Antisense Oligonucleotide Shows Seizure Frequency Reductions in Dravet Syndrome

Key Takeaways

• Median convulsive seizure frequency reductions of up to 90.91% were observed in the highest-dose cohort.
• After 36 months, approximately 95% of participants were rated as improved by clinicians and caregivers.
• Zorevunersen is designed to address SCN1A haploinsufficiency, the genetic mechanism underlying Dravet syndrome.

Zorevunersen (Stoke Therapeutics, Bedford, MA)—an investigational antisense oligonucleotide treatment for SCN1A haploinsufficiency in children and adolescents with Dravet syndrome—was associated with reductions in convulsive seizure frequency and improvements in clinical assessments with an acceptable safety profile according to results from phase 1/2a clinical trials and open-label extension (OLE) studies. The findings were published in The New England Journal of Medicine, and according to study authors support the continued development of zorevunersen for the treatment of this severe channelopathy.

Researchers enrolled 81 pediatric participants (aged 2 to 18 years) across 2 phase 1/2a, open-label, multicenter studies: MONARCH (NCT04442295) and ADMIRAL (ISRCTN99651026). Eligible participants had confirmed SCN1A pathogenic variants and ≥4 convulsive seizures during the 28-day observation period despite concurrent antiseizure medications. Zorevunersen was delivered intrathecally in single- or multiple-ascending doses (10–70 mg). Subsequently, 75 participants were enrolled into 2 OLE studies (SWALLOWTAIL [NCT04740476] and LONGWING [ISRCTN12811235]) and received ≤45 mg every 4 months for up to 36 months. The primary end points were the safety profile and pharmacokinetics of treatment with zorevunersen, while secondary and exploratory end points included seizure frequency, clinical status (Clinical and Caregiver Global Impression of Change assessments), quality of life (European Quality of Life Visual Analogue Scale [EQ-VAS]), and adaptive behavior (Vineland Adaptive Behavior Scales, Third Edition [Vineland-3]). The studies were open-label and did not include placebo control groups.

Key results include the following:

• Participants receiving 70 mg in the phase 1/2a studies achieved median reductions in convulsive seizure frequency ranging from 58.82% to 90.91% through 20 months of OLE treatment.
• At 36 months, approximately 95% of participants were rated as improved by clinicians and caregivers.
• Adaptive behavior gains were observed across multiple Vineland-3 subdomains, including expressive (+7.56 points) and receptive (+6.06 points) communication.
• Most adverse events were mild to moderate: Post-lumbar puncture syndrome (in 25% of participants in the phase 1/2a trials) and elevated cerebrospinal fluid (CSF) protein (in 44% of participants in the OLE studies).
• 1 participant had suspected unexpected serious adverse reactions potentially related to treatment, while 2 participants died from sudden unexpected death in epilepsy (SUDEP) that was attributable to underlying disease and not associated with treatment.

Source: Laux L, Sullivan J, Perry MS, et al. Zorevunersen in children and adolescents with Dravet syndrome. N Engl J Med. 2026;394:969-982. doi:10.1056/NEJMoa250629