Stoke Therapeutics is set to initiate a Phase 3 clinical trial of STK-001 in 2024, an investigational therapy for children and adolescents with Dravet syndrome. This decision follows positive safety and efficacy data from the Phase 1/2a MONARCH (NCT04442295) and ADMIRAL (ISRCTN99651026) trials. The new data, expected as early as mid-year, will provide further insights into the optimal dosing strategy for the pivotal Phase 3 study.
Promising Phase 1/2a Results
Interim results from the ongoing MONARCH and ADMIRAL trials, reported late last year, demonstrated that STK-001 safely and effectively reduced the frequency of seizures. Specifically, data from 27 patients who received three STK-001 doses (up to 45 mg) showed that nearly three-quarters (74%) experienced fewer convulsive seizures three months after their last dose compared with one month after their first dose.
"These data support our belief that we are entering a new era in the treatment of this disease — a shift from seizure management to syndrome management — one that could have a profound impact for patients and caregivers," said Edward Kaye, MD, Stoke’s CEO.
STK-001: Restoring NaV1.1 Levels
Dravet syndrome is characterized by defects in one of the two copies of the SCN1A gene, leading to reduced production of NaV1.1, a crucial subunit of a sodium ion channel protein involved in transmitting electrical signals in the brain. This deficiency results in seizures and other symptoms, often unresponsive to conventional treatments.
STK-001, administered via injection directly into the spinal canal, is designed to restore normal levels of NaV1.1 in nerve cells by enhancing its expression from the patient’s single healthy copy of the SCN1A gene. This mechanism is believed to reduce seizure frequency and improve overall clinical status and quality of life.
Ongoing Data Collection and Trial Design
The MONARCH trial's 45-mg multiple-dose group was recently expanded to include 10 additional patients, with data expected by mid-year. Dosing is also ongoing in the 70-mg dose group of ADMIRAL, which was also recently expanded, with results anticipated later in the second half of 2023. MONARCH participants have the option to continue STK-001 treatment in the SWALLOWTAIL open-label extension (OLE) study (NCT04740476), while ADMIRAL participants can enroll in the LONGWING OLE study (ISRCTN12811235). Early SWALLOWTAIL results suggest that longer STK-001 treatment maintains lower seizure rates.
Addressing Unmet Needs in Dravet Syndrome
While several anti-seizure medications, including Diacomit (stiripentol), Fintepla (fenfluramine), and Epidiolex, have been approved for Dravet syndrome in recent years, a significant gap remains in addressing the full scope of the syndrome. STK-001 represents a potential disease-modifying approach that could improve seizure control and address the non-seizure aspects of the disease that negatively impact health and quality of life.
Interim data showed that STK-001 safely reduced seizure rates by 55% in the 45-mg dose group, 20% in the 30-mg dose groups, and 41% in those who received 20-mg injections. Similar drops in seizure frequency were observed in patients also taking Fintepla.
With additional data anticipated in 2023, Stoke Therapeutics expects to finalize the dose level and frequency for the Phase 3 program, paving the way for a potential new treatment paradigm in Dravet syndrome.
