Encoded's ETX101 Cuts Dravet Seizures 76% at Dose Level 3 and Tracks Toward Neurotypical Development in Children Treated Before Age 2
An AAV9 gene-regulation therapy delivered durable, dose-dependent seizure control and early signs of neurodevelopmental rescue through 52 weeks, just as the pivotal study begins dosing.
Overview
Encoded Therapeutics presented an expanded dataset from its Phase 1/2 POLARIS program for ETX101, an investigational AAV9-based gene regulation therapy for SCN1A+ Dravet syndrome, during the Presidential Symposium of the 29th Annual Meeting of the American Society of Gene & Cell Therapy on May 13, according to a release from BioSpace. From Week 5 through Week 52, a single intracerebroventricular dose produced approximately a 76% median reduction in monthly countable seizure frequency at dose level 3 (n=3), with continued dose-dependent activity at the top tested dose, dose level 4. Children treated before age 2 showed cognitive trajectories generally consistent with neurotypical development across the 52-week observation period — a divergence from the developmental stagnation seen in the ENVISION natural history study.
The readout lands one week after Encoded reported the first patient had been dosed in the pivotal ENDEAVOR Part 2 study, per a separate BioSpace release, transitioning the program into late-stage clinical development.
What We Know
ETX101 is delivered by a single intracerebroventricular (ICV) injection and is designed to increase expression of the SCN1A gene to restore sodium channel function in inhibitory interneurons, according to BioSpace. The analyses presented at ASGCT reflect a data cutoff of April 10, 2026.
On the efficacy side, BioSpace reported a roughly 76% median monthly countable seizure frequency (MCSF) reduction at DL3 from Week 5 through Week 52 in three patients, observed during a developmental window typically associated with increasing seizure burden despite standard-of-care antiseizure medicines. Early DL4 data showed continued dose-dependent antiseizure activity, with the strongest response in patients who did not receive sirolimus (n=4); the company said sirolimus appears to dampen the therapeutic signal by reducing protein expression, and that no safety differences were observed between patients who received sirolimus and those who did not.
In parallel, neurodevelopmental measures improved across the cohort. Patients who reached 52 weeks of observation (n=9) showed gains across multiple domains of the Vineland Adaptive Behavior Scales (VABS-3), with the most notable changes in receptive and expressive communication and motor function, according to BioSpace. In patients treated before age 2, progressive cognitive gains were evident as early as Week 16 (n=11) and continued through Week 52 (n=4), measured by the Bayley Scales of Infant and Toddler Development (Bayley-4), with trajectories generally consistent with neurotypical development.
Safety has been consistent with the AAV class. BioSpace reported no treatment- or procedure-related serious adverse events across all four dose levels; the most common treatment-related adverse events were transaminase elevations, a known AAV class effect, which were clinically asymptomatic and resolved in all participants. STAT News, reporting on the same dataset, framed the readout around the trade-off introduced by concurrent sirolimus use.
“Watching these young children not only achieve durable seizure reduction but also show early evidence of neurodevelopmental rescue is truly remarkable. These data reinforce our belief that ETX101 has the potential to change the course of the disease and future outlook for the Dravet community,” Sal Rico, M.D., Ph.D., Chief Medical Officer of Encoded, said in the BioSpace release.
Mary Anne Meskis, CEO of the Dravet Syndrome Foundation, framed the data from a patient-advocacy perspective. “Parents of children with Dravet syndrome live with the fear of every seizure and the heartbreak of watching development stall,” she said in the same release.
The Pivotal Trial
The POLARIS program comprises multiple Phase 1-3 clinical trials. Its first phase includes three ongoing open-label, multicenter dose-escalation studies — ENDEAVOR Part 1 (US), EXPEDITION (UK), and WAYFINDER (Australia) — in infants and young children aged 6 months to 7 years, with ENDEAVOR Part 1B actively enrolling children and adolescents aged 4 to 18 years, BioSpace reported.
The pivotal ENDEAVOR Part 2 study is a randomized, double-blind, sham delayed-treatment controlled trial in 30 patients with SCN1A+ Dravet syndrome aged 6 months to under 4 years, with a primary endpoint of percent change from baseline in MCSF at 52 weeks, according to BioSpace. Encoded said it has completed an Initial Comprehensive Multidisciplinary Regenerative Medicine Advanced Therapy meeting with the FDA and aligned with the agency on the pivotal study design supporting a planned Biologics License Application submission. The company said in a May 6 release that the first patient had been dosed in ENDEAVOR Part 2, with enrollment expected to complete by the end of 2026 and initial data anticipated by the end of 2027. ETX101 has received Breakthrough Therapy, Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug designations from the FDA, plus Orphan designation from the European Medicines Agency, per BioSpace.
Dr. Adam Numis, Associate Professor of Neurology and Pediatrics at UCSF and Principal Investigator for the ENDEAVOR studies, said in the May 6 release that “promising open-label data from the initial Phase 1/2 studies generated significant interest” from the Dravet community.
What We Don’t Know
The Phase 1/2 cohorts presented at ASGCT are small — efficacy at DL3 rests on three patients, the headline Bayley-4 Week 52 readout rests on four patients, and the DL4 sirolimus-free subgroup rests on four — and the trials are open-label, leaving randomized, sham-controlled evidence to the ongoing ENDEAVOR Part 2 study and its 52-week primary endpoint. The sirolimus interaction is a meaningful clinical question for any future AAV regimen, and Encoded’s mechanistic explanation — reduced protein expression by sirolimus — has not yet been peer-reviewed; the readout was a conference presentation rather than a journal publication. Durability beyond 52 weeks, the response curve at DL4 as more patients are dosed, and whether the early Bayley-4 trajectories hold up over multi-year follow-up all remain open. Encoded expects initial pivotal data by the end of 2027, BioSpace reported.