Zorevunersen Demonstrates Potential as a Disease‑modifying Therapy in Patients with Dravet Syndrome Through Durable Seizure Reduction and Improvements in Cognition, Behavior, and Quality of Life Through 36 Months of Treatment in Open-label Extension Studies
Linda Laux1, Kelly G. Knupp2, Andreas Brunklaus3, J Helen Cross4, M Scott Perry5, Joseph Sullivan6, Archana Desurkar7, John M Schreiber8, Colin M Roberts9, James W Wheless10, Elaine C Wirrell11, Pam Ventola12, Brian Werneburg13, Jessie Lynch13, Fei Wang13, Kimberly A Parkerson13, Barry Ticho13
1Ann & Robert H. Lurie Children's Hospital of Chicago, 2Children's Hospital Colorado, 3University of Glasgow, 4University College London NIHR BRC Great Ormond Street Institute of Child Health, 5Cook Children's Medical Center, 6Benioff Children’s Hospital, University of California San Francisco, 7Sheffield Children's Hospital NHS Foundation Trust, 8Children's National Hospital, 9Oregon Health & Science University, 10Le Bonheur Children's Hospital, University of Tennessee Health Science Center, 11Mayo Clinic, 12Cogstate Ltd, 13Stoke Therapeutics
Objective:
To evaluate the effects of zorevunersen in patients with Dravet syndrome (DS).
Background:
DS is a severe developmental and epileptic encephalopathy primarily caused by haploinsufficiency of the NaV1.1-encoding gene, SCN1A. Despite treatment with best-available standard-of-care (SoC) with multiple antiseizure medications, patients with DS continue to experience frequent seizures and persistent neurodevelopmental deficits. Zorevunersen is an investigational antisense oligonucleotide designed to upregulate NaV1.1 expression by leveraging the wild-type SCN1A copy, thereby targeting a primary cause of DS. Phase 1/2a and open-label extension (OLE) studies of zorevunersen have demonstrated reductions in seizure frequency and improvements in cognition, behavior, and quality of life (QoL).
Design/Methods:
In the Phase 1/2a studies (NCT04442295[USA]/2020-006016-24[UK]), patients on best-available SoC received single/multiple loading doses of zorevunersen (≤70 mg). Eligible patients entered the OLEs (NCT04740476[USA]/2021-005626-14[UK]) and received zorevunersen (≤45 mg) every 4 months. Seizure frequency, cognition and behavior (Vineland-3), QoL (EQ-VAS), overall clinical status (CGI-C/CaGI-C), and safety were evaluated.
Results:
As of May 30, 2025, 75 of 81 patients from the Phase 1/2a studies had entered the OLEs. Patients experienced substantial and durable seizure reductions through Month 36 of the OLEs. Vineland-3 subdomain scores improved over time, with least squares mean changes from OLE baseline to Month 36 of 7.56 and 6.06 in Expressive and Receptive Communication raw scores, respectively. EQ-VAS scores also improved, with observed mean increases from naive baseline to Month 20 of 11.5 (n=51) and 32.1 (n=7) in all patients and patients who received multiple 70 mg doses, respectively.
Zorevunersen was generally well tolerated. Increased cerebrospinal fluid protein was the most common treatment-related adverse event in the OLEs (44.0%, n=33/75), with no associated clinical manifestations observed.
Conclusions:
Substantial and durable seizure reductions and continuing improvements in cognition, behavior, and QoL support the potential of zorevunersen as a disease-modifying therapy and warrant further evaluation in the ongoing Phase 3 study.
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