Optic Atrophy, Autosomal Dominant

BEDFORD, Mass.--( BUSINESS WIRE )-- Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company dedicated to addressing the underlying cause of severe diseases by upregulating protein expression with RNA-based medicines, today announced strategic priorities and anticipated milestones for 2024. “Over the last three years we have generated a comprehensive set of data from 81 patients that support STK-001 as potentially the first disease-modifying medicine for Dravet syndrome. 2024 is all about advancing this potential new medicine toward a registrational study,” said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. “The recent 2-year data from our BUTTERFLY natural history study make it clear that even the best available anti-seizure medicines are inadequate. These data show continued high seizure burden and stagnation of neurodevelopment, which are in stark contrast to the improvements we see across the studies of STK-001. Results from clinical studies anticipated in the first quarter are expected to give us the data necessary to request meetings with regulators to discuss our Phase 3 plans.” Updates and Anticipated Milestones STK-001: Dravet Syndrome In December, at the American Epilepsy Society annual meeting, the Company presented data supporting the continued advancement of STK-001 as a disease-modifying potential new medicine for the treatment of Dravet syndrome. Two-year natural history study data showed a lack of improvement among patients who are taking the best available anti-seizure medicines. In contrast, substantial and sustained reductions in seizure frequency and improvements in cognition and behavior were observed in clinical studies of STK-001. Modeling data suggest that higher STK-001 drug exposure in brain leads to greater seizure reductions. Single and multiple doses of STK-001 up to 70mg have been generally well tolerated to date. In the first quarter of 2024, the Company plans to report additional clinical and modeling data from 81 patients treated in the Phase 1/2a studies of STK-001 (MONARCH and ADMIRAL) and the two ongoing open-label extension studies (OLE) (SWALLOWTAIL and LONGWING), including: Safety, pharmacokinetic (PK) modeling, and cerebrospinal fluid (CSF) results; Seizure frequency data from ~20 patients who received 1, 2, or 3 initial doses of 70mg of STK-001 and were followed for six months; The effects of repeat doses of STK-001 (30mg, 45mg) on seizure frequency and cognition and behavior from patients treated in the SWALLOWTAIL and LONGWING OLE studies. Pending the results of the Q1 data readout, the Company plans to proceed with Phase 3 preparation activities, including discussions with global regulatory agencies, availability of chronic toxicology data, preparation of the investigator brochure, submission of a final protocol to regulatory agencies and institutional review boards (IRB). Pipeline STK-002: Autosomal Dominant Optic Atrophy (ADOA): FALCON natural history study is fully enrolled. Phase 1 study (OSPREY) of STK-002 is expected to start in the UK in 2024. The Company’s collaboration with Acadia Pharmaceuticals 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) is ongoing. The collaboration includes Rett syndrome ( MECP2 ), SYNGAP1, and an undisclosed neurodevelopmental target of mutual interest. Cash Position and Financial Guidance Stoke ended the third quarter of 2023 with $214.7 million in cash, cash equivalents and marketable securities, anticipated to fund operations to the end of 2025. Stoke’s Presentation at the 42nd Annual J.P. Morgan Healthcare Conference Dr. Edward Kaye will discuss Stoke’s strategic priorities and anticipated milestones in a presentation at the 42nd Annual J.P. Morgan Healthcare Conference on Wednesday, January 10, 2024, at 6:45 p.m. ET (3:45 p.m. PT). A live audio webcast of the presentation will be available on the Investors & News section of Stoke’s website at https://investor.stoketherapeutics.com/ and can be accessed by following this Link . A replay of the webcast will be available for 30 days following the presentation. About Dravet Syndrome Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life. Dravet syndrome is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, disruptions of the autonomic nervous system and mood disorders. The disease is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. There are no approved disease-modifying therapies for people living with Dravet syndrome. One out of 16,000 babies are born with Dravet syndrome, which is not concentrated in a particular geographic area or ethnic group. About STK-001 STK-001 is an investigational new medicine for the treatment of Dravet syndrome currently being evaluated in ongoing clinical trials. Stoke believes that STK-001, a proprietary antisense oligonucleotide (ASO), has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. STK-001 has been granted orphan drug designation by the FDA and the EMA, and rare pediatric disease designation by the FDA as a potential new treatment for Dravet syndrome. About the Phase 1/2a MONARCH Study (United States) The MONARCH study is a Phase 1/2a open-label study of children and adolescents ages 2 to 18 who have an established