STK-001 Continues to Show Promise as an Anti-seizure Therapy
Interim data from two clinical trials point to treatment's safety and efficacy
STK-001, Stoke Therapeutics’ investigational therapy, continues to show promise in safely reducing seizures among children and adolescents with Dravet syndrome, according to new interim data from the ongoing Phase 1/2a MONARCH and ADMIRAL trials.
“We are encouraged by the data from our ongoing studies of STK-001, which continue to demonstrate favorable safety findings and reductions in seizure frequency among a highly [treatment-resistant] group of patients,” Barry Ticho, MD, PhD, Stoke’s chief medical officer, said in a company press release providing financial and business updates.
“Half of the patients in these studies were taking four or more anti-seizure medicines, including [Fintepla (fenfluramine)], setting a high bar for STK-001 to demonstrate additional benefit. Even so, 74% of patients experienced a reduction in seizure frequency following three doses of STK-001,” Ticho added.
A median seizure frequency decline of 55% was observed among patients given three STK-001 injections, directly into the spinal canal, at 45 mg — the highest dose tested so far.
“Based on these data, we believe we have entered the therapeutic range, which is translating to a clinical benefit for patients,” Ticho said.
The findings were recently detailed in a company webinar, and further details are expected to be presented at the 2022 American Epilepsy Society Annual Meeting, to be held Dec. 2–6 in Nashville, Tennessee.
Outcomes of additional patients given multiple injections at the 45 mg dose and patients treated with 70 mg STK-001 injections are expected next year.
STK-001 works by increasing the production of NaV1.1, which is impaired in most Dravet patients due to mutations in one of the two copies of the SCN1A gene.
NaV1.1 is part of a sodium channel protein responsible for the transmission of electrical signals in the brain, and low NaV1.1 levels can lead to seizures and other symptoms of Dravet syndrome.
The therapy received orphan drug designation in both the U.S. and Europe and rare pediatric disease designation in the U.S. for Dravet. These are expected to accelerate its clinical development and regulatory review.
MONARCH and ADMIRAL trials
Two ongoing, parallel, open-label Phase 1/2a trials — MONARCH (NCT04442295) in the U.S. and ADMIRAL (ISRCTN99651026) in the U.K. — are testing STK-001 in children and adolescents with a genetically confirmed diagnosis of Dravet.
In both trials, main goals include assessing the therapy’s safety, tolerability, pharmacokinetics (its movement into, through, and out of the body), and levels in the cerebrospinal fluid (CSF, the liquid surrounding the brain and spinal cord).
Changes in seizure frequency, overall clinical status, and quality of life are being evaluated as secondary goals.
While MONARCH is testing both single and multiple increasing doses of STK-001 (10, 20, 30, and 45 mg), ADMIRAL is evaluating multiple increasing doses (30, 40, or 70 mg). Participants are followed for six months after the last doses, which in the multiple dosing groups corresponds to the third injection.
Newly announced results concerned data from up to 55 patients (28 girls and 27 boys) given one or three STK-001 injections (up to 45 mg) and followed for up to six months. Most were white (87.2%), and they had a median age of 13 years (range, 2–18 years).
Similar to previous interim results, updated safety findings from the 55 patients showed that all doses were well-tolerated. Most commonly reported adverse events were vomiting, headache, and seizure.
Treatment-related adverse events were seen in almost a third of patients (27%), but all were deemed of mild to moderate severity. No withdrawal due to adverse events was reported.
There was a dose-dependent increase in blood STK-001 levels, and the therapy’s pharmacokinetics profile was consistent between patients given the same dose level in both trials.
Also, STK-001 levels were measurable in the CSF for up to six months following single and multiple injections, “indicating sustained exposure of STK-001 in the brain,” Stoke stated in the release.
Efficacy data, concerning 27 patients who received three STK-001 injections and who were followed for three months after their last dose, showed that 74% of them experienced a reduction in convulsive seizure frequency when compared with about one month after their first dose (baseline).
Seizure frequency dropped by 55% in patients given 45 mg doses, by 20% in those in the 30 mg dose group, and by 41% in patients given 20 mg injections. While 50.9% of patients were also simultaneously taking Fintepla, comparable seizure reductions were observed between those receiving or not receiving the approved therapy.
Also, seizure drops were more evident among the younger age group (ages 2–12).
MONARCH’s 45 mg multiple-dose group was recently expanded to evaluate up to 10 additional patients, while an expansion of ADMIRAL’s 70 mg dose group is planned, pending a safety review.
Patients completing the trials may enter their corresponding open-label extension studies: SWALLOWTAIL (NCT04740476) for MONARCH (with continued treatment at a maximum dose of 30 mg), and the LONGWING (ISRCTN12811235) for ADMIRAL (with a maximum 45 mg dose treatment).
A preliminary analysis from a small group of SWALLOWTAIL’s participants showed that the decrease in seizure frequency was sustained with ongoing treatment. Early signs of improvements were also seen for some nonseizure symptoms, such as executive function deficits.