in humans
10
50
100
150
Perc
enta
ge o
f Nav
1.1
Pro
tein
in W
T B
rain
Placebo 14 weeksSTK-001 14 weeks
Wild type Dravet mouse Wild type Dravet mouse
Placebo 7 weeksSTK-001 7 weeks
7 weeks 14 weeks
Increase in Nav1.1 protein expression after 7 and 14 weeks
Placebo (7 weeks)
STK-001 (7 weeks)
Placebo (14 weeks)
STK-001 (14 weeks)
Wild-type mice
Wild-typemice
Dravet syndrome mice
Dravet syndrome mice
Perc
enta
ge o
f Na v
1.1
prot
ein
in w
ild-t
ype
brai
n
STK-001 Significantly Reduces Premature Mortality in Dravet Syndrome Mice
14 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
STK-001 DS mouse (n = 34)
0 10 20 30 40 50 60 70 80 900
20
40
60
80
100
Postnatal days
Perc
ent s
urvi
val
Placebo Wild-type
Placebo DS mouse (n = 62)
STK-001 Wild-type****
Significant improvements in survival among Dravet syndromemice after STK-001 administration (20µg) at postnatal day 2
****p<0.0001
Source: Z. Han, C. Chen, A. Christiansen, S. Ji, Q. Lin, C. Anumonwo, C. Liu, S. C. Leiser, I. Aznarez, G. Liau, L. L. Isom, Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Sci. Transl. Med. 12, eaaz6100 (2020).
Source: Stoke data, presented at AES 2019
STK-001 Significantly Reduces Spontaneous Seizures in Dravet Syndrome Mice
15 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
76% of mice treated with STK-001 were seizure-free compared to 48% of placebo-treated mice
0 1 20
5
10
15
20
Number of seizures
Num
ber o
f mic
e
PlaceboSTK-001
≥
48%
76%
38%
14%
80% reduction in the average number of spontaneous seizures compared to placebo (p<0.05)
As measured between postnatal days (PND) 22 and 46 in Dravet syndrome mice after a single 20 µg injection of STK-001 at PND 2
PBS STK-0010
5
10
15
20
25
Numb
er of
seizu
res
*
Placebo
* = p<0.05
STK-001 Achieves Broad Distribution and Increases Nav1.1 Protein Expression in NHPs (n=3)
16 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Exposure of STK-001 observed in all brain regions except pons and thalamus Nav1.1 protein levels increased up to 3-fold
Cerebell
um
Hypothala
mus
Limbic
Lobe
Medulla
Midbrain
Motor Corte
x
Occipita
l Corte
x
Parieta
l Corte
xPons
Prefrontal
Cortex
Temporal
Cortex
Thalamus
0
1000
2000
3000
4000
STK
-001
in b
rain
tiss
ue (n
g/g)
Cerebell
um
Hypothala
mus
Limbic
Lobe
Medulla
Midbrain
Motor Corte
x
Occipita
l Corte
x
Parieta
l Corte
xPons
Prefrontal
Cortex
Temporal
Cortex
Thalamus
0
5
10
15
NaV1
.1 (n
g)/T
issu
e(m
g)
PlaceboSTK-001
* *
Source: Stoke data, presented at AES 2019
.* = p<0.05
Pivotal Preclinical Single and Multiple-Dose Toxicology Studies in NHPs Showed STK-001 Well-Tolerated
Key safety findings from GLP studies*
No observed adverse events at highest dose tested
No change in platelet counts or renal/hepatic function
No adverse histopathology in brain, spinal cord, liver and kidney
17 © Copyright 2020 Stoke Therapeutics, Inc. All rights reservedSource: Stoke data
IT=Intrathecal, NHP= non-human primate
The no observed adverse effect level (NOAEL) in the GLP studies in NHPs exceeds the highest human equivalent dose that we plan to administer in our Phase 1/2a clinical study
* In non-GLP studies in NHPs, at levels above the NOAEL, hind limb paresis was observed; at extremely high dose levels, acute convulsions were observed.