diagnosis of Dravet syndrome and have evidence of a genetic mutation in the SCN1A gene. The primary objectives for the study are to assess the safety and tolerability of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective is to assess the efficacy as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency. Stoke also intends to measure non-seizure aspects of the disease, such as quality of life, as secondary endpoints. Patients who participated in the MONARCH study and meet study entry criteria are eligible to continue treatment in SWALLOWTAIL, an open-label extension (OLE) study designed to evaluate the long-term safety and tolerability of repeat doses of STK-001. We expect that SWALLOWTAIL will also provide valuable information on the preliminary effects of STK-001 on seizures along with non-seizure aspects of the disease, such as quality of life and cognition. Dosing in SWALLOWTAIL is ongoing. About the Phase 1/2a ADMIRAL Study (United Kingdom) The ADMIRAL study was a Phase 1/2a open-label study of children and adolescents ages 2 to <18 who have an established diagnosis of Dravet syndrome and have evidence of a genetic mutation in the SCN1A gene. The primary objectives for the study were to assess the safety and tolerability of multiple doses of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective was to assess the effect of multiple doses of STK-001 as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency. Stoke also measured non-seizure aspects of the disease, such as overall clinical status and quality of life, as secondary endpoints. Patients who participated in the ADMIRAL study and met study entry criteria were eligible to continue treatment in LONGWING, an open-label extension (OLE) study designed to evaluate the long-term safety and tolerability of repeat doses of STK-001. We expect that LONGWING will also provide valuable information on the preliminary effects of STK-001 on seizures along with non-seizure aspects of the disease, such as quality of life and cognition. Dosing in LONGWING is ongoing. About the BUTTERFLY Observational Study The BUTTERFLY study was a multicenter, longitudinal, prospective, observational study of children and adolescents ages 2 to 18 who have been diagnosed with Dravet syndrome as a result of an SCN1A gene mutation. This observational study was designed to evaluate neurodevelopmental status and change from baseline to 24 months. Secondary and exploratory endpoints in the study evaluated changes in other disease measures, including seizures and additional non-seizure comorbidities. No investigational medications or other treatments were provided. Participants continued to receive their usual care, including anti-seizure medications, and were observed by a team of doctors and nurses over time for up to two years. The study was conducted at approximately 20 sites in the United States. About Autosomal Dominant Optic Atrophy (ADOA) Autosomal dominant optic atrophy (ADOA) is the most common inherited optic nerve disorder. It is a rare disease that causes progressive and irreversible vision loss in both eyes starting in the first decade of life. Severity can vary and the rate of vision loss can be difficult to predict. Roughly half of people with ADOA fail driving standards and up to 46% are registered as legally blind. More than 400 OPA1 mutations have been reported in people diagnosed with ADOA. Currently there is no approved treatment for people living with ADOA. ADOA affects approximately one in 30,000 people globally with a higher incidence in Denmark of one in 10,000 due to a founder effect. For more information about ADOA, visit https://www.stoketherapeutics.com/disease-areas/adoa/ . 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 Stoke’s proprietary TANGO (Targeted Augmentation of Nuclear Gene Output) approach, Stoke is developing antisense oligonucleotides (ASOs) to selectively restore protein levels. Stoke’s 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 the development of STK-002 for the treatment of autosomal dominant optic atrophy (ADOA), the most common inherited optic nerve disorder. Stoke’s 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/ . 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 the ability of STK-001 to treat the underlying causes of Dravet syndrome and reduce seizures or show improvements in behavior or cognition at the indicated dosing levels or at all; the timing and expected progress of clinical trials, data readouts and presentations for STK-001 and STK-002; the timing of regulatory interactions or the outcome thereof; and the Company’s cash runway. Statements including words such as “anticipate,” “plan,” “will,” “continue,” “expect,” 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 prove incorrect or do not fully materialize, could cause our results to differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, risks and uncertainties related to: the Company’s ability to advance, obtain regulatory approval of, and ultimately commercialize its product candidates; the timing of data readouts and interim and final results of preclinical and clinical trials; positive results in a clinical trial may not be replicated in subsequent trials or successes