Authors :
Presenting Author: Nigel Colenbier, PhD – Clouds of Care NV, Ghent, Belgium
Caroline Neura, M.D. – Centre for Cognitive Neuroscience, Salzburg, Austria
Gert Vanhollebeke, Ph.D. – Clouds of Care NV, Ghent, Belgium
Velislava Zoteva, M.Sc. – Clouds of Care NV, Ghent, Belgium
Emiel Vereycken, M.Sc. – Clouds of Care NV, Ghent, Belgium
Barry Ticho, M.D., Ph.D. – Stoke Therapeutics
Kimberly A. Parkerson, M.D., Ph.D. – Stoke Therapeutics
Pieter van Mierlo, PhD – Clouds of Care, NV, Ghent, Belgium
Rationale:
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy primarily caused by haploinsufficiency of the voltage-gated sodium channel α subunit 1 gene (SCN1A) gene encoding NaV1.1. Electroencephalogram (EEG) δ-power is markedly elevated in patients with DS relative to age-matched neurotypical peers and correlates with symptom severity, supporting its potential as a quantitative biomarker of disease pathophysiology and treatment response. We evaluated δ-power as a candidate biomarker of abnormal brain function in Phase 1/2a studies of zorevunersen, an investigational antisense oligonucleotide designed to upregulate NaV1.1 expression by leveraging the wild-type SCN1A copy. Methods:
The MONARCH/ADMIRAL Phase 1/2a open-label, multicenter studies of zorevunersen in patients with DS aged 2–18 years (NCT04442295 [USA]/2020-006016-24 [UK]). Combined analysis included assessment of routine EEGs from 74 patients receiving single or multiple doses of ≤70 mg zorevunersen. From each 1- to 2-hour EEG recording at baseline and 12 and 24 weeks after last dose, 15 minutes of pre-processed data were analyzed. Power spectra (1–32 Hz, log-scaled) were computed using Morlet wavelet decomposition. The main EEG endpoint, δ-power, was obtained by averaging the power within 1–4 Hz across electrodes. Exploratory analyses examined associations between δ-power changes and zorevunersen doses, seizure frequency (≥50% seizure frequency reduction considered as response), and clinical scores assessed by Vineland-3.Results:
Zorevunersen treatment resulted in a δ-power reduction from baseline. EEG δ-power tended to improve in a dose-dependent manner at 12 and 24 weeks after last dose, with significant negative correlations between zorevunersen dose and δ-power (Week 12, r= −0.59; Week 24, r=−0.52; Fig. 1). An exploratory complete-case analysis of seizure frequency indicated that zorevunersen response was associated with the magnitude of δ-power change seen in EEG data segments (excluding seizure activity) across visits (Fig. 2A). Trends in key Vineland-3 domain scores suggested that individuals with a stronger δ-power response at Week 24 showed greater clinical improvement; these trends were not observed at Week 12 (Fig. 2B).
Conclusions:
Zorevunersen was associated with dose-dependent improvements in the elevated δ-power, a characteristic of DS. Changes in EEG δ-power were associated with seizure reduction and improvement in some relevant clinical domains at 24 weeks after last dose. Although EEG changes were seen as early as 12 weeks after treatment, clinical changes manifested at 24 weeks, indicating that δ-power changes may precede and support potential clinical improvements. The potential beneficial effects of zorevunersen on neuronal activity are consistent with its mechanism of action. Our findings support EEG δ-power as a potential biomarker for DS following use of disease-modifying therapies and suggest that it may detect neurophysiological changes before observable clinical improvements. These preliminary findings should be confirmed in a larger, adequately powered study.
Funding:
Stoke Therapeutics