Investigational Zorevunersen Linked to Adaptive Gains in Dravet Syndrome

A matching-adjusted indirect comparison presented at the 16th European Epilepsy Congress found that patients with Dravet syndrome (DS) treated with zorevunersen (Stoke Therapeutics) showed substantial and durable improvements in adaptive functioning and behavior over approximately 2 years, in contrast to minimal change observed among natural history patients receiving standard antiseizure therapy.¹

The analysis, presented alongside long-term safety and exposure data spanning more than 260 patient-years of treatment, added to evidence on the investigational antisense oligonucleotide's potential effect on outcomes beyond seizure frequency.

Study design

The comparison drew on data from the phase 1/2a and open-label extension (OLE) studies of zorevunersen (ADMIRAL and LONGWING) and the 2-year BUTTERFLY natural history study, matching baseline characteristics between cohorts using matching-adjusted indirect comparison weighting.^1,3 Longitudinal change in Vineland-3 subdomain scores, a validated measure of adaptive functioning and behavior, was evaluated using mixed-effects models for repeated measures.

The phase 1/2a studies enrolled 81 patients with Dravet syndrome (median age, 10 years; range, 2 to 18), of whom 75 continued into the OLE studies (median age, 11 years; range, 2 to 19) with maintenance dosing every 4 months.^1,2 At baseline, 81% of patients were taking 3 or more antiseizure medications and 51% were taking 4 or more, most commonly clobazam, fenfluramine, cannabidiol, and valproate compounds.¹

Adaptive functioning results

Among patients receiving a phase 3-like dosing regimen of zorevunersen (two 70-mg or three 45-mg loading doses followed by 45-mg maintenance every 4 months), statistically significant improvements from OLE baseline (P <.01) were observed across 5 key Vineland-3 subdomains, expressive communication, receptive communication, interpersonal relationships, personal skills, and coping skills, at each annual assessment through 4 years of treatment. Additional improvements were observed in play and leisure (P <.01) and fine motor subdomains (P <.03). By contrast, natural history patients in the BUTTERFLY study showed minimal change across these same subdomains over a comparable, roughly 2-year period.^1,3

“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,” J. Helen Cross, MB, ChB, PhD, professor at University College London, said in a statement.⁴ “The continuing improvements in cognition and behavior shown in these studies suggest zorevunersen has the potential to narrow the developmental gap between these children and their neurotypical peers, helping them gain more independence.”

Safety and long-term exposure

As of the data cutoffs reported, more than 930 doses of zorevunersen had been administered across the phase 1/2a and OLE studies, with total exposure reaching 260.7 patient-years and a maximum treatment duration of 5.33 years. Additional findings included:

• In the phase 1/2a studies, 30% (24 of 81) of patients experienced a study drug-related treatment-emergent adverse event (TEAE), most commonly cerebrospinal fluid (CSF) protein elevation (14%) and procedural vomiting (5%); 22% (18 of 81) experienced a treatment-emergent serious adverse event (TESAE), with 17 of 18 assessed as unrelated to study drug.
• In the OLE studies, 56% (42 of 75) of patients experienced a study drug-related TEAE, and 31% (23 of 75) experienced a TESAE, all assessed as unrelated to study drug.
• CSF protein elevation occurred in 94% (68 of 72) of evaluable OLE patients and was classified as a TEAE in 59% of those cases; no serious or severe clinical manifestations tied to CSF protein elevation were observed, and 1 patient discontinued treatment because of it.
• One death in the phase 1/2a studies and 2 deaths in the OLE studies (from sudden unexpected death in epilepsy and malnutrition) were reported, each assessed as unrelated to study drug.
• As of the February 19, 2026, data cutoff, 58 of 75 patients (77%) remained in the OLE studies; most discontinuations occurred 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.⁴ “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.”

Ongoing phase 3 development

Zorevunersen is also being evaluated 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.⁶ Enrollment across the United States, United Kingdom, and Japan has been completed, and Stoke Therapeutics has said a phase 3 data readout is anticipated in mid-2027, with a rolling new drug application submission planned to begin in the first half of that year.⁷

In late 2025, NeurologyLive launched a Special Report series following zorevunersen and the next chapter of treatment for DS. In the clip below, epilepsy expert Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at UCSF, describes the extensive planning that went into structuring the EMPEROR trial, from dose selection and duration to endpoint timing. He explains how the trial balances the need for statistical power and ethical feasibility, using a sham-controlled design with defined primary and secondary endpoints.

REFERENCES
1. Brunklaus A, Cross JH, Knupp KG, et al. Zorevunersen demonstrates potential as a disease-modifying therapy in patients with Dravet syndrome: a matching-adjusted indirect comparison between natural history and patients receiving zorevunersen. Poster P0803. Presented at: 16th European Epilepsy Congress; September 5-9, 2026; Athens, Greece.
2. Laux L, et al. Zorevunersen in children and adolescents with Dravet syndrome. N Engl J Med. 2026;394(10):969-982. doi:10.1056/NEJMoa2506295
3. Sullivan J, et al. Natural history of children and adolescents with Dravet syndrome: a 24-month follow-up. Neurology. 2025;105:e214388. doi:10.1212/WNL.0000000000214388
4. Stoke Therapeutics and Biogen present long-term clinical data that support the disease-modifying potential of zorevunersen, an investigational medicine for the treatment of Dravet syndrome, at the 16th European Epilepsy Congress (EEC). News release. Published September 3, 2026. Accessed September 4, 2026. https://investors.biogen.com/news-releases/news-release-details/stoke-therapeutics-and-biogen-present-long-term-clinical-data
5. Stoke Therapeutics and Biogen announce presentations of clinical data from studies of zorevunersen, an investigational medicine for the treatment of Dravet syndrome, at the 16th European Epilepsy Congress (EEC). News release. Published September 1, 2026. Accessed September 4, 2026. https://www.biospace.com/press-releases/stoke-therapeutics-and-biogen-announce-presentations-of-clinical-data-from-studies-of-zorevunersen-an-investigational-medicine-for-the-treatment-of-dravet-syndrome-at-the-16th-european-epilepsy-congress-eec
6. A study of zorevunersen in participants with Dravet syndrome (EMPEROR). ClinicalTrials.gov identifier: NCT06872125. Accessed September 4, 2026. https://clinicaltrials.gov/study/NCT06872125
7. Stoke Therapeutics announces updates to timelines for the completion of enrollment and phase 3 data readout from EMPEROR study. News release. Published January 11, 2026. Accessed September 4, 2026. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-updates-timelines-completion