A matching-adjusted comparison of patients with Dravet syndrome (DS) found that those treated with the investigational drug zorevunersen showed meaningful and lasting improvements in adaptive functioning and behavior over about two years—unlike those on standard antiseizure therapy, who saw little change. The analysis, presented at the 16th European Epilepsy Congress, adds to evidence that the antisense oligonucleotide may address outcomes beyond seizure control.
The study compared data from Stoke Therapeutics’ phase 1/2a and open-label extension (OLE) trials—ADMIRAL and LONGWING—with the BUTTERFLY natural history study, which tracked DS patients receiving standard care. Researchers matched baseline characteristics between groups using statistical weighting to ensure comparability, employing a matching-adjusted indirect comparison method. They then measured changes in Vineland-3 subdomain scores, a validated tool assessing adaptive skills like communication, social interaction, and daily living, using mixed-effects models for repeated measures to evaluate longitudinal changes.
The phase 1/2a studies enrolled 81 patients (median age: 10; range: 2 to 18), with 75 continuing into OLE. At baseline, 81% were on three or more antiseizure medications, and 51% took four or more—commonly clobazam, fenfluramine, cannabidiol, and valproate. Patients received a phase 3-like dosing regimen: two 70-mg or three 45-mg loading doses followed by 45-mg maintenance every four months, with the OLE cohort’s median age increasing to 11 years (range: 2 to 19).
By the fourth year, those on zorevunersen showed statistically significant gains (P < .01) across five key Vineland-3 subdomains: expressive communication, receptive communication, interpersonal relationships, personal skills, and coping skills. Additional improvements appeared in play/leisure (P < .01) and fine motor skills (P < .03). Improvements were observed at each annual assessment through four years of treatment, demonstrating durable effects. In contrast, natural history patients in BUTTERFLY showed minimal change across these same subdomains over a comparable, roughly 2-year period.
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Beyond seizures: Dravet syndrome’s hidden developmental toll
“Seizures are the most acute symptom of Dravet syndrome, but the disease affects nearly every aspect of a child’s development, from their ability to communicate with loved ones to skills like dressing and feeding themselves,” said J. Helen Cross, MB, ChB, PhD, professor at University College London.
The analysis included long-term safety data spanning more than 260.7 patient-years of treatment, with a maximum treatment duration of 5.33 years. More than 930 doses had been administered by the data cutoff. In the phase 1/2a studies, 30% of patients experienced drug-related adverse events, most commonly cerebrospinal fluid (CSF) protein elevation (14%) and procedural vomiting (5%). Serious adverse events occurred in 22%, but all were deemed unrelated to zorevunersen.
In the OLE studies, 56% reported drug-related events, and 31% had serious adverse events—again, all unrelated to the drug. CSF protein elevation was observed in 94% of evaluable patients, classified as a treatment-emergent adverse event in 59%, but no serious or severe clinical manifestations were tied to it. One patient discontinued due to the elevation. Three deaths occurred across both studies, one in phase 1/2a and two in OLE, each from sudden unexpected death in epilepsy or malnutrition, assessed as unrelated to zorevunersen.
Safety profile reveals long-term tolerability challenges
As of February 19, 2026, 77% of OLE patients remained in the study, with most discontinuations occurring in lower-dose groups. “For patients with a chronic disease like Dravet syndrome, safety and tolerability are critically important,” said Stephanie Fradette, PharmD, head of the rare neurology development unit at Biogen. “The ongoing open-label extension studies will continue to grow the body of evidence shaping our understanding of zorevunersen’s long-term safety as well as its potential to address the underlying genetic cause of Dravet syndrome and improve outcomes for patients.”
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Zorevunersen is also being tested in EMPEROR (NCT06872125), a global, double-blind, randomized, sham-controlled phase 3 trial assessing efficacy, safety, and tolerability in children and adolescents with Dravet syndrome carrying confirmed SCN1A variants.
Phase 3 trial tests zorevunersen’s potential breakthrough
The trial’s design, including dose selection and duration, aims to balance statistical rigor with ethical feasibility. The EMPEROR study employs a double-blind, randomized approach with defined primary and secondary endpoints, ensuring robust evaluation of both efficacy and safety. Epilepsy expert Joseph Sullivan, director of the Pediatric Epilepsy Center at UCSF, noted in a NeurologyLive interview that the study’s structure reflects extensive planning to ensure meaningful results while minimizing risk to participants, including careful consideration of dose duration and endpoint timing.
If approved, zorevunersen would mark a shift in DS treatment, moving beyond symptom management to potential disease modification. Unlike prior therapies focused solely on reducing seizures, its effects on adaptive functioning suggest it may address the broader developmental challenges faced by patients. The phase 3 trial’s outcomes will be critical in determining whether these early signals translate into regulatory approval.