Gene Therapy ETX101 Shows Sustained Seizure Reductions, Neurodevelopmental Gains in Updated POLARIS Data

Updated phase 1/2 data from the POLARIS clinical development program demonstrated sustained reductions in seizure frequency and progressive improvements across cognitive and adaptive behavior measures following a single administration of investigational ETX101 (Encoded Therapeutics) in children with SCN1A+ Dravet syndrome. The findings, presented at the 16th European Epilepsy Congress in Athens, Greece, included follow-up through52 weeks for seizure outcomes and up to76 weeks for selected neurodevelopmental measures.¹

At dose level 3 (DL3; n = 5) and dose level 4 (DL4; n = 9), participants experienced median reductions in monthly countable seizure frequency (MCSF) of approximately 76% and 60%, respectively, from week 5 through week 52 or their latest available study visit. Among those who completed 52 weeks of observation, median MCSF reductions at month 12 were approximately 79% in the DL3 group (n = 3) and 89% in the DL4 group (n = 5).

"With longer follow-up and additional data available, we are encouraged by the magnitude and durability of seizure reduction following a single administration of ETX101,” said Sal Rico, MD, PhD, Chief Medical Officer of Encoded. “Importantly, the emerging clinical profile extends beyond seizure control, with continued improvements across cognitive and adaptive behavior measures supporting the potential to address the broader manifestations of Dravet syndrome”

Seizure Reductions Remain Sustained Through 52 Weeks

The updated seizure findings showed continued reductions following a single ETX101 administration. Across the cumulative analysis from week 5 through week 52 or the participant's latest study visit, median MCSF declined by approximately 76% with DL3 and 60% with DL4.Among participants with a full 52 weeks of observation, reductions were approximately 79% with DL3 and 89% with DL4 during weeks 49-52.¹

These data extend the earlier seizure findings presented at AES 2025. In that analysis, investigators observed a dose-dependent effect on MCSF, with a median 78% reduction emerging at week 32 among the small DL3 cohort. Investigators also reported reductions in seizure severity, rescue medication use, and hospitalizations at lower dose levels.²

In comments to NeurologyLive following the earlier presentation, Joseph Sullivan, MD, noted that the durability of seizure reduction was an important aspect of the initial findings, while longer-term data for participants receiving DL4 were still emerging.² The current update provides additional follow-up for the DL4 population, although the cohort remains small.

Neurodevelopmental Measures Continue to Show Gains

Beyond seizure control, the updated POLARIS findings included measures of cognition and adaptive behavior, areas of substantial clinical importance in Dravet syndrome.

Among participants treated before 2 years of age, Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) cognitive growth scale values demonstrated continued gains over time. With up to 76 weeks of follow-up, Encoded reported that developmental trajectories continued to diverge from the stagnation observed in the ENVISION natural history study and approached the range expected for neurotypical children.¹

Adaptive behavior, assessed using the Vineland Adaptive Behavior Scales, Third Edition (VABS-3), also showed progressive improvements across evaluated domains, including communication, motor skills, socialization, and daily living skills. Gains in receptive and expressive communication and motor function were particularly notable, according to the company.

The findings build on the earlier data when investigators reported improvements across multiple VABS-3 domains, including fine and gross motor skills, interpersonal relationships, personal skills, and receptive and expressive communication.²

At that presentation, Sullivan described the magnitude of developmental change observed among participants with longer follow-up as notable, particularly in communication measures. He also pointed to the importance of cognitive development as an early marker of disease trajectory, noting that children 24 months or younger in the ENVISION natural history cohort had demonstrated cognitive stagnation over time.²

The updated analysis extends the observation period for these measures, but the neurodevelopmental findings remain based on small, open-label cohorts and comparisons with natural-history trajectories rather than a randomized placebo-controlled efficacy analysis.

Safety Profile and Advancement into Later-Stage Development

ETX101 continued to demonstrate a favorable safety profile across all 4 dose levels, according to Encoded. With up to 117 weeks of follow-up, there were no treatment- or procedure-related serious adverse events reported.¹

Treatment-related adverse events included transaminase elevations in 7 of 21 participants and thrombocytopenia in 3 of 21 participants. All were clinically asymptomatic and resolved, according to the company.

The POLARIS clinical development program currently includes multiple phase 1/2 studies evaluating ETX101 in children and adolescents with SCN1A+ Dravet syndrome. ENDEAVOR Part 1 in the United States, EXPEDITION in the United Kingdom, and WAYFINDER in Australia are evaluating the therapy in children aged 6 months to 7 years, while ENDEAVOR Part 1B is enrolling older children and adolescents aged 4 to 18 years.

The pivotal ENDEAVOR Part 2 study is also evaluating ETX101 in children aged 6 months to 4 years, with seizure and neurodevelopmental outcomes among the measures being assessed.

The updated findings provide longer-term evidence from the early-stage program supporting continued investigation of ETX101. However, the small sample sizes, open-label design of the phase 1/2 studies, and reliance in part on comparisons with natural-history data remain important considerations when interpreting the observed seizure and developmental changes.

As the program progresses into pivotal testing, randomized data will be important for determining whether the seizure and neurodevelopmental trajectories observed to date translate into a treatment effect attributable to ETX101.

REFERENCES
1. Encoded Therapeutics Presents Updated Data from POLARIS Phase 1/2 Trials of ETX101 Gene Therapy in Dravet Syndrome at the 16th European Epilepsy Congress. Encoded Therapeutics. News Release. September 8, 2026. Accessed: September 9, 2026. https://www.businesswire.com/news/home/20260908732226/en/Encoded-Therapeutics-Presents-Updated-Data-from-POLARIS-Phase-12-Trials-of-ETX101-Gene-Therapy-in-Dravet-Syndrome-at-the-16th-European-Epilepsy-Congress
2. 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.