Stoke Therapeutics’ Zorevunersen Shows Promise in Treating Dravet Syndrome
For children with Dravet syndrome, a rare and severe genetic epilepsy, developmental delays often begin after an initial period of normal development. Now, Stoke Therapeutics is developing zorevunersen, an experimental drug aimed at not only reducing seizures but also restoring lost developmental function. Recent clinical trial data suggest significant progress in both areas.
Understanding Dravet Syndrome
Dravet syndrome is a genetic epilepsy characterized by frequent, prolonged seizures that typically begin in the first year of life. It’s classified as a developmental and epileptic encephalopathy due to the associated developmental delays and cognitive impairment. Approximately 85% of cases are linked to a mutation in the SCN1A gene.
Children with Dravet syndrome often experience neurotypical development for the first 18 to 24 months, after which their development plateaus. As Ian Smith, CEO of Stoke Therapeutics, explained, individuals with Dravet syndrome can reach ages 10, 15, or 20 while functioning at the level of a two-year-ancient, potentially facing challenges with speech, recognition, and basic self-care.
How Zorevunersen Works
Zorevunersen is an investigational antisense oligonucleotide designed to address the underlying cause of Dravet syndrome – SCN1A haploinsufficiency. The drug aims to boost the production of functional NaV1.1 protein in brain cells by targeting the non-mutated copy of the SCN1A gene.
Clinical Trial Results: Seizure Reduction and Developmental Improvements
Phase 1/2a clinical trials and open-label extension studies have demonstrated promising results. Zorevunersen, in combination with standard anti-seizure medications, has been associated with reductions in convulsive seizure frequency and improvements in clinical assessments. Median convulsive seizure frequency reductions of up to 90.91% were observed in the highest-dose cohort.
Improvements were also seen in measures of cognition and behavior, specifically using an assessment called Vineland-3, which evaluates adaptive behavior skills like motor skills and communication. After three years, approximately 95% of participants in the open-label extension program were rated as improved by clinicians and caregivers.
Safety and Side Effects
In Stoke’s phase 1/2 studies, most adverse events were mild or moderate. One patient experienced a suspected unexpected serious adverse event related to zorevunersen, and another withdrew due to an adverse event. Two patients died from sudden unexpected death in epilepsy (SUDEP), and one from malnutrition—all unrelated to zorevunersen.
The Path Forward: Phase 3 Trials and Regulatory Outlook
Stoke Therapeutics has initiated a phase 3 trial, dubbed Emperor, with anticipated enrollment of 150 patients across the U.S., U.K., and Japan. The primary goal is to reduce seizures at 28 weeks, with a secondary endpoint focused on Vineland scores at Week 52. The company expects to complete enrollment by the second quarter of 2026 and anticipates a rolling new drug application by mid-2027.
Zorevunersen has received breakthrough therapy, orphan drug, and rare pediatric disease designations from the FDA. Stoke is collaborating with Biogen, which holds exclusive commercialization rights outside of North America.