Gene Therapy ETX101 Demonstrates Significant Effects on Seizure Reduction, Neurodevelopmental Outcomes in POLARIS Phase 1/2 Program

At the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, investigators presented promising preliminary efficacy, safety, and neurodevelopmental data from the phase 1/2 POLARIS program testing ETX101 (Encoded Therapeutics), a one-time gene regulation therapy, in young children with Dravet syndrome (DS). All told, the interim results showed that the agent was well tolerated, with dose-dependent effects on seizure outcomes and substantial impacts on neurodevelopment and cognition, further supporting its continued development.¹

Considered the first clinical data for an investigational, one-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), while 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 (ASMs), including fenfluramine in 36.8% of cases.

At week 32, investigators observed a dose-dependent effect on monthly countable seizure frequency (MCSF), 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, lead investigator Joseph Sullivan, MD, 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."

ETX101 utilizes a clinically validated adeno-associated virus (AAV) capsid that has been extensively used in clinical trials for central nervous system disorders. The gene therapy, which is currently being studied across 3, phase 1/2 trials, 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.

Sullivan, director of the Pediatric Epilepsy Center at UCSF, added, "One key advantage of this therapy is that it has cell specificity—the target is to increase SCN1A production specifically in the GABAergic inhibitory interneurons that drive the underlying biology of Dravet syndrome."

The phase 1/2 trials of POLARIS include ENDEAVOR (NCT05419492), WAYFINDER (NCT06112275), and EXPEDITION (NCT06283212), which are all open-label and dose-escalating in nature. 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.

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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.

"The developmental gains seen over 52 weeks in natural history (cohorts) were achieved in the first 16 weeks of treatment (with ETX101)," Sullivan said. "When we look at the small cohort with 52-week follow-up, there’s a magnitude of change that we’ve never seen before: dramatic improvements, specifically in the areas of expressive and receptive communication–which we know based on a lot of caregiver surveys is one of the most important developmental domains for these patients."

He added, "If you can’t talk to your child, or your child can’t communicate with you, that has a downstream impact on so many other things. We were thrilled to see this magnitude of impact. Again, this was in patients who were still in some of these lower dose level cohorts."

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. In ENVISION, cognition was the only Bayley domain to decline significantly over one year in participants 24 months or less, underscoring its importance as an early marker and priority for targeted intervention. 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.

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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.