in early stage clinical trials may not be predictive of results in later stage trials; preliminary interim data readouts of ongoing trials may show results that change when such trials are completed; the Company’s ability to fund development activities and achieve development goals into 2025; the Company’s ability to protect its intellectual property; the direct or indirect impact of global business, political and macroeconomic conditions, including inflation, interest rate volatility, cybersecurity events, uncertainty with respect to the federal budget, instability in the global banking system and volatile market conditions, and global events, including public health crises, and ongoing geopolitical conflicts, such as the conflicts in Ukraine and the Middle East; and other risks and uncertainties described under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, its quarterly reports on Form 10-Q, and the other 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.

– Data from clinical studies of STK-001 demonstrated clinical benefit for patients ages 2 to 18 years old, including reductions in seizures and improvements in cognition and behavior that support the potential for disease modification – – Analysis of 72 patients treated in STK-001 clinical trials suggests that higher STK-001 drug exposure in brain leads to greater seizure reductions – – Two-year data from the longest prospective natural history study of Dravet syndrome showed that, on average, patients experienced no meaningful improvement in convulsive seizure frequency and exhibited widening gaps in cognition and behavior despite treatment with the best available anti-seizure medicines – BEDFORD, Mass.--(BUSINESS WIRE)-- Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company dedicated to addressing the underlying cause of severe diseases by upregulating protein expression with RNA-based medicines, today announced highlights from presentations of clinical data at the American Epilepsy Society (AES) 2023 Annual Meeting December 1 – 5, in Orlando, Florida. Together, these data support the company’s continued progress to develop STK-001 as the first disease-modifying medicine for the treatment of Dravet syndrome. “The comprehensive set of data being presented at AES are giving us a very good understanding of how STK-001 works and its potential to address not only seizures, but many of the non-seizure effects of Dravet syndrome,” said Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics. “The substantial and sustained reductions in seizure frequency and improvements in cognition and behavior observed in our STK-001 clinical studies give us confidence that we are addressing the root cause of Dravet syndrome. In addition, the correlation between higher STK-001 exposure levels in brain and reductions in seizure frequency shown in our modeling data provides additional confidence in the clinical benefits observed among patients treated with STK-001 at higher doses and for longer periods of time. These findings are in stark contrast to the data from our two-year natural history study that show a lack of improvement among patients who are taking the best available anti-seizure medicines.” “Dravet syndrome goes far beyond seizures, and as children grow up, they experience a complex array of life-altering challenges, including developmental delays, movement and balance issues and delayed language and speech,” said Joseph Sullivan, M.D., FAES, Professor of Neurology and Pediatrics and Director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco, and a prominent researcher in Dravet syndrome. “On average, patients enrolled in the BUTTERFLY natural history study were taking 3.5 anti-seizure medicines. Despite this, they continued to experience similarly high rates of seizure frequency throughout the study and fell further and further behind their neurotypical peers in aspects of cognition and behavior, including their ability to communicate and use gross motor and fine motor skills. These findings highlight the critical need for a new approach to treating this disease, one that can improve the treatment of seizures and go beyond that to address the debilitating cognitive and behavioral aspects of this disease.” Highlights from the Company’s presentations of data at the meeting, include: BUTTERFLY Natural History Study of Patients with Dravet Syndrome Ages 2 to 18: Despite treatment with the best available anti-seizure medicines, on average, patients continued to experience convulsive seizures over 24 months at similar frequency to baseline. No statistically significant change from baseline in the majority of Vineland-III measures (an established instrument for assessing developmental disabilities) was observed and the rate of improvement on multiple clinical measures, including key domains of the Vineland-III, was substantially below neurotypical peers. Gaps in neurodevelopment continued to widen throughout the study among patients with Dravet syndrome compared to their age-matched neurotypical peers. MONARCH & ADMIRAL Interim Analyses: Single and multiple doses of STK-001 up to 70mg were generally well tolerated. The multiple dose 70mg cohort showed the greatest reductions in convulsive