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|Item 1.01.|| |
Entry into a Material Definitive Agreement.
On January 9, 2022, Stoke Therapeutics, Inc., a Delaware corporation (the “Company”) entered into a License and Collaboration Agreement (the “Agreement”) with Acadia Pharmaceuticals Inc. (“Acadia”) for the discovery, development and commercialization of novel RNA-based medicines for the treatment of severe and rare genetic neurodevelopmental disease of the central nervous system (“CNS”). The Agreement focuses on the targets SYNGAP1, MECP2 (Rett syndrome), and an undisclosed neurodevelopmental target of mutual interest. In connection with each target, the parties will collaborate to identify potential treatments for further development and commercialization as licensed products. With respect to SYNGAP1, the parties have agreed to co-develop and co-commercialize licensed products for such target globally, and in connection therewith the Company granted to Acadia worldwide, co-exclusive (with the Company) licenses for such licensed products. With respect to MECP2 and the neurodevelopmental target, the Company granted to Acadia worldwide, exclusive licenses to develop and commercialize licensed products for such targets.
Pursuant to the Agreement, Acadia will pay the Company an upfront payment in the amount of $60,000,000. Acadia will fund the research to identify potential licensed products for MECP2 and the neurodevelopmental target, and the parties will equally fund the research to identify potential licensed products for SYNGAP1. The Company is eligible to receive up to $907,500,000 in potential total milestone payments based upon the achievement of certain development, regulatory, first commercial sales and sales milestone events across the programs for the three targets, assuming each milestone were achieved at least once. With respect to licensed products for MECP2 and the neurodevelopmental target, the Company is also eligible to receive tiered royalties at percentages ranging from the mid-single digits to the mid-teens on future net sales by Acadia of licensed products worldwide. Royalties payable under the Agreement are subject to standard royalty reductions. For SYNGAP1 licensed products that the parties are co-developing and co-commercializing, the Company will be responsible for 50% of the development and commercialization costs and will receive 50% of the profits from global commercialization.
With respect to each SYNGAP1 licensed product being co-developed or co-commercialized, the Agreement will remain in effect, unless earlier terminated, until the parties have agreed to permanently abandon the further development and commercialization of such licensed product. With respect to licensed products for MECP2 and the neurodevelopmental target, the Agreement will remain in effect, unless earlier terminated, until the expiration, on a country-by-country and licensed product-by-licensed product basis, of the applicable royalty term, at which point the license for such licensed product shall become fully paid-up, royalty-free, perpetual and irrevocable in such country.
The Agreement also contains customary provisions for termination by Acadia for convenience and by either party for cause, including for material breach (subject to cure). The Company has standard reversion rights in connection with certain early termination events.
The foregoing description of the terms of the Agreement does not purport to be complete and is qualified in its entirety by reference to the full text of the Agreement, a copy of which will be filed with the Securities and Exchange Commission as an exhibit to the Company’s Quarterly Report on Form 10-Q for the quarter ending March 30, 2022.
|Item 2.02.|| |
Results of Operations and Financial Condition
On January 10, 2022, the Company plans to present certain preliminary financial and operating information in connection with a presentation (the “Presentation”) at the J.P. Morgan Healthcare Conference, including that the Company expects to report that it had cash, cash equivalents, marketable securities and restricted cash of approximately $220.4 million, and approximately 36.9 million shares of common stock outstanding, as of December 31, 2021.
The Company’s audited financial statements for the fiscal year ended December 31, 2021, are not yet available. Accordingly, the preliminary financial information included in the Presentation is an estimate subject to the completion of the Company’s financial closing procedures and any adjustments that may result from the completion of the audit of the Company’s financial statements. The preliminary financial information may differ materially from the actual results that will be reflected in the Company’s audited financial statements when they are completed and publicly disclosed.
The information in this Item 2.02 shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1924, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any other filing under the Exchange Act or the Securities Act of 1933, as amended (the “Securities Act”), except as expressly set forth by specific reference in such a filing.
|Item 7.01.|| |
The Company is furnishing the Presentation, a full copy of which is attached hereto as Exhibit 99.1.
On January 10, 2022, the Company and Acadia issued a joint press release, announcing their entry into the Agreement. A copy of the press release is attached hereto as Exhibit 99.2.
The information furnished with this report, including Exhibit 99.1 and Exhibit 99.2, shall not be deemed “filed” for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any other filing under the Exchange Act or the Securities Act, except as expressly set forth by specific reference in such a filing.
|Item 8.01|| |
The Company also reported that its cash, cash equivalents, marketable securities and restricted cash, including the upfront payment payable by Acadia pursuant to the Agreement, are expected to fund operations into the second half of 2024.
