Zorevunersen Cuts Convulsive Seizures in Children With Dravet Syndrome

Moving Beyond Symptom Management in Dravet Syndrome

Dravet syndrome is a severe developmental and epileptic encephalopathy driven primarily by loss-of-function variants in the SCN1A gene, which encodes a critical voltage-gated sodium channel [1, 2]. Clinical management relies on symptomatic polytherapy with traditional antiseizure medications, which often fail to achieve seizure freedom and do not address the profound cognitive stagnation, motor impairments, and elevated mortality risk associated with the condition [3, 4]. Because conventional drugs cannot correct the underlying molecular deficit, researchers have increasingly focused on precision therapies, such as antisense oligonucleotides (synthetic nucleic acid strands that bind to specific RNA molecules to alter protein production), to directly modulate gene expression [1, 5]. A newly published phase 1-2a clinical trial of 81 children and adolescents evaluated zorevunersen, an antisense oligonucleotide designed to up-regulate sodium channel production, to determine if it can safely alter the disease trajectory [6]. The study demonstrated that patients receiving up to 70 mg of zorevunersen experienced a median change from baseline in convulsive-seizure frequency ranging from -58.82% to -90.91% over 20 months, offering clinicians a targeted strategy that may improve both seizure control and long-term neurodevelopmental outcomes [6].

Targeting the Genetic Deficit: Trial Design and Dosing

Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency, a genetic state where a single functional copy of a gene fails to produce enough protein for normal cellular function. Because of this underlying deficit, risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with Dravet syndrome than in the general population with epilepsy. To target the root cause of the disease, researchers evaluated zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels. By boosting the expression of these critical sodium channels, the therapy aims to restore normal neuronal excitability and reduce the severe seizure burden characteristic of the condition.

A total of 81 patients were enrolled in the phase 1-2a studies, which consisted of two open-label, multicenter trials named MONARCH and ADMIRAL. The study population included patients 2 to 18 years of age with Dravet syndrome who were already receiving standard antiseizure medications. To evaluate dosing parameters, patients were assigned to either a single-ascending-dose cohort or a multiple-ascending-dose cohort. In the single-ascending-dose cohort, zorevunersen (10 to 70 mg) was administered on day 1 only. In the multiple-ascending-dose cohort, zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period.

Following the initial trials, patients eligible for rollover transitioned to two open-label extension studies (SWALLOWTAIL and LONGWING), where they continued to receive zorevunersen at doses of 45 mg or less every 4 months. As of May 30, 2025, a total of 75 patients had entered the extension studies. The primary analysis assessed the safety and pharmacokinetics of zorevunersen, while clinical effects were also evaluated to gauge the impact of the drug on seizure frequency and neurodevelopment. The studies were supported by Stoke Therapeutics, with MONARCH and SWALLOWTAIL registered under ClinicalTrials.gov numbers NCT04442295 and NCT04740476, and ADMIRAL and LONGWING registered under ISRCTN Registry numbers ISRCTN99651026 and ISRCTN12811235.

Safety Profile and Adverse Events

The safety analysis revealed that most adverse events reported in the studies were mild or moderate in severity. Because zorevunersen requires administration into the spinal canal, procedural side effects were a primary focus of the safety monitoring. During the phase 1-2a studies, the most common adverse event was post-lumbar puncture syndrome, occurring in 25% of patients. As participants transitioned into the long-term extension studies, the safety profile shifted to reflect ongoing treatment. In these extension phases, the most common adverse event was an elevated protein level in cerebrospinal fluid, occurring in 45% of patients. For practicing neurologists and pediatricians, these findings indicate that patients on this antisense oligonucleotide therapy will require routine monitoring of cerebrospinal fluid parameters and proactive management of fluid-related procedural changes.

While the therapy was generally tolerated by the majority of the cohort, the researchers documented several severe outcomes that require clinical consideration. Specifically, one patient had suspected unexpected serious adverse reactions, and one patient had an adverse event that led to study withdrawal. The investigators also recorded three mortalities during the study period. Two patients died from sudden unexpected death in epilepsy, which is a known and severe risk inherent to the underlying Dravet syndrome pathology, and one patient died from malnutrition. These severe events underscore the medically fragile nature of this pediatric population and highlight the necessity for comprehensive, multidisciplinary monitoring throughout the course of treatment.

Long-Term Seizure Reduction and Clinical Outcomes

The primary efficacy analysis focused on the cohort of patients who received the highest initial dosing regimen. Specifically, patients who received 70 mg of zorevunersen (administered as one, two, or three doses) in the phase 1-2a studies, followed by maintenance doses of up to 45 mg in the extension studies, experienced substantial reductions in seizure burden. The researchers reported a median change from baseline in convulsive-seizure frequency ranging from -58.82% to -90.91%. This sustained reduction in convulsive-seizure frequency was observed across 1-month intervals during the first 20 months of the extension studies. For clinicians managing Dravet syndrome, achieving this degree of seizure control over nearly two years represents a meaningful stabilization of a typically refractory condition, potentially reducing hospital admissions and rescue medication use.

Beyond seizure control, the long-term data indicated broader neurodevelopmental and functional benefits. The data supported improvements in overall clinical status, quality of life, and adaptive behavior with continued treatment for up to 36 months in the extension studies. Adaptive behavior encompasses the practical, everyday skills required to function safely and independently, which are often severely impaired in children with this epileptic encephalopathy. Based on these findings, the authors concluded that the safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome. By directly addressing the underlying genetic deficit rather than merely suppressing symptoms, this therapy offers a targeted strategy to alter the long-term clinical trajectory of the disease.

References

1. Balestrini S, Scheffer IE. Ameliorating Seizures in Dravet Syndrome: A Review of Newly Approved and Investigational Drugs, RNA and Gene-Based Therapies. CNS Drugs. 2026. doi:10.1007/s40263-026-01276-x

2. Dinoi G, Canfora I, D’Agnano D, et al. From Symptomatic Therapies to Disease-Modifying Approaches for Neuronal Sodium Channel Disorders. International Journal of Molecular Sciences. 2025. doi:10.3390/ijms27010032

3. Samanta D, Bhatia S, Hunter SE, et al. Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies.. Pediatric neurology. 2025. doi:10.1016/j.pediatrneurol.2025.04.010

4. Sullivan J, Perry ΜS, Scheffer IE, et al. Cognitive stagnation and executive function deficits in young children with SCN1A + Dravet syndrome: Detailed characterization of onset, progression, and impact in the ENVISION natural history study. Epilepsia. 2025. doi:10.1111/epi.70015

5. Wang S, Perucca E, Berkovic SF, Perucca P. Precision therapies for genetic epilepsies in 2025: Promises and pitfalls. Epilepsia Open. 2025. doi:10.1002/epi4.70065

6. Laux L, Sullivan J, Perry MS, et al. Zorevunersen in Children and Adolescents with Dravet Syndrome.. The New England journal of medicine. 2026. doi:10.1056/NEJMoa2506295