FDA allows testing of STK-001 at single high dose in MONARCH trial

70 mg dose of Dravet treatment in US study to mirror parallel UK trial dosing

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by Steve Bryson, PhD |

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A higher single dose of STK-001 will be administered in the U.S.-based Phase 1/2a MONARCH trial that is testing Stoke Therapeutics’ experimental therapy in children and adolescents with Dravet syndrome.

The U.S. Food and Drug Administration (FDA) allowed Stoke to test a 70 mg dose in the MONARCH study (NCT04442295), which will complement the ongoing testing of multiple 70 mg doses in the parallel Phase 1/2a ADMIRAL trial (ISRCTN99651026) taking place in the U.K.

A partial FDA hold on Stoke’s MONARCH trial, starting in 2020, limited dosing to 20 mg based on preclinical data. The agency gradually has allowed dose increases based on trial data at current dose levels. Still, MONARCH remains on partial clinical hold for testing multiple doses above 45 mg.

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

MONARCH, ADMIRAL trial findings at 70 mg dose expected by year’s end

Interim findings showed that three 45 mg doses of STK-001 safely reduced seizure frequency by 55% in both trials. Data readouts on multiple 45 mg doses of STK-001 in MONARCH are anticipated by mid-year, while findings with 70 mg treatment from both studies are expected later in the year.

“There is an urgent need for a disease-modifying approach to treat Dravet syndrome, a devastating disease with effects that go beyond seizures and impact quality of life for patients and their families,” Barry Ticho, MD, PhD, Stoke’s chief medical officer, said in a company press release. “We thank the FDA for its timely review of the clinical data from our ongoing studies.”

The new 70 mg group is expected “to provide information about the potential effects and durability” of a single treatment at that dose, Ticho added. “We look forward to dosing the first patient in the coming weeks and to be able to include preliminary findings … in the second half of 2023.”

Most Dravet cases are caused by mutations in one of the two copies of the SCN1A gene, which encodes NaV1.1, part of a sodium channel protein that helps transmit electrical signals in the brain.

Such mutations result in NaV1.1 deficiency and Dravet symptom onset, including seizures, some of which do not adequately respond to current disease treatments.

STK-001, injected directly into the spinal canal, is designed to increase NaV1.1 production, potentially reducing seizure frequency and improving overall health and life quality.

The parallel MONARCH and ADMIRAL trials are testing the therapy in up to nearly 140 children and adolescents with a genetically confirmed diagnosis of Dravet.

MONARCH’s participants are receiving single or multiple increasing doses of STK-001 at 10, 20, 30, and 45 mg, and will now also be given a single 70 mg dose. Multiple increasing doses — at 30, 40, or 70 mg — are being given to those in the ADMIRAL study. Of note, treatment starting at 10 mg in MONARCH is given only to those in the single ascending dose group.

Study findings expected to support Phase 3 testing of STK-001

The trials’ main goals are to assess the safety, tolerability, and pharmacological properties of STK-001. Secondary measures include the therapy’s impact on seizure rate, overall health, and quality of life. Follow-up exams will run for six months after the last dose, representing the third injection for those receiving multiple doses.

Interim findings showed all doses up to 45 mg were well tolerated, with vomiting, headache, and seizures being the most common adverse events reported. Nearly one-third of patients experienced treatment-related side effects, but all were mild to moderate in severity.

No patient discontinued treatment due to adverse events.

Blood STK-001 levels rose in a dose-dependent manner, and how the therapy moved into, through, and out of the body was consistent between participants given the same dose level across both trials.

In addition to the 55% reduction in seizure frequency seen with 45 mg doses of STK-001, patients in the 30 mg group saw their seizure rate drop by 20% and those on 20 mg experienced a 41% drop.

Nearly three-quarters (74%) of patients given three STK-001 doses (up to 45 mg) experienced a reduction in seizure frequency three months after their last dose relative to frequency at one month after their first dose.

Stoke expects to complete both studies this year. Results are intended to support the launch of a Phase 3 program in 2024.

Eligible MONARCH participants may enter an open-label extension study, called SWALLOWTAIL (NCT04740476), to continue treatment at a dose up to 30 mg. Likewise, ADMIRAL patients can join the LONGWING trial (ISRCTN12811235), which has already begun dosing, to receive up to 45 mg of STK-001.

“We expect that LONGWING will also provide valuable information on the preliminary effects of STK-001 on seizures along with non-seizure aspects of the disease, such as quality of life and cognition,” Stoke noted in the release.

Fewer seizures with ongoing treatment were seen in a small group of SWALLOWTAIL patients, with early signs of an easing in symptoms such as difficulties in decision-making.

STK-001 received orphan drug and rare pediatric disease status in the U.S. and orphan drug designation in Europe for treating Dravet syndrome. These designations are meant to expedite therapy development and regulatory review.