seizure frequency, outperforming all lower dose groups. Patients treated with 2 or 3 initial doses of 70mg experienced substantial and sustained reductions in convulsive seizure frequency. SWALLOWTAIL & LONGWING Open Label Extension (OLE) studies: Approximately 90% of patients who completed participation in Phase 1/2a studies of STK-001 enrolled in one of these OLE studies. Multiple doses of STK-001 up to 45mg given every 4 months were generally well tolerated. In addition to durable reductions in convulsive seizure frequency throughout the course of treatment, data indicated substantial improvements in multiple assessments of cognition and behavior over 12 months. These data support the potential for disease-modification with STK-001. PK Model for STK-001: A relationship between STK-001 brain exposures and convulsive seizure frequency was evaluated based on 72 patients treated in the Phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL OLE study in children and adolescents with Dravet syndrome. The exposure-seizure analysis demonstrated that higher STK-001 brain exposure leads to greater reductions in convulsive seizure frequency (R=-0.23, P<0.001). Details of the Company’s presentations can be found in the table below. All presentations are available for download on the Stoke Therapeutics website under the Investors & News tab. Title Presenter Date 24-Month Analysis of BUTTERFLY: A Prospective, Observational Study to Investigate Cognition and Other Non-seizure Comorbidities in Children & Adolescents with Dravet Syndrome (DS) Joseph Sullivan, M.D., FAES, Professor of Neurology and Pediatrics and Director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco Poster Number: 1.233 Saturday, Dec. 2 12:00 PM EST Oral Presentation: Monday, Dec. 4 3:15 PM EST MONARCH & ADMIRAL: Phase 1/2a Studies in US & UK Investigating Safety and Drug Exposure of STK-001, an Antisense Oligonucleotide (ASO), in Children & Adolescents with Dravet Syndrome (DS) Helen Cross, MB ChB, Ph.D., Professor, The Prince of Wales’s Chair of Childhood Epilepsy and Head of the Developmental Neuroscience Programme at University College London Great Ormond Street Institute of Child Health, Honorary Consultant in Paediatric Neurology, President of the International League Against Epilepsy Poster Number: 1.276 Saturday, Dec. 2 12:00 PM EST SWALLOWTAIL & LONGWING: Open-Label Extension (OLE) Studies for Children and Adolescents with Dravet Syndrome (DS) who Previously Participated in a Study of Antisense Oligonucleotide (ASO) STK-001 Archana Desurkar M.D., Consultant Paediatric Neurologist at Sheffield Children’s Hospital National Health Service Foundation Trust Poster Number: 1.279 Saturday, Dec. 2 12:00 PM EST Utilization of a Pharmacokinetic (PK) Model for STK-001 in Patients with Dravet Syndrome (DS) To Support Selection of Dosing Regimens in Clinic Meena, Ph.D., Senior Vice President of Translational DMPK and Clinical Pharmacology at Stoke Therapeutics Poster Number: 3.110 Monday, Dec. 4 12:00 PM EST About Dravet Syndrome Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life. Dravet syndrome is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, disruptions of the autonomic nervous system and mood disorders. The disease is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. There are no approved disease-modifying therapies for people living with Dravet syndrome. One out of 16,000 babies are born with Dravet syndrome, which is not concentrated in a particular geographic area or ethnic group. About STK-001 STK-001 is an investigational new medicine for the treatment of Dravet syndrome currently being evaluated in ongoing clinical trials. Stoke believes that STK-001, a proprietary antisense oligonucleotide (ASO), has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. STK-001 has been granted orphan drug designation by the FDA and the EMA, and rare pediatric disease designation by the FDA as a potential new treatment for Dravet syndrome. About the Phase 1/2a MONARCH Study (United States) The MONARCH study is a Phase 1/2a open-label study of children and adolescents ages 2 to 18 who have an established diagnosis of Dravet syndrome and have evidence of a genetic mutation in the SCN1A gene. The primary objectives for the study are to assess the safety and tolerability of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective is to assess the efficacy as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency. Stoke also intends to measure non-seizure aspects of the disease, such as quality of life, as secondary endpoints. Additional information about the MONARCH study can be found at . Patients who participated in the MONARCH study and meet study entry criteria are eligible to continue treatment in SWALLOWTAIL, an open-label extension (OLE) study designed to evaluate the long-term safety and tolerability of repeat doses of STK-001. We expect that SWALLOWTAIL will also provide valuable information on the preliminary effects of STK-001 on seizures along with non-seizure aspects of the disease, such as quality of life and cognition. Enrollment and dosing in SWALLOWTAIL are ongoing. About the Phase 1/2a ADMIRAL Study (United Kingdom) The ADMIRAL study is a Phase 1/2a open-label