Quantitative EEG Analysis in Patients with Dravet Syndrome (DS) Treated in the Phase 1/2a MONARCH Study of STK-001, an Antisense Oligonucleotide (ASO)
Abstract number :
3.225
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2022
Submission ID :
2204753
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Kimberly Parkerson, MD – Stoke Therapeutics; Pieter Van Mierlo, NA – Epilog; Eline Van Vlierberghe, NA – Epilog; Linda Laux, MD – Ann & Robert H. Lurie Children's Hospital of Chicago; Javier Avendaño, MD – Stoke Therapeutics; Barry Ticho, MD, PhD – Stoke Therapeutics
Rationale: Dravet syndrome (DS) is a severe and 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 performed quantitative EEG analyses on recordings from the Phase 1/2a MONARCH study of STK-001, an investigational ASO treatment designed to upregulate Nav1.1 protein expression in the brain by leveraging the wild-type (non-mutant) copy of SCN1A.
Methods: MONARCH (NCT04442295) is an ongoing, Phase 1/2a open-label, multi-center, study in the US of single and multiple ascending doses of STK-001 in patients with DS aged 2-18 years grouped by age (2-12 and 13-18 years). We analyzed 1-2 hours EEGs collected at baseline, 12- and 24-weeks post-treatment. Interictal epileptiform discharges (IEDs) were detected in the EEG and the spike rate per hour was computed. Spectral power analysis was performed in the delta, theta, alpha, and beta bands to assess peak frequency and mean power over time.
Results: Spikes were detected in only 7/24 recordings (29%) obtained from 12 patients. Spectral analysis of 19 1-hour recordings at baseline revealed a mean alpha/theta power ratio over time of < 1 across age groups (0.73±0.19 standard deviation (SD) in 2-12 years and 0.85±0.24 SD in 13-18 years). With doses above 10 mg, 6/8 and 7/8 patients in the 2-12 years group showed decreases in mean theta and alpha over time, respectively, between baseline and 12 weeks post-treatment. Subsequently, 3/4 and 4/4 patients re-increased towards baseline at 24 weeks post-treatment. No trends were observed in theta or alpha peak frequency between baseline and 12 weeks post-treatment (n=19). Additional available spectral analysis data will be reported.
Conclusions: Spike analysis of 1-2 hours EEGs in this cohort seems not informative as spikes were detected in too few recordings to draw conclusions. Greater theta compared with alpha power in younger and older age groups is consistent with prior data showing increased theta and decreased alpha in children with DS after 6 years compared with controls (Holmes et al 2012). Initial trends indicate modulation of theta and alpha power may be a useful tool following treatment with STK-001.
Reference:
Holmes et al. Brain Dev. 2012;34(6):469-477.
Funding: Stoke Therapeutics
Clinical Epilepsy