Exploring One-Time Gene Regulation Therapy EXT101 in Dravet Syndrome: The Phase 1/2 POLARIS Program

Welcome to NeurologyLive^®'s Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month’s spotlight is the phase 1/2 POLARIS program of EXT101 (Encoded Therapeutics), an adeno-associated virus (AAV)-mediated candidate for gene regulation therapy, for the treatment of SCN1A+ Dravet syndrome (DS).

“We know that the main cell type implicated in the cause of DS is the GABAergic inhibitory interneurons. You have haploinsufficiency in those GABAergic inhibitory interneurons, which results in excessive excitation and decreased inhibition across neuronal networks,” principal investigator Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at UCSF, told NeurologyLive at the 2025 American Epilepsy Society (AES) Annual Meeting, where the first clinical results of ETX101 were presented.

“A lot of the therapies that we are now looking at are trying to restore that haploinsufficiency,” he added. “I think one key advantage of this therapy is that it has cell specificity. The target is to actually increase SCN1A production specifically in the GABAergic inhibitory interneurons. That cell specificity is really important, because that is where the disease biology is centered.”

POLARIS Program

The POLARIS program has 3 ongoing clinical trials: ENDEAVOR (NCT05419492), WAYFINDER (NCT06112275), and EXPEDITION (NCT06283212), which are all open-label and dose-escalating studies across the United States, the United Kingdom, and Australia.¹ In these trials, eligible patients are 6 months to 7 years of age, have a predicted loss-of-function, pathogenic or likely pathogenic SCN1A variant, experienced their first seizure between the ages of 3 and 15 months, and are currently on standard-of-care antiseizure medications.

“We are really trying to enrich the study population to include children under 3 years of age, because based on the natural history studies, this early time period is when we see the developmental departure from typical development. That early window is potentially the best opportunity to intervene and have the greatest disease modifying impact,” Sullivan said. “More patients have been enrolled in dose levels 3 and 4 because we want to understand whether there is a differential response between doses, and we also want to give the therapy enough time to work.”

Interim Phase 1/2 Data

The preliminary data on efficacy, safety, and neurodevelopmental outcomes of ETX101 from POLARIS program were recently presented at the 2025 AES Annual Meeting, held December 5-9 in Atlanta, Georgia. All told, the interim results showed that the gene therapy was well tolerated, with dose-dependent effects on seizure outcomes and substantial impacts on neurodevelopment and cognition, further supporting its continued development.²

Considered the first clinical data for an investigational, 1-time, cell-type selective, gene regulation treatment in DS, the presented research included 19 patients who had received a single dose of ETX101 across 4 dose levels as of November 10, 2025. Safety data were available for all participants (n = 19), whereas efficacy measures (Vineland-3, Bayley-4) were available at Week 16 (n = 10) for dose levels (DL) 1–3 and at Week 52 (n = 4) for DL1 and DL2. The median age at dosing was 24 months, an age associated with increasing seizure burden, with participants receiving 2–4 antiseizure medications, including fenfluramine (Fintepla; UCB) in 36.8% of cases.

At 32 weeks, investigators observed a dose-dependent effect on monthly countable seizure frequency, with a median 78% substantial reduction emerging at DL3 (n = 3). Notably, treatment with ETX101 led to reductions in seizure severity, rescue medication use, and hospitalizations even at lower doses. Regarding the effect on seizure reduction, Sullivan told NeurologyLive that, "This highlights the potential for a one-time with durability of effect over that period of time. As for dose level 4, there have been patients who’ve received this dosage, but we don’t have the long-term efficacy signal for those patients yet, and so that will hopefully be coming early next year."

Safety Results

Safety, an important piece of the puzzle for gene therapies, was also reassuring for ETX101. Overall, 23 treatment-emergent adverse events (TEAEs) were recorded in 9 patients, such as transient neutropenia, thrombocytopenia, and elevated serum ALT, AST, GGT, and LDH . The most common treatment-related TEAEs were clinically asymptomatic transaminase elevations in four patients, resolving without intervention in three cases and with a brief course of steroids in one. Notably, no changes were observed on brain MRIs at Weeks 28 and 52, and to date no treatment-related serious TEAEs or dose-limiting toxicities have been reported.

