Stoke Therapeutics' zorevunersen, an investigational antisense oligonucleotide (ASO), has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of Dravet syndrome. This designation is specifically for patients with a confirmed mutation in the SCN1A gene that is not associated with gain-of-function. Zorevunersen is under development as a potential disease-modifying medicine for Dravet syndrome, a severe and progressive genetic epilepsy affecting approximately 1 in 16,000 babies.
The FDA's decision is supported by clinical data from Phase 1/2a and open-label extension (OLE) studies, which demonstrated substantial and sustained reductions in seizure frequency and continuous improvements in multiple measures of cognition and behavior. These effects were observed on top of the best available anti-seizure medicines, the current standard of care. Zorevunersen was generally well tolerated across the studies, with more than 600 doses administered to patients, some of whom have been on treatment for more than three years.
Shamim Ruff, Chief Regulatory Affairs Officer at Stoke Therapeutics, stated, "The FDA’s Breakthrough Therapy designation for zorevunersen is supported by promising clinical data that suggest that zorevunersen has the potential to demonstrate substantial improvement over current treatments for Dravet syndrome. By helping the body restore naturally occurring NaV1.1 protein levels, zorevunersen is designed to treat the underlying cause of the disease."
Mechanism of Action
Dravet syndrome is characterized by frequent, prolonged, and refractory seizures, beginning within the first year of life. It is often associated with intellectual disability, developmental delays, and an increased risk of sudden unexpected death in epilepsy (SUDEP). There are currently no approved disease-modifying therapies for Dravet syndrome.
Zorevunersen (STK-001) is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels. By restoring NaV1.1 levels, zorevunersen aims to reduce both the occurrence of seizures and significant non-seizure comorbidities associated with Dravet syndrome.
Clinical Trial Data
Data from Phase 1/2a and open-label extension (OLE) studies of zorevunersen demonstrated clinically meaningful outcomes. Patients treated with zorevunersen experienced substantial and sustained reductions in seizure frequency and continuous improvements in multiple measures of cognition and behavior. These effects were observed on top of the best available anti-seizure medicines, the current standard of care.
In the MONARCH and ADMIRAL trials, 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, compared with baseline. Within 36 weeks of treatment with zorevunersen, data showed significant improvements in clinical status and quality of life. All ADMIRAL cohorts demonstrated gains in Vineland-3 Adaptive Behavior Scale subdomains, including Receptive Communication (5.778), Expressive Communication (3.272), Personal Skills (2.030), Interpersonal Relationships (3.096), Coping Skills (0.700), Gross Motor (3.517), and Fine Motor (1.993).
Regulatory Path Forward
With Breakthrough Therapy designation, zorevunersen gains access to Fast Track designation features, intensive guidance on an efficient drug development program, and an organizational commitment involving senior FDA managers. Stoke Therapeutics is currently in discussions with the FDA and other global regulatory agencies regarding a global, randomized, controlled Phase 3 registrational study of zorevunersen. The company plans to provide an update on its Phase 3 registrational plans by the end of the year.
Mary Anne Meskis, Executive Director of the Dravet Syndrome Foundation, commented, "This designation brings new hope to the many patients with Dravet syndrome who continue to experience treatment-resistant seizures and a myriad of health and quality of life complications despite the availability of symptomatic treatments."