STK-001 Has Potential to Address the Genetic Cause of Dravet Syndrome
18 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Preclinical data support the use of STK-001 in Dravet syndrome:
Single dose restores NaV1.1 from 50% to near normal levels for >3 months in Dravet syndrome mice
Significantly reduces mortality and seizure frequency in Dravet syndrome mouse model
Selective target engagement may limit potential off-target effects
Broadly distributes in the brains of non-human primates with intrathecal delivery
Well-tolerated at pharmacologically-active dose levels in non-human primates
Able to dose titrate with wide therapeutic window
BUTTERFLY Observational Study Ongoing
19 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
• Two-year observational study of children and adolescents ages 2-18
• Designed to evaluate seizure frequency and non-seizure comorbidities associated with Dravet syndrome, including:
- Intellectual disabilities
- Developmental disabilities
- Motor impairment
- Speech impairment
- Behavioral problems
- Sleep abnormalities
Enrollment and Dosing in MONARCH Phase 1/2a Trial is Ongoing
• Open-label study of children and adolescents ages 2-18 with Dravet syndrome
First patient dosed August 2020 Plan to enroll ~48 patients at ~20 sites in the U.S. Primary endpoints: safety and tolerability of a single-ascending dose, characterize human
pharmacokinetics
Secondary endpoints: change in seizure frequency over 12-weeks, quality of life
• Two-part trial design:
Single ascending dose (SAD) portion (previously, Part A) will now be designed to evaluate three dose levels: 10mg, 20mg and 30mg; higher doses remain on FDA partial clinical hold
Subject to FDA review, a multiple ascending dose portion (MAD) will be added to the study to evaluate monthly doses up to 30mg for three months
For each dose level, sentinel group ages 13-18, followed by group ages 2-12
• Preliminary data expected in 2021
20 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
TANGO is Well Suited for Treatment of Eye Diseases
Benefits of focusing on the eye for ASOs• Localized delivery• Immune privileged and small treatment space (0.05% of total body weight) • Contralateral control for clinical trials• Availability of non-invasive measurements that reflect functional outcome (e.g. OCT)Advantages of TANGO for the eye • Intravitreal delivery has safety & patient acceptance advantage over subretinal delivery• Stoke preclinical data demonstrates long-term effects of up to 12 months• Tunable and reversible control of level and specificity of protein expression • No formulation or viral vector requirement• Approved product precedence (Vitravene for cytomegalovirus retinitis)• Potential to target large genes
21 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
OPA1 Protein Deficiency is the #1 Cause of Autosomal Dominant Optic Atrophy (ADOA), the Most Common Inherited Optic Nerve Disorder
• Autosomal dominant optic atrophy (ADOA) is the most common inherited optic nerve disorder seen in clinical practice
• ADOA causes progressive and irreversible vision loss in both eyes starting in the first decade of life. Many children progress to blindness
• The disease affects 1/30,000 people globally with a higher incidence of ~ 1/10,000 in Denmark due to a founder effect
• 65%-90% of ADOA is caused by loss of function mutations in one allele of the OPA1 gene which leads to haploinsufficiency and disease manifestation
• >400 different OPA1 mutations reported in ADOA patientsSources: Yu-Wai-Man P et al. The Prevalence and Natural History of Dominant Optic Atrophy Due to OPA1 Mutations. Ophthalmology. 2010 August; 117(8): 1538-1546; Yu-Wai-Man P, Chinnery PF. Dominant Optic Atrophy: Novel OPA1 Mutations and Revised Prevalence Estimates. Ophthalmology. Vol. 120, Number 8, August 2013: 1712-1712; 3. P. Amati-Bonneau P et al. OPA1-associated disorders: phenotypes and pathophysiology. The International Journal of Biochemistry & Cell Biology 41, 1855-1865 (2009); “What is ADOA?” Autosomal Dominant Optic Atrophy Association. Accessed May 6, 2020, from https://www.adoaa.org/what-is-adoa; Lenaers G, Hamel C, Delettre C, et al. Dominant optic atrophy. Orphanet J Rare Dis 7, 46 (2012); Chun BY and Rizzo JF III. Dominant optic atrophy: updates on the pathophysiology and clinical manifestations of optic atrophy 1 mutation. Curr Opin Ophthalmol 2016; 27:475-480; Le Roux B, Lenaers G, Zanlonghi X et al. OPA1: 516 unique variants and 831 patients registered in an updated centralized Variome database. Orphanet J Rare Dis 14, 214 (2019).