Cautionary Note Regarding Forward-Looking Statements
This report 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, statements regarding: receipt of upfront payments; receipt of potential milestone payments under the SYNGAP1 collaboration; receipt of potential milestones and royalty payments under the MECP2 program and the third program; the ability to develop new treatments for neurodevelopmental diseases; expectations regarding the proposed transaction with Acadia; and the Company’s expected cash, cash equivalents, marketable securities and restricted cash as of December 31, 2021. Statements including words such as “believe,” “plan,” “will,” “continue,” “expect,” “may,” or “ongoing” and statements in the future tense are forward-looking statements. These forward-looking statements involve risks and uncertainties, as well as assumptions, which, if they do not fully materialize or prove incorrect, could cause the Company’s results to differ materially from those expressed or implied by such forward-looking statements. Forward-looking statements are subject to risks and uncertainties that may cause the company’s actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to the Company’s ability to advance its product candidates, obtain regulatory approval of and ultimately commercialize its product candidates, the timing and results of preclinical and clinical trials, the company’s ability to fund development activities and achieve development goals, the Company’s ability to protect intellectual property and other risks and uncertainties described under the heading “Risk Factors” in documents the Company files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof.
|Item 9.01|| |
Financial Statements and Exhibits.
|99.1||Presentation, dated as of January 2022|
|99.2||Joint Press Release, dated as of January 10, 2022.|
|104||Cover Page Interactive Data File (the cover page XBRL tags are embedded within the inline XBRL document).|
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|STOKE THERAPEUTICS, INC.|
|Date: January 10, 2022||By:|
|Stephen J. Tulipano|
|Chief Financial Officer|
Exhibit 99.1 Stoke Therapeutics NASDAQ: STOK Edward M. Kaye, M.D. Chief 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 tics s 3 3
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, 3501 (2020).
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; Djémié 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 * ROS = Reactive Oxygen Species
TANGO ASO Increases OPA1 Protein and ATP Linked Mitochondrial Respiration in ADOA Patient Cells ASO treatment increased OPA1 protein levels in ASO treatment increased ATP linked respiration OPA1 deficient ADOA patient cells in OPA1 deficient ADOA patient cells 200 ** **** **** 140 150 120 100 * healthy control **** mock 100 80 patient 1 patient 1 60 patient 2 patient 2 50 40 20 0 0 Source (left graph): Stoke data Source (right graph): Venkatesh A, et al. Antisense oligonucleotide mediated increase in OPA1 improves mitochondrial function in fibroblasts derived from patients with © Copyright 2022 Stoke Therapeutics 21 autosomal dominant optic atrophy (ADOA). Presented at The Association for Research in Vision and Ophthalmology; May 1-7, 2021. Normalized OPA1 protein expression ATP linked respiration
Summary of Key Preclinical Data Increase OPA1 protein and ATP linked ✓ respiration in ADOA patient cells Result in dose-dependent increases in ✓ TANGO ASOs Have the OPA1 protein expression in rabbit retina Potential to Address the Were well tolerated for up to 29 days ✓ Genetic Cause of ADOA after intravitreal injection in rabbit Preclinical toxicology studies ongoing in 2022 to support future clinical trials for STK-002 Sources: Venkatesh A, et al. Antisense oligonucleotide mediated increase in OPA1 improves mitochondrial function in fibroblasts derived from patients with autosomal dominant optic atrophy © © C Co op pyr yrigh ight t 2022 2022 S Sto toke ke T Th he er ra ap pe eu utic tics s 22 22 (ADOA). Presented at The Association for Research in Vision and Ophthalmology; May 1-7, 2021.Venkatesh A, et al. Antisense oligonucleotide mediated increase of OPA1 expression using TANGO technology for treatment of autosomal dominant optic atrophy. Presented at The Association for Research in Vision and Ophthalmology; May 3-7, 2020; Baltimore, MD.
