PDF: MONARCH/ADMIRAL (Zorevunersen in Dravet Syndrome)
(2026)Objective
To evaluate the safety and efficacy of zorevunersen, an antisense oligonucleotide that upregulates NaV1.1 sodium channels, in children and adolescents with Dravet syndrome
Study Summary
• Most adverse events were mild or moderate; post-lumbar puncture syndrome in 25%, elevated CSF protein in 45% during extensions; 2 deaths from SUDEP and 1 from malnutrition (consistent with natural history of Dravet syndrome)
Intervention
Intrathecal zorevunersen (antisense oligonucleotide targeting SCN1A to upregulate NaV1.1) at doses up to 70 mg
Inclusion Criteria
Children and adolescents aged 2-18 years with Dravet syndrome receiving standard antiseizure medications
Study Design
Arms: Single-ascending dose (10-70 mg) and multiple-ascending dose (20-70 mg) cohorts, with extension at up to 45 mg every 4 months
Patients per Arm: 81 patients in phase 1-2a; 75 entered extension studies
Outcome
• Improvements in clinical status, quality of life, language, motor skills, and adaptive behavior over 36 months
• Post-lumbar puncture syndrome 25%, elevated CSF protein 45%; 2 SUDEP deaths, 1 malnutrition death
Bottom Line
Zorevunersen at 70 mg doses reduced convulsive-seizure frequency by 59-91% over 20 months in children with Dravet syndrome, with improvements in clinical status, quality of life, and adaptive behavior sustained over 36 months. This represents the first disease-modifying therapy targeting the underlying SCN1A haploinsufficiency in Dravet syndrome.
Major Points
- Zorevunersen (antisense oligonucleotide targeting SCN1A) showed dose-dependent seizure reduction in Dravet syndrome.
- Phase 1b/2a open-label dose-escalation + Phase 2 randomized placebo-controlled trial.
- Intrathecal administration every 12 weeks. Multiple dose cohorts tested.
- Targets haploinsufficiency mechanism — upregulates NaV1.1 expression from the functional allele.
- First ASO therapy targeting sodium channel gene for epilepsy — novel mechanism.
- ADMIRAL (Phase 2): primary endpoint is change in convulsive seizure frequency.
- Reported preliminary safety and tolerability data — no major safety concerns.
- Rare disease trial: Dravet syndrome affects ~1:15,000-20,000 births.
- Sponsored by Stoke Therapeutics (acquired by Ionis). Orphan drug designation.
- Represents precision medicine approach — genotype-directed ASO therapy for genetic epilepsy.
Study Design
- Study Type
- Two phase 1-2a, open-label, multicenter, dose-escalation trials with open-label extension studies
- Randomization
- No
- Blinding
- Open-label
- Sample Size
- 81
- Follow-up
- Up to 36 months in extension studies
Primary Outcome
Definition: Change in convulsive-seizure frequency from baseline
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Open-label design without placebo control limits causal inference
- Small sample size across multiple dose cohorts
- Intrathecal administration requires repeated lumbar punctures in pediatric patients
- SUDEP deaths occurred, though consistent with natural history of Dravet syndrome
Citation
Laux L et al. N Engl J Med. 2026;394(10):969-982. DOI: 10.1056/NEJMoa2506295