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Multiple doses of STK-001, an investigational antisense oligonucleotide to treat Dravet syndrome, were well tolerated and showed trends toward fewer seizures, interim analyses of phase I/IIa trial data showed.

In a combined analysis of the early U.S.-based and U.K.-based ADMIRAL studies, the drug showed mild or moderate adverse effects and no significant safety problems, reported Linda Laux, MD, of Northwestern University Feinberg School of Medicine in Chicago, at the American Epilepsy Society annual meeting.

Dravet syndrome is a progressive genetic epilepsy with frequent, refractory seizures that often start in the first year of life. In more than 80% of patients, the disease is caused by which encodes the voltage-gated sodium channel type 1 alpha subunit (Nav1.1) protein.

STK-001 is designed to upregulate Nav1.1 protein expression from the nonmutant copy of the SCN1A gene to restore Nav1.1 levels.

No disease-modifying treatments currently are available for Dravet syndrome, Laux noted. In 2018, cannabidiol (Epidiolex) became the first drug approved for the disease; low-dose fenfluramine (Fintepla) followed in 2020.

"Children with Dravet syndrome have numerous non-seizure comorbidities that markedly affect their lives," she told 名媛直播. "These comorbidities include developmental impairment, intellectual disability, gait and motor abnormalities, and behavior and mood concerns."

"STK-001, by increasing the functional protein expression of Nav1.1, has the potential to address the underlying genetic cause of Dravet syndrome and, hopefully, improve not only seizures but the non-seizure comorbidities as well," she added.

The open-label phase I/IIa studies aimed to identify the optimal dose for a pivotal study. "The preliminary data from the MONARCH and ADMIRAL studies show that STK-001 is well tolerated with no significant safety concerns related to the study drug," Laux noted.

"This data also show a trend towards reduction of seizures in patients with Dravet syndrome, especially in the younger patient cohort and for the 45-mg dosing cohort," she added.

Across both studies, 55 children and adolescents with Dravet syndrome received one or more intrathecal doses of STK-001 ranging from 10 mg to 45 mg. About half of the study group was 2 to 12 years old (49.1%); the remainder were 13 to 17.

Ten participants were in the 45-mg cohort and 18 were in the 30-mg cohort; these groups received multiple doses of STK-001. Baseline convulsive seizure frequencies ranged from 10 to 54 over a 28-day period.

An interim analysis of six participants treated with three doses of STK-001 45 mg showed a 55.2% median reduction from baseline in convulsive seizure frequency, measured from day 29 after the first dose to 3 months after receiving the last dose. In the 30-mg group, 17 participants showed a 20.1% median reduction in convulsive seizure frequency in the same period. Seizure reductions were more apparent in children ages 2 to 12.

Seizure reductions were similar with or without concomitant fenfluramine. Reductions in seizure frequency began after the first dose and continued with additional treatment, Laux noted.

In the interim analysis, 27.3% of participants (15/55) had experienced a treatment-emergent adverse event related to STK-001; all were mild to moderate. Five participants had cerebrospinal fluid protein increase and one participant had proteinuria.

No new significant neurologic exam findings or lower extremity weakness related to STK-001 treatment emerged in the trials. One sudden unexpected death in epilepsy (SUDEP) and one life-threatening event (near drowning) occurred; neither were related to the study drug.

Preliminary data from a small group of patients in the open-label extension study of 30-mg dosing indicated reductions in convulsive seizure frequency were maintained with ongoing treatment. Safety was similar to that seen in MONARCH and ADMIRAL. Outcomes for patients receiving 45 mg and 70 mg doses are expected next year.