Abstract Details

Title 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

Topic Child Neurology and Developmental Neurology

Presentation(s) S19 - Emerging Therapies in Child Neurology (4:42 PM-4:54 PM)

Poster/Presentation
Number 007

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 Na_V1.1-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 Na_V1.1 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.

Authors/Disclosures
Linda Laux, MD (Childrens Hospital) PRESENTER	Dr. Laux has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke Therapeutics. Dr. Laux has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex.
Kelly G. Knupp, MD (Children's Hospital Colorado)	The institution of Dr. Knupp has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Harmony. Dr. Knupp has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsy Research.
Andreas Brunklaus, MD	Prof. Brunklaus has received personal compensation in the range of $0-$499 for serving as a Consultant for Servier. Prof. Brunklaus has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke Therapeutics. Prof. Brunklaus has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke Therapeutics. Prof. Brunklaus has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Encoded Therapeutics. Prof. Brunklaus has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biocodex. Prof. Brunklaus has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Prof. Brunklaus has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biocodex. Prof. Brunklaus has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB.
J. Helen Cross (UCL-Institute of Child Health)	Dr. Cross has nothing to disclose.
M. S. Perry, MD (Cook Childrens Medical Center)	Dr. Perry has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for stoke therapeutics. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Marinus. Dr. Perry has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for jazz pharmaceuticals. Dr. Perry has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for pyros. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for azurity. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Perry has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke Therapeutics. Dr. Perry has stock in Praxis Precision Medicine. Dr. Perry has stock in Biohaven. Dr. Perry has stock in Rapport. Dr. Perry has stock in Alto Neurosciences. Dr. Perry has a non-compensated relationship as a president with child neurology foundation that is relevant to AAN interests or activities. Dr. Perry has a non-compensated relationship as a President with Pediatric Epilepsy Research Consortium that is relevant to AAN interests or activities.
Joseph Sullivan, MD	Dr. Sullivan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biocodex. Dr. Sullivan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. Dr. Sullivan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ceribell. Dr. Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Xenon. Dr. Sullivan has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Epilepsy Study Consortium. Dr. Sullivan has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuropace. Dr. Sullivan has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for Various firms. Dr. Sullivan has stock in Harmony.
Archana Desurkar, MD, MBBS, MRCPCH	Dr. Desurkar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for biocodex. Dr. Desurkar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for STOKE therapeutics. Dr. Desurkar has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB.
John M. Schreiber, MD (Children'S National Medical Center)	Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Xenon. Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zogenix. The institution of Dr. Schreiber has received research support from Dravet Syndrome Foundation.
Colin M. Roberts, MD (Pediatric Neurology CDRC-P)	Dr. Roberts has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Roberts has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke. Dr. Roberts has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Encoded.
James W. Wheless, MD, FAAP, FACP, FAAN, FAES, FCNS, FAAN (UTHSC-Pediatric Neurology)	Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Azurity. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving as a Consultant for LivaNova. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for LivaNova. Dr. Wheless has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB. Dr. Wheless has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurelius.
Elaine C. Wirrell, MD, FAAN (Mayo Clinic/Dept of Child Neurology)	Dr. Wirrell has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biocodex. Dr. Wirrell has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Encoded. Dr. Wirrell has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurocrine. Dr. Wirrell has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GRIN. Dr. Wirrell has received publishing royalties from a publication relating to health care.
Pam Ventola, PhD	Dr. Ventola has received personal compensation for serving as an employee of Cogstate. The institution of Dr. Ventola has received research support from NIH.
Brian Werneburg (Stoke Therapeutics)	Mr. Werneburg has received personal compensation for serving as an employee of Stoke Therapeutics.
Jessie Lynch	Mrs. Lynch has received personal compensation for serving as an employee of Stoke Therapeutics. Mrs. Lynch has stock in Stoke Therapeutics.
Fei Wang, PhD	Fei Wang, PhD has received personal compensation for serving as an employee of Stoke Therapeutics.
Kimberly A. Parkerson, MD, PhD	Dr. Parkerson has received personal compensation for serving as an employee of Stoke Therapeutics. Dr. Parkerson has stock in Stoke Therapeutics.
Barry S. Ticho, MD, PhD (Biogen Idec)	Dr. Ticho has received personal compensation for serving as an employee of Stoke Therapeutics.

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