Objective:

To evaluate electroencephalogram (EEG) δ-power as a candidate biomarker of zorevunersen treatment response in patients with Dravet syndrome (DS).

Background:

DS is a severe developmental and epileptic encephalopathy primarily caused by haploinsufficiency of the voltage-gated sodium channel α subunit 1 gene (SCN1A) encoding Na_V1.1. EEG δ-power is elevated in patients with DS relative to age-matched neurotypical peers and warrants exploration as a potential biomarker to assess disease modification induced by therapies such as zorevunersen. Zorevunersen is an investigational antisense oligonucleotide designed to upregulate Na_V1.1 expression by leveraging the wild-type SCN1A copy.

Design/Methods:

In Phase 1/2a open-label, multicenter studies of zorevunersen in patients with DS aged 2–18 years (NCT04442295 [USA]/2020-006016-24 [UK]), analyses included routine EEGs from 74 patients receiving ≤70 mg zorevunersen doses. From each 1–2-hour EEG recording at baseline and 12 and 24 weeks after last dose, 15 minutes of pre-processed data (excluding seizure activity) were analyzed. Power spectra (1–32 Hz, log-scaled) were computed using Morlet wavelet decomposition. EEG δ-power (1–4 Hz) was averaged across electrodes. Exploratory analyses examined associations between δ-power changes and zorevunersen dose, seizure frequency (≥50% reduction), and Vineland-3 scores.

Results:

EEG δ-power reduction was dose-dependent at 12 and 24 weeks after last dose of zorevunersen (Week 12 [n=71], r=−0.55, p<0.0001; Week 24 [n=68], r=−0.52, p<0.0001). Clinical responder status was associated with the magnitude of δ-power change across visits. EEG δ-power reductions at 24 weeks after last dose were associated with improvement in some Vineland-3 subdomain scores. 

Conclusions:

Dose-dependent changes in δ-power were observed at both timepoints, yet clinical changes emerged 24 weeks after last dose, suggesting δ-power changes may precede and support potential clinical improvements. These findings are consistent with zorevunersen's mechanism and support EEG δ-power as a potential biomarker to capture neurophysiological changes in DS following disease-modifying therapies. Confirmation in a larger study is needed.