Biogen and Stoke Therapeutics announced promising new data for zorevunersen, an investigational antisense oligonucleotide for Dravet syndrome, showing improvements in cognition and behavior at Week 68 using a Phase 3 dosing regimen. The findings were presented at the 16th European Paediatric Neurology Society (EPNS) Congress and provide critical insights for the ongoing Phase 3 EMPEROR study design.
Novel Analysis Supports Phase 3 Study Design
The companies conducted a mixed-effects model for repeated measures (MMRM) analysis to evaluate the potential effects of the Phase 3 zorevunersen dosing regimen on patient cognition and behavior. The model utilized clinical data from patients in the Phase 1/2a ADMIRAL study and the LONGWING open label extension (OLE) study.
Patients who received a total cumulative dose consistent with the Phase 3 EMPEROR regimen—two loading doses of 70mg followed by two maintenance doses of 45mg—showed improvements in cognition and behavior. These improvements contrasted with findings from the BUTTERFLY natural history study, where patients with Dravet syndrome received standard-of-care anti-seizure medicines.
"Natural history data shows the limitations of treating this disease with anti-seizure medicines," said Dr. Andreas Brunklaus, Consultant Paediatric Neurologist at the Royal Hospital for Children in Glasgow and study investigator. "The zorevunersen data give us early evidence that this new genetically-targeted approach could address the underlying cause of Dravet syndrome, resulting in additional seizure control and offer patients the opportunity to experience improvements in cognition and behavior."
Key Secondary Endpoints Validated
The analysis supports the selection of five sub-domains of the Vineland-3 Adaptive Behavior Scales as key secondary endpoints in the Phase 3 EMPEROR study: Receptive Communication, Expressive Communication, Interpersonal Relationships, Coping Skills, and Personal Skills.
"Effects on behavior and cognition are a key secondary endpoint in our Phase 3 EMPEROR study," said Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics. "Feedback from caregivers and clinicians, and analyses like this one, give us insight into which assessments have the greatest potential to demonstrate meaningful effects for patients within the year-long treatment period."
Addressing Unmet Medical Need
Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by severe, recurrent seizures as well as significant cognitive and behavioral impairments. More than 90 percent of patients continue to experience seizures despite treatment with the best available anti-seizure medicines. Currently, up to 38,000 people are living with Dravet syndrome in the United States (~16,000), United Kingdom, EU-4 (Germany, France, Italy, Spain) and Japan.
"Most patients with Dravet syndrome continue to experience seizures despite treatment with the best available anti-seizure medicines, and there are currently no medications approved that address the underlying cognitive and behavioral aspects of the disease," said Katherine Dawson, M.D., Head of the Therapeutics Development Unit at Biogen.
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. Most cases of Dravet syndrome are caused by mutations in one copy of the SCN1A gene, leading to insufficient levels of NaV1.1 protein in neuronal cells in the brain.
The investigational therapy has received orphan drug designation from both the FDA and EMA. The FDA has also granted zorevunersen rare pediatric disease designation and Breakthrough Therapy Designation for the treatment of Dravet syndrome with a confirmed mutation not associated with gain-of-function in the SCN1A gene.
Previous Clinical Data
Previously presented data from the Phase 1/2a and OLE studies showed substantial and durable reductions in major motor seizure frequency on top of standard anti-seizure medicines, with improvements in multiple measures of cognition and behavior through two years of treatment. Data indicated responses may be better among patients who received loading doses of 70mg followed by maintenance doses of 45mg. Zorevunersen was generally well-tolerated across these studies.
Strategic Collaboration
Stoke Therapeutics and Biogen have established a strategic collaboration to develop and commercialize zorevunersen for Dravet syndrome. Under the agreement, Stoke retains exclusive rights for zorevunersen in the United States, Canada, and Mexico, while Biogen receives exclusive rest-of-world commercialization rights.
