Abstracts

Rationale: Dravet syndrome is a severe and progressive genetic epilepsy that typically begins in the first year of life and is characterized by frequent, prolonged, and refractory seizures. Non-seizure comorbidities include intellectual disability, ataxia/motor abnormalities, behavioral problems, speech impairment, sleep disturbances, and a high risk for sudden unexpected death. Approximately 85% of DS cases are caused by de novo, spontaneous, heterozygous loss of function mutations in the SCN1A gene which encodes the voltage-gated sodium channel type 1 α 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 reducing both occurrence of seizures and significant non-seizure comorbidities.

Methods: ADMIRAL is a phase 1/2a open-label, multi-center study in the UK of patients ages 2-18 years with a DS diagnosis including disease onset prior to 12 months of age with recurrent seizures (focal motor, hemiconvulsive, or generalized tonic-clonic) and with genetically confirmed SCN1A variant. ADMIRAL primarily aims to assess safety, tolerability, and PK) of multiple ascending doses (MAD; 30mg up to 70mg) of intrathecally (IT) administered STK-001. Each dose level will include at least 4 patients grouped by age (two patients 13-18 years followed by two 2-12 years). Additional dose cohorts may be added with maximum enrollment of up to 60 patients. Secondary objectives are the percentage change from baseline in convulsive seizure frequency, overall clinical status, and quality of life. Patients will be observed for a 28-day baseline period prior to dosing to evaluate seizure frequency. On Day 1, patients undergo cerebrospinal fluid (CSF) collection followed by a single IT administration of STK-001; this is repeated on Days 57 and 85. There is a 6-month follow-up after the last dose. Adverse events are monitored continuously, and plasma is collected for PK at multiple times. Seizure frequency, overall clinical status, and quality of life will be evaluated. At the end of this study, patients meeting criteria will have the option to enter an open-label extension (OLE) study.

Results: ADMIRAL will provide insight into the safety, tolerability, and PK of STK-001 in patients with DS. Data on seizure frequency, overall clinical status, and quality of life may provide evidence of clinical effect. Available demographics and preliminary safety data from the first cohort will be reported.

Conclusions: STK-001 has the potential to be the first-in-class, disease-modifying therapy to address the genetic cause of DS by upregulating Na_v1.1 protein levels and to potentially reduce both occurrence of seizures and non-seizure comorbidities. Together with the US MONARCH study, the ADMIRAL data may better inform future clinical trials on appropriate and effective STK-001 dosing.

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