Abstracts

Rationale: DS is a severe and progressive genetic epilepsy that typically begins in the first year of life and is characterized by high seizure frequency and severity, intellectual disability, motor abnormalities, and a high risk of SUDEP. Most cases are caused by spontaneous, heterozygous loss of function mutations in the SCN1A gene, which encodes for voltage-gated sodium channel type 1α subunit (Na_v1.1) protein. STK-001 is an investigational ASO treatment designed to upregulate Na_v1.1 protein expression by leveraging the non-mutant (wild-type) copy of SCN1A gene to restore physiological Na_v1.1 levels, thereby potentially reducing seizures and non-seizure comorbidities.

Methods: MONARCH (NCT04442295) is an ongoing US study of patients with DS aged 2-18 yrs assessing safety, PK, and CSF exposure of intrathecally (IT) administered single ascending doses (SAD; 10, 20, and 30mg) and multiple ascending doses (MAD; 20 and 30mg) of STK-001. Eligible patients have confirmed DS and a genetically confirmed SCN1A variant. Cohorts include ≥4 patients grouped by age (2-12 and 13-18 yrs). Patients are observed for 28 days before dosing to evaluate seizure frequency. On Day 1, patients undergo CSF collection followed by administration of STK-001. For MAD, CSF collection and injections are repeated at Weeks 4 and 8. Adverse events (AEs) and seizure frequency are monitored throughout with plasma collected for PK at multiple time points.

Results: 21 patients were included in this interim analysis (IA). Despite concomitant use of multiple anti-seizure medicines (ASMs), patients had a high seizure burden. Patients had a median of 17 convulsive seizures during the 28-day observation period prior to 1st STK-001 dose. At baseline, >85% (18/21) and 67% (14/21) of patients were taking ≥3 or ≥4 concomitant ASMs as maintenance therapy, respectively. At the time of the IA, single doses of STK-001 up to 30mg and multiple doses of 20mg, were well-tolerated with no study drug-related safety concerns. 14% (3/21) of patients had a study drug-related treatment-emergent (TE) AE; however, none were in the 2 higher dose groups (30mg SAD or 20mg MAD). 19% (4/21) of patients had a serious TEAE (SAE), none were related to study drug. A dose-proportional increase in STK-001 exposure was observed in plasma PK and CSF. A population PK model was developed to predict STK-001 brain levels. More than 95% of patients are projected to achieve pharmacologically active STK-001 brain levels with 3 monthly doses of 30mg. 73% (8/11) of SAD patients experienced a reduction in convulsive seizure frequency from baseline to the time period Days 29-84, with trend more evident in patients 2-12 yrs old.

Conclusions: The MONARCH IA provides positive safety data as well as more clarity on STK-001 doses that are likely to be pharmacologically active in patients with DS. There was a trend toward reduced convulsive seizure frequency. These data support continued development of STK-001 as the first disease-modifying precision medicine for DS.

Funding: Please list any funding that was received in support of this abstract.: Stoke Therapeutics.