Advancing Disease Modification in Dravet Syndrome

Abstract

Zorevunersen in Children and Adolescents with Dravet Syndrome.

Laux L, Sullivan J, Perry MS, Brunklaus A, Desurkar A, Schreiber JM, Roberts CM, Knupp KG, Wheless JW, Wirrell EC, Ventola P, Wang F, Meena, Lynch J, Parkerson KA, Ticho B, Cross JH; MONARCH, ADMIRAL, SWALLOWTAIL, and LONGWING Study Groups. N Engl J Med. 2026 Mar 5;394(10):969–982. doi: 10.1056/NEJMoa2506295. PMID: 41780062.

Background: Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate Na_V1.1 sodium channels, in patients with Dravet syndrome are not known. Methods: We enrolled patients 2 to 18 years of age with Dravet syndrome who were receiving standard antiseizure medications in two phase 1–2a, open-label, multicenter studies (MONARCH and ADMIRAL). Patients were included in either a single-ascending-dose cohort, in which zorevunersen (10 to 70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period. Patients eligible for rollover to the two open-label extension studies (SWALLOWTAIL and LONGWING) continued to receive zorevunersen (≤45 mg) every 4 months. The safety and pharmacokinetics of zorevunersen were assessed in the primary analysis; clinical effects were also evaluated. Results: A total of 81 patients were enrolled in the phase 1–2a studies. As of May 30, 2025, a total of 75 patients had entered the extension studies. Most adverse events were mild or moderate. The most common adverse event was post-lumbar puncture syndrome (in 25% of patients) in the phase 1–2a studies and was an elevated protein level in cerebrospinal fluid (in 45%) in the extension studies. One patient had suspected unexpected serious adverse reactions, 1 had an adverse event that led to study withdrawal, 2 died from sudden unexpected death in epilepsy, and 1 died from malnutrition. Patients who received 70 mg of zorevunersen (one, two, or three doses) in the phase 1–2a studies, followed by up to 45 mg in the extension studies, had a median change from baseline in convulsive-seizure frequency ranging from −58.82% to −90.91% across 1-month intervals during the first 20 months of the extension studies. 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. Conclusions: The safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome. (Supported by Stoke Therapeutics; MONARCH and SWALLOWTAIL ClinicalTrials.gov numbers, NCT04442295 and NCT04740476, respectively; ADMIRAL and LONGWING ISRCTN Registry numbers, ISRCTN99651026 and ISRCTN12811235, respectively.).

Commentary

The treatment landscape for Dravet Syndrome (DS) has significantly evolved over the past decade from the introduction of syndrome-specific antiseizure medications, such as fenfluramine ¹ and cannabidiol, ² to the identification of antisense oligonucleotides (ASOs) which could increase the expression of functional SCN1A mRNA. ³ Disease-modifying precision therapies are on the horizon, and the results of phase 1-2a and open-label extension studies reported by Laux and colleagues demonstrate significant promise for the future. ⁴

DS is a severe, developmental, and epileptic encephalopathy (DEE) with onset typically within the first 6-12 months of life with recurrent febrile and afebrile status epilepticus, developmental regression, cognitive, behavioral, and communication impairment, and significantly increased risk of sudden unexpected death in epilepsy (SUDEP) compared to other epilepsies.^4–6 DS is most commonly due to de novo pathogenic variants in the SCN1A gene resulting in haploinsufficiency with reduced expression of Nav1.1 sodium channels and impaired inhibitory interneuron function. ⁷ Treatment in DS and other epileptic encephalopathies has predominantly focused on seizure with antiseizure medications. ⁸ Zorevunersen is an ASO designed to increase productive SCN1A mRNA and restore Nav1.1 expression, directly targeting the underlying channelopathy, with the goal of improving seizure and non-seizure outcomes in DS. ⁴

Laux et al. present the results from the phase 1-2a open-label trials, known as the MONARCH and ADMIRAL studies in the United States and United Kingdom, respectively, as well as the interim results from the ongoing open-label extension studies SWALLOWTAIL and LONGWING. ⁴ The MONARCH study included a single-ascending-dose cohort where patients received zorevunersen 10, 20, 30, 45, or 70 mg on day 1 only and multiple-ascending-dose cohorts of zorevunersen, 20, 30, or 45 mg on days 1, 29, and 57. The ADMIRAL study included multiple-ascending-dose cohorts of 30, 45, or 70 mg on days 1, 57, and 85, with a subgroup in the 70 mg multiple-ascending-dose cohort receiving only 2 doses on days 1 and 57. For the extension studies, patients received three doses of 45 mg administered on day 1, at week 16, and week 32 and then every 16 weeks until study discontinuation.

