STK-001 Seen to Reduce Seizures in Children With Severe Dravet

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Single and multiple doses of Stoke Therapeutics’ investigational therapy STK-001 were well-tolerated and led to a significant reduction in the frequency of convulsive seizures among children and adolescents with Dravet syndrome in the first three months of follow-up, interim data from the ongoing Phase 1/2a MONARCH trial show.

These findings are particularly promising since the patients enrolled have severe disease and almost all — 90.9% — were receiving at least three anti-seizure treatments.

“Seeing an early trend toward reduction in seizure frequency at these relatively low dose levels is very encouraging, especially given that more than 90 percent of patients were taking three or more concomitant anti-seizure medications as maintenance therapy during the study,” Linda Laux​, MD, associate professor of pediatrics in neurology and epilepsy at Northwestern University Feinberg School of Medicine and the trial’s lead researcher, said in a press release.

Laux​, also an attending physician at the Ann & Robert H. Lurie Children’s Hospital of Chicago, presented the findings in a poster titled “Interim Safety, PK, and CSF Exposure Data from the Phase 1/2a MONARCH Study of STK-001, an Antisense Oligonucleotide (ASO), in Children and Adolescents with Dravet Syndrome (DS),” at the American Epilepsy Society (AES) 2021 Annual Meeting, held recently in Chicago.

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Trial Data Show STK-001 Safe, Likely Effective at Reducing Seizures

STK-001 works by increasing the production of NaV1.1, a subunit of a sodium channel protein responsible for the transmission of electrical signals in the brain. The protein’s production is impaired in most Dravet patients due to mutations in one of the two copies of the SCN1A gene.

The open-label MONARCH trial (NCT04442295), sponsored by Stoke, is evaluating STK-001’s safety, tolerability, and preliminary efficacy in children and adolescents with Dravet syndrome who carry SCN1A mutations. It also is examining the therapy’s pharmacokinetics, or its movement into, through, and out of the body.

Ongoing at 18 clinical sites across the U.S., the trial is actively enrolling Dravet patients ages 2 to 18. More information on U.S. contacts and locations can be found here.

The newly announced interim efficacy data from MONARCH concern 17 patients, of which 13 were given a single injection of STK-001 at 10, 20, or 30 mg, and followed from one month (29 days) to almost three months (84 days). The other four patients received multiple 20 mg injections, every four weeks or about one once per month. The results from five patients were excluded from the efficacy analysis due to incorrect or insufficient dosing, and failure to meet a minimum seizures criteria.

More than 70% of patients — 12 of 17 — treated with STK-001 experienced a reduction in convulsive seizure frequency when compared with the start of the trial (baseline), the data show.

Across all groups, there was a median reduction of 17% to 37% in the frequency of convulsive seizures from days 29 and 84 when compared with baseline.

In particular, all seven younger patients — those ages 2-12 — experienced a reduction in convulsive seizures, with a lessening of seizure frequency also observed among those ages 13-18.

Safety data, available for the 22 patients treated to date, showed that both single doses of STK-001 up to 30 mg and multiple doses of 20 mg were well-tolerated with no safety concerns.

Treatment-related adverse events (side effects) were seen in 18.2% of patients, but not deemed severe. The most common adverse events included headache, vomiting, seizure, irritability, and back pain.

A total of 22.7% of patients developed a serious adverse event, but these were not deemed related to STK-001.

Pharmacokinetics analyses showed a dose-dependent increase, with increasing single doses, in the levels of STK-001 in both blood and samples of cerebral spinal fluid — the fluid surrounding the brain and spinal cord, known as CSF.

Also, in the multiple-dose group, the mean concentration of STK-001 in the CSF increased from the first to the second dosing, indicative of an “accumulation of STK-001 in CNS tissues with repeated monthly dosing,” the researchers wrote.

“STK-001 is designed to target the underlying cause of Dravet syndrome to potentially address both seizures and non-seizure comorbidities [other co-existing medical problems],” said Barry Ticho, MD, PhD, chief medical officer of Stoke Therapeutics.

“These initial data give us confidence that STK-001 is having an effect on the disease,” Ticho said. “Based on our pharmacokinetic model, we believe that sustained higher exposure levels in the brain may lead to greater reductions in seizure frequency and potentially also improvements in some of the non-seizure comorbidities.”

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All participants given a single dose of STK-001 chose to enter the open-label extension SWALLOWTAIL study (NCT04740476), in which they will receive up to three injections  — one every four months — at the same dose level as in MONARCH.

To date, none of the patients have discontinued treatment in the SWALLOWTAIL trial, according to Stoke.

A parallel Phase 1/2a trial ongoing in the U.K., called ADMIRAL, is evaluating multiple doses of up to 70mg of STK-001. The trial is actively enrolling Dravet patients, ages 2 to 18, and more information is available here.

“We are pleased with the initial clinical findings from MONARCH, and the SWALLOWTAIL open-label extension study, and look forward to continuing our clinical progress in collaboration with the Dravet community,” Ticho said.

The company presented two additional posters at the AES meeting. One poster covered a preclinical study testing STK-001 in non-human primates, while the second poster described BUTTERFLY, an observational study assessing cognition and other non-seizure impairments in children and adolescents with Dravet.