Abstracts

Rationale: Stoke Therapeutics is developing STK-001, an ASO for the treatment of DS. DS is caused by de novo pathogenic mutations in the SCN1A gene leading to haploinsufficiency of voltage-gated sodium channel type 1 α subunit (Na_v1.1) protein. STK-001 is designed to upregulate Na_v1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological Na_v1.1 levels, thereby reducing both occurrence of seizures and substantial non-seizure comorbidities. The study objective was to provide simulations in the DS pediatric population to support intrathecal (IT) dosing selection for phase 1/2a trials by identifying the potentially safe and efficacious dose range for single and multiple ascending dose regimens.

Methods: A semi-mechanistic population PK model was developed based on STK-001 concentration profiles collected in 95 NHP after single IT administration from 2 to 30 mg and multiple IT administrations of 4, 10, or 30 mg. Allometric and maturation scaling was included in the model simulations to predict exposure in patients with DS aged 2-18 years based on published data taking into account: i) scaling for interspecies extrapolation; ii) age differences in brain/CSF volumes and in body weight; and iii) reduced height and weight growth trend in DS patients. Monte Carlo simulations were performed at single dose and two repeat dosing regimens: 1) 3 doses to be administered every 4 weeks (Q4W) and 2) 3 doses at Days 1, 57, and 85. Safety margins were obtained by comparing the simulated PK profiles in plasma, cerebrospinal fluid (CSF), and brain compartments to ones in 1.5-kg NHP after the 4th dose Q4W at the no-observed adverse effect level (NOAEL).

Results: Observed time-concentration profiles in plasma, CSF, and brain compartments were adequately described using a 14 compartments model (Figure 1) with parallel linear and saturable elimination from the plasma compartment and a lag time for the dose input. Overall, in plasma and CSF compartments, the margins of safety were lower for younger groups (2- < 8 years old) than for older groups (8- < 12 and 12-≤18 years old), but the margins of safety were similar in brain across the different age groups. Exposure margins in plasma, CSF, and brain compartments were obtained to support the clinical dosing up to 70 mg. External validation of the population PK model was performed by over-lapping observed concentrations in humans with 95% confidence intervals of the predicted concentrations (2.5th -97.5th percentiles) based on 1000 replicates of the NHP model scaled to human, considering dose regimen, age, and weight of each subject.

Conclusions: The PK model developed with NHP data along with published data for animal-human scaling was leveraged to support dosing recommendations in pediatric patients with DS. The model simulations will be further validated with data from an ongoing phase 1/2a clinical trial in patients with DS receiving STK-001.

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