Collaboration with Acadia Pharmaceuticals to Pursue RNA-Based Treatments for Severe & Rare Genetic Neurodevelopmental Diseases Collaboration leverages Stoke’s proprietary TANGO research platform and Acadia’s expertise in neurology drug development and commercialization 3 targets focused on severe and rare genetic Stoke receives a $60M upfront payment neurodevelopmental diseases of the central and potential milestones up to $907M as nervous system well as royalties on future sales • Acadia receives exclusive worldwide licenses for: • Acadia fully funds the research and • Rett syndrome (MECP2) preclinical development activities for Rett • Undisclosed neurodevelopmental target syndrome (MECP2) and undisclosed neurodevelopmental program • 50:50 co-development co-commercialization of SYNGAP1 • Share 50/50 in all world-wide costs and future profits for SYNGAP1 program © Copyright 2022 Stoke Therapeutics 23
Rett Syndrome: A Severe, Debilitating Neurological Disorder females are born with Rett 2 1 out of 10,000 to15,000 syndrome ~33% of cases caused by hypomorphic 3 Symptoms include : mutations of the MECP2 1 • Loss of purposeful hand use gene Period of rapid • Involuntary hand movements such as handwringing decline typically begins between • Loss of speech RESULTING in • Loss of mobility or gait disturbances 6 to 18 4 months Partial loss of 4 of patients have epilepsy 60-80% function of the MeCP2 protein Note: All seizure types have been reported in Rett syndrome. Complex partial and generalized tonic-clonic are the most common 1 2 Sources: RettBase (http://mecp2.chw.edu.au/); GnomAD (https://gnomad.broadinstitute.org); NOMAD; National Institutes 3 4 of Health – National Institute of Neurological Disorders and Stroke; International Rett Syndrome Foundation; Operta et al., © Copyright 2022 Stoke Therapeutics 24 Brain Behav 2019
SYNGAP1 Syndrome: A Severe Intellectual Disability / Developmental and Epileptic Encephalopathy (ID/DEE) >80% ~1-2 out of 100,000 children are born with SYNGAP1-ID/DEE of cases caused by a HAPLOINSUFFICIENCY 1 of the SYNGAP1 gene 100% 1-2% of patients have developmental delay of all intellectual disability RESULTING in 2 3 cases or intellectual disability ~50% 84% 50% of patients have autism and other SynGAP protein of patients have 3 behavioral abnormalities 3 expression generalized epilepsy 1 Sources: Parker et al., American Journal of Medical Genetics, 2015; Jimenez-Gomez et al., Journal of Neurodevelopmental 2 Disorders, 2019; SYNGAP1 Resource Guide, Second Edition; An Overview of SYNGAP1 Basic Biology and Clinical Description. 3 Bridge the Gap SYNGAP (now SYNGAP1 Foundation); SynGAP Research Fund; SYNGAP1-Related Intellectual Disability: © Copyright 2022 Stoke Therapeutics 25 https://www.ncbi.nlm.nih.gov/books/NBK537721/#_syngap1-id_Clinical_Characteristics_
Investing In Our Pipeline PROGRAM TARGET DISCOVERY & PRECLINICAL PHASE 1/2 PHASE 3 PARTNER Central Nervous System 100% Stoke Dravet Syndrome SCN1A STK-001 Global Stoke: Acadia SYNGAP1 SYNGAP1 Syndrome 50:50 Acadia Rett Syndrome MECP2 Worldwide License Acadia Undisclosed Undisclosed Worldwide License Ophthalmology 100% Stoke OPA1 STK-002 ADOA Global © Copyright 2022 Stoke Therapeutics 26
Our Strategy For 2022 Advance our wholly owned CNS and eye programs and expand the scope of our drug discovery efforts Develop & Expand Advance STK-001 for Advance STK-002 for Pipeline Dravet Syndrome ADOA • Additional clinical data on STK-001 • Conduct preclinical toxicology studies • Continue discovery efforts to identify (30mg MAD) anticipated in 2H22 to support future clinical trials for new targets • Initiate dosing >30mg in MONARCH STK-002 • Execute on collaboration with Acadia and ADMIRAL• Begin enrollment in prospective ADOA natural history study • Present additional preclinical data for STK-002 at scientific forum © © © C C Co o op p pyr yr yrigh igh ight t t 2022 2022 2022 S S Sto to toke ke ke T T Th h he e er r ra a ap p pe e eu u utic tic tics s s 27 27 27
Current Liquidity Including Upfront from Acadia Anticipated to Fund Operations into the Second Half of 2024 $220.4M* 36.9M Cash, Cash Equivalents, Common Shares Outstanding Marketable Securities, and Restricted Cash (unaudited) as of 12/31/2021 (unaudited) as of 12/31/2021 © © C Co op pyr yrigh ight t 2022 2022 S Sto toke ke T Th he er ra ap pe eu utic tics s 28 28 *Does not include the $60 Million Upfront from Acadia
Q&A © Copyright 2022 Stoke Therapeutics 29
Acadia Pharmaceuticals and Stoke Therapeutics Announce Collaboration to Pursue Multiple RNA-based Treatments for Severe and Rare Genetic
- Establishes co-development and co-commercialization agreement for Stokes SYNGAP1 preclinical program
- Acadia receives exclusive worldwide licenses for two additional preclinical programs: Rett syndrome (MECP2) and undisclosed neurodevelopmental target
- Combines Stokes TANGO research platform with Acadias expertise in neurology drug development and commercialization
- Stoke receives a $60 million upfront payment and potential milestone payments of up to $907 million and royalties on future sales
SAN DIEGO, CA and BEDFORD, MA, January 10, 2022 Acadia Pharmaceuticals Inc. (Nasdaq: ACAD) and Stoke Therapeutics, Inc. (Nasdaq: STOK) announced today that the companies have entered a collaboration to discover, develop and commercialize novel RNA-based medicines for the potential treatment of severe and rare genetic neurodevelopmental diseases of the central nervous system (CNS). The collaboration includes SYNGAP1 syndrome, Rett syndrome (MECP2), and an undisclosed neurodevelopmental target of mutual interest.
