SYNGAP1

Neuroscientists say they have found a new function for the SYNGAP1 gene, a DNA sequence that controls memory and learning in mammals, including mice and humans. Johns Hopkins Medicine neuroscientists say they have found a new function for the SYNGAP1 gene, a DNA sequence that controls memory and learning in mammals, including mice and humans. The finding, published March 1 in Science, may affect the development of therapies designed for children with SYNGAP1 mutations, who have a range of neurodevelopmental disorders marked by intellectual disability, autistic-like behaviors, and epilepsy. In general, SYNGAP1, as well as other genes, control learning and memory by making proteins that regulate the strength of synapses -- the connections between brain cells. Previously, the researchers say, the SYNGAP1 gene was thought to work exclusively by encoding a protein that behaves like an enzyme, regulating chemical reactions that lead to changes in the strength of synapses. Now, the scientists say, their experiments in mice show that protein encoded by the gene may also function more like a so-called scaffolding protein that regulates synaptic plasticity, or how synapses get stronger or weaker over time, independent of its enzyme activity. The SynGAP protein appears to act as a traffic manager, they say, directing where and what brain proteins are at synapses. With his team, Richard Huganir, Ph.D., Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences and director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine, first isolated the SYNGAP1 gene in 1998. SynGAP proteins are very abundant at the synapse, says Huganir, and it has long been thought that SynGAP's main role was to spark enzymatic chemical reactions that regulate synapse strength. But, working with the SynGAP protein, Huganir and others had begun to see that SynGAP proteins have a strange property when they interact with the major synaptic scaffolding protein, PSD-95. They morph into liquid droplets. "For an enzymatic protein, that structural transformation is unusual," says Huganir. To tease out and understand the purpose of SynGAP's peculiar liquid transformation, Huganir, neuroscience instructor Yoichi Araki and Huganir's research team at Johns Hopkins designed experiments in neurons in which they inserted mutations in the so-called GAP domain of the SYNGAP1 gene that would remove the enzymatic function of SynGAP without affecting its structure. The Johns Hopkins team found that, even without the enzymatic activity, the synapse worked normally, suggesting that the structural property alone is very important for SynGAP function. The research team next did the same type of genetic engineering in mice to remove the enzymatic function of SynGAP, and found similar results: Synapses behaved normally, with no problems in synaptic plasticity, and the mice had no difficulty in learning and memory behaviors. The research team says this indicates that SynGAP's structural property was sufficient for normal cognitive behavior. To understand how SynGAP's structure regulates synapses, the scientists analyzed synapses more closely to find that SynGAP protein competed with the binding of AMPA receptor/TARP complexes, a bundle of neurotransmitter proteins that strengthens synapses, and the PSD-95 scaffolding protein. The experiments suggest that, at rest, SynGAP tightly binds to PSD-95, not allowing it to bind to any other proteins in the synapse. However, during synaptic plasticity, learning and memory, SynGAP protein disconnected from PSD-95, left the synapse and allowed neurotransmitter receptor complexes to bind to PSD-95. This made the synapse stronger and increased transmission between brain cells. "This sequence happens without the catalytic activity typical of SynGAP," says Huganir. Rather, SynGAP corrals PSD-95 when bound to it, but when SynGAP leaves this synapse, PSD-95 is open to bind to AMPA receptor/TARP complexes. In children with SynGAP mutations, about half the number of SynGAP proteins are in the synapse. With fewer SynGAP proteins, PSD-95 may bind more with the AMPA receptor/TARP complexes, changing neuronal connections and creating the increased brain cell activity characteristic of epileptic seizures common among children with SynGAP mutations. Huganir says that both functions of SynGAP -- enzymatic and the "traffic management" action of a scaffolding protein -- may now be important in finding treatments for SynGAP-related neurodevelopmental disorders. Their research also suggests that targeting just one function of SynGAP alone may not be enough to have a significant impact. In addition to Araki and Huganir, Johns Hopkins scientists who authored the report on the research are Kacey Rajkovich, Elizabeth Gerber, Timothy Gamache, Richard Johnson, Thanh Hai Tran, Bian Liu, Qianwen Zhu, Ingie Hong and Alfredo Kirkwood. Funding for the research was provided by the National Institutes of Health (R01MH112151, R01NS036715, T32MH015330) and the SynGAP Research Fund.

