Analyzing Zorevunersen in Phase 3 Registrational Study for Dravet Syndrome: The EMPEROR Trial

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy marked by frequent, difficult-to-control seizures and significant cognitive, behavioral, and motor impairments. Most cases of the seizure disorder result from mutations in 1 copy of the SCN1A gene, causing reduced NaV1.1 protein in brain neurons. Despite available treatment with antiseizure medications, over 90% of patients with DS continue to experience seizures.¹ Zorevunersen (Stoke Therapeutics/Biogen), an investigational therapy for DS, is designed to upregulate Nav1.1 protein expression from the nonmutant copy of the SCN1A gene to restore physiological Nav1.1 levels.

The antisense oligonucleotide (ASO) therapy is currently being investigated in the 60-week, phase 3 EMPEROR (NCT06872125) among 150 anticipated patients with DS who have a confirmed variant in the SCN1A gene not associated with a gain of function. The primary end point of the trial is the change from baseline in major motor seizure frequency, with secondary end points that include change in behavior and cognition, clinical status, and health-related quality of life. Participants will also have the opportunity to enroll in an open label extension study and receive zorevunersen if they meet eligibility criteria at the end of the trial.²

Joseph Sullivan, MD, FAES

(Credit: UCSF)

“By targeting the underlying etiology of DS, upregulation of the Nav1.1 protein has the potential to have a positive impact on more than just seizures. While seizure control remains an unmet need, if we are able to precisely target the underlying cause, this may result in improvement of the other common co-morbidities that impact cognitive function, behavior, sleep and motor skills which all are important determinants of overall quality of life,” Joseph Sullivan, MD, FAES, professor of neurology and pediatrics, and director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco, told NeurologyLive^®.

Eligible patients are children aged 2 to under 18 years with a clinical diagnosis of DS confirmed by the Epilepsy Study Consortium. They must have seizure onset before 12 months of age and no other known cause for their DS symptoms.³ Patients are required to have a documented pathogenic, likely pathogenic, or uncertain variant in the SCN1A gene. Additionally, patients must experience a minimum number of major motor seizures during a 6-week observation period and have previously tried at least 2 interventions without adequate seizure control or because of adverse events. Ongoing maintenance antiseizure medications and other seizure interventions must be stable, including any cannabinoid-based products.

Patients are excluded if they have an SCN1A variant associated with gain-of-function or are currently on a maintenance antiseizure medication that primarily blocks sodium channels (e.g., phenytoin, carbamazepine, lamotrigine). Those receiving neuromodulation therapies, except vagus nerve stimulation, are also ineligible. Additional exclusions include the emergence of a new seizure type or reemergence of a past seizure type during the baseline period or experiencing more than 1 seizure-related hospitalization during that time.

“The EMPEROR trial design includes a sham control arm which allows us to assess changes in seizures and cognition in a blinded manner which adds scientific validity to the overall outcomes,” Sullivan added. “The duration of the trial allows for longitudinal assessment of cognition over an extended period of time which we hope will demonstrate a better developmental trajectory than what we know based on the natural history alone. If successful, this would lend further support to zorevunursen being a disease modifying therapy.”

Zorevunersen was first tested in the phase 1/2 MONARCH (NCT04740476) and ADMIRAL (NCT04442295) studies as well as their extensions, SWALLOWTAIL and LONGWING. Across the MONARCH and ADMIRAL trials, 81 patients with DS were enrolled. MONARCH (US) included single- and multiple-ascending dose phases, while ADMIRAL (UK) focused on multiple doses up to 70 mg of zorevunersen. Despite over 85% of participants using 3 or more antiseizure medications, median baseline seizure frequency remained high at 17 per 28 days, highlighting DS's refractory nature. Remarkably, patients receiving 2 or 3 doses of 70 mg of the agent experienced median seizure reductions of 85% at 3 months and 74% at 6 months.^4,5

Beyond seizure control, zorevunersen showed broad benefits, including clinical and quality-of-life improvements. In the 70 mg SAD and MAD cohorts, EuroQol 5-Dimension Youth scores improved by 7.756, with positive caregiver and clinician feedback on the Caregiver and Clinical Global Impression of Change scales. Across ADMIRAL cohorts, adaptive behavior gains were noted in Vineland-3 subdomains, including Receptive Communication (5.778), Personal Skills (2.030), and Gross Motor (3.517).

In the studies, zorevunsersen was considered safe and well tolerated at doses up to 70 mg. Overall, 30% of treated patients experienced a study drug-related treatment-emergent adverse event (TEAE), which mainly consisted of cerebrospinal fluid (CSF) protein elevations and procedural vomiting. Grade 3 or higher TEAEs were observed in 13 patients (16%), and 1 patient experienced a fatal event of presumed sudden death in epilepsy that was considered not related to the study drug. Notably, there were no TEAEs that led to study withdrawal.

“If zorevunersen is approved, I see this as being a first line treatment for patients with DS and would offer this to my patients as soon as I am able to.While treatment with ASMs known to be effective in DS will still be necessary, it is my hope that zorevunersen will have a positive impact on all aspects of the disease trajectory and also reduce the need for multiple ASMs,” Sullivan told NeurologyLive.

REFERENCES
1. Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet Syndrome in a US Population. Pediatrics. 2015;136(5):e1310-e1315. doi:10.1542/peds.2015-1807
2. Stoke Therapeutics Announces Alignment with Global Regulatory Agencies and Plans to Initiate a Phase 3 Study of Zorevunersen as Potentially the First Disease-Modifying Medicine for the Treatment of Dravet Syndrome. News Release. Stoke Therapeutics. Published January 7, 2025. Accessed August 20, 2025. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-alignment-global-regulatory
3. Stoke Therapeutics and Biogen Announce First Patient Dosed in Phase 3 EMPEROR Study of Zorevunersen, a Potential Disease-Modifying Treatment for Dravet Syndrome. News Release. Stoke Therapeutics. Published April 11,2025. Accessed August 20, 2025. https://www.businesswire.com/news/home/20250811088079/en/Stoke-Therapeutics-and-Biogen-Announce-First-Patient-Dosed-in-Phase-3-EMPEROR-Study-of-Zorevunersen-a-Potential-Disease-Modifying-Treatment-for-Dravet-Syndrome
4. Sullivan J, Cross HJ, Desurkar A, et al. Zorevunersen (STK-001) Demonstrates Potential for Disease Modification Including Reductions in Seizures and Improvements in Cognition and Behavior in Children and Adolescents with Dravet Syndrome (DS). Presented at: 2024 AES Annual Meeting
5. Cross HJ, Laux L, Sullivan J, et al. MONARCH and ADMIRAL: Open-label, Phase 1/2a studies in USA and UK investigating safety, drug exposure, and clinical effect of zorevunersen (STK-001), an antisense oligonucleotide, in children and adolescents with Dravet syndrome. Presented at: EEC