Antisense oligonucleotide therapy for dravet syndrome: A critical review of the evidence for disease modification with zorevunersen

Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency, and no approved disease-modifying therapy addresses its underlying channelopathy. Zorevunersen, an intrathecal splice-modulating antisense oligonucleotide, is designed to increase NaV1.1 expression. This critical narrative review appraises the available human evidence for disease modification using explicit operational criteria and a documented, provenance-based search. The peer-reviewed evidence base centers on two open-label phases 1–2a studies (MONARCH and ADMIRAL; n=81) and their open-label extensions (SWALLOWTAIL and LONGWING; n=75; data cut May 30, 2025). In descriptive analyses, median convulsive-seizure reductions ranged from −58.8% to −90.9% across one-month intervals through Month 20 in the 70-mg subgroup, and at Month 36 both clinicians and caregivers rated 94.7% of patients with available assessments as at least minimally improved; least-squares mean Vineland-3 raw-score changes were 7.56 (expressive) and 6.06 (receptive). Dose-group comparisons were post hoc; confidence intervals were not adjusted for multiplicity, and late extension outcomes were based on available data without a concurrent control. We conclude that current human evidence supports a hypothesis of disease modification but does not establish it, and we delineate what the randomized, sham-controlled EMPEROR trial can and cannot confirm, with implications for patients, clinicians, and the communication of preliminary results.