Encoded Therapeutics, Inc.

Four presentations highlight expansion of the company’s CNS pipeline and vector engineering platform Preclinical data presented supports potential to advance programs in Angelman Syndrome and Lennox-Gastaut Syndrome Proof-of-concept data demonstrating knock-down of neuropathic pain (SCN9A) and Alzheimer’s disease (MAPT) targets showcase advancements in the company’s vector engineering platform SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Encoded Therapeutics Inc., a biotechnology company developing genetic medicines for severe central nervous system (CNS) disorders, today highlights oral and poster presentations on the Company’s preclinical gene therapy programs and vector engineering platform at the 27th ASGCT Annual Meeting being held May 7 – 11, 2024 in Baltimore, MD. “We are thrilled to share multiple advancements across our portfolio of precision genetic medicines, showcasing substantial progress across various fronts. These data underscore our platform’s potential to deliver precision therapies for a range of CNS diseases,” said Stephanie Tagliatela, Chief Scientific Officer at Encoded. “Alongside clinical advancement of our lead program, ETX101 for SCN1A+ Dravet syndrome, we are poised to nominate multiple programs to development in 2025, marking yet another significant milestone.” Oral Presentation Title: GABA Selective AAV-mediated Gene Therapy Provides Durable Seizure Protection in Multiple Refractory Epilepsy Models (Abstract #19) Session: AAV Vectors - Preclinical and Proof-of-Concept: Therapy Focus Date & Time: Tuesday, May 7, 1:45–2:00 p.m. ET Location: Ballroom 2 Epilepsy affects approximately 1% of the population, with nearly one third of cases failing to respond to first- and second-line treatments. Encoded’s vector engineering platform has enabled the development of GABA-selective AAV-mediated gene therapies designed to potentiate GABAergic neurotransmission and modulate the circuit dysfunction underlying refractory epilepsies. Our lead candidate reduced seizure incidence and severity in two biologically distinct seizure assays with no adverse impact on body weight, motor function or locomotion. Furthermore, the top candidate is well-tolerated in non-human primates (NHP) even at high doses. These data support further development of our candidate gene therapy for the treatment for refractory epilepsies. Poster Presentations Title: Advancing Gene Therapy for STXBP1-related Disorders Through Targeted Vector Engineering: Efficacy and Safety Results in Mice and Non-Human Primates (Abstract #508) Date & Time: Wednesday, May 8, 5:30–7:00 p.m. ET Location: Exhibit Hall STXBP1-related disorders (STXBP1-RD) result from loss-of-function variants in STXBP1, causing severe developmental delay and treatment-resistant epilepsy. Encoded has engineered AAV9 vectors that drive potent expression within CNS tissue while reducing off-target expression in dorsal root ganglia (DRG) and non-neuronal tissues. These engineered AAV9-STXBP1 vectors achieved robust, dose-dependent improvements in seizure, cognitive, and motor phenotypes in Stxbp1+/- mice, with no observed dose-limiting toxicity. In NHPs, the engineered vectors showed strong CNS expression and were well-tolerated. Furthermore, the inclusion of a DRG de-targeting element reduced expression within the DRG and spinal cord by >10-fold, ameliorating microscopic DRG-related findings. These findings establish proof-of-concept for an AAV9-based gene therapy for STXBP1-RD and support the use of modular regulatory element engineering to drive desired expression profiles within the CNS. Title: A Vectorized miRNA-based Approach to Unsilence UBE3A in Angelman Syndrome (Abstract #1125) Date & Time: Thursday, May 9, 5:30–7:00 p.m. ET Location: Exhibit Hall Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by intellectual disability, ataxia, and seizures. AS is caused by loss-of-function of the maternally-inherited UBE3A gene. Unsilencing of the paternal copy of UBE3A has the potential address the underlying cause of the disease while mitigating the risk of UBE3A overexpression-related toxicity. We demonstrated that an AAV-based miRNA vector was capable of upregulating paternal UBE3A and correcting multiple phenotypes in the AS mouse model. Encoded’s lead miRNA candidate was well-tolerated in NHPs and demonstrated potent unsilencing of paternal UBE3A in critical brain regions. Collectively, these data support further development an AAV-based miRNA treatment approach for Angelman Syndrome. Title: Identification of Potent and Selective AAV-miRNA Candidates to Knockdown Non-Monogenic Neurological Targets SCN9A (Pain) and MAPT (Tauopathies) (Abstract #1601) Date & Time: Friday, May 10, 5:30–7:00 p.m. ET Location: Exhibit Hall Encoded's innovative AAV-mediated miRNA platform offers a promising strategy for long-term knockdown of target genes in the central and peripheral nervous systems. We identified potent and target-specific miRNA candidates to effectively knock down two clinically relevant, non-monogenic