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.

BOSTON, Nov. 28, 2023 (GLOBE NEWSWIRE) -- Praxis Precision Medicines, Inc. (NASDAQ: PRAX), a clinical-stage biopharmaceutical company translating genetic insights into the development of therapies for central nervous system (CNS) disorders characterized by neuronal excitation-inhibition imbalance, today announced that it will deliver presentations on its epilepsy programs at the following upcoming meetings in Orlando, Florida. Presentations at the American Epilepsy Society (AES) Annual Meeting, as well as related scientific and patient advocacy meetings, will cover new patient data, updates on clinical progress and new paradigms for developing epilepsy therapies. AES Annual Meeting, being held December 1-5, 2023Behind the Seizure (BTS) Scientific Exhibit, being held on December 3, 2023Partners Against Mortality in Epilepsy (PAME) Conference, being held on November 30, 2023SYNGAP1 Conference, being held on November 30, 2023The Cute Syndrome Foundation (TCSF) SCN8A Clinician, Researcher, and Family Gathering, being held on December 1, 2023 “It’s an incredibly exciting time for Praxis and our epilepsy portfolio, as we share updates from first-in-patient and Phase 2 studies for elsunersen (PRAX-222), PRAX-562 and PRAX-628,” said Marcio Souza, president and chief executive officer of Praxis. “We look forward to presenting data spanning our Solidus and Cerebrum platforms at AES and related meetings in Florida, with presentations also set to highlight novel approaches to define efficient preclinical models and sensitive biomarkers for accelerating drug development for the patient populations we are seeking to serve. Our epilepsy programs have the potential to significantly impact the lives of patients and their families, and we are grateful for the opportunity to discuss these programs with the epilepsy community at multiple important meetings this week.” Praxis at AES 2023 | Orange County Convention Center Meet us at booth #421 to learn about the largest pipeline of precision epilepsy programs Head to one of our presentations listed below or visit us at the BTS Scientific Exhibit on December 3, 08:00 a.m. - 11:00 a.m. ET EMBRAVE: A Clinical Trial of PRAX-222, a Novel Antisense Oligonucleotide, in Pediatric Participants with Early Onset SCN2A Developmental and Epileptic Encephalopathy Session Date/Time: Monday, December 4, 12:00 p.m. - 2:00 p.m. ETAbstract number: 3.198Summary: Preliminary results from Part 1 of the EMBRAVE study demonstrate elsunersen tolerability and unprecedented efficacy, highlighting its potential to be the first disease-modifying treatment in early onset SCN2A developmental and epileptic encephalopathy (SCN2A-DEE). PRAX-628 is a Next Generation, Functionally Selective Small Molecule with Potent Anti-Seizure Activity and Potential as Best-in-Class Treatment for Focal Epilepsy Session Date/Time: Monday, December 4, 12:00 p.m. - 2:00 p.m. ET; platform talk at 5:00 p.m. ET [Platform D | Epilepsy Therapies] Abstract number: 3.258Summary: Combined preclinical and clinical data demonstrate PRAX-628 is differentiated from standard of care, with the potential to be best-in-class for focal epilepsy. In vivo studies demonstrate unprecedented potent anticonvulsant activity in the maximal electroshock seizure (MES) model, a highly predictive translational model for efficacy in focal epilepsy, while first-in-human findings demonstrate that PRAX-628 is well tolerated at exposures >15x the predicted efficacious exposure from mouse MES. A Novel Method to Define an EEG Composite for the Detection of Drug Effects of Next Generation Small Molecules for Epilepsy Session Date/Time: Monday, December 4, 12:00 p.m. - 2:00 p.m. ETAbstract number: 3.455Summary: Application of machine learning methods to complex EEG data has the potential to accelerate drug development in epilepsy by revealing pharmacodynamic effects of novel agents that are clearly distinguishable from placebo. In this study, we demonstrate applicability of a quantitative EEG composite to three distinct next generation small molecules, with expected generalizability to any small molecule, independent of class/target. Translational Concordance of Preclinical Seizure Models in Focal and Generalized Epilepsies Session Date/Time: Monday, December 4, 12:00 p.m. - 2:00 p.m. ETAbstract number: 3.458Summary: This study provides novel insights into the clinical validity of commonly used preclinical seizure models across the clinical epilepsy spectrum. Using a newly developed scoring matrix to assess translational concordance and predictability, mouse MES, audiogenic and 6-Hz 32 mA emerge as three acute seizure models with greatest predictive validity and versatility for ASM drug