ETX101 Gene Therapy Shows Early Developmental, Seizure Benefits in Dravet Syndrome

Interim findings from the ongoing POLARIS phase 1/2 program suggest that Encoded Therapeutics’ investigational gene therapy ETX101 may produce substantial seizure reductions and early neurodevelopmental improvements in young children with SCN1A-positive Dravet syndrome, supporting continued advancement of the program as it enters pivotal-stage development.¹

Presented at the 2026 American Society of Gene and Cell Therapy (ASGCT) Annual Meeting, the updated data included outcomes from 21 treated participants across the ENDEAVOR, WAYFINDER, and EXPEDITION studies, which together comprise the broader POLARIS clinical program evaluating ETX101, an AAV9-mediated gene regulation therapy designed to selectively upregulate endogenous SCN1A expression in GABAergic inhibitory interneurons.

Dravet syndrome, a severe developmental and epileptic encephalopathy most commonly caused by SCN1A haploinsufficiency, is associated with drug-resistant seizures, developmental slowing, and elevated mortality risk beginning in infancy. Current antiseizure medications may reduce seizure burden but do not directly address the underlying genetic deficit or alter long-term neurodevelopmental trajectory. ETX101 was engineered to overcome historical gene therapy limitations associated with the large SCN1A coding sequence and the need for cell-type specificity. Previous preclinical work published in Human Gene Therapy demonstrated that the therapy’s engineered transcription factor approach could selectively increase SCN1A expression in inhibitory interneurons, laying the groundwork for clinical development.²

The ASGCT presentation comes just days after Encoded announced dosing of the first patient in the pivotal ENDEAVOR Part 2 study, marking the program’s transition into late-stage clinical development. The company also initiated dosing in the ENDEAVOR Part 1B expansion cohort, which is evaluating ETX101 in older children and adolescents aged 4 to 18 years.

“Promising open-label data from the initial Phase 1/2 studies generated significant interest from the Dravet community, and dosing the first patients at the University of California, San Francisco in the pivotal and expansion studies is an important step forward for families affected by this disease,” Adam Numis, MD, associate professor of neurology and pediatrics at UCSF and principal investigator for the ENDEAVOR studies, said in a company statement.³

As of January 26, 2026, investigators reported that ETX101 had been administered to 21 participants, with follow-up extending up to 91 weeks. Across the cohort, no treatment-related serious adverse events or dose-limiting toxicities were observed. The most commonly reported treatment-emergent adverse event was transaminase elevation, occurring in 6 participants.

Among participants treated at the higher dose levels (DL3/DL4) who received prednisolone without sirolimus, investigators observed a median 83.5% reduction in monthly countable seizure frequency through Week 28 on top of standard-of-care antiseizure medications. These reductions appeared durable among participants with longer-term follow-up.¹

By comparison, participants who received sirolimus demonstrated a lower median seizure reduction of 45.4%, resulting in an aggregate median seizure reduction of 75.7% across all high-dose participants. Investigators noted that preliminary mechanistic in vitro data suggested sirolimus may impair ETX101 functional activity through mTORC1-dependent suppression of protein translation, a finding researchers described as potentially important for the broader field of CNS-directed AAV gene therapies.

Beyond seizure control, the updated dataset also included early signals suggesting possible effects on adaptive functioning and developmental trajectory. Clinically meaningful improvements were observed across Vineland Adaptive Behavior Scales, Third Edition (VABS-3) subdomains as early as Week 16, with gains increasing through Week 52 in participants with longer follow-up. Communication-related improvements reportedly reached up to 20 growth scale values at 1 year, which investigators noted represented approximately 5-fold greater improvement than expected from natural history cohorts.

In younger participants aged 24 months or younger, Bayley-4 cognitive assessments demonstrated what investigators described as early evidence of developmental rescue. Rather than the developmental plateau commonly observed in Dravet syndrome, treated participants showed rates of cognitive skill acquisition that more closely paralleled neurotypical developmental trajectories beginning as early as Week 16. Preliminary Week 52 findings suggested these gains may persist over time.¹

“This therapy is designed to target SCN1A and address the underlying genetic cause of disease,” Numis said in the release.³ “Evaluating this approach across infants, children, and adolescents reflects our dedicated effort to understand its potential to meaningfully alter disease trajectory in the broader patient population.”

ETX101 has previously received FDA Breakthrough Therapy designation and was recently selected for the agency’s Chemistry, Manufacturing, and Controls Development and Readiness Pilot Program, which is intended to help align manufacturing readiness with accelerated clinical development timelines. Enrollment in the pivotal ENDEAVOR Part 2 study is expected to be completed by the end of 2026, with initial data anticipated in late 2027.³

REFERENCES
1. Sullivan J, Scheffer IE, Howell KB, et al. Safety and efficacy of ETX101, an investigational AAV9-based gene therapy for SCN1A+ Dravet syndrome: interim results from the POLARIS phase 1/2 clinical trials. Presented at: American Society of Gene and Cell Therapy Annual Meeting; May 2026; New Orleans, LA.
2. Tanenhaus A, et al. Cell-selective gene regulation therapy rescues Dravet syndrome phenotypes in preclinical models. Hum Gene Ther. 2022;33(11-12):579-597. doi:10.1089/hum.2021.248.
3. Encoded Therapeutics doses first patient in pivotal ENDEAVOR Part 2 study of ETX101 for Dravet syndrome. News release. Encoded Therapeutics. April 2026. https://www.pharmiweb.com/press-release/2026-05-06/encoded-therapeutics-doses-first-patient-in-pivotal-study-of-etx101-for-dravet-syndrome-and-reports