Findings from these studies were presented by the company in a poster, titled “Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a Prevents SUDEP in a mouse model of Dravet Syndrome,” during the recent American Epilepsy Society (AES) Annual Meeting in Baltimore.
A small RNA molecule called an antisense oligonucleotide, STK-001 boosts the production of NaV1.1, a sub-unit of a sodium channel. NaV1.1 is responsible for the transmission of electrical signals in the brain. RNA is the molecule that serves as a template for the production of proteins.
In children with Dravet syndrome, mutations in the SCN1A gene disrupt the production of NaV1.1, leading to seizures and increasing the risk of sudden unexpected death in epilepsy (SUDEP). By restoring the levels of the NaV1.1 protein, STK-001 aims to reduce the frequency of seizures and other symptoms associated with Dravet.
New data from preclinical studies, presented by the company at the annual meeting, showed that a single injection of STK-001 in the brain of 2-day-old or 14-day-old mice with Dravet led to significant increases in the production of NaV1.1 that were clear when the animals reached the age of three months.
Moreover, STK-001 led to significant improvements in the animals’ survival, which was measured by comparing the percentage of mice that reached the age of three months when given the medication versus a placebo. This was true for mice receiving the treatment both two days (97% versus 23%) and 14 days after birth (85% versus 64%).
Electroencephalography (EEG) recordings — used to analyze the brain’s electrical activity and to study seizures — showed that 76% of the animals treated with STK-001 when they were two days old remained seizure-free between postnatal days 22 and 46. Meanwhile, less than half of those treated with a placebo (48%) achieved the same outcome.
Further, the results showed that STK-001 reduced the average number of spontaneous seizures detected between postnatal days 22 and 46 by 80% compared with the placebo.
“The data on STK-001 from this mouse model give us confidence in our approach to treating the underlying cause of Dravet syndrome by restoring NaV1.1 protein expression to near normal levels,” Edward M. Kaye, MD, CEO of Stoke Therapeutics, said in a press release.
“The reductions in mortality previously observed with STK-001 were compelling and the new EEG data provide further evidence of the potential for STK-001 to impact Dravet syndrome by reducing seizure frequency and possibly preventing seizures entirely. What is particularly remarkable is that these data were generated from a spontaneous seizure model, which we believe accurately reflects the clinical situation in people with Dravet syndrome,” Kaye said.
“Although we cannot make a direct correlation, these data are encouraging because they suggest a potential for STK-001 to reduce seizure frequency in Dravet syndrome patients. Showing a 50% improvement in the number of DS mice that had no detectable seizures is a significant finding, particularly considering the high seizure burden associated with Dravet syndrome,” said Lori Isom, PhD, chair of pharmacology at the University of Michigan Medical School.
In addition to these encouraging results in a mouse model of Dravet, Stoke Therapeutics presented data describing the distribution, safety, and tolerability of STK-001 in a non-humane primate. That data was presented in another poster, titled “TANGO oligonucleotides for the treatment of Dravet Syndrome: Safety, biodistribution and pharmacology in the non-human primate.”
The study findings showed that STK-001 had a favorable safety and pharmacokinetic profile. Pharmacokinetics is the study of the time course of a drug’s absorption, distribution, metabolism, and excretion through the body.
Stoke said these preliminary results support STK-001’s continued development as a future therapy for infants and children with Dravet.
Data from this last study will be included in the investigational new drug application Stoke is planning to submit to the U.S. Food and Drug Administration (FDA) in the beginning of 2020. The company plans to request authorization to launch the first clinical trial of STK-001 in human patients with Dravet.