Spectral EEG Analysis Demonstrates Decreased Slow-wave Activity in Patients with Dravet Syndrome (DS) After Treatment with STK-001, an Antisense Oligonucleotide (ASO)
Abstract number :
3.407
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
370
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Nigel Colenbier, PhD – Epilog, Clouds of Care NV
Caroline Neuray, MD – Epilog, Clouds of Care
Pieter van Mierlo, PhD – Epilog, Clouds of Care
Ekatherina Garzón J, Msc. – Epilog, Clouds of Care NV
Emiel Vereycken, Msc. – Epilog, Clouds of Care NV
Barry Ticho, MD, PHD – Stoke Therapeutics
Kimberly Parkerson, MD – Stoke Therapeutics, Massachusetts, United States of America
Rationale: Dravet Syndrome (DS) is a severe, progressive genetic developmental and epileptic encephalopathy that typically begins in the first year of life. Approximately 85% of cases are caused by heterozygous, loss-of-function de novo mutations in the SCN1A gene, which encodes the voltage-gated sodium channel type 1 α subunit (Nav1.1). We conducted spectral EEG analyses using recordings from the Phase 1/2a and Open-Label Extension (OLE) studies of STK-001 to evaluate potential electrophysiologic markers of treatment effect. These analyses compared data from patients prior to and after receiving investigational STK-001 ASO treatment, designed to upregulate Nav1.1 protein expression by leveraging the wild-type (non-mutant) SCN1A messenger RNA, at different dose levels.
Methods: MONARCH (NCT04442295) and ADMIRAL (EudraCT Number 2020-006016-24) were Phase 1/2a open-label, multicenter studies of STK-001 in patients with DS aged 2-18y in the US and UK, respectively. The combined analysis was based on data from 74 DS patients (37 females, on average aged 9.3y) treated with single or multiple intrathecal doses of 10mg, 20mg, 30mg, 45mg or 70mg, in either of these two studies. EEG recordings of 1-2 hours collected at baseline, at 12- and 24-weeks after last dose in the Phase1/2a studies, as well as at week 48 in the corresponding open-label extensions (OLE) were analyzed. Welch’s method was applied to estimate the power spectra across 6-second pre-processed epochs. Spectral band power was evaluated for the Delta (1–3.5 Hz), Theta (3.5–7.5 Hz), Alpha (7.5–13 Hz), Beta (13–30 Hz), and Gamma (30–100 Hz) bands.
Results: Figure 1 illustrates the effect of different STK-001 dose levels on spectral power in DS patients. A decreasing trend in Delta, Theta, and Alpha power was observed post-treatment compared to baseline, with more pronounced decreases at higher doses. This trend was not evident in the Beta and Gamma bands, indicating a dose-dependent treatment effect on slower-wave activity. Figure 2 shows the persistence of this treatment effect in the Delta, Theta, and Alpha bands, recorded up to 6 months following treatment in the Phase 1/2a studies. The treatment effect may potentially extend into the OLE period, but caution is advised as the OLE data, particularly for the 70 mg dose, is incomplete.
Conclusions: Our study demonstrates that spectral EEG analysis can reliably capture treatment effects on the CNS, in DS patients following STK-001 ASO administration. This is indicated by decreased slow-wave activity compared to baseline, (reduced power in the Delta, Theta and Alpha bands) that are more pronounced at higher STK-001 ASO dose levels. Moreover, these changes persisted for many months post-treatment, suggesting a sustained effect of STK-001. Collectively, these findings support the utility of EEG-derived metrics for evaluating treatment effect by quantifying treatment-induced EEG changes in DS patients and indicate changes in power following STK-001 treatment that may predict improved cognitive function.
Funding: Stoke therapeutics
Anti-seizure Medications