Full Press Release Details
Executive Officer th 40 Annual J.P. Morgan Healthcare Conference January 10, 2022 Copyr igh Cot p2022 yrigh t S2022 toke T Sh to er ke ap T eh ue tic ras peutics 1
Disclaimer 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, or should 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 to be 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 any information 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, or
circumstances 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: the ability of our TANGO platform to design medicines to increase protein production and the expected benefits thereof; expectations regarding our aspirations to execute in the clinic
with STK- 001, advance to the clinic with STK-002, and expand our pipeline through internal discovery and collaboration; the ability of STK-001 to treat the underlying causes of Dravet syndrome and reduce seizures; the ability of STK-002 to treat
the underlying causes of Autosomal Dominant Optic Atrophy (ADOA); the preclinical data and study results regarding OPA1; our future operating results, financial position and liquidity; our expectations about timing and execution of anticipated
milestones, responses to regulatory authorities, expected nomination of future product candidates and timing thereof; our expectations, plans, aspirations and goals, including those related to the goals of our collaboration with Acadia; and our
preliminary cash, cash equivalents, marketable securities and restricted cash and shares outstanding as of December 31, 2021. 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 as assumptions, which, if they do not fully materialize or prove
incorrect, could cause our results to differ materially from those expressed or implied by such statements, including: our ability to develop, obtain regulatory approval for and commercialize STK-001, STK-002, and future product candidates,
including any future product candidates nominated for SYNGAP1 or MECP2; the timing and results of preclinical studies and clinical trials; the risk that positive results in a clinical trial may not be replicated 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 adequately manage clinical activities, unexpected concerns that may arise from additional
data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, 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 other proprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives, including our collaboration with Acadia; risks relating to
technology failures or breaches; our dependence on collaborators, including Acadia, 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; the direct and indirect impact of COVID-19 on our business, financial condition and operations, including on our expenses, supply chain, strategic partners, research and development costs, clinical trials and employees; risks associated
with current and potential future healthcare reforms; 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 in other 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 this presentation. 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 such statements 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 for forming your own view of the potential future performance of Stoke. Copyright 2022 Stoke Therapeutics 2
Addressing the underlying cause of severe diseases by upregulating
protein expression with RNA-based medicines Execute in the clinic with STK-001, the first potential disease-modifying approach for the treatment of Dravet syndrome Boldly Restoring Advance to the clinic with STK-002, the first potential Genetic
Health disease-modifying approach for the treatment of Autosomal Dominant Optic Atrophy (ADOA) Expand pipeline through internal discovery and collaboration C Co op pyr yrigh ight t 2022 2022 S Sto toke ke T Th he er ra ap pe eu utic
A Differentiated Platform for the Discovery and Development of Novel
RNA-Based Medicines Proprietary RNA therapeutics platform Disease-modifying approach (TANGO) We aim to address the underlying Targets pre-mRNA splicing to restore cause of severe diseases target protein to near-normal levels Clinical stage with
emerging pipeline Broad therapeutic potential Phase 1/2a studies ongoing with STK-001 ~1,200 monogenic disease genes for Dravet syndrome (DS). Preclinical and ~6,500 additional genes with development initiated for STK-002 for TANGO target signatures
autosomal dominant optic atrophy (ADOA) Copyright 2022 Stoke Therapeutics 4 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,
Our compounds aim to restore protein Targeted levels by increasing
protein production from the functional copy of a gene and: Augmentation of Selectively boost expression only in tissues Nuclear where the protein is normally expressed Offer one drug for diseases caused by many Gene different loss-of-function
mutations Output Apply to genes of diverse size: can be used to address small or large gene targets C Co op pyr yrigh ight t 2022 2022 S Sto toke ke T Th he er ra ap pe eu utic tics s 5 5
Haploinsufficiency Haploinsufficiency without TANGO-ASO with TANGO-ASO =
50% increased functional functional protein expression protein 6
2021 Execution Initiated Swallowtail Open Label Extension (OLE) study of
STK-001 1H2021 2H2021 Initiated multiple ascending dose (MAD) study of STK-001 (MONARCH) 3Q2021 Reported preliminary safety, PK, and CSF data (SAD portion of MONARCH) 2H2021 Initiated (MAD) study of STK-001 in the U.K.