Despite the fact that it was a phase 1/2 trial primarily focused on safety, the study revealed clinically significant gains across Vineland-3 (n = 16) and Bayley-4, scales of development. On Vineland-3, patients on the gene therapy demonstrated improvements in various domains, including fine motor, gross motor, interpersonal relationships, personal skills, and most notably, receptive and expressive communication.

“Development was a critical outcome for us because DS is a developmental and epileptic encephalopathy. Although seizure control is important, our ultimate goal is to alter the developmental trajectory,” Sullivan added. “What was particularly remarkable was what we saw in the small cohort with 52 week follow up. The magnitude of developmental change was something we have really never seen before, especially in expressive and receptive communication. Based on caregiver surveys and clinical experience, communication is one of the most important developmental domains for these patients, because the inability to communicate has a significant downstream impact on quality of life.”

Cognition Outcomes

In terms of cognition, assessed through Bayley-4 sub-domains, ETX101-treated patients aged 24 months or less months did not show early stagnation and instead experienced an accelerated rate of skill acquisition, catching up with neurotypical peers and demonstrating sustained development over time. “The rate of acquisition surpassed what we would expect in neurotypical development, not in the sense that these children were developing beyond typical expectations, but rather that they were catching up and narrowing the developmental gap,” Sullivan said. Notably, there was a patient in DL1 who showed sustained neurotypical development over 52 weeks of treatment, contrasting the typical course for patients with DS.

Mechanism of Action

ETX101 utilizes a clinically validated AAV capsid that has been extensively used in clinical trials for central nervous system disorders. The gene therapy is delivered via an ICV infusion, further enhancing the delivery of the drug to key brain structures critical for seizures and neurocognition. For this drug, AAV9 enters the cell by endocytosis in a receptor-mediated manner to deliver the therapeutic transgene, which predominantly exists as a non-replicating episome.

FDA Designations

Earlier this year, in January 2026, the FDA granted breakthrough therapy designation to ETX101 for the treatment of SCN1A+ DS. Encoded Therapeutics noted that this designation is in addition to regenerative medicine advanced therapy, fast track, orphan drug, and rare pediatric disease designations, all previously granted by the agency.³ The company’s investigational new drug application for ETX101 was cleared by the FDA in February 2024. Simultaneously, the Australia Therapeutic Goods Administration approved the gene therapy for initiation in clinical trials under the Clinical Trial Approval scheme.⁴

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REFERENCES
1. Sullivan J, Scheffer IE, Howell KB, et al. POLARIS Phase 1/2 Program Interim Safety and Preliminary Efficacy Results of ETX101, a One-Time Gene Regulation Therapy, in Young Children with Dravet Syndrome. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. ABSTRACT 1.308.
2. Encoded Therapeutics Presents Positive Interim Efficacy Data from Initial Dose Levels of Phase 1/2 Trials Evaluating ETX101 Gene Therapy in Dravet Syndrome. News release. Encoded Therapeutics. December 5, 2025. Accessed March 24, 2026. https://encoded.com/press-releases/encoded-therapeutics-presents-positive-interim-efficacy-data-from-initial-dose-levels-of-phase-1-2-trials-evaluating-etx101-gene-therapy-in-dravet-syndrome/
3. Encoded Therapeutics Announces US IND Clearance and Australian CTA Approval for Dravet Syndrome Gene Therapy Candidate ETX101. News release. Encoded Therapeutics. February 6, 2024. Accessed March 24, 2026. https://encoded.com/press-releases/encoded-therapeutics-announces-us-ind-clearance-and-australian-cta-approval-for-dravet-syndrome-gene-therapy-candidate-etx101/
4. Encoded Therapeutics Announces U.S. FDA Breakthrough Therapy Designation Granted to ETX101 for the Treatment of Dravet Syndrome. News release. Encoded Therapeutics. January 12, 2026. Accessed March 24, 2026. https://encoded.com/press-releases/encoded-therapeutics-announces-u-s-fda-breakthrough-therapy-designation-granted-to-etx101-for-the-treatment-of-dravet-syndrome/