Stoke Reports New Positive Data from Phase 1/2a Studies in Dravet Syndrome

Rare Daily Staff

Stoke Therapeutics reported positive new safety and efficacy data from patients treated with its experimental STK-001 in the two ongoing phase 1/2a studies and an ongoing open-label extension study in children and adolescents with the rare, genetic epilepsy Dravet syndrome.

The company said the observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population. It said that the new data suggest clinical benefit for patients 2 to 18 years of age treated with multiple doses of STK-001.

“Together these data support the potential for STK-001 to address the underlying cause of Dravet syndrome by treating both seizures and the cognitive and behavioral issues that make this disease so complex and devastating,” said Edward Kaye, CEO of Stoke Therapeutics. “Our ongoing studies are providing a better understanding of a dose and dosing regimen that may generate substantial and sustained benefits for patients, while continuing to be generally well tolerated.”

The company said it is on track to complete the phase 1/2a studies by year-end and expects to share data from the two studies as well as the open-label extension studies in the first quarter of 2024.

Dravet syndrome is a severe and progressive epilepsy characterized by frequent, prolonged, and refractory seizures, beginning within the first year of life. It is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, disruptions of the autonomic nervous system and mood disorders. The disease is classified as developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. There are no approved disease-modifying therapies for people living with Dravet syndrome.

STK-001 is an experimental medicine for the treatment of Dravet syndrome currently being evaluated in ongoing clinical trials. Stoke believes that STK-001, a proprietary antisense oligonucleotide, has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. STK-001 has been granted orphan drug designation by the FDA and the EMA, and rare pediatric disease designation by the FDA as a potential new treatment for Dravet syndrome.

MONARCH and ADMIRAL are multi-center, phase 1/2a studies of children and adolescents who have an established diagnosis of Dravet syndrome. The primary objectives for MONARCH in the United States and ADMIRAL in the United Kingdom are to assess the safety and tolerability of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective is to assess the efficacy of STK-001 as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency.

The combined efficacy analysis reported by the company was based on clinically evaluable data from 45 patients who were treated with multiple doses (30mg, 45mg, 70mg) in either of these two ongoing studies. The greatest reduction in convulsive seizure frequency has been observed among the small number (n=11) of patients treated with two or three doses of 70mg in the ADMIRAL study. The analysis of the 70mg multiple dose cohort from ADMIRAL study consists primarily of patients treated with three doses of STK-001. The company anticipates that the remaining ADMIRAL study data will consist primarily of patients treated with two doses of 70mg.

STK-001 was generally well-tolerated among 74 patients treated with single and multiple doses of 10mg to 70mg in the phase 1/2a studies and there were no discontinuations related to study drug. Some 32 percent of patients experienced a treatment-emergent adverse event (TEAE) that was related to study drug. The most common TEAEs related to study drug were CSF protein elevations, vomiting, and irritability. A total of 20 percent of patients had a treatment-emergent serious adverse event. The TESAEs experienced by 14 of the 15 were not considered related to study drug.

One patient who received multiple doses of 70mg STK-001 in the ADMIRAL study experienced a Suspected Unexpected Serious Adverse Reactions that were attributed by the investigator to STK-001. The patient went on to complete the study.

Subsequently, the study protocol for ADMIRAL was amended to allow investigators to decide whether to administer two or three doses of STK-001 (70mg) in the ADMIRAL study before patients would be eligible to enroll in the LONGWING OLE.

Photo: Edward Kaye, CEO of Stoke Therapeutics