discovery. Praxis at PAME 2023 | Rosen Centre Hotel EMBRAVE: A Clinical Trial of PRAX-222, a Novel Antisense Oligonucleotide, in Pediatric Participants with Early Onset SCN2A Developmental and Epileptic Encephalopathy Session Date/Time: Thursday, November 30, 5:00 p.m. - 6:30 p.m. ETPoster number: 32Summary: Preliminary results from Part 1 of the EMBRAVE study demonstrate elsunersen tolerability and unprecedented efficacy, highlighting its potential to be the first disease-modifying treatment in early onset SCN2A-DEE. EMBOLD: A Clinical Trial of PRAX-562 in Subjects with Developmental and Epileptic Encephalopathies Followed by an Open-Label Extension Session Date/Time: Thursday, November 30, 5:00 p.m. - 6:30 p.m. ETPoster number: 38Summary: EMBOLD is the first and only DEE trial to offer a decentralized clinical trial option, balancing clinical rigor with flexibility and convenience for participants and their families. EMBOLD will provide important findings regarding the safety, tolerability, efficacy and pharmacokinetics of PRAX-562 as a potential first- and best-in-class treatment for pediatric patients with SCN2A-DEE and SCN8A-DEE. Praxis at SYNGAP1 2023 | Embassy Suites Hotel Progress Toward the Discovery of an ASO for Therapeutic Upregulation of SYNGAP1 Session Date/Time: Thursday, November 30, 1:30 p.m. - 1:45 p.m. ET | Session 4: Therapeutic Strategies to Fix SYNGAP1Oral presentation highlighting preclinical updates from our SYNGAP1 ASO platform at the annual scientific conference hosted by the SYNGAP Research Fund Praxis at TCSF 2023 | Sheraton Orlando Lake Buena Vista Resort PRAX-562: Reflection and Direction on a Next Generation Anti-Seizure Small Molecule in Development for SCN8A-DEE Session Date/Time: Friday, December 1, 6:15 p.m. ETOral presentation highlighting clinical updates from our PRAX-562 small molecule platform at the annual clinician, researcher, and family gathering for SCN8A About elsunersen (PRAX-222)Elsunersen is an ASO designed to selectively decrease SCN2A gene expression, directly targeting the underlying cause of early-seizure-onset SCN2A-DEE to treat seizures and other symptoms in patients with gain-of-function SCN2A mutations. In vitro studies of elsunersen have demonstrated reduction in both SCN2A gene expression and protein levels. In vivo, elsunersen has demonstrated significant, dose-dependent reduction in seizures, improvement in behavioral and locomotor activity and increased survival in SCN2A mouse models, with potential to be the first disease-modifying treatment for SCN2A-DEE. Elsunersen has received Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation (RPD) from the FDA, and ODD and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA) for the treatment of SCN2A-DEE. The elsunersen program is ongoing under a collaboration with Ionis Pharmaceutics, Inc., and RogCon, Inc. About PRAX-562PRAX-562 is a first-in-class small molecule in development for the treatment of DEE as a preferential inhibitor of persistent sodium current, shown to be a key driver of seizure symptoms in early onset SCN2A-DEE and SCN8A-DEE. PRAX-562’s mechanism of sodium channel block is consistent with superior selectivity for disease state sodium channel (NaV) channel hyperexcitability. In vivo studies of PRAX-562 have demonstrated dose-dependent inhibition of seizures up to complete control of seizure activity in SCN2A, SCN8A and other DEE mouse models. PRAX-562 has been generally well-tolerated in three Phase 1 studies and has demonstrated biomarker changes indicative of NaV channel blocking effects. PRAX-562 has received ODD and RPD from the FDA, and ODD from the European Medicines Agency for the treatment of SCN2A-DEE and SCN8A-DEE. To learn more about the EMBOLD study, please visit https://www.emboldstudy.org/. About PRAX-628PRAX-628 is a next-generation, functionally selective small molecule targeting the hyperexcitable state of sodium-channels in the brain that is currently being developed as a once daily, oral treatment for adult focal onset epilepsy. Preclinical data demonstrates PRAX-628 is differentiated from standard of care, with the potential to be best-in-class for focal epilepsy. In vitro, PRAX-628 has demonstrated superior selectivity for disease-state NaV channel hyperexcitability. In vivo studies of PRAX-628 have demonstrated unprecedented potency in the maximal electroshock seizure (MES) model, a highly predictive translational model for efficacy in focal epilepsy. Data from the PRAX-628-101 study demonstrated that PRAX-628 can be safely dosed in healthy subjects to greater than 15 times the predicted human equivalent of the rodent MES EC50. About SCN2A-DEESCN2A-DEE is a debilitating monogenic epilepsy disorder caused by a variant in the SCN2A