AES Presentations Highlight Zorevunersen as Disease-Modifying Treatment for Dravet Syndrome

At the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, several data presentations, including a long-term open-label extension, further supported zorevunersen (Stoke Therapeutics), an investigational antisense oligonucleotide, as a disease-modifying treatment for Dravet syndrome (DS).

Long-term open-label results from M. Scott Perry, MD, detailed sustained clinical benefits, while Kelly Knupp’s, MD, poster showed increases in seizure-free days, improved quality of life, and better overall clinical status. Additional electrophysiologic analyses from Epilog researchers, including Pieter van Mierlo, MD, and Nigel Colenbier, MD, demonstrated characteristic EEG abnormalities in untreated patients and measurable improvements following treatment. Collectively, these studies provided a multidimensional view of zorevunersen’s impact across clinical, patient-reported, and electrophysiologic outcomes.

Long-Term Efficacy Findings

The analyses were from the phase 1/2a MONARCH and ADMIRAL studies (NCT04442295) and their open-label extensions, SWALLOWTAIL (NCT04740476) and LONGWING. A propensity score–weighted comparison, designed to balance baseline differences between treated patients and those in a natural history cohort, demonstrated that individuals who began therapy with two 70-mg loading doses of zorevunersen had a substantial 73.6% reduction in median convulsive seizure frequency six months after their final dose —mirroring the timing of the Week 28 primary endpoint used in the phase 3 program.

"Over the last four years we have gained an increasing appreciation for the potential to change the course of Dravet syndrome with new disease-modifying medicines. Open-label data from the zorevunersen clinical studies have been highly encouraging, bringing hope and anticipation to the Dravet community," Scott Perry, MD, Head of Neurosciences and Director of the Jane and John Justin Institute for Mind Health and Medical Director of the Genetic Epilepsy Clinic at Cook Children’s Medical Center, said in a statement. “In addition, the new propensity score weighted analysis comparing zorevunersen treatment to patients treated with the current standard of care gives us further context for the improvements we’re seeing in patients living with this devastating disease."

Over that same period, they gained a median of seven additional convulsive seizure-free days per 28-day cycle—ranging from 2 to 20—resulting in a total median of 24 seizure-free days per month. In the open-label extensions, these individuals continued on 45-mg maintenance dosing every four months and sustained robust improvements, with median convulsive seizure-frequency reductions ranging from 53.0% to 87.0% from their naïve baseline through Month 8.

Sustained dosing at 45 mg was associated with continued gains, including measurable improvements across multiple Vineland-3 cognitive and behavioral domains at 18 months, several of which reached statistical significance. These benefits aligned with exposure levels expected for the key secondary endpoint in the ongoing phase 3 EMPEROR trial (NCT) and remained durable through 24 months, the longest follow-up available from the BUTTERFLY natural history dataset.

Safety Data

To date, a total of 81 patients received at least 1 dose of zorevunersen across the phase 1/2a and open-label extension studies, with more than 800 doses administered to date. Overall, the therapy has been generally well tolerated. Study drug–related TEAEs occurred in 30% (24/81) of patients in phase 1/2a and 53% (40/75) in the OLE, with the most common event being CSF protein elevations. These elevations were reported in 14% (11/81) of phase 1/2a patients and 45% (33/75) of OLE patients, and levels exceeding 50 mg/dL occurred in 42% (34/81) and 86% (62/72), respectively. Although one patient discontinued because of elevated CSF protein, no associated clinical symptoms were observed.

Treatment-emergent serious adverse events were reported in 22% (18/81) of Phase 1/2a participants and 29% (22/75) in the OLE, with all events deemed unrelated to zorevunersen except for one case classified as a SUSAR. Three deaths were reported across the studies—two attributed to SUDEP and one to malnutrition—with none considered related to treatment.

Related Content

NeurologyLive® recently hosted an Insights series program featuring Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at UCSF, and Perry, to discuss the zorevunersen clinical trial program and its long-term data. In this clip below, Sullivan 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.

Click here for more AES 2025 coverage.

REFERENCES
1. Biogen and Stoke Therapeutics Present Data that Further Support the Disease-Modifying Potential of Zorevunersen, an Investigational Medicine for the Treatment of Dravet Syndrome, at the 2025 American Epilepsy Society (AES) Annual Meeting. News release. Stoke Therapeutics. December 5, 2025. Accessed December 7, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-and-stoke-therapeutics-present-data-further-support
2. Sullivan J, Perry MS, Brunklaus A, et al. Zorevunersen Continues to Demonstrate Potential as a Disease-modifying Therapy in Long-term Open-label Extension Studies of Patients with Dravet Syndrome. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. ABSTRACT 2.341.
3. Knupp K, Sullivan J, Perry MS, et al. Zorevunersen Demonstrates Disease-modifying Potential in Patients with Dravet Syndrome with Increases in Seizure-free Days, Improvements in Quality of Life, and Benefits in Overall Functioning. 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. ABSTRACT 2.341. ABSTRACT 1.379