First look at ETX101 suggests early benefits for children with Dravet
Interim trial data show seizure and developmental gains in young children
ETX101, an investigational one-time gene therapy being developed by Encoded Therapeutics for children with Dravet syndrome, has shown a favorable safety profile and early signs of benefit in an ongoing clinical program.
Called the POLARIS program, the clinical effort includes three Phase 1/2 trials of ETX101: ENDEAVOR (NCT05419492) in the U.S., EXPEDITION (NCT06283212) in the U.K., and WAYFINDER (NCT06112275) in Australia.
The U.S. and U.K. studies are currently enrolling children ages 6 to 47 months (up to nearly 4 years old). The Australian study is no longer recruiting, but enrolled children ages 6 to 83 months (up to about 7 years old). Across all three, the main goal is to evaluate safety and see whether ETX101 can reduce seizure frequency.
Early trial findings highlight safety and early seizure-reduction signals
Interim results from the study, titled “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,” were presented at this year’s American Epilepsy Society (AES) Annual Meeting, held Oct. 5-9, in Atlanta, Georgia.
“While early, the emerging clinical impact of ETX101 underscores its potential as a one-time, disease-modifying medicine for Dravet syndrome,” Kartik Ramamoorthi, PhD, Encoded’s CEO, said in a company press release. “We’re incredibly grateful to the study participants and their families, clinicians, and advocacy partners whose commitment and collaboration have made this progress possible.”
“We look forward to presenting efficacy data from the fourth and final dose level as we seek to advance ETX101 toward a pivotal clinical trial in 2026,” Ramamoorthi added.
Dravet syndrome is primarily caused by mutations in the SCN1A gene, which provides instructions for making a protein that forms part of the sodium channel NaV1.1. This channel helps certain nerve cells in the brain send signals properly. When NaV1.1 is impaired, abnormal signaling can lead to frequent seizures and other Dravet symptoms.
ETX101 is designed to address the underlying cause of Dravet by improving NaV1.1 sodium channel function, potentially easing symptoms. The therapy is delivered through a single intracerebroventricular infusion, meaning it is administered directly into the brain’s fluid-filled spaces, called ventricles, to reach target cells.
In the ongoing POLARIS program, 19 children with a diagnosis of Dravet caused by SCN1A mutations, and who experienced drug-resistant seizures despite treatment with available anti-seizure medications, have received ETX101 across four escalating dose levels.
These early signals of developmental rescue in our youngest patients offer real hope for families facing the challenges of living with this disease.
According to interim data, the therapy was generally well tolerated at all doses, with no treatment-related serious side effects reported. It also showed dose-dependent, sustained reductions in monthly seizure frequency across the first three dose levels.
Among the three children treated at the third dose level, participants experienced a median 78% reduction in monthly seizures over a seven-month observation period, which the company noted is typically associated with increasing seizure burden.
Beyond seizure reduction, signs of neurodevelopmental improvement were also observed. Four children treated at the first two dose levels and followed for 52 weeks (about one year) showed meaningful developmental gains compared with untreated children in the ENVISION natural history study. The most notable gains were in expressive communication, motor skills, self-care, and social interaction.
Among four of five children treated before age 2, accelerated cognitive skill acquisition was seen as early as 16 weeks (about four months), with continued gains through one year. These improvements contrasted with the developmental slowing and eventual plateau seen after age 2 in the ENVISION study.
“These results point to the possibility of a one-time treatment that not only reduces seizures, but also addresses the profound neurodevelopmental stagnation that affects the ability of children with Dravet syndrome to communicate, learn, and function independently,” said Joseph Sullivan, MD, director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco, and principal investigator on the ENDEAVOR study. “These early signals of developmental rescue in our youngest patients offer real hope for families facing the challenges of living with this disease.”
Regulatory designations reflect the therapy’s potential impact
ETX101 recently received regenerative medicine advanced therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA). This status is granted to therapies for serious conditions that show early clinical promise and is meant to speed up development and allow more frequent FDA interactions.
The therapy has also been granted rare pediatric disease status in the U.S. and orphan drug designation in both the U.S. and European Union. These designations help encourage development of treatments for rare diseases. If ETX101 is approved, orphan status would also provide a period of market exclusivity.
ETX101 has also received fast-track designation from the FDA, which is designed to speed the development and review of therapies for serious conditions with unmet medical needs. This status allows for more frequent communication with the FDA and the potential for expedited review.
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