Abstract Details

Title Electrophysiological Improvements in Patients with Dravet Syndrome Following Treatment with Zorevunersen, an Investigational Antisense Oligonucleotide

Topic Child Neurology and Developmental Neurology

Presentation(s) S19 - Emerging Therapies in Child Neurology (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

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.

Authors/Disclosures
Nigel Colenbier, PhD PRESENTER	Mr. Colenbier has received personal compensation for serving as an employee of clouds of care.
Caroline Neuray (Epilog, Clouds of Care NV)	The institution of Caroline Neuray has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Clouds of Care. The institution of Caroline Neuray has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Saniona.
Gert Vanhollebeke, PhD	Dr. Vanhollebeke has received personal compensation for serving as an employee of Clouds of Care.
Velislava Zoteva, PhD	Dr. Zoteva has received personal compensation for serving as an employee of Clouds of Care.
Emiel Vereycken	Mr. Vereycken has nothing to disclose.
Kimberly A. Parkerson, MD, PhD	Dr. Parkerson has received personal compensation for serving as an employee of Stoke Therapeutics. Dr. Parkerson has stock in Stoke Therapeutics.
Barry S. Ticho, MD, PhD (Biogen Idec)	Dr. Ticho has received personal compensation for serving as an employee of Stoke Therapeutics.
Pieter van Mierlo, PhD	Prof. van Mierlo has received personal compensation for serving as an employee of Clouds of Care. Prof. van Mierlo has stock in Clouds of Care.

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