study of children and adolescents ages 2 to <18 who have an established diagnosis of Dravet syndrome and have evidence of a genetic mutation in the SCN1A gene. The primary objectives for the study are to assess the safety and tolerability of multiple doses of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective is to assess the effect of multiple doses of STK-001 as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency. Stoke also intends to measure non-seizure aspects of the disease, such as overall clinical status and quality of life, as secondary endpoints. Patients who participated in the ADMIRAL study and meet study entry criteria are eligible to continue treatment in LONGWING, an open-label extension (OLE) study designed to evaluate the long-term safety and tolerability of repeat doses of STK-001. We expect that LONGWING will also provide valuable information on the preliminary effects of STK-001 on seizures along with non-seizure aspects of the disease, such as quality of life and cognition. Enrollment and dosing in LONGWING are ongoing. About the BUTTERFLY Observational Study The BUTTERFLY study is a multicenter, longitudinal, prospective, observational study of children and adolescents ages 2 to 18 who have been diagnosed with Dravet syndrome as a result of an SCN1A gene mutation. This observational study was designed to evaluate neurodevelopmental status and change from baseline to 24 months. Secondary and exploratory endpoints in the study evaluated changes in other disease measures, including seizures and additional non-seizure comorbidities. No investigational medications or other treatments were provided. Participants continued to receive their usual care, including anti-seizure medications, and were observed by a team of doctors and nurses over time for up to two years. The study was conducted at approximately 20 sites in the United States. 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 Stoke’s proprietary TANGO (Targeted Augmentation of Nuclear Gene Output) approach, Stoke is developing antisense oligonucleotides (ASOs) to selectively restore protein levels. Stoke’s 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 the development of STK-002 for the treatment of autosomal dominant optic atrophy (ADOA), the most common inherited optic nerve disorder. Stoke’s 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 or follow Stoke on X @StokeTx. 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 the ability of STK-001 to treat the underlying causes of Dravet syndrome and reduce seizures or show improvements in non-seizure comorbidities at the indicated dosing levels or at all, and the timing and presentation of data at AES 2023. Statements including words such as “plan,” “will,” “continue,” “expect,” 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 prove incorrect or do not fully materialize, could cause our results to differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, risks and uncertainties related to: the Company’s ability to advance, obtain regulatory approval of and ultimately commercialize its product candidates; the timing and results of preclinical and clinical trials; the risk that positive results in a clinical trial may not be replicated in subsequent trials or successes in early stage clinical trials may not be predictive of results in later stage trials and preliminary interim data readouts of ongoing trials may show results that change when such trials are completed; the Company’s ability to fund development activities and achieve development goals; the Company’s ability to protect its intellectual property; and other risks and uncertainties described under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, its quarterly reports on Form 10-Q, and the other 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.

STK-001: Q1 2024 readout expected to include end of Phase 1/2a study results and longer-term data on the effects of repeat dosing on seizure frequency, cognition, and behavior from the ongoing open-label extension (OLE) studies STK-001: Company then plans to meet with regulators to discuss a Phase 3 study design; Update expected in 1H 2024 As of September 30, 2023, Company had $214.7 million in cash, cash equivalents and marketable securities, anticipated to fund operations to the end of 2025 BEDFORD, Mass.--(BUSINESS WIRE)-- Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company dedicated to addressing the underlying cause of severe diseases by upregulating protein expression with RNA-based medicines, today reported financial results for the third quarter of 2023 and provided business updates including those related to STK-001, the Company’s proprietary antisense oligonucleotide (ASO) which is in development by Stoke as the first potential medicine to address the genetic cause of Dravet syndrome. “Our recent data analyses from studies of STK-001 showed substantial and sustained reductions in convulsive seizure frequency among patients with Dravet syndrome who were already receiving the best available anti-seizure medicines,” said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. “Even more striking are the observed improvements in multiple measures of cognition and