FDA, developer align on pivotal study of Dravet syndrome gene therapy ETX101
Testing treatment in children 'an important step toward regulatory approval'
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Encoded Therapeutics has met with the U.S. Food and Drug Administration (FDA) and the two have aligned on the design of a pivotal clinical trial to support a potential approval filing for ETX101, a one-time gene therapy designed to address the underlying cause of Dravet syndrome.
ETX101 is expected to reduce seizures in children with Dravet. Dosing in the Phase 1/2 study is expected to begin in the coming months, the developer announced in a company press release following the meeting.
This clinical study is the second part of the ongoing ENDEAVOR (NCT05419492) trial and is recruiting an estimated 30 children with Dravet syndrome, ages 6 months to 4 years. All participants will receive a single infusion of ETX101, which is delivered by intracerebroventricular administration, or into the brain’s fluid-filled spaces, called ventricles.
“Our alignment with the FDA on the pivotal study design marks an important step toward regulatory approval of ETX101 for children with Dravet syndrome,” said Sal Rico, MD, PhD, chief medical officer at Encoded. “This study design provides a rigorous and efficient path to evaluate ETX101 in the youngest population where we have the greatest opportunity to demonstrate a rapid and transformative benefit.”
This part of the study is now recruiting patients in the U.S., with additional sites in the U.K. and Australia opening soon. The company expects to complete enrollment by the end of this year and report initial data by the end of next year, according to the release.
The meeting with the FDA was held some months after ETX101 was awarded regenerative medicine advanced therapy (RMAT) status by the agency. That designation allows a drug maker frequent interactions with the FDA during the therapy development process.
The goal was to review the study design and give clear guidance early on. That was expected to help speed development of ETX101, with the study designed to collect enough clinical data to support filing of a planned biologics license application for its approval.
Dravet is most often caused by mutations in the SCN1A gene that affect the production of sodium channels, proteins that help nerve cells fire electrical signals. This is thought to result in excessive firing that leads to frequent seizures beginning in early infancy. Other symptoms of Dravet include slower development and problems with sleep and body temperature regulation.
Gene therapy designed to target root cause of Dravet
ETX101 uses a harmless, modified virus to deliver genetic instructions into nerve cells in the brain. Instead of replacing the mutated SCN1A gene, it increases its activity. This helps restore the function of inhibitory interneurons, nerve cells that normally dampen excessive electrical activity. The goal is to provide long-lasting benefit after a single intracerebroventricular infusion by targeting the root cause of Dravet syndrome.
Encoded is testing ETX101 in a clinical program called POLARIS, which comprises ENDEAVOR and two other Phase 1/2 clinical studies — EXPEDITION (NCT06283212) in the U.K. and WAYFINDER (NCT06112275) in Australia. Interim data showed that escalating doses of ETX101 have been well tolerated, and a single intracerebroventricular infusion at the highest dose reduced monthly countable seizure frequency (MCSF) by 87%.
The ongoing ENDEAVOR study is evaluating the safety and effectiveness of ETX101 in patients with a confirmed disease-causing mutation in the SCN1A gene. Part 1A involves infants ages 6 months to younger than 36 months, or 3 years of age. It follows an open-label, dose-escalation design, meaning all patients receive ETX101 and the dose is gradually increased to find a safe and effective level.
Part 1B involves older children and adolescents, ages 4 to younger than 18, and also follows an open-label design. Its main goal is to focus on how safe and well-tolerated ETX101 is, while also evaluating early signs of effectiveness by looking at changes in MCSF. It is currently running only in the U.S., with initial data expected toward the end of this year, according to the company.
Part 2 is a randomized, double-blinded clinical study, meaning patients are randomly assigned to receive either ETX101 or a sham procedure, and neither families nor doctors know who received the gene therapy. Its main goal is to monitor the percent change in MCSF over the period from five to 52 weeks, or one year, after the intracerebroventricular infusion.
Secondary goals include monitoring side effects or complications related to the gene therapy or the procedure. The researchers will also evaluate cognitive development, assessed using the Bayley Scales of Infant and Toddler Development (Bayley-4) for thinking, learning, and problem-solving skills. Everyday skills such as communication, social interaction, and motor abilities will also be assessed, using the Vineland Adaptive Behavior Scales (Vineland-3).
“We are proud to also announce that initiation of both ENDEAVOR Part 1B and Part 2 is already underway, demonstrating our ability to rapidly translate regulatory feedback into clinical execution,” Rico said.
Patient dosing expected to start by end of June
Rico said participants will start receiving treatment in the coming months.
“We expect patient dosing in both studies to begin in [the second quarter of 2026], marking another meaningful advance in our ETX101 program and continuing our work on behalf of the Dravet community,” Rico said.