gene, associated with early mortality. The SCN2A gene is critical in the formation of sodium channel proteins in the brain, which control the flow of sodium ions into neurons. This movement of sodium ions is a major component of generating electrical signals called action potentials, the way in which the cells communicate. SCN2A-DEE is characterized by a broad spectrum of phenotypes. Early-onset SCN2A-DEE presents before three months and can lead to profound impact on patients, including drug-resistant seizures, significant cognitive impairment, movement disorders such as dystonia or ataxia and problems in other body systems such as gastrointestinal or ocular. Currently there are no approved treatments for SCN2A-DEE, and the standard-of-care typically involves a regimen of many concurrent anti-seizure medications as well as medications to manage co-morbidities. Despite these interventions, more than 70% of early-onset SCN2A-DEE patients live with uncontrolled seizures, and approximately 75% live with severe intellectual disability with patients rarely surviving beyond their teenage years. About SCN8A-DEESCN8A-DEE is a rare developmental and epileptic encephalopathy caused by a variant in the SCN8A gene. The SCN8A gene is critical in the formation of sodium channel proteins in the brain, which control the follow of sodium ions into neurons. This movement of sodium ions is a major component of generating electrical signals called action potentials, the way in which the cells communicate. Patients suffer from recurrent, typically drug-resistant seizures which start as early as the first day of life. The seizures can be of multiple different types, up to dozens per day, with poor response to current treatment options. Patients with SCN8A-DEE have significant cognitive disabilities, ranging from moderate to severe; often movement disorders, such as dystonia or ataxia; and problems in other body systems such as gastrointestinal or ocular. SCN8A-DEE patients also may experience autonomic features such as increases or decreases in heart rate, abnormal breathing and cyanosis. About PraxisPraxis Precision Medicines is a clinical-stage biopharmaceutical company translating insights from genetic epilepsies into the development of therapies for CNS disorders characterized by neuronal excitation-inhibition imbalance. Praxis is applying genetic insights to the discovery and development of therapies for rare and more prevalent neurological disorders through our proprietary small molecule platform, Cerebrum™, and antisense oligonucleotide (ASO) platform, Solidus™, using our understanding of shared biological targets and circuits in the brain. Praxis has established a diversified, multimodal CNS portfolio including multiple programs across movement disorders and epilepsy, with four clinical-stage product candidates. For more information, please visit www.praxismedicines.com and follow us on Facebook, LinkedIn and Twitter/X. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws, including express or implied statements regarding Praxis’ future expectations, plans and prospects, including, without limitation, statements regarding the development of our product candidates, including the design of clinical trials and the treatment potential of Praxis’ product candidates, as well as other statements containing the words “anticipate,” “believe,” “continue,” “could,” “endeavor,” “estimate,” “expect,” “anticipate,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “seek,” “should,” “target,” “will” or “would” and similar expressions that constitute forward-looking statements under the Private Securities Litigation Reform Act of 1995. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation: uncertainties inherent in clinical trials; reported interim data from ongoing studies and trials differing materially from final data from preclinical studies and completed clinical trials; the expected timing of clinical trials, data readouts and the results thereof, and submissions for regulatory approval or review by governmental authorities; regulatory approvals to conduct trials; Praxis’ anticipated cash runway; and other risks concerning Praxis’ programs and operations as described in its Annual Report on Form 10-K for the year ended December 31, 2022, its Quarterly Reports on Form 10-Q and other filings made with the Securities and Exchange Commission. Although Praxis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on information and factors currently known by Praxis. As a result, you are cautioned not to rely on these forward-looking statements. Any forward-looking statement made in this press release speaks only as of the date on which it is made. Praxis undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.