Stoke’s Phase 3 Trial of STK-001 for Dravet Planned for Next Year

New data from Phase 1/2a trials may be released by mid-2023

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by Steve Bryson, PhD |

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New safety and efficacy data from two Phase 1/2a clinical trials testing STK-001, Stoke Therapeutics’ investigational treatment for children and adolescents with Dravet syndrome, are expected as early as mid-year.

Interim results from the ongoing Phase 1/2a MONARCH (NCT04442295) and ADMIRAL (ISRCTN99651026) trials, reported late last year, demonstrated that STK-001 safely and effectively reduced the frequency of seizures.

“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,” Edward Kaye, MD, Stoke’s CEO, said in a company press release.

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Additional data expected to inform dose level and frequency for Phase 3 trial

MONARCH’s 45-mg multiple-dose group was recently expanded to 10 additional patients, in which dosing is currently ongoing, with data expected by mid-year. Dosing is also continuing in the 70-mg dose group of ADMIRAL, which was also recently expanded, with results anticipated later in the second half of 2023.

“With additional data anticipated in 2023, we expect to be in a position to select a dose level and dose frequency in order to initiate a Phase 3 program in 2024,” Kaye added.

In Dravet, defects in one of the two copies of the SCN1A gene lead to a reduced production of NaV1.1 — a subunit of a sodium ion channel protein that plays a role in the transmission of electrical signals in the brain. As a result, people with Dravet experience seizures and other symptoms, some of which are unresponsive to treatments.

“In recent years our understanding of Dravet syndrome has improved dramatically. We now know what causes it and the effects it has on patients as they age,” said Joseph Sullivan, MD, a professor of neurology and pediatrics, and the director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco.

Dravet patients are typically treated with anti-seizure medications. Therapies more recently approved by the U.S. Food and Drug Administration (FDA) include the add-on medications Diacomit (stiripentol) and Fintepla (fenfluramine), and Epidiolex, a cannabis derivative.

“Even though three new medications have been approved by the FDA in the last five years for the treatment of seizures associated with Dravet syndrome, none of them address the full scope of the syndrome,” Sullivan said. “That leaves a significant gap in our ability to effectively care for our patients.”

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

STK-001 designed to restore normal levels of NaV1.1 in nerve cells

STK-001, injected directly into the spinal canal, is designed to restore normal levels of NaV1.1 in nerve cells by increasing its expression, or production, from a patient’s single healthy copy of the SCN1A gene. As such, the therapy is thought to help reduce seizure frequency and improve overall clinical status and quality of life.

“By restoring native gene expression, potential disease-modifying approaches are positioned to improve seizure control and address the non-seizure aspects of the disease that negatively impact health and quality of life for people living with this disease,” Sullivan said.

STK-001 is being evaluated in two parallel, open-label Phase 1/2a trials: MONARCH in the U.S. and ADMIRAL in the U.K. Both studies are investigating the therapy’s safety, tolerability, and pharmacological properties, as well as its impact on seizure rate, overall clinical status, and quality of life.

In MONARCH, participants are receiving either single or multiple increasing doses of STK-001 (10, 20, 30, and 45 mg), while in ADMIRAL, patients are being given multiple increasing doses (30, 40, or 70 mg). All will be followed for six months after their last dose, which corresponds to the third injection in multiple dosing groups.

Interim efficacy data from the two trials, for 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.

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Interim data show STK-001 reduces seizure rates significantly

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 seen in those also taking Fintepla.

“Our recent data showed the first evidence that upregulating protein expression with STK-001 to target the underlying cause of Dravet syndrome can reduce seizure frequency in children and adolescents who are already taking several anti-seizure medicines, including [Fintepla],” Kaye said.

MONARCH’s participants have the option of continuing STK-001 treatment in the SWALLOWTAIL open-label extension (OLE) study (NCT04740476), while the LONGWING OLE study (ISRCTN12811235) is open to ADMIRAL participants.

Early SWALLOWTAIL results suggested that longer STK-001 treatment maintains lower seizure rates.

STK-001 has been granted orphan drug and rare pediatric disease designations in the U.S. and orphan drug status in Europe for Dravet. These are expected to expedite the therapy’s clinical development and regulatory review.