FDA, developer align on key details of treatment approval request in Dravet
Stoke now testing potential seizure-reducing therapy in large trial
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Stoke Therapeutics says it’s aligned with the U.S. Food and Drug Administration (FDA) on key aspects of a planned application seeking approval of zorevunersen for Dravet syndrome — including how to analyze data from an ongoing Phase 3 clinical trial testing the potential anti-seizure med.
According to the developer, its “successful meeting with the FDA” focused on the analysis of five years of safety and effectiveness data from earlier Phase 1/2a trials and their ongoing extensions, as well as the details of Stokes’ new drug application (NDA). This included the planned submission timeline for the application, as well as the clinical data that will support the therapy’s possible approval.
The meeting also covered Stokes’ planned approach to analyzing cognitive and behavioral data — a key secondary endpoint — from the now-underway late-stage EMPEROR trial (NCT06872125), which is assessing zorevunersen’s use in children and adolescents with Dravet. The experimental therapy, administered via direct injections into the spinal canal, is designed to reduce the seizures that mark Dravet.
Results from EMPEROR, which is still recruiting participants ages 2 to 17 at several sites worldwide, and the NDA submission are expected in the second half of 2027. If the trial data are positive and the FDA accepts the application, the treatment could potentially be approved and launched in the U.S. in early 2028.
“We are encouraged by our productive dialogue with the FDA and the Agency’s deepening understanding of the severity of Dravet syndrome and need for better treatments, and 5 years of safety and efficacy data for zorevunersen,” Ian F. Smith, CEO and director of Stoke, said in a company press release.
Dravet, a severe form of infantile-onset epilepsy, is mainly caused by mutations in the SCN1A gene. This gene provides instructions for making part of NaV1.1, a sodium channel that helps regulate nerve signaling in the brain. Most patients have one working and one mutated copy of the gene, resulting in too little functional NaV1.1. That can lead to excessive brain activity and recurrent seizures, as well as developmental, cognitive, behavioral, and sleep symptoms, and other neurological problems.
Seizures in Dravet can be difficult to control with anti-seizure medications, and there are no therapies approved to date that address the underlying cause of the disease.
Zorevunersen aims to target underlying disease
Zorevunersen is being developed as “a first-in-class potential disease-modifying treatment” for Dravet, according to Stoke. It contains an antisense oligonucleotide, a small piece of genetic material designed to help cells produce more functional NaV1.1 from the healthy copy of the SCN1A gene. By increasing NaV1.1 production, the treatment aims to improve nerve signaling and reduce seizures.
The EMPEROR trial is evaluating the safety and effectiveness of zorevunersen in children with Dravet who have motor seizures despite treatment with anti-seizure meds. Participants are randomly assigned to receive zorevunersen or a sham procedure, given two months apart and then once every three to four months. Those given the therapy are receiving two initial 70 mg doses, followed by 45 mg maintenance doses.
The trial’s main goal is to assess changes in motor seizure frequency after about seven months. Secondary outcomes include changes in development, behavior, cognition, and clinical status, as well as quality of life. After completing the first part of the study, participants may continue receiving the treatment in an open-label extension study, in which all will receive zorevunersen.
Stoke also plans to analyze four prespecified domains of the Vineland Adaptive Behavior Scales (Vineland-3), which assess how well people manage everyday activities and social interactions. The domains cover communication skills, such as the ability to communicate and understand others, and personal skills needed to perform everyday tasks. Participants’ interpersonal relationships, which refer to the ability to form relationships and respond appropriately in social situations, will also be assessed.
The company said these measures were selected based on input from clinicians and caregivers, as well as for their potential to capture meaningful changes in the neurodevelopmental effects of Dravet during one year of treatment.
“We are pleased with the Agency’s willingness to accept a multicomponent assessment of Vineland-3 data measuring changes in cognition and behavior from patients treated in the Phase 3 EMPEROR study,” Smith said. “We believe this is the most appropriate way to capture the effects of zorevunersen on people with Dravet syndrome who experience a wide range of debilitating neurodevelopmental impacts.”
2 earlier studies still following patients
Zorevunersen is also being tested in two ongoing open-label extension studies: SWALLOWTAIL (NCT04740476) and LONGWING (ISRCTN12811235). These followed the completion of the main Phase 1/2a clinical trials MONARCH (NCT04442295) and ADMIRAL (ISRCTN99651026).
Results from the Phase 1/2a studies and their extensions suggest that zorevunersen was associated with a reduction in seizure frequency that was sustained over four years of treatment. Improvements in communication, motor skills, socialization, daily living, and quality of life were also seen. Overall, zorevunersen was well tolerated, with some patients receiving treatment for longer than five years.
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