Authors :
Presenting Author: J Helen Cross, MD – UCL-Great Ormond Street Institute of Child Health; Great Ormond Street Hospital
Joseph Sullivan, MD – University of California San Francisco; Archana Desurkar, MD – SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST); John Schreiber, MD – Children's National Hospital; Linda Laux, MD – Ann & Robert H. Lurie Children's Hospital of Chicago; Colin Roberts, MD – OHSU; Javier Avendaño, MD – Stoke Therapeutics; Jessie Lynch, PhD – Stoke Therapeutics; Charlene Brathwaite, BA – Stoke Therapeutics; Meena M, PhD – Stoke Therapeutics; James Stutely, BS – Stephanie L Rock; Fei Wang, PhD – Stoke Therapeutics; Kimberly Parkerson, MD – Stoke Therapeutics; Barry Ticho, MD – Stoke Therapeutics
Rationale:
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) protein. DS is characterized by high seizure frequency (SF) and severity, intellectual disability, ataxia/motor abnormalities, and a high risk of sudden unexplained death in epilepsy. STK-001 is an investigational ASO treatment designed to upregulate Nav1.1 protein expression in the brain by leveraging the wild-type (non-mutant) copy of SCN1A to restore physiological Nav1.1 levels, thereby potentially reducing both SF and non-seizure comorbidities.
Methods:
MONARCH (NCT04442295) and ADMIRAL (2020-006016-24) are ongoing studies of patients with DS aged two to eighteen years assessing safety, tolerability, plasma pharmacokinetics, and CSF exposure of intrathecally (IT) administered ascending doses of STK-001. Patients have disease onset < 12 months old with recurrent seizures and a confirmed clinically relevant SCN1A variant. Patients are grouped by age (two to twelve and thirteen to eighteen years) and SF is observed for 28 days before dosing and followed for six months after last dose. Adverse events (AEs) are monitored continuously, with plasma and CSF collected for STK-001 exposure at multiple times.
Results: As of April 13, 2023, 74 patients received ≥1 dose of STK-001 (10-70 mg/dose) in MONARCH or ADMIRAL. Safety findings are in the table. Total plasma exposure (AUCinf) increased dose proportionally from 10 mg to 70 mg following a single dose or first dose in MAD cohorts. STK-001 levels were detected in CSF up to 6 months post single dose for 10 to 45 mg cohorts (data up to six months are not available for 70 mg dose cohort). Following repeat dosing, a trend towards increased STK-001 levels was observed suggesting accumulation in the CNS. Previously presented data showed a 55% median reduction in convulsive seizure frequency from the 45 mg dose cohort. New data from additional patients treated with 45 mg and 70 mg will be presented.
Conclusions:
Data indicates that STK-001 is overall well-tolerated and potential benefit-risk remains favorable in single and multiple doses up to 70 mg/dose. Data support continued STK-001 development as the first potential disease-modifying approach to treat DS. This data will help inform future STK-001 clinical studies.
Funding: Stoke Therapeutics