(ADMIRAL) 2H2021 Initiated ADOA natural history data collection YE2021 Identified clinical candidate for the treatment of ADOA Copyright 2022 Stoke Therapeutics 7
Dravet Syndrome: A Severe, Progressive Genetic Epilepsy 1 out of 16,000
~35,000 85% babies are born with Dravet syndrome of cases caused by a people affected in the U.S., Canada, HAPLOINSUFFICIENCY Japan, Germany, France and the UK of the SCN1A gene of children and adolescents with Dravet Up to syndrome die before
adulthood, due to RESULTING in 1 SUDEP , prolonged seizures, seizure- 20% related accidents or infections 50% Seizures are not adequately controlled in Dravet syndrome is not concentrated Na 1.1 protein V of people with in a particular geographic
area or expression Dravet syndrome 90% ethnic group 1 Sudden Unexpected Death in Epilepsy Sources: 2018 Health Advances Report; Dj mi et al., Molecular Genetics & Genomic Medicine, 2016; Lagae et al., Copyright 2022 Stoke
Therapeutics 8 Developmental Medicine & Child Neurology, 2017; Nabbout et al., Orphanet Journal of Rare Diseases, 2013
No Approved Disease-Modifying Therapies for Dravet Syndrome Non-Seizure
Comorbidities of Dravet Syndrome Are Not Addressed by Current Therapies Intellectual disability Developmental delays Movement and balance issues Language and speech disturbances Growth defects Sleep
abnormalities Disruptions of the autonomic nervous system Mood disorders Dravet syndrome is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the
disease Copyright 2022 Stoke Therapeutics 9
Non-Seizure Comorbidities of DS are Progressive and Measurable Gap in
overall intellectual development and adaptive function between patients and neurotypical children appears to widen with age Results from the VABS Assessment Adaptive Behavior Composite (ABC)* 100 80 60 Initial findings showed: Validation of
standard cognitive measures 40 for use in DS patients Substantially decreased neurocognitive abilities despite 20 the use of multiple anti-seizure medications A gap in adaptive functioning was observed in VABS* 0 testing 24 48 72 96
120 144 168 192 216 (n=36, 2-18 year-olds). Study ongoing. Age (m) * VABS = Vineland Adaptive Behavior Scales * ABC score based on Communication, Daily Living, and Socialization domains and expressed relative to normative mean of 100
Copyright 2022 Stoke Therapeutics 10 Source: BUTTERFLY: An Observational Study to Investigate Cognition and Other Non-seizure Comorbidities in Children and Adolescents with Dravet Syndrome (DS) (AES 2021). Standard Score
STK-001 Significantly Reduces Premature Mortality in DS Mice After a
Single Dose Significant improvements in survival after STK-001 administration at postnatal day 2 p<0.0001 PBS wild-type (n=46) STK-001 wild-type (n=27) +/- STK-001 SCN1a (n=34) +/- PBS SCN1a (n=62) Postnatal days Sources: 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 Copyright 2022 Stoke Therapeutics 11 increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse
model of Dravet syndrome. Sci. Transl. Med. 12, eaaz6100 (2020). Survival (%)
Single dose restores Na 1.1 to near- V normal levels for >3
months in DS mice Significantly reduces mortality and seizure frequency in DS mice Preclinical Findings Support Clinical Development Achieves broad distribution and increases Na 1.1 protein expression in NHPs V of STK-001
Well-tolerated as shown in single and multiple-dose toxicology studies in NHPs Sources: Targeted Augmentation of Nuclear Gene Output (TANGO) of SCN1A reduces seizures and rescues parvalbumin positive interneuron firing frequency in a mouse
