Biogen and Stoke Therapeutics Reach Collaborative Agreement for Development of Disease-Modifying Therapy Zorevunersen

Edward M. Kaye, MD

Credit: Stoke Therapeutics

Stoke Therapeutics, the developers of zorevunersen, an investigational, potentially disease-modifying treatment for Dravet syndrome (DS), and Biogen, have entered a collaborative agreement to develop and commercialize the agent going forward. Stoke retains exclusive rights for zorevunersen in the United States, Canada, and Mexico, while Biogen receives exclusive rest of world commercialization rights.¹

Zorevunersen, an antisense oligonucleotide designed to treat the underlying cause of DS, is currently being investigated in a global, phase 3 study that is expected to be used as part of a future submission to regulatory authorities. Otherwise known as EMPEROR, the study is expected to begin in the second quarter of this year, with data anticipated in the second half of 2027.

As part of the new collaborative agreement, Stoke will receive a $165 million upfront payment upon closing, with Biogen covering 30% of zorevunersen’s clinical development costs and Stoke 70%. Stoke may earn up to $385 million in milestone payments and tiered royalties from low double digits to high teens on Biogen’s net sales. Biogen also has an option to license follow-on SCN1A-targeting antisense oligonucleotide products outside the U.S., Canada, and Mexico, with additional milestone, cost-sharing, and royalty terms.

"With Biogen’s deep experience in neurology and track record of success in commercializing high-value disease-modifying medicines for rare genetic diseases globally, we aim to lead the treatment of Dravet syndrome into a new era by delivering zorevunersen to all patients who could benefit," Edward M. Kaye, MD, chief executive officer at Stoke, said in a statement.¹ "Additionally, this collaboration provides cash flows, that when combined with Stoke’s financial position, support the company through to mid-2028."

EMPEROR, a 60-week trial, is expected to include 150 patients with DS who have a confirmed variant in the SCN1A gene not associated with a gain of function. The study, which includes a 52-week treatment period, along with an optional open-label extension, will use reductions in major motor seizure frequency as the primary end point. Additional secondary end points include durability of effect on major motor seizure frequency, as well as improvements in behavior and cognition on Vineland-3 subdomains, which comprise expressive communication, receptive communication, interpersonal relationships, coping skills, and personal skills.²

Priya Singhal, MD, MPH

"This collaboration broadens our late-stage pipeline with the addition of a Phase 3-ready disease modifying investigational medicine and allows us to leverage our rare disease product commercialization expertise and global footprint," Priya Singhal, MD, MPH, head of development at Biogen, said in a statement.¹ "The reductions in seizures in patients already receiving standard of care medicines, together with the improvements in multiple measures of cognition and behavior, demonstrate the potential of zorevunersen as the first disease modifying medicine that addresses the underlying cause of Dravet syndrome."

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 three 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.^3,4

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.

At the 2024 American Epilepsy Society (AES) Annual Meeting, Barry Ticho, MD, PhD, chief medical officer at Stoke, sat down to discuss the latest data on zorevunersen, as well as the FDA’s decision to grant breakthrough therapy designation to the agent. In the clip below, he discussed how the planned phase 3 trial will aim to confirm the therapy’s effects, as well as the potential impact the treatment could bring to patients if the study results are successful.

REFERENCES
1. Biogen and Stoke Therapeutics Enter into Collaboration to Develop and Commercialize Zorevunersen for the Treatment of Dravet Syndrome, a Rare Genetic Epilepsy Associated with Refractory Seizures and Neurodevelopmental Impairments. News release. Biogen. February 18, 2025. Accessed February 18, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-and-stoke-therapeutics-enter-collaboration-develop-and
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. January 7, 2025. Accessed February 18, 2025. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-alignment-global-regulatory
3. 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
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