Zorevunersen Shows Promise as Disease-Modifying Therapy in Dravet Syndrome: Study

In the MONARCH and ADMIRAL trials, which were open-label, multicenter phase 1-2a studies, participants ranging from 2 to 18 years of age with confirmed Dravet syndrome and already taking antiseizure drugs were enrolled in the study. They were randomized into one of the single-ascending-dose cohorts or the multiple-ascending-dose cohort. In the single ascending dose cohort, the drug was given once daily to the participants on the first day in a dose range of 10 mg to 70 mg. In the multiple ascending dose cohort, the drug in the dose range of 20 mg to 70 mg was given to the participants 2 to 3 times daily for 3 months.

Patients who had received the initial trials had the opportunity to receive the zorevunersen doses of up to 45 mg every four months in the two open-label extension studies, SWALLOWTAIL and LONGWING. In the main studies, the safety, pharmacokinetic, seizure, and clinical effects evaluations were conducted. However, the results of the extension studies provided the opportunity for the assessment of the durability of the treatments.

Key findings:

The results from the combined phase 1–2a and the extension study indicated several findings.

• A total of 81 patients were involved in the initial studies, and 75 were involved in the long-term extension studies.

• The most common adverse event reported was post-lumbar puncture syndrome, reported in 25% of the patients in the initial studies, and increased cerebrospinal fluid protein levels were reported in 45% of the patients in the extension studies.

• The treatment with dosages of 70 mg and then maintenance doses of up to 45 mg resulted in a reduction in the median convulsive seizure frequency ranging from -58.82% to -90.91% over the monthly intervals during the first 20 months of the study.

• Improvements were noted in the clinical status, quality of life, and adaptive behavior when the treatment was continued for up to 36 months.

• The adverse reactions reported were few, including one suspected unexpected serious reaction, one treatment discontinuation due to adverse reactions, and deaths due to sudden unexpected death in epilepsy and malnutrition.

The clinical evidence available on the drug demonstrates that it has a well-tolerable safety profile and, most encouragingly, has shown positive early indications of clinical efficacy in the treatment of Dravet syndrome. Decreases in the frequency of seizures, as well as quality of life and adaptive behaviors during the long-term administration of the drug, suggest that this antisense therapy could potentially represent a novel disease-modifying therapeutic intervention targeting the underlying genetic cause of the disease.

Reference:

Laux, L., Sullivan, J., Perry, M. S., Brunklaus, A., Desurkar, A., Schreiber, J. M., Roberts, C. M., Knupp, K. G., Wheless, J. W., Wirrell, E. C., Ventola, P., Wang, F., Meena, Lynch, J., Parkerson, K. A., Ticho, B., & Cross, J. H. (2026). Zorevunersen in children and adolescents with Dravet syndrome. The New England Journal of Medicine, 394(10), 969–982. https://doi.org/10.1056/nejmoa2506295