STK-001 lowers seizures, aids cognition and behavior, trials finding
Updated data from Phase 1/2a studies show treatment generally well tolerated
Treatment with STK-001 led to a marked reduction in seizure frequency, and aided cognition and behavior, among children and adolescents with Dravet syndrome in early clinical trials, according to new findings announced by the therapy’s developer Stoke Therapeutics.
“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,” Edward M. Kaye, MD, CEO of Stoke, said in a company press release.
Stoke is conducting two parallel, open-label Phase 1/2a clinical trials of STK-001 in young people with Dravet syndrome: MONARCH (NCT04442295), being run at sites in the U.S., and ADMIRAL (ISRCTN99651026), which is being conducted in the U.K. Both studies mainly are evaluating the safety profile and pharmacological properties of the experimental therapy, with secondary goals looking into its efficacy.
“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,” Kaye said.
Seizure frequency dropped by 80% three months after last dose in five patients
Most cases of Dravet syndrome are caused by mutations that disrupt the production of the protein NaV1.1. STK-001 is designed to increase NaV1.1 protein production; the therapy is administered via injection into the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord.
New trial data show that patients experienced a reduction in seizure frequency following treatment with STK-001.
The most profound reductions were seen among the 11 patients in the ADMIRAL study who were given two or three injections of STK-001 at a high dose of 70 mg. Data from five evaluable patients showed a drop in seizure frequency of 80% at three months after the last dose. At six months after the last dose, seizure frequency was reduced by 89% for the three patients with evaluable data.
One patient given multiple injections at this higher dose experienced a serious health issue that trial investigators deemed likely to be a side effect of STK-001. The study’s protocol was amended to give investigators the flexibility to choose whether to administer two or three 70 mg injections. According to Stoke, subsequent data from ADMIRAL are expected to mainly include patients given two high-dose injections.
Apart from this one event, no serious side effects related to STK-001 have been reported, according to Stoke. The MONARCH study recently was authorized to test a single injection of STK-001 at 70 mg, but data from these patients are not yet available.
Data from both ADMIRAL and MONARCH also showed a reduction in seizure frequency for patients given lower doses of STK-001. Among evaluable patients given three injections at 45 mg, the average reduction was 19% at three months and 45% at six months after the last dose. For those given three injections at 30 mg, the average reduction was 27% at three months and 4% at six months.
“The patients in these studies were already taking the best available anti-seizure medicines, making the additional observed reductions in seizures quite meaningful,” said Joseph Sullivan, MD, a professor of neurology and pediatrics at the University of California San Francisco.
In addition to the one serious event reported for a patient given 70 mg, side effects related to STK-001 have been reported in about one-third (32%) of patients in MONARCH or ADMIRAL. The most common side effects include irritability, vomiting, and elevated levels of protein in the CSF.
Patients who complete the MONARCH trial have the option to continue treatment into an open-label extension study called  SWALLOWTAIL (NCT04740476). Evaluable data were available for 26 of its 44 patients, being given STK-001 at doses of 30 or 45 mg every four months.
Dravet syndrome treatment that may address seizures and life quality
Durable reductions in seizure frequency are observed in SWALLOWTAIL, and Stoke also reports that patients experienced “substantial improvements” from the study’s start in standardized measures of communication ability, motor skills, and executive function (the ability to regulate one’s own behaviors). Ratings of disease severity done by clinicians and caregivers also have shown improvement.
“One of the most exciting things we are seeing is the early sign that, for the first time, we may have a therapy that can address the syndrome, in addition to the seizures,” Sullivan said. “What we know from the natural history data is that the profound deficits in cognitive functioning among patients with Dravet syndrome do not tend to improve on their own, which makes the improvements indicated in multiple assessments of cognition and behavior compelling.”
Safety data from SWALLOWTAIL are generally consistent with those from MONARCH and ADMIRAL, though rates of elevated protein in the CSF have been somewhat higher in the extension study, Stoke reported. One SWALLOWTAIL patient stopped treatment due to elevated CSF protein levels, but so far no patient with this side effect has experienced notable clinical issues related to these level changes.
Stoke plans to present findings from these studies at medical conferences later this year. End-of-study data from MONARCH and ADMIRAL are expected early next year; pending results from these studies, Stoke is planning to launch a Phase 3 trial of STK-001 in Dravet patients in 2024.
“We are on track to complete the Phase 1/2a studies by year-end and look forward to sharing these data, and data from the open-label extension studies, in the first quarter of 2024,” Kaye said.
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