Stoke, Biogen announce data from open-label extension studies of zorevunersen

Stoke Therapeutics (STOK) and Biogen (BIIB) announced data from Phase 1/2a and open-label extension studies of zorevunersen that support the potential for zorevunersen to be the first disease-modifying medicine for Dravet syndrome. Findings were presented at the 36th International Epilepsy Congress in Lisbon, Portugal. Data support the EMPEROR Phase 3 study of zorevunersen that is now underway to further evaluate this investigational antisense oligonucleotide. Data presented from the Phase 1/2a and open-label extension studies represent more than four years of clinical experience with zorevunersen. Across the studies, substantial and durable reductions in major motor seizure frequency and continuing improvements in cognition, behavior and quality of life were shown on top of standard anti-seizure regimens. More than 700 doses of zorevunersen have been administered to date. The Phase 1/2a studies evaluated single and multiple doses of zorevunersen up to 70mg with a primary endpoint of safety. Effects on major motor seizure frequency were evaluated as a secondary endpoint. A dose relationship was demonstrated among patients treated with multiple doses of zorevunersen. Patients treated with an initial 2 or 3 doses of 70mg experienced the most substantial reductions in seizures. A median reduction in seizures of 84.8% and a median increase of eight seizure-free days per 28 days were observed at 3 months after the last dose. Patients who received initial 70mg doses of zorevunersen in the Phase 1/2a studies also showed the most substantial improvements in quality-of-life outcomes as measured by the EuroQol Visual Analog Scale, a component of the Euro-Qol-5D Youth. Following treatment in the Phase 1/2a studies, 94% of eligible patients continued treatment in the OLEs. Through three years, 77% of these patients remain in the studies. Overall, reductions in major motor seizure frequency were sustained through three years of treatment in the OLE studies. The most substantial reductions in seizure frequency were observed among patients treated with initial doses of 70mg in the Phase 1/2a studies. Standard assessments are used in the OLE studies to evaluate neurodevelopment, functioning, clinical status and quality of life for all patients. Vineland Adaptive Behavior Scales, Third Edition was used to measure changes in communication, motor skills, socialization and daily living. Subdomains of Vineland-3 were measured using raw scores and compared to each patient’s baseline at OLE entry. Continuing improvements were demonstrated among patients who received zorevunersen every four months in the OLEs. Through three years, data indicated improvements of 4.3-9.7 raw score points across eight key subdomains, including 7.6 points in expressive communication and 6.1 points in receptive communication. Caregivers have identified a 1-3 point change in raw scores for Vineland-3 subscales as meaningful. Patients also experienced ongoing improvements in quality of life as measured by EQ-VAS, with an 18-point improvement demonstrated through three years. EQ-VAS is a validated visual analogue scale ranging from 0 to 100. Eighty-one patients received at least one dose of zorevunersen and have been evaluated for safety. Zorevunersen has been generally well tolerated across the Phase 1/2a and OLE studies. Study drug related treatment emergent adverse events were observed in 30% and 53% of patients treated in the Phase 1/2a and OLE studies, respectively. The most common study drug related TEAE was CSF protein elevations reported in 14% of patients in the Phase 1/2a studies and 44% of patients in the OLE studies. CSF protein elevations occurred in 42% of patients in the Phase 1/2a studies and 86% of patients in the OLE studies. No related clinical manifestations have been observed although one patient discontinued treatment due to elevated CSF protein levels. Treatment-emergent serious adverse events were reported in 22% and 29% of patients in the Phase 1/2a and OLE studies, respectively, all of which were assessed to be unrelated to study drug except one patient who experienced SUSARs.