Authors :
Presenting Author: Meena M, PhD – Stoke Therapeutics
Yanyan Cui, PhD – Stoke Therapeutics; Susovan Mohapatra, PhD – Stoke Therapeutics; Barry Ticho, MD – Stoke Therapeutics; Olivier Barriere, PhD – Certara USA, Inc; Amandine Manon, PhD – Certara USA, Inc; Nathalie Gosselin, PhD – Certara USA, Inc
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 (Na
v1.1) 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 Na
v1.1 protein expression in the brain by leveraging the wild-type (non-mutant) copy of
SCN1A to restore physiological Na
v1.1 levels, thereby potentially reducing both SF and non-seizure comorbidities. Non-clinical PK/PD studies informed the minimum STK-001 brain levels required to elicit 2-fold increase in Na
v1.1 levels which is the desired pharmacology. Methods:
The study objective was to provide simulations in the DS pediatric population to predict dose and frequency that would lead to pharmacologically active levels of STK-001 in brain. A semi-mechanistic population PK model was developed based on STK-001 concentration profiles collected in 141 non-human primates (NHP) after single or multiple intrathecal administrations. NHP model was scaled to predict exposure in patients with DS aged two to eighteen years based on published data taking into account: i) scaling for interspecies extrapolation; ii) age differences in brain/cerebrospinal fluid (CSF) volumes and in body weight; and iii) reduced height and weight growth trend. Monte Carlo simulations were performed to support 2 Phase 1/2 study dosing regimens: 1. Three doses administered every four weeks (Q4W), 2. Three doses at Days 1, 57, and 85, and 3) Administration every four months (Q4M) for open-label extension (OLE) studies. Safety margins were obtained by comparing simulated PK profiles in plasma, CSF, brain, and spinal cord compartments to ones in 1.5-kg NHP from either 13-week repeat dose study or 45-week chronic study.
Results:
Observed time-concentration profiles in plasma, CSF, and brain compartments in NHP were adequately described using a 15-compartment NHP model with parallel linear and saturable elimination from the plasma compartment and lag time for dose input. Validation of scaled population PK model in human was performed by over-lapping observed plasma and CSF concentrations from ongoing Phase 1/2 studies in US and UK and OLE study in US with 95% confidence intervals of the predicted concentrations (2.5 to 97.5 percentiles) in patients with DS.
Conclusions:
The PK model developed with NHP data along with published data for animal to human scaling was leveraged to predict dosing regimens with adequate safety margins and that would lead to pharmacologically active levels in brain tissues in patients with DS. The model will be further validated or adjusted using data from ongoing Phase 1/2 and OLE studies in patients with DS receiving STK-001.
Funding: Stoke Therapeutics