Stoke Announces Phase 3 EMPEROR Registrational Study for Zorevunersen in Dravet Syndrome

Edward M. Kaye, MD

Following successful conversations and alignment with regulatory agencies, Stoke Therapeutics has announced the design of its phase 3 registrational trial, dubbed EMPEROR, that will test the effects of zorevunersen, an investigational antisense medicine, in children and adolescents with Dravet syndrome (DS). Expected to initiate in mid-2025, the study will include 150 patients with DS who have a confirmed variant in the SCN1A gene not associated with a gain of function.¹

The global study, which spans across the United Kingdom, the United States, European Union, and Japan, lasts a total of 60 weeks, and is comprised of an 8-week baseline period followed by a 52-week treatment period. Using reductions in major motor seizure frequency as the primary end point, the trial is expected to have data read out by the end of 2027, pending enrollment and study timelines. Following the double-blind portion, patients will be eligible to continue zorevunersen as part of an open-label extension study.

In EMPEROR, patients will be given either sham or 2 loading doses of 70 mg zorevunersen followed by 2 maintenance doses of 45 mg over 52 weeks. Additional secondary end points include durability of effect on major motor seizure frequency, as well as improvements in behavior and cognition on Vinelined-3 subdomains, which include expressive communication, receptive communication, interpersonal relationships, coping skills, and personal skills. The study will also implement other additional outcomes, such as safety, Clinical Global Impression of Change, Caregiver Global Impression of Change, and the Bayley Scales of Infant Development.

"Alignment around a global Phase 3 study design for zorevunersen puts us one step closer to our goal of delivering the first disease-modifying medicine for the treatment of Dravet syndrome," Edward M. Kaye, MD, chief executive officer at Stoke, said in a statement.¹ "The level of attention and enthusiasm from clinicians, patient organizations and regulatory authorities for this study speaks to the shared understanding that current treatments are inadequate."

He added, "Their support also underscores a belief in the data from our clinical studies that demonstrated substantial and durable reductions in seizure frequency and improvements across multiple measures of cognition and behavior, when treated with a similar dosing regimen. We look forward to continuing to work together with a sense of purpose and urgency as we prepare to initiate the EMPEROR study by mid-year."

Recently, at the 2024 American Epilepsy Society (AES) Annual Meeting, Stoke led a number of presentations that supported the phase 3 dosing regimen. The new data included 9 patients who received 2 or 3 initial doses of 70 mg of zorevunersen in a phase 1/2 study and then continued treatment in an OLE where they received at least 2 doses of 45 mg. Results showed that patients experienced an 87% median reduction in convulsive seizure frequency by month 8 (4 months after the second 45mg dose). Over 2 years of ongoing maintenance treatment in the OLEs, these treated individuals showed continued improvements in cognition and behavior, with additional gains observed within the first nine months of the Phase 1/2a study.²

Zorevunersen, also known as STK-001, is delivered intrathecally, allowing the oligonucleotide to reach the brain and restore sodium channel levels back to normal. To date, 81 children have been treated with the drug, with some children on it for more than 3 years. Overall, the agent has been considered well tolerated, with elevated cerebrospinal fluid—a lab finding consistent with class effects of intrathecal antisense oligonucleotides—as the only main safety finding. In December 2024, it was granted breakthrough therapy designation by the FDA for its potential as a disease-modifying treatment for DS.³

Kelly Knupp, MD, MSCS

"I have participated as an investigator in many clinical research studies, nearly all of which have been designed to test the next best anti-seizure medicine,” Kelly Knupp, MD, MSCS, Dravet Program Director and Epilepsy Program Lead at Children’s Hospital Colorado, said in a statement.¹ "What families and we as clinicians now want are medicines that go beyond reducing seizures to address the neurodevelopmental issues associated with Dravet syndrome, including giving patients the ability to communicate with the people around them and achieve a certain level of independence, which cannot be achieved with today’s standard of care."

She added, "This is the first Phase 3 study to assess the effects of a disease-modifying medicine on seizures as well as multiple aspects of cognition and behavior, which could lead us into a new era in the treatment of Dravet syndrome."

The efficacy and safety of zorevunersen was first on display in the phase 1/2 MONACH (NCT04740476) and ADRIMAL (NCT04442295) studies as well as their extensions, SWALLOWTAIL and LONGWING. Across the MONARCH and ADMIRAL trials, 81 patients with DS were enrolled from an initial 97 screened. The US-based MONARCH trial included single-ascending dose (SAD) and multiple ascending dose (MAD) phases, while the UK-based ADMIRAL trial focused on MAD phases with doses up to 70 mg of STK-001. Despite over 85% of participants using three or more antiseizure medications, their median baseline convulsive seizure frequency was 17 per 28 days, reflecting the refractory nature of DS. Notably, patients who received 2 or 3 doses of 70 mg of STK-001 achieved median seizure reductions of 85% at 3 months and 74% at 6 months post-treatment.⁴

Beyond seizure control, significant improvements in clinical status and quality of life were observed. In the 70 mg SAD and MAD cohorts, the predicted improvement on the EuroQol 5-Dimension Youth questionnaire was 7.756, with caregivers and clinicians reporting positive changes on the Caregiver and Clinical Global Impression of Change scales. Additionally, gains in adaptive behavior were recorded across all ADMIRAL cohorts, with improvements noted in Vineland-3 subdomains such as Receptive Communication (5.778), Personal Skills (2.030), and Gross Motor (3.517), highlighting the broad benefits of STK-001 therapy.

REFERENCES
1. 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. January 7, 2025. Accessed January 7, 2025. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-alignment-global-regulatory
2. 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;
3. Stoke Therapeutics Receives FDA Breakthrough Therapy Designation for Zorevunersen for the Treatment of Dravet Syndrome. News release. Stoke Therapeutics. December 4, 2024. Accessed January 7, 2025. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-receives-fda-breakthrough-therapy-designation/
4. 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