Abstracts

Rationale:
Dravet syndrome (DS) is a severe and progressive developmental and epileptic encephalopathy that begins in the first year of life and is characterized by high seizure frequency and severity, intellectual disability, and a high risk of sudden unexpected death in epilepsy. Approximately 85% of DS cases are caused by spontaneous, heterozygous loss of function mutations in the SCN1A gene which encodes the voltage-gated sodium channel α subunit NaV1.1. Upregulating NaV1.1 protein expression may restore functioning neurons and prevent the occurrence of seizures and significant non-seizure comorbidities. STK-001 is an investigational antisense oligonucleotide treatment using a unique platform, Targeted Augmentation of Nuclear Gene Output (TANGO) that exploits naturally occurring nonproductive splicing events to increase NaV1.1 protein expression. Current treatments focus on seizure control. STK-001 may be the first precision medicine approach for DS. This clinical study aims to primarily assess the safety, tolerability and pharmacokinetics of intrathecally administered STK-001. Secondary objectives aim to evaluate the effect of STK-001 on convulsive seizure frequency, overall clinical status and quality of life in Dravet syndrome patients.
Method:
This phase 1/2a open-label single ascending dose study includes patients aged 2-18 years with disease onset prior to 12 months of age with recurrent seizures (focal motor, hemiconvulsive or generalized tonic-clonic) and genetically confirmed SCN1A variant. 2 cohorts based on age (2-12 and 13-18 years) will be administered a single dose of STK-001 intrathecally (IT). Each cohort will enroll up to 4 patients with an option to dose up to 3 additional patients per cohort at the same level based on clinical assessment. All patients will have a 28-day observation period evaluating seizure frequency. On Day 1, patients undergo cerebral spinal fluid (CSF) collection followed by a single IT administration of STK-001 and 24-hour post-dose assessment. There will be a 6-month follow-up period after dosing. Adverse events are monitored throughout the study. Plasma and CSF will be collected at multiple timepoints. Patients will also keep a seizure/sleep diary the full duration of the study.
Results:
This study will provide insight into the safety, tolerability, and pharmacokinetic profile of ascending doses of STK-001 in DS patients. In addition, the impact of STK-001 on frequency of convulsive seizures and quality of life may indicate the initial clinical effect of the individual doses.
Conclusion:
STK-001 has the potential to be the first disease-modifying therapy to address the genetic cause of DS by restoring physiological NaV1.1 levels and reducing both occurrence of seizures and significant non-seizure comorbidities. The dose implications of this study may better inform future clinical trials on the appropriate and effective dosing for efficacy measures.
Funding:
:Sponsored by Stoke Therapeutics