Stokes RNA-based approach to upregulating healthy proteins offers very exciting new possibilities for the treatment of rare, neurodevelopmental diseases like Rett syndrome, said Steve Davis, Chief Executive Officer of Acadia Pharmaceuticals. Combining Stokes capabilities with Acadias extensive expertise in neuroscience drug development and commercialization enables us to push harder and faster in exploring some of the new frontiers in rare central nervous system disorders. We are excited to have the opportunity to further build our Rett syndrome franchise and pursue treatments in SYNGAP1 syndrome and other neurodevelopmental disorders.
Rett syndrome and SYNGAP1 syndrome are two severe, intractable diseases of the central nervous system and both are associated with developmental delays, motor function loss, autism, seizures and other comorbidities that impact quality of life for patients and their families, said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. Acadia shares our deep commitment to improving outcomes for people living with neurodevelopmental disorders. We believe their late-stage development and commercialization capabilities, in addition to their neuroscience expertise, complement our discovery research efforts and clinical learnings from our work in Dravet syndrome. Together, we believe we have a significant opportunity to improve treatment options by delivering new disease-modifying medicines to people who need them.
Terms of Collaboration
Under the terms of the agreement, Stoke will receive an upfront payment of $60 million from Acadia and is eligible to receive up to $907 million in milestones as well as royalties on future sales.
For the SYNGAP1 program, the two companies will jointly share global research, development and commercialization responsibilities and share 50/50 in all worldwide costs and future profits. In addition, Stoke is eligible to receive potential development, regulatory, first commercial sales and sales milestones.
For the Rett syndrome (MECP2) and the undisclosed neurodevelopmental program, Stoke will lead research and pre-clinical development activities, while Acadia will lead clinical development and commercialization activities. Acadia will fully fund the research and pre-clinical development activities related to these two targets and Stoke is eligible to receive potential development, regulatory, first commercial sales and sales milestones as well as tiered royalty payments on worldwide sales starting in the mid-single digit range and escalating to the mid-teens based on revenue levels.
About SYNGAP1 Syndrome
SYNGAP1 syndrome is a rare neurological disorder characterized by moderate to severe intellectual disability that is evident in early childhood. Mutations in the SYNGAP1 gene (which produces the SynGAP protein) were first identified in 2009 and since then, an increasing number of children with SYNGAP1 syndrome have been identified. Normal levels of SynGAP protein are essential for proper brain function and development. Mutations in the SYNGAP1 gene also play an important role in the development of epileptic encephalopathies (DEEs). The severity and onset of symptoms can vary from patient to patient. SYNGAP1 syndrome is characterized by developmental delay or intellectual disability, generalized epilepsy, and autism spectrum disorder (ASD) and other behavioral abnormalities. More than 80% of cases of SYNGAP1 syndrome are caused by a haploinsufficiency of the SYNGAP1 gene. SYNGAP1 syndrome is estimated to account for 1% to 2% of all intellectual disability cases. There are currently no approved treatments for SYNGAP1 syndrome.