Participants were patients aged 2-18 years with an established diagnosis of DS experiencing four or more convulsive seizures during the 28-day observation period. The primary endpoints of the MONARCH-ADMIRAL studies were the safety profile, plasma pharmacokinetic measurements and measure of exposure in cerebrospinal fluid with single dose and multiple doses of zorevunersen. The SWALLOWTAIL-LONGWING open-label extension studies’ primary endpoint was the safety profile of multiple doses of zorevunersen. Common secondary endpoints were change from baseline in frequency of convulsive seizures calculated in 1-month intervals, change from baseline and overall clinical status measured with the clinician and caregiver global impression of change scales, and assessment of baseline change in quality of life (QOL) measured by the European Quality of Life Visual Analogue Scale. Exploratory endpoints included measures of seizure frequency and change in adaptive behavior as measured by the Vineland Adaptive Behavior Scales, third addition (Vineland-3).

Eighty-one participants received at least one dose of zorevunersen and 80 completed the study. 95% (58/61) from the MONARCH study and 89% (17/19) from the ADMIRAL study enrolled in the SWALLOWTAIL-LONGWING studies, with 75 patients remaining enrolled at the data cutoff.

Most adverse events were mild or moderate, seen in 96% of ADMIRAL-MONARCH and 100% of SWALLOWTAIL-LONGWING participants, with post-lumbar puncture syndrome (25%) and elevated CSF protein levels (29%) being the most common. Treatment-related adverse events were seen in 30% and 50% of participants, respectively. Serious treatment-related adverse events were reported in one patient, who experienced progressive neurologic deterioration and cortical visual impairment, highlighting the need for continued monitoring of side effects.

Baseline median number of convulsive seizures was 17 (range 4-2335.4) with the median change from baseline across dose cohorts at 3 and 6 months of −42.81% and −57.3%, respectively, among patients who received a single 70 mg dose, and −84.80% and −73.61%, respectively, among those who received two or three doses of 70 mg. Those who received zorevunersen doses less than 70 mg in the phase 1-2a studies had a median change in the open extension studies of −6.94% to −77.38% across 1-month intervals through the 36 months of the extension studies. For those who received 70 mg dose (one, two, or three doses), the median change from baseline ranged from −58.82% to −90.91% through month 20 of the extension studies. Based on this, the authors found that among those who received multiple doses of 70 mg in the phase 1-2a studies, median reduction in seizure frequency was the greatest, although the study design did not support formal statistical comparisons between dose cohorts.

At the end of the phase 1-2a studies and at months 36 of the extension studies, clinician and caregiver global impression of change scales were performed, with clinicians rating 84% minimally improved, much improved, or very much improved and caregivers rating the same for 95% of patients. In the extension studies, both clinicians and caregivers rated 95% of patients improved. Regarding adaptive behavior, patients in ADMIRAL and LONGWING studies demonstrated improvements in expressive and receptive communication domains. Overall, treatment was associated with improvements in overall clinical status, QOL, and in adaptive behavior based on the scales. However, it should be noted that in the absence of blinding, there is a high-risk of bias based on caregiver-reported outcomes in QOL and adaptive behavior.

These results of these studies are encouraging, but given the open-label design, lack of control group or a sham/placebo arm, and small sample size, they need to be interpreted with cautious optimism. These studies were primarily designed to assess safety and dose-related measures; therefore, conclusions regarding the efficacy of zorevunersen are limited. The authors acknowledge these limitations and the need for future phase 3 studies.

The implications of these results go beyond DS and provide evidence for disease-modifying therapies. Improvements seen in adaptive behavior and global functioning would certainly distinguish zorevunersen from existing therapies; however, our ability to define disease modification will need to be individualized for each DEE. The observed gains in communication and adaptive skills are encouraging but require careful longitudinal comparison with natural history cohorts. That being said, developmental impairments in DS often occur independently of seizure burden underscoring the importance of disease-specific therapies over standard antiseizure therapies alone.

This pivotal study sets this stage for future clinical trials and the development of therapies aimed at the pathophysiology behind DEEs. While the findings are preliminary, they provide hope that outcomes beyond seizure control can be modified with precision therapy. Results of the ongoing phase 3 EMPEROR trial of zorevunersen (NCT06872125) will be critical to answer these ongoing questions.