Biogen and Stoke Therapeutics have entered into a collaboration to develop and commercialize zorevunersen, an investigational antisense oligonucleotide (ASO) for Dravet syndrome, in all territories outside the United States, Canada, and Mexico. The agreement, announced Tuesday, combines Stoke's expertise in RNA-based medicines with Biogen's global reach in neurology and rare diseases.
Zorevunersen targets the underlying genetic cause of Dravet syndrome, a severe form of epilepsy that begins in childhood. Most cases of Dravet syndrome are caused by mutations in the SCN1A gene, leading to a deficiency in the NaV1.1 sodium channel protein. Zorevunersen is designed to upregulate NaV1.1 protein expression from the non-mutated copy of the SCN1A gene, aiming to restore physiological protein levels and reduce both seizures and non-seizure comorbidities.
EMPEROR Phase 3 Study
Stoke Therapeutics recently announced alignment with global regulatory agencies on the design of the Phase 3 EMPEROR study of zorevunersen. The global, randomized, double-blind, sham-controlled trial is expected to enroll approximately 150 patients with Dravet syndrome between the ages of 2 and 18. Participants must have a confirmed SCN1A gene variant not associated with a gain of function.
The EMPEROR study will evaluate two loading doses of 70mg followed by two maintenance doses of 45mg over 52 weeks, compared to a sham. The primary endpoint is the percent change from baseline in major motor seizure frequency. Key secondary endpoints include the durability of effect on major motor seizure frequency and improvements in cognition and behavior, as measured by the Vineland-3 scale. Additional endpoints include safety, Clinician Global Impression of Change (CGI-C), Caregiver Global Impression of Change (CaGI-C), and the Bayley Scales of Infant Development (BSID-IV).
The study is on track to initiate in the second quarter of 2025, with a pivotal data readout expected in the second half of 2027. Stoke will continue to lead global development and retain exclusive development and commercialization rights for zorevunersen in the U.S., Canada, and Mexico.
Financial Terms
Under the terms of the agreement, Stoke will receive an upfront payment of $165 million from Biogen. The parties will share external clinical development costs for zorevunersen, with Biogen covering 30% and Stoke covering 70%. Stoke may also receive up to $385 million in development and commercial milestone payments. Additionally, Stoke will be eligible to receive tiered royalties on potential net sales in the Biogen territory, ranging from low double digits to high teens.
Stoke has also granted Biogen an option to license rights outside of the U.S., Canada, and Mexico to certain future follow-on ASO products targeting SCN1A, in exchange for separate milestone, cost sharing, and royalty considerations.
Clinical Data and Regulatory Status
Zorevunersen has been granted orphan drug designation by the FDA and the EMA, as well as rare pediatric disease designation and Breakthrough Therapy Designation by the FDA for the treatment of Dravet syndrome with a confirmed mutation, not associated with gain-of-function, in the SCN1A gene.
Data from a Phase 1/2a study and an open-label extension study (OLE) showed that patients treated with zorevunersen experienced an 87% median reduction in convulsive seizure frequency at month eight (four months after the second dose of 45mg). Patients also experienced continuing improvements in multiple measures of cognition and behavior as measured by the Vineland-3 through 2 years of treatment with ongoing maintenance dosing in the OLEs. Zorevunersen has been generally well tolerated across the studies, with more than 600 doses administered to patients across multiple studies, some remaining on treatment for more than three years.
Expert Commentary
"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," said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. "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."
Dr. Kelly Knupp, M.D., MSCS, Professor of Pediatrics and Neurology at the University of Colorado, Anshutz Medical Campus and the Dravet Program Director and Epilepsy Program Lead at Children's Hospital Colorado, added, "What families and we as clinicians now want are medicines that go beyond reducing seizures to address the neurodevelopmental issues associated with Dravet syndrome... 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."
