Stoke Therapeutics and Biogen have announced the dosing of the first patient in their pivotal Phase 3 EMPEROR study of zorevunersen for Dravet syndrome, marking a critical milestone in the development of what could become the first disease-modifying treatment for this severe genetic epilepsy. The global, randomized, sham-controlled trial will evaluate the investigational antisense oligonucleotide over a 52-week treatment period.
Study Design and Patient Population
The EMPEROR study will enroll patients with Dravet syndrome between ages 2 and 18 who have confirmed variants in the SCN1A gene not associated with gain of function. Following an 8-week baseline period, participants will be randomized 1:1 to receive either zorevunersen or sham treatment for 52 weeks.
Patients in the active treatment arm will receive two 70mg loading doses on Day 1 and Week 8, followed by two 45mg maintenance doses at Week 24 and Week 40. All participants will continue receiving standard of care anti-seizure medicines throughout the study period.
The primary endpoint focuses on change in major motor seizure frequency measured at Week 28. Key secondary endpoints include seizure frequency changes at Week 52 and improvements in behavior and cognition as measured by Vineland-3 subdomains, including expressive communication, receptive communication, interpersonal relationships, coping skills and personal skills.
Clinical Rationale and Previous Results
"Our Phase 1/2 and open-label extension studies have provided a large dataset to support our understanding of zorevunersen and guide the EMPEROR study design, including dosing, duration and selection and powering of the endpoints," said Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics. "Given the severity of this disease and the limitations of current treatments, the substantial and durable reductions in seizures and continuing improvements in cognition and behavior support our belief that zorevunersen may improve outcomes for patients with Dravet syndrome."
Katherine Dawson, M.D., Head of the Therapeutics Development Unit at Biogen, emphasized the unmet medical need: "Despite treatment with available anti-seizure medicines, no approved medications currently address the underlying cognitive and behavioral aspects of this rare, genetic disease."
Disease Burden and Treatment Landscape
Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by severe, recurrent seizures and significant cognitive and behavioral impairments. Most cases result from mutations in one copy of the SCN1A gene, leading to insufficient levels of NaV1.1 protein in neuronal cells in the brain.
More than 90 percent of patients continue to experience seizures despite treatment with the best available anti-seizure medicines. The disease burden extends beyond seizures to include intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, and mood disorders. Patients face a higher risk of sudden unexpected death in epilepsy (SUDEP) compared to the general epilepsy population.
Currently, an estimated 38,000 people are living with Dravet syndrome globally, including approximately 16,000 in the United States, with additional patients in the UK, EU-4 countries, and Japan.
Mechanism of Action and Regulatory Status
Zorevunersen is designed to treat the underlying cause of Dravet syndrome by increasing NaV1.1 protein production in brain cells from the non-mutated copy of the SCN1A gene. This mechanism aims to reduce seizure frequency beyond what current anti-seizure medicines achieve while improving neurodevelopment, cognition, and behavior.
The drug has received significant regulatory recognition, including orphan drug designation from both the FDA and EMA. The FDA has also granted zorevunersen rare pediatric disease designation and Breakthrough Therapy Designation for treating Dravet syndrome with confirmed SCN1A gene mutations not associated with gain-of-function.
Clinical Perspective and Global Reach
Joseph Sullivan, M.D., FAES, principal investigator and Professor of Neurology and Pediatrics at the University of California San Francisco, highlighted the study's significance: "Providing additional relief from seizures remains an important clinical outcome, but the potential to address the underlying genetic cause to also address neurodevelopmental symptoms signals a fundamentally new way of treating the disease. The urgent need for treatments is evident in the high degree of interest in the EMPEROR study."
The EMPEROR clinical trial has initiated in the United States, United Kingdom, and Japan, with plans for expansion into Europe. Eligible participants will be offered ongoing treatment with zorevunersen through an open-label extension study.
Partnership and Development Strategy
Under their strategic collaboration, Stoke Therapeutics retains exclusive rights for zorevunersen in the United States, Canada, and Mexico, while Biogen holds exclusive commercialization rights for the rest of the world. The partnership leverages Stoke's proprietary TANGO (Targeted Augmentation of Nuclear Gene Output) approach, which uses antisense oligonucleotides to selectively restore naturally-occurring protein levels in diseases caused by haploinsufficiency.