22 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
TANGO ASOs Have the Potential to Be a First-In-Class Precision Medicine for ADOA
• There are currently no available treatments for autosomal dominant optic atrophy
• Corrective aids such as glasses or contacts do not help improve vision lost to the disease
• ADOA causes deterioration of the optic nerves (arrow in A), which can be observed on OCT (B)
• Stoke’s TANGO ASOs target the underlying cause of ADOA by utilizing a non-productive splicing event in the OPA1 gene to increase productive OPA1 mRNA & protein expression in retinal ganglion cells
Source: Lenaers et al. Dominant optic atrophy. Orphanet Journal of Rare Diseases 2012, 7:46
23 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
OCT
retinal nerve fiber layer thickness
OPA1 is Critical for Normal Mitochondrial Function and Cellular Metabolism
• OPA1 encodes a dynamin-like mitochondrial GTPase that is a key mediator of mitochondria fusion/fission which is critical for ATP synthesis and other important mitochondrial functions.
• Insufficient OPA1 activity causes mitochondria dysfunction with consequent insufficient ATP production, excess reactive oxygen species (ROS) production and eventual cell death.
• Retinal ganglion cells are high energy demanding cells and particularly susceptible to loss of ATP production and mitochondrial dysfunction
24 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
• Novel exon inclusion event (Exon X) identified in the OPA1 gene introduces a premature termination codon (PTC)
• Exon X inclusion produces a non-productive mRNA that is degraded by non-sense mediated decay (NMD), producing no protein
• Inhibition of NMD with cycloheximide allows for evaluation of the abundance of this event in vitro
protein
Exon A
productive mRNA protein
XNon-productive mRNA
Exon BExon X
*PTC
25 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
DMSO 10ug/mL 50ug/mLCycloheximide
A B
A BX
Human embryonic kidney 293 (HEK293) cells
OPA1 non-productive splicing event was detected in vitro in various cell lines
A Non-Productive mRNA Splicing Event in OPA1 Was Identified and Validated
Rabbit ASO Demonstrates Dose-Dependent OPA1 Protein Increase in Rabbit Retina
• Retinal exposure of ST-1102 ASO was elevated with increased dosing• Dose-dependent target engagement seen at all three time-points examined• Protein increase of OPA1 protein observed at both Day 15 and Day 29 of study
Target engagement; Day 29 OPA1 protein; Day 29ASO exposure in retina; Day 29
PBS ST-1102; 0.23mg
OPA1
Actin
OD OD ODOS OS OSU3079 U3094 U3109U3064 U3092
OD OS ODOD OSU3134
OS
PBS0.0
40.1
20.2
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10
15
% N
MD
Exo
n In
clus
ion
ST-1102 (mg/eye)PBS
0.04
0.12
0.23
0.0
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1.0
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2.0
Rela
tive
OPA
1 pr
otei
n(β
-act
in n
orm
aliz
atio
n)
ST-1102 (mg/eye)
0.04
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0.23
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60000
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exp
osur
e (n
g/g)
ST-1102 (mg/eye)
*
* *
*
*
*P<0.0005 by one-way ANOVA compared to PBS groupOD: oculus dextrus (right eye), OS: oculus sinister (left eye)
Day 15 Day 29
Day 1
Euthanize and collect retinal tissueFemale NZW rabbits
Single intravitreal (IVT) injection of vehicle/ASO (n=3/group)
Day 8
26 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
Human ASO Demonstrates ATP Upregulation in OPA1 Haploinsufficient HEK293 Cells
N= 3