neuronal targets: SCN9A and MAPT. SCN9A encodes the NaV1.7 sodium channel, which is associated with pain sensation, while MAPT encodes the microtubule protein, Tau, which is implicated in Alzheimer's disease neuropathology. Encoded's miRNA candidates demonstrated potent, dose-dependent, and selective knockdown of SCN9A in human iPSC sensory neurons and in mouse dorsal root ganglion sensory neurons, establishing proof-of-concept for miRNA-based inhibition of NaV1.7. Similarly, MAPT candidates significantly reduced Tau protein levels in vitro and in vivo. These findings support advancement of SCN9A and MAPT candidates to NHP studies and showcase the potential of vectorized miRNA knockdown as a promising treatment avenue for various neurological disorders. About Encoded Therapeutics Encoded Therapeutics is a clinical-stage genetic medicines company developing potentially disease-modifying therapies to improve the lives of people with severe CNS disorders. Our proprietary vector engineering approach combines novel regulatory elements and payloads with AAV vectors to unlock innovative solutions for debilitating, intractable CNS conditions. At the forefront is our flagship clinical program, ETX101 for Dravet syndrome, which targets the underlying cause of the disorder to enable highly selective upregulation of SCN1A for potentially long-lasting benefit. In parallel, we are advancing a pipeline of potentially best-in-class programs to address significant unmet needs across both monogenic and prevalent CNS conditions. For more information, please visit . View source version on businesswire.com: Contacts Jennifer Gorzelany communications@encoded.com 650-515-9695 Source: Encoded Therapeutics Inc. View this news release online at:

Four newly disclosed programs follow clinical-stage Dravet syndrome gene therapy ETX101 Non-human primate (NHP) data support non-monogenic program in Lennox-Gastaut syndrome and demonstrate proof-of-concept for vectorized miRNA-based UBE3A upregulation in Angelman syndrome Promising early data suggest potential next generation therapeutics for neuropathic pain & Alzheimer’s disease SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Encoded Therapeutics Inc., a biotechnology company developing genetic medicines for severe central nervous system (CNS) disorders, today unveiled multiple pipeline programs ahead of the 27th ASGCT Annual meeting on May 7 - 11, 2024 in Baltimore, MD. Presentations will highlight progress of preclinical programs for Angelman syndrome, Lennox-Gastaut syndrome (LGS), STXBP1-related disorders (STXBP1-RD), Alzheimer’s disease (MAPT) and neuropathic pain (SCN9A), together with innovations in the company’s vector engineering platform. “Our ASGCT presentations showcase the depth and versatility of our vector engineering platform to develop highly specific precision therapies for CNS disorders with high unmet need,” said Stephanie Tagliatela, Chief Scientific Officer at Encoded. “Combining our novel regulatory elements and transgenes provides control of expression in target cells, potentially enabling treatment of devastating, intractable diseases. Building on our strong foundation in neuroscience, we are leveraging the experience and infrastructure established for our Dravet syndrome program, ETX101, to rapidly advance our promising pipeline of potentially best-in-class gene therapies.” Platform Innovations Encoded is engineering precision and selectivity into gene therapy constructs by combining highly selective and potent regulatory elements (REs) with novel transgenes to customize expression and functionality while minimizing off-target effects. These modular elements are compatible with multiple capsids and gene delivery systems. Novel REs developed by Encoded include those for GABA selectivity to target expression to GABAergic (inhibitory) interneurons, utilized by the clinical-stage program ETX101 for Dravet syndrome and the preclinical program for LGS. For STXBP1-RD, regulatory element engineering has been harnessed to drive potent, neuron-specific expression in the brain, while de-targeting expression in dorsal root ganglia (DRG). Engineered transgenes include transcription factors (eTFs) that upregulate the expression of endogenous genes as well miRNA sequences derived from Encoded’s miRNA discovery platform. A miRNA approach is utilized by the Angelman syndrome, Alzheimer’s disease and neuropathic pain programs, each of which demonstrate robust gene silencing or knockdown of their respective targets. “The data we’re sharing at ASGCT highlights our platform’s ability to achieve precise, targeted expression of transgenes with unique functionality, addressing technical limitations that exist today. This enables us to potentially unlock first-in-class gene therapies in monogenic disorders, like Dravet and Angelman syndromes, while also advancing potentially best-in-class gene therapies into more common diseases such as LGS, Alzheimer’s disease and neuropathic pain,” said Encoded CEO Kartik Ramamoorthi, Ph.D. “This is a significant