The phase 1/2a studies are expected to be complete by the end of 2023, with data from the open-label extension studies to be shared in early 2024.
Stroke Therapeutics announced new positive findings from 2 ongoing phase 1/2a studies assessing its investigational antisense oligonucleotide STK-001 in children and adults with Dravet syndrome (DS). All told, data from both the MONARCH (NCT04740476) and ADMIRAL (NCT04442295) studies and the SWALLOWTAIL open-label extension showed clinical benefit with the agent, demonstrated by reductions in convulsive seizure frequency, as well as substantial improvements in cognitive and behavior.
Combining available data from 45 patients who were treated with multiple doses (30 mg, 45 mg, 70 mg) in either MONARCH or ADMIRAL, findings showed that the greatest reduction in convulsive seizure frequency was among those (n = 11) treated with 2 or 3 doses of 70 mg in the ADMIRAL study. All told, investigators observed median reductions of 80% (n = 6) and 89% (n = 3) in the multiple-ascending dose (MAD) 70 mg cohort of ADMIRAL at 3 and 6 months postdose, respectively.
"The patients in these studies were already taking the best available anti-seizure medicines, making