behavior, which have not been seen in studies of the current standard of care. These data, along with encouraging feedback from clinicians, support our belief that STK-001 is a disease-modifying approach that is moving treatment beyond seizure management to address the syndrome. We are on track to complete the Phase 1/2a studies by year-end and will use those data along with additional OLE data to support our proposed Phase 3 dosing regimen for discussion with global regulatory agencies.” Third Quarter 2023 Business Highlights and Recent Developments Dravet Syndrome: STK-001 In July, the Company shared positive new safety and efficacy data from the ongoing studies of STK-001 in children and adolescents with Dravet syndrome that suggest clinical benefit for patients ages 2 to 18 years old, including reductions in seizures and improvements in cognition and behavior that support the potential for disease modification. Single and multiple doses of STK-001 up to 70mg have been generally well tolerated. In September at the 35th International Epilepsy Congress, the Company presented a new pharmacokinetic (PK) analysis of 61 patients treated in STK-001 clinical trials, demonstrating a correlation between higher STK-001 drug exposure in brain and greater reductions in seizure frequency over time. Upcoming Anticipated Milestones Dravet Syndrome: STK-001 The Company plans to present data from the ongoing clinical studies at the American Epilepsy Society (AES) December 1-5, 2023, in Orlando, Fla. In the first quarter of 2024, the Company plans to report additional clinical and modeling data from patients treated in the Phase 1/2a studies MONARCH and ADMIRAL and the two open-label extension studies (OLE) SWALLOWTAIL and LONGWING of STK-001 in children and adolescents with Dravet syndrome. These data are anticipated to help finalize a proposed pivotal study design for discussion with regulators. Following an analysis of these data, the Company plans to meet with regulators to discuss a Phase 3 study design. An update on Phase 3 planning is anticipated in the first half of 2024. Autosomal Dominant Optic Atrophy (ADOA): STK-002 The Company plans to initiate the Phase 1 study (OSPREY) of STK-002 in the UK in early 2024. Third Quarter 2023 and Year-to-Date Financial Results As of September 30, 2023, Stoke had $214.7 million in cash, cash equivalents, and marketable securities, which is anticipated to fund operations to the end of 2025. Revenue recognized for upfront license fees and services provided from a License and Collaboration Agreement with Acadia Pharmaceuticals for the three months ended September 30, 2023, was $3.3 million, compared to $2.9 million for the same period in 2022. Net loss for the three months ended September 30, 2023, was $24.5 million, or $0.55 per share, compared to $26.1 million, or $0.66 per share, for the same period in 2022. Research and development expenses for the three months ended September 30, 2023, were $20.3 million, compared to $20.1 million for the same period in 2022. General and administrative expenses for the three months ended September 30, 2023, were $10.3 million, compared to $9.9 million for the same period in 2022. Revenue recognized for upfront license fees and services provided from a License and Collaboration Agreement for the nine months ended September 30, 2023, was $6.0 million, compared to $9.1 million for the same period in 2022. Net loss for the nine months ended September 30, 2023, was $77.7 million, or $1.78 per share, compared to $75.4 million, or $1.95 per share, for the same period in 2022. Research and development expenses for the nine months ended September 30, 2023, were $60.5 million, compared to $56.8 million for the same period in 2022. General and administrative expenses for the nine months ended September 30, 2023, were $30.7 million, compared to $29.5 million for the same period in 2022. The increase in operating expenses for the three and nine months ended September 30, 2023 over the same periods in 2022 primarily relate to increases in costs associated with personnel, third party contracts, consulting, facilities and others associated with development activities for STK-001 and STK-002, research on additional therapeutics and growing a public corporation. About Dravet Syndrome Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life. Dravet syndrome is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, disruptions of the autonomic nervous system and mood disorders. The disease is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. There are no approved disease-modifying therapies for people living with Dravet syndrome. One out of 16,000 babies are born with Dravet syndrome, which is not concentrated in a particular geographic area or ethnic group. About STK-001 STK-001 is an investigational new medicine for the treatment of Dravet syndrome currently being evaluated in ongoing clinical trials. Stoke believes that STK-001, a proprietary antisense oligonucleotide (ASO), has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. STK-001 has been granted orphan drug designation by the FDA and the EMA, and rare pediatric disease designation by the FDA as a potential new treatment for Dravet syndrome. About