maturation of our pipeline, and future success in these indications has the potential to transform the lives of many people living with severe CNS diseases.” ASGCT Annual Meeting Presentations Oral Presentation Details Title: GABA Selective AAV-mediated Gene Therapy Provides Durable Seizure Protection in Multiple Refractory Epilepsy Models (Abstract #19) Session: AAV Vectors - Preclinical and Proof-of-Concept: Therapy Focus Date & Time: Tuesday, May 7, 1:45–2:00 p.m. ET Location: Ballroom 2 Poster Presentation Details Title: Advancing Gene Therapy for STXBP1-related Disorders Through Targeted Vector Engineering: Efficacy and Safety Results in Mice and Non-Human Primates (Abstract #508) Date & Time: Wednesday, May 8, 5:30–7:00 p.m. ET Location: Exhibit Hall Title: A Vectorized miRNA-based Approach to Unsilence UBE3A in Angelman Syndrome (Abstract #1125) Date & Time: Thursday, May 9, 5:30–7:00 p.m. ET Location: Exhibit Hall Title: Identification of Potent and Selective AAV-miRNA Candidates to Knockdown Non-Monogenic Neurological Targets SCN9A (Pain) and MAPT (Tauopathies) (Abstract #1601) Date & Time: Friday, May 10, 5:30–7:00 p.m. ET Location: Exhibit Hall Scientific Symposium Details Title: Searching for Goldilocks – Scaling for AAV Clinical Dose Prediction Presentation: Dose Scaling from Preclinical Models to First-In-Human (FIH) for Local CNS AAV Gene Therapies Date & Time: Thursday, May 9, 8:00–8:25 a.m. ET Location: Ballroom 4 Presenter: Stephanie Tagliatela Full abstracts are available on the ASGCT meeting website. About Encoded Therapeutics Encoded Therapeutics is a clinical-stage genetic medicines company developing potentially disease-modifying therapies to improve the lives of people with severe CNS disorders. Our proprietary vector engineering approach combines novel regulatory elements and payloads with AAV vectors to unlock innovative solutions for debilitating, intractable CNS conditions. At the forefront is our flagship clinical program, ETX101 for Dravet syndrome, which targets the underlying cause of the disorder to enable highly selective upregulation of SCN1A for potentially long-lasting benefit. In parallel, we are advancing a pipeline of potentially best-in-class programs to address significant unmet needs across both monogenic and prevalent CNS conditions. Harnessing our proprietary technology platform and expertise, we are able to efficiently advance programs from discovery through clinical development. Encoded is committed to pioneering breakthrough treatments for CNS disorders. For more information, please visit .

Pictured: A hand pointing to an upward stock chart on a screen/iStock, tadamichi Stoke Therapeutics on Monday reported positive Phase I/IIa data for its Dravet syndrome candidate and now hopes to leapfrog straight into a registrational study. The news sent the company’s stock skyrocketing 98% in Tuesday morning trading. Patients receiving a 70-mg dose of STK-001 achieved median reductions of 85% in convulsive seizure frequency at three months, on top of their current regimen of anti-seizure medicines. An open label extension study showed continued dosing of 30 mg and 45 mg, respectively, achieved durable seizure reduction and “clinically meaningful” improvements in cognition and behavior over 12 months. Stoke reported the improvements are in “stark contrast” to a natural history study that showed most patients not only had no meaningful reduction of seizures, but also had widening gaps in cognition and behavior despite treatment with anti-seizure medications. The FDA has now cleared patients to receive three doses at 70 mg followed by continued dosing at 45 mg. Stoke announced plans to meet with the agency regarding a registrational study of that treatment plan. Dravet syndrome is a rare, severe genetic epilepsy that begins in the first treatment of life. It’s characterized by prolonged, repeated and sometimes febrile seizures that are treatment resistant. It carries a higher mortality rate than other epileptic conditions, with up to 20% of children never reaching adulthood. Most children with the syndrome also suffer from intellectual disability and development delays among other comorbidities. There is no cure and current anti-seizure medicines often do not offer the seizure control needed. Stoke’s candidate has the potential to be the first disease-modifying therapy targeting the genetic cause of Dravet syndrome. Administered by spinal tap, the antisense oligonucleotide leverages the non-mutated copy of the patient’s gene to restore function of the lacking sodium channel protein. This is a vastly different approach than current anti-seizure medications which work by reducing abnormal electrical activity in the brain. Encoded Therapeutics received IND clearance from the FDA in February 2024 for its Dravet syndrome gene therapy candidate. The treatment aims to be a one-time gene regulation therapy targeting the SCN1A gene. The two-part, Phase I/II trial will begin in the first half of this year. Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.