ETX101 tied to seizure reductions in Dravet gene therapy trials
One-time treatment also linked to developmental gains
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A one-time treatment with Encoded Therapeutics’ experimental gene therapy ETX101 was generally well tolerated and associated with seizure reductions for up to one year in children with Dravet syndrome, a severe form of epilepsy that begins in infancy.
That’s according to new data from the first phase of an ongoing clinical program, called POLARIS, evaluating escalating doses of ETX101 in infants and young children, ages 6 months to 7 years, across three Phase 1/2 studies: ENDEAVOR (NCT05419492) in the U.S., EXPEDITION (NCT06283212) in the U.K., and WAYFINDER (NCT06112275) in Australia.
The new findings, presented at this year’s American Society of Gene and Cell Therapy annual meeting, also suggest ETX101 may support aspects of children’s neurodevelopment, according to Encoded. In particular, the company said children treated before age 2 showed cognitive trajectories that diverged from the developmental slowing or plateauing often seen in children with Dravet.
Early data suggest developmental gains
“Watching these young children not only achieve durable seizure reduction but also show early evidence of neurodevelopmental rescue is truly remarkable,” Sal Rico, MD, PhD, chief medical officer of Encoded, said in a press release. “These data reinforce our belief that ETX101 has the potential to change the course of disease and future outlook for the Dravet community.”
EXPEDITION and WAYFINDER have completed enrollment, while the expansion part of the ENDEAVOR trial continues enrolling children and adolescents, ages 4 to younger than 18 years, in the U.S. Meanwhile, following recent alignment with the U.S. Food and Drug Administration (FDA) on the study design, the pivotal ENDEAVOR Part 2 study is now recruiting an estimated 30 children with Dravet, ages 6 months to younger than 4 years, in the U.S. and Australia, with additional sites in the U.K. expected to open soon.
Dravet is mainly caused by mutations in the SCN1A gene that reduce the function of NaV1.1, a sodium channel important for signaling in certain inhibitory nerve cells in the brain. This ultimately leads to frequent seizures and other Dravet symptoms, including developmental, cognitive, and behavioral problems.
ETX101 is an AAV9-based gene regulation therapy designed to increase SCN1A gene expression and restore sodium channel function in inhibitory nerve cells. The one-time gene therapy is delivered via an injection into fluid-filled cavities in the brain called ventricles.
In the first phase of the POLARIS program, 19 children with a diagnosis of Dravet caused by SCN1A mutations and seizures that remained uncontrolled despite standard anti-seizure medications had received ETX101 across four escalating dose levels.
Seizure reductions seen through one year
Earlier POLARIS findings had already suggested ETX101 was generally well tolerated and associated with seizure reductions, while also showing early signs of developmental progress in young children with Dravet. The data showed the therapy had a favorable safety profile and was associated with dose-dependent seizure reductions through the third dose level, alongside early signs of gains in communication, motor skills, and social functioning.
The newly presented findings now expand on those earlier observations with longer follow-up, early data from the fourth dose level, and additional evidence related to seizure control and neurodevelopment.
ETX101 showed a favorable safety profile and was generally well tolerated across all dose levels, with no treatment- or procedure-related serious adverse events reported. The most common treatment-related adverse events were asymptomatic liver enzyme elevations, which resolved in all participants. Its anti-seizure effects also remained durable through 52 weeks, or about one year, with seizure reductions generally increasing at higher dose levels.
Among three children treated at the third dose level, monthly countable seizure frequency fell by a median of about 76% from week 5 through week 52, which Encoded noted is a developmental window typically associated with increasing seizure burden despite standard anti-seizure medications.
Early findings from the fourth dose level also point to continued dose-dependent anti-seizure activity, with the strongest responses observed among four children who did not receive sirolimus, also known as rapamycin and sold as Rapamune, an immunosuppressive medication sometimes used alongside gene therapies.
Sirolimus may affect treatment response
The company said the finding aligned with preclinical studies suggesting that sirolimus may dampen ETX101’s therapeutic effect by reducing protein expression, though safety outcomes were similar regardless of sirolimus use.
Beyond seizure control, the updated findings provided additional evidence that ETX101 may support aspects of children’s neurodevelopment, according to Encoded. Among nine children who completed 52 weeks of follow-up, caregivers reported meaningful developmental gains in receptive and expressive communication, motor function, self-care, and social interaction.
The clearest developmental signs continued to emerge among children treated before age 2. Progressive cognitive gains were evident as early as week 16, or about four months, after treatment in 11 children and continued through one year among four with 52 weeks of follow-up.
Compared with children in the ENVISION natural history study, those treated with ETX101 showed developmental trajectories generally consistent with neurotypical development over a year, rather than the slowing or plateauing in cognitive progress often seen as children with Dravet grow older, Encoded noted.
“Parents of children with Dravet syndrome live with the fear of every seizure and the heartbreak of watching development stall,” said Mary Anne Meskis, CEO of the Dravet Syndrome Foundation. “To see the early and robust seizure reductions paired with meaningful developmental gains is profoundly encouraging. Families have been waiting for therapies that don’t just manage symptoms but give their children a chance to keep learning and growing.”