the Phase 1/2a MONARCH Study (United States) The MONARCH study is a Phase 1/2a open-label study of children and adolescents ages 2 to 18 who have an established diagnosis of Dravet syndrome and have evidence of a genetic mutation in the SCN1A gene. The primary objectives for the study are to assess the safety and tolerability of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective is to assess the efficacy as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency. Stoke also intends to measure non-seizure aspects of the disease, such as quality of life, as secondary endpoints. Additional information about the MONARCH study can be found at . Patients who participated in the MONARCH study and meet study entry criteria are eligible to continue treatment in SWALLOWTAIL, an open-label extension (OLE) study designed to evaluate the long-term safety and tolerability of repeat doses of STK-001. We expect that SWALLOWTAIL will also provide valuable information on the preliminary effects of STK-001 on seizures along with non-seizure aspects of the disease, such as quality of life and cognition. Enrollment and dosing in SWALLOWTAIL are ongoing. About the Phase 1/2a ADMIRAL Study (United Kingdom) The ADMIRAL study is a Phase 1/2a open-label study of children and adolescents ages 2 to <18 who have an established diagnosis of Dravet syndrome and have evidence of a genetic mutation in the SCN1A gene. The primary objectives for the study are to assess the safety and tolerability of multiple doses of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective is to assess the effect of multiple doses of STK-001 as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency. Stoke also intends to measure non-seizure aspects of the disease, such as overall clinical status and quality of life, as secondary endpoints. Patients who participated in the ADMIRAL study and meet study entry criteria are eligible to continue treatment in LONGWING, an open-label extension (OLE) study designed to evaluate the long-term safety and tolerability of repeat doses of STK-001. We expect that LONGWING will also provide valuable information on the preliminary effects of STK-001 on seizures along with non-seizure aspects of the disease, such as quality of life and cognition. Enrollment and dosing in LONGWING are ongoing. About Autosomal Dominant Optic Atrophy (ADOA) Autosomal dominant optic atrophy (ADOA) is the most common inherited optic nerve disorder. It is a rare disease that causes progressive and irreversible vision loss in both eyes starting in the first decade of life. Severity can vary and the rate of vision loss can be difficult to predict. Roughly half of people with ADOA fail driving standards and up to 46% are registered as legally blind. More than 400 OPA1 mutations have been reported in people diagnosed with ADOA. Currently there is no approved treatment for people living with ADOA. ADOA affects approximately one in 30,000 people globally with a higher incidence in Denmark of one in 10,000 due to a founder effect. About STK-002 STK-002 is a proprietary antisense oligonucleotide (ASO) in preclinical development for the treatment of Autosomal Dominant Optic Atrophy (ADOA). Approximately 80% of individuals with ADOA experience symptoms before age 10, typically beginning between the ages of 4 and 6. Stoke believes that STK-002 has the potential to be the first disease-modifying therapy for people living with ADOA. An estimated 65% to 90% of cases are caused by mutations in the OPA1 gene, most of which lead to a haploinsufficiency resulting in 50% OPA1 protein expression and disease manifestation. STK-002 is designed to upregulate OPA1 protein expression by leveraging the non-mutant (wild-type) copy of the OPA1 gene to restore OPA1 protein expression with the aim to stop or slow vision loss in patients with ADOA. Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-002. STK-002 has been granted orphan drug designation by the FDA as a potential new treatment for ADOA and the company has received authorization of its CTA from the MHRA. About the Phase 1 OSPREY Study (United Kingdom) The OSPREY study is a Phase 1 open-label study of children and adults ages 6 to 55 who have an established diagnosis of ADOA and have evidence of a genetic mutation in the OPA1 gene. The primary objectives for the study are to assess the safety and tolerability of single ascending doses of STK-002, as well as to determine the exposure in blood. A secondary objective is to assess efficacy following intravitreal (IVT) administration of STK-002 in one eye of each patient as measured by changes in visual function and ocular structure as well as quality of life in patients with ADOA. Enrollment and dosing are anticipated to begin in early 2024. About the FALCON Study FALCON is a multicenter, prospective natural history study of people ages 8 to 60 who have an established clinical diagnosis of ADOA that is caused by a heterozygous OPA1 gene variant. No investigational medications or other treatments will be provided. The study enrolled 48 patients across 10 sites in the U.S., U.K., Italy and Denmark. Patients undergo assessments at baseline, 6 months, 12 months, 18 months, and 24 months. There will be no additional follow-up period. About TANGO TANGO (Targeted Augmentation of Nuclear Gene Output) is Stoke’s proprietary research platform. Stoke’s 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 Stoke’s proprietary TANGO (Targeted Augmentation of Nuclear Gene Output) approach, Stoke is developing antisense oligonucleotides (ASOs) to selectively restore protein levels. Stoke’s 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 the development of STK-002 for the treatment of autosomal dominant optic atrophy (ADOA), the most common inherited optic nerve disorder. Stoke’s 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 or follow Stoke on X @StokeTx. 