About Rett Syndrome
Rett syndrome is a rare, debilitating neurological disorder that occurs primarily in females following apparently normal development for the first six months of life. Rett syndrome is often misdiagnosed as autism, cerebral palsy, or non-specific developmental delay. Rett syndrome is caused by mutations on the X chromosome on a gene called MECP2. There are more than 200 different mutations found on the MECP2 gene that interfere with its ability to generate a normal gene product. Rett syndrome occurs worldwide in approximately one of every 10,000 to 15,000 female births and in the United States impacts 6,000 to 9,000 patients. Rett syndrome causes problems in brain function that are responsible for cognitive, sensory, emotional, motor and autonomic function. Typically, with symptoms presenting between 6 to 18 months of age, patients experience a period of rapid decline with loss of purposeful hand use (fine motor skills), development of hand stereotypies, absent or impaired mobility (gross motor skills), loss of communication skills (including eye contact) and inability to independently conduct activities of daily living. Symptoms also include seizures, disorganized breathing patterns, an abnormal side-to-side curvature of the spine (scoliosis), and sleep disturbances. Currently, there are no FDA-approved medicines for the treatment of Rett syndrome.
TANGO (Targeted Augmentation of Nuclear Gene Output) is Stokes proprietary research platform. Stokes initial application for this technology are diseases in which one copy of a gene functions normally and the other is mutated, also called haploinsufficiencies. In these cases, the mutated gene does not produce its share of protein, resulting in disease. Using the TANGO approach and a deep understanding of RNA science, Stoke researchers design antisense oligonucleotides (ASOs) that bind to pre-mRNA and help the functional (or wild-type) genes produce more protein. TANGO aims to restore missing proteins by increasing or stoking protein output from healthy genes, thus compensating for the mutant copy of the gene.
About Stoke Therapeutics
Stoke Therapeutics (Nasdaq: STOK), is a biotechnology company dedicated to addressing the underlying cause of severe diseases by upregulating protein expression with RNA-based medicines. Using Stokes proprietary TANGO (Targeted Augmentation of Nuclear Gene Output) approach, Stoke is developing antisense oligonucleotides (ASOs) to selectively restore protein levels. Stokes first compound, STK-001, is in clinical testing for the treatment of Dravet syndrome, a severe and progressive genetic epilepsy. Dravet syndrome is one of many diseases caused by a haploinsufficiency, in which a loss of ~50% of normal protein levels leads to disease. Stoke is pursuing treatment for a second haploinsufficient disease, autosomal dominant optic atrophy (ADOA), the most common inherited optic nerve disorder. Stokes initial focus is haploinsufficiencies and diseases of the central nervous system and the eye, although proof of concept has been demonstrated in other organs, tissues, and systems, supporting its belief in the broad potential for its proprietary approach. Stoke is headquartered in Bedford, Massachusetts with offices in Cambridge, Massachusetts. For more information, visit https://www.stoketherapeutics.com/ or follow Stoke on Twitter at @StokeTx.
About Acadia Pharmaceuticals
Acadia is advancing breakthroughs in neuroscience to elevate life. For more than 25 years Acadia has been working at the forefront of healthcare to bring vital solutions to people who need them most. Acadia developed and commercialized the first and only approved therapy for hallucinations and delusions associated with Parkinsons disease psychosis. Acadias late-stage development efforts are focused on treating psychosis in patients with dementia, the negative symptoms of schizophrenia and Rett syndrome. Acadias early-stage development efforts are focused on novel approaches to pain management, cognition and neuropsychiatric symptoms in central nervous system disorders. For more information, visit us at www.acadia-pharm.com and follow us on LinkedIn and Twitter.
Stokes Cautionary Note Regarding Forward-Looking Statements
This press release 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, statements regarding: receipt of upfront payments; receipt of potential milestone payments under the SYNGAP1 collaboration; receipt of potential milestones and royalty payments under the MECP2 program and the third program; the ability to develop new treatments for neurodevelopmental disorders; and expectations regarding the proposed transaction with Acadia. Statements including words such as believe, will, eligible, or potential, and any other statements in the future tense are forward-looking statements. 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 forward-looking statements. Forward-looking statements are subject to risks and uncertainties that may cause the companys actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to: Stokes ability to develop and identify potential product candidates; that if Acadia were to breach or terminate the collaboration, Stoke would not obtain the anticipated financial or other benefits; the possibility that Stoke and Acadia may not be successful in their development efforts under any of the collaborations and that, even if successful, Stoke and Acadia may be unable to successfully commercialize any resulting product candidates; and other risks and uncertainties described under the heading Risk Factors in documents Stoke files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release and Stoke undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof.
Acadias Forward-Looking Statement
Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements include but are not limited to statements regarding the timing of future events. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks and uncertainties inherent in drug development, approval and commercialization. For a discussion of these and other factors, please refer to Acadias annual report on Form 10-K for the year ended December 31, 2020 as well as Acadias subsequent filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements are qualified in their entirety by this cautionary statement and Acadia undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof, except as required by law.
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