PDF: MONARCH/ADMIRAL (Zorevunersen in Dravet Syndrome)
(2026)Objective
To evaluate intrathecal zorevunersen, an antisense oligonucleotide targeting SCN1A, in children and adolescents with Dravet syndrome.
Study Summary
• Improvements in clinical status, quality of life, and adaptive behavior were sustained over 36 months
• This is the first disease-modifying therapy targeting the underlying SCN1A haploinsufficiency, upregulating NaV1.1 expression
Intervention
Intrathecal zorevunersen (antisense oligonucleotide; single- and multiple-ascending doses 10-70 mg, then up to 45 mg every 4 months in extension)
Inclusion Criteria
Age 2-18 years with clinically diagnosed Dravet syndrome and confirmed SCN1A pathogenic variant, on standard antiseizure medications.
Study Design
Arms: Single-ascending dose vs Multiple-ascending dose vs Extension (open-label dose cohorts)
Patients per Arm: Dose-escalation cohorts (n per cohort not specified in source)
Outcome
• Clinical status, quality of life, and adaptive behavior improved and were sustained over 36 months
• AEs: post-lumbar puncture syndrome 25%, elevated CSF protein 45% during extensions
• 3 deaths (2 SUDEP, 1 malnutrition)
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