• Adenosine triphosphate (ATP) is produced by the mitochondria and is the key energy carrying molecule in cells
• OPA1 protein is a crucial mediator of mitochondria health
• Here we evaluated the impact of restoration of OPA1 protein in haploinsufficient HEKs
• A 20% ATP deficit was observed in OPA1 +/- HEK293
• Treatment with ASO-14 restored ATP levels to ~90% of control cells
*one-way ANOVA# t-test
Mock
ASO-14Mock
ASO-140.0
0.2
0.4
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0.8
1.0
1.2AT
P/To
tal p
rote
in
OPA1+/+ OPA1+/-
*****
N= 1
Mock
ASO-14Mock
ASO-140
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150
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aliz
ed O
pa1/
actin
expr
essi
on
OPA1+/+ OPA1+/-
******
###
27 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.
** = P value 0.0006
*** = P value <0.0001
### = P value 0.0006
28 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Dose-dependent decreases in non-productive OPA1 mRNA and increases in OPA1 protein expression in vitro and in vivo.
Increases in OPA1 protein levels in the retina of wild-type rabbits that correlated with increases in the level of the test ASO.
An increase in OPA1 protein expression to approximately 75% of wild-type levels in an OPA1 haploinsufficient (OPA1 +/-) cell line.
The rabbit surrogate ASO was well tolerated for up to 29 days (maximum days evaluated) after intravitreal injection.
Approach leverages upregulation of the wild-type allele and can potentially be used to treat ADOA due to loss of OPA1 activity in a mutation-independent manner.
Preclinical Data Support the Use of Stoke’s TANGO Technology to Treat ADOA
Increase in OPA1 protein levels in OPA1+/- cells correlated with a substantial restoration of mitochondrial function as measured by ATP synthesis.
We plan to initiate Lead Optimization to potentially identify a Clinical Candidate in 2021
2020
Early 2020: FDA communicated that Part A of MONARCH may proceed with dosing
2H 2020: Began enrollment and dosing of patients in MONARCH in Aug. 2020
2H 2020: Nominate new candidate for preclinical development in an additional genetic disease
Continuously evaluate potential collaborations to expand the pipeline
Build the organization and capabilities to scale as a clinical-stage company
Stoke Becomes a Clinical-Stage Company
Rapidly Scaling Stoke to Support Growth as a Clinical-Stage Company
29 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
2019
2018
Stoke is Poised to Enter the Clinic
Stoke is Launched • Closed $40M Series A financing
• Nominated Dravet syndrome as lead program; generated in-vivo proof of concept
• Completed FDA pre-IND meeting
• Closed $90M Series B financing
• Built robust intellectual property estate
• Completed $163.3M Initial Public Offering
• Received FDA orphan drug designation for STK-001, a potential disease modifying medicine for Dravet syndrome
• Enrolled first patient in the BUTTERFLY observational study
• Presented preclinical data supporting efficacy of STK-001
• Submitted IND for STK-001 to the U.S. FDA
Current Financials Anticipated to Fund Operations into 2023
30 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Cash, Cash Equivalents and Restricted Cashas of 09/30/2020 $191.7 million
Common Shares Outstandingas of 09/30/2020 33,361,188
The Commitment that Drives Stoke
31 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved
Copyright Stoke Therapeutics, Inc.Not for publication or distribution
32 © Copyright 2020 Stoke Therapeutics, Inc. All rights reserved© Copyright 2020 Stoke Therapeutics, Inc. All rights reserved.