model of Dravet syndrome (AES 2020). Wengert ER, Wagley PK, Strohm SM, Reza N, Wenker IC, Gaykema RP, Christiansen A, Liau G, Patel MK. Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and
reduces seizures in a mouse model of Dravet Syndrome. Brain Res. 2022;1775:147743. Stoke data. C Co op pyr yrigh ight t 2022 2022 S Sto toke ke T Th he er ra ap pe eu utic tics s 12 12 TANGO oligonucleotides for the treatment of Dravet
Syndrome: Safety, biodistribution and pharmacology in the non-human primate (AES 2019)
Phase 1/2a Trials of STK-001 for Dravet Syndrome are Ongoing Parallel
studies in the US & UK evaluating children and adolescents ages 2 to 18 years old Design Evaluation of STK-001 (up to 45mg*) Evaluation of STK-001 (up to 70mg) SAD: Enrollment ongoing @45mg Status MAD: Enrollment and dosing
ongoing @30mg MAD: Enrollment and dosing ongoing @30mg Target Enrollment ~90 Up to 60 Safety and tolerability of SAD and MAD dose levels Safety and tolerability of MAD dose levels Primary Endpoint Characterize human pharmacokinetics (PK) and
cerebrospinal fluid (CSF) drug exposure Secondary Endpoint Change in seizure frequency, overall clinical status, and quality of life Open-Label Enrollment and Enrollment expected Extension dosing is ongoing to begin in 2Q22 *Doses >45mg remain on
FDA partial clinical hold. Sources: Interim Safety, PK, and CSF Exposure Data from the Phase 1/2a MONARCH Study of STK-001, an Antisense Oligonucleotide (ASO), in Children and Adolescents with Dravet Copyright 2022 Stoke Therapeutics 13
Syndrome (AES 2021). ADMIRAL: A UK Study of the Safety and Pharmacokinetics of Antisense Oligonucleotide STK-001 in Children and Adolescents with Dravet Syndrome (AES 2021).
Patients Treated with STK-001 Experienced Reductions in Convulsive
Seizure Frequency 70.6% (12/17) of patients including all patients ages 2-12 (n=7) experienced a reduction from baseline in convulsive seizure frequency measured from Day 29 to Day 84 Reductions in seizure frequency were also observed among patients
ages 13-18 Patients (13 to 18 Years) Combined by Cohort Patients (2 to 12 Years) Combined by Cohort 50 50 25 25 0 0 -25 -25 -50 -50 -75 -75 Cohort A1 (10mg; N=3) Cohort A1 (10mg; N=1) Day 29-84 Day 29-84 Cohort A2 (20mg; N=2) Cohort A2 (20mg; N=2)
Cohort A3 (30mg; N=3) Cohort A3 (30mg; N=2) Cohort B1 (20mg MAD; N=2) Cohort B1 (20mg MAD; N=2) Copyright 2022 Stoke Therapeutics 14 Source: Interim Safety, PK, and CSF Exposure Data from the Phase 1/2a MONARCH Study of STK-001, an Antisense
Oligonucleotide (AS0), in Children and Adolescents with Dravet Syndrome (DS) (AES 2021) Median % Change from Baseline Median % Change from Baseline
Median % Change from Baseline in Seizure Frequency More Evident >4
Weeks After Dosing Patients (All Ages) Combined by Cohort: Patients (All Ages) Combined by Cohort: Day 29-84 Day 1-84 0 0 -17% -25 -25 -37% -50 -50 Day 29-84 Day 1-84 Copyright 2022 Stoke Therapeutics 15 Source: Interim Safety, PK, and CSF
Exposure Data from the Phase 1/2a MONARCH Study of STK-001, an Antisense Oligonucleotide (AS0), in Children and Adolescents with Dravet Syndrome (DS) (AES 2021) Median % Change from Baseline Median % Change from Baseline
3 Monthly 30mg Doses of STK-001 Projected to Achieve Pharmacologically
Active Brain Levels in >95% of Patients Plasma and CSF exposure data from MONARCH can be used to predict STK-001 brain levels in patients Pharmacologically active range Pharmacologic effect likely lasts beyond timepoint when STK-001 brain
