Novel antisense oligonucleotide shows disease-modifying potential in Dravet syndrome

In children with Dravet syndrome, treatment with the investigational antisense oligonucleotide zorevunersen appears safe and efficacious, with seizure frequency reductions of up to 90 percent and improvements in nonseizure symptoms, according to two phase 1–2a studies (MONARCH and ADMIRAL) and the corresponding open-label extension studies (SWALLOWTAIL and LONGWING).

Safety outcomes

Most adverse events (AEs) were mild or moderate in severity, and the most common were post–lumbar puncture syndrome in the MONARCH–ADMIRAL studies (25 percent) and elevated cerebral spinal fluid protein level in the SWALLOWTAIL–LONGWING studies (45 percent). [N Engl J Med 2026;394:969-982]

Serious AEs occurred in 22 percent of patients in the MONARCH–ADMIRAL studies and in 29 percent of those in the SWALLOWTAIL– LONGWING studies. The most common of these were seizure (5 percent in both MONARCH–ADMIRAL and SWALLOWTAIL–LONGWING studies) and status epilepticus (1 percent and 5 percent, respectively). Serious AEs were deemed related to treatment in a single patient.

One patient had suspected unexpected serious adverse reactions, one had an AE that led to study withdrawal, two died from sudden unexpected death in epilepsy, and one died from malnutrition.

Efficacy outcomes

Among patients who received 70 mg of zorevunersen (one, two, or three doses) in the MONARCH–ADMIRAL studies, followed by up to 45 mg in the SWALLOWTAIL–LONGWING studies, the frequency of convulsive seizure decreased. The median reduction ranged from 58.82 percent to 90.91 percent across 1-month intervals during the first 20 months of the extension studies.

“Although the study design did not support formal statistical comparisons between dose cohorts, the median reductions in seizure frequency were largest among patients who received multiple doses of 70 mg of zorevunersen in the phase 1–2a studies, a finding consistent with a dose–effect relationship,” the investigators noted.

“Continued treatment in the extension studies appeared to be associated with stabilized reductions in the frequency of convulsive seizures through 36 months,” they added.

In addition, zorevunersen was associated with improvements in overall clinical status, quality of life, and adaptive behaviour. These outcomes, according to the investigators, “would be consistent with the mechanism of zorevunersen of up-regulating SCN1A in the context of the most common underlying cause of Dravet syndrome.”

Disease modification

“Overall, these data support the potential for disease modification with zorevunersen,” according to the investigators.

Formerly called STK-001, zorevunersen was designed to target the channelopathy underlying Dravet syndrome to address both seizure and nonseizure symptoms. This represents a step in the right direction, given that the goal of current standard care—which includes the use of antiseizure medications, dietary therapy, neuromodulation, or a combination of these approaches—is seizure control, according to the investigators.

“However, these treatments do not lead to seizure control in most patients, and their effect on nonseizure symptoms is minimal. Moreover, reductions in seizure frequency may not necessarily correspond to improvements in nonseizure outcomes, which are a major concern of caregivers,” they said. [Dev Med Child Neurol 2018;60:63-72; Epilepsy Behav 2017;74:81-86; Epilepsia 2024;65:322-337]

A phase 3 randomized controlled trial for zorevunersen is ongoing, with the drug being assessed at an initial dose of 70 mg and continued dose of 45 mg.

MONARCH and ADMIRAL included a total of 81 Dravet syndrome patients between 2 and 18 years of age who were receiving standard antiseizure medications. These patients were allocated to either a single-ascending-dose cohort, in which zorevunersen (10–70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which the drug (20–70 mg) was administered two or three times in a 3-month period.

A total of 75 patients entered SWALLOWTAIL and LONGWING and continued to receive zorevunersen (≤45 mg) every 4 months.