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: the Company’s quarterly results and cash runway; its future operating results, financial position and liquidity; the ability of STK-001 to treat the underlying causes of Dravet syndrome and reduce seizures or show improvements in behavior or cognition; the ability of STK-002 to treat the underlying causes of ADOA; the timing and expected progress of clinical trials, data readouts and presentations; the timing or receipt of regulatory interactions or approvals; the ability of TANGO to design medicines to increase protein production and the expected benefits thereof. Statements including words such as “plan,” “will,” “continue,” “expect,” 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 prove incorrect or do not fully materialize, could cause our results to differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, 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; positive results in a clinical trial may not be replicated in subsequent trials or successes in early stage clinical trials may not be predictive of results in later stage trials; preliminary interim data readouts of ongoing trials may show results that change when such trials are completed; the Company’s ability to fund development activities and achieve development goals to the end of 2025; the Company’s ability to protect its intellectual property; and other risks and uncertainties described under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, its quarterly reports on Form 10-Q, and the other 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. Financial Tables Follow Stoke Therapeutics, Inc. Consolidated balance sheets (in thousands, except share and per share amounts) (unaudited) September 30, December 31, 2023 2022 Assets Current assets: Cash and cash equivalents $ 189,977 $ 113,556 Marketable securities 24,741 116,039 Prepaid expenses 10,936 10,932 Other current assets 4,269 2,955 Interest receivable 96 588 Total current assets $ 230,019 $ 244,070 Restricted cash 569 569 Operating lease right-of-use assets 3,084 4,753 Property and equipment, net 6,217 6,675 Total assets $ 239,889 $ 256,067 Liabilities and stockholders’ equity Current liabilities: Accounts payable $ 3,076 $ 766 Accrued and other current liabilities 13,390 15,748 Deferred revenue - current portion 8,735 14,880 Total current liabilities $ 25,201 $ 31,394 Deferred revenue - net of current portion 40,730 36,856 Other long term liabilities 959 2,968 Total long term liabilities 41,689 39,824 Total liabilities $ 66,890 $ 71,218 Stockholders’ equity Common stock, par value of $0.0001 per share; 300,000,000 shares authorized, 44,293,115 and 39,439,575 shares issued and outstanding as of September 30, 2023 and December 31, 2022, respectively 4 4 Additional paid-in capital 548,033 483,170 Accumulated other comprehensive loss (147 ) (1,175 ) Accumulated deficit (374,891 ) (297,150 ) Total stockholders’ equity $ 172,999 $ 184,849 Total liabilities and stockholders’ equity $ 239,889 $ 256,067 Stoke Therapeutics, Inc. Consolidated statements of operations and comprehensive loss (in thousands, except share and per share amounts) (unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2023 2022 2023 2022 Revenue $ 3,308 $ 2,905 $ 5,978 $ 9,137 Operating expenses: Research and development 20,271 20,109 60,453 56,777 General and administrative 10,271 9,944 30,712 29,540 Total operating expenses 30,542 30,053 91,165 86,317 Loss from operations (27,234 ) (27,148 ) (85,187 ) (77,180 ) Other income: Interest income (expense), net 2,651 995 7,321 1,643 Other income (expense), net 41 42 125 125 Total other income 2,692 1,037 7,446 1,768 Net loss $ (24,542 ) $ (26,111 ) $ (77,741 ) $ (75,412 ) Net loss per share, basic and diluted $ (0.55 ) $ (0.66 ) $ (1.78 ) $ (1.95 ) Weighted-average common shares outstanding, basic and diluted 44,266,017 39,420,310 43,669,987 38,716,615 Comprehensive loss: Net loss $ (24,542 ) $ (26,111 ) $ (77,741 ) $ (75,412 ) Other comprehensive gain (loss): Unrealized gain (loss) on marketable securities 232 (427 ) 1,028 (1,535 ) Total other comprehensive loss $ 232 $ (427 ) $ 1,028 $ (1,535 ) Comprehensive loss $ (24,310 ) $ (26,538 ) $ (76,713 ) $ (76,947 ) View source version on businesswire.com: Contacts Stoke Media & Investor Contacts: Dawn Kalmar Chief Communications Officer dkalmar@stoketherapeutics.com 781-303-8302 Eric Rojas Vice President, Investor Relations IR@stoketherapeutics.com 617-312-2754 Source: Stoke Therapeutics, Inc. 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