concentration falls below minimum level Copyright 2022 Stoke Therapeutics 16 Source: Interim Safety, PK, and CSF Exposure Data from the Phase 1/2a MONARCH Study of STK-001, an Antisense Oligonucleotide (AS0), in Children and Adolescents with
Dravet Syndrome (DS) (AES 2021)
Summary of Ph1/2a MONARCH Interim Data Single doses up to 30mg and
three 20mg doses were well tolerated with no safety concerns related to study drug STK-001 Has Potential to Plasma and CSF data from MONARCH correlated well with model and likely predict STK-001 brain Address the Genetic Cause
levels in patients of Dravet Syndrome (DS) Trend toward seizure reduction observed in DS patients following dosing of STK-001 3 monthly doses (30mg) predicted to achieve pharmacological active brain levels in >95% of patients
Preliminary clinical data from multiple 30mg doses of STK-001 expected in the second half of 2022 C Co op pyr yrigh ight t 2022 2022 S Sto toke ke T Th he er ra ap pe eu utic tics s 17 17
Autosomal Dominant Optic Atrophy (ADOA): A Severe, Progressive Optic
Nerve Disorder 65-90% 1 out of 30,000 ~18,000 of cases caused by mutations in one allele Up to people affected in the U.S., Canada, people are affected globally with a of the OPA1 gene, most Japan, Germany, France and the UK higher incidence of ~1
out of 10,000 in of which lead to a 46% Denmark due to a founder effect HAPLOINSUFFICIENCY of patients are registered legally blind RESULTING in 80% >400 50% of patients are Different OPA1 mutations Na 1.1 protein OP V A1 protein symptomatic
reported in ADOA patients expression expression and disease by age 10 manifestation Sources: Yu-Wai-Man P et al. Ophthalmology, 2010; Yu-Wai-Man P, Chinnery PF. Ophthalmology, 2013; P. Amati-Bonneau P et al. The International Journal of Biochemistry
& Cell Biology, 2009; Lenaers G, Hamel C, Delettre C, et al. Orphanet J Rare Dis, 2012; Chun BY and Rizzo JF III. Curr Opin Ophthalmol, 2016; Le Roux B, Lenaers G, Zanlonghi X et al. Orphanet J Rare Dis, Copyright 2022 Stoke Therapeutics
18 2019; "What is ADOA?" Autosomal Dominant Optic Atrophy Association. Accessed May 6, 2020, from https://www.adoaa.org/what-is-adoa;
No Approved Disease-Modifying Therapies for ADOA Simulation of Optic
Neuropathy Healthy Vision Most common inherited optic nerve disorder Leads to central field defects and reduced color vision in both eyes Severity can vary; rate of vision loss difficult to predict Supportive services
and low-vision aids are offered for patients Healthy ADOA patient Sources: Yu-Wai-Man P et al. Ophthalmology, 2010; Yu-Wai-Man P, Chinnery PF. Ophthalmology, 2013; Lenaers G, Hamel C, Delettre C, et al. Orphanet J Rare Dis, 2012; Chun BY and Rizzo
JF III. Curr Opin Ophthalmol, 2016 Copyright 2022 Stoke Therapeutics 19 Image of child sourced from ICR, Ophthalmology Center Barcelona. Accessed Jan. 8, 2021 from https://icrcat.com/en/eye-conditions/leber-hereditary-optic-neuropathy/
Credit: Lhon Eye Society Sweden. Image shown depicts Leber Hereditary Optic Neuropathy, which presents visual effects similar to ADOA.
OPA1 is Critical for Normal Mitochondrial Function and Cellular
Metabolism Healthy ADOA Retinal ganglion cells have very high energy (ATP) requirements Impaired mitochondrial function leads to cell death OPA1 +/+ OPA1 +/- OPA1 is critical for Mitochondrial Bioenergetics Functional
Mitochondrial Bioenergetic Dysfunction mitochondrial function and Cristae Structural Stability Cristae Structural Disruption energy production Antioxidant Defense Oxidative Stress Cell Survival Cell Death Copyright 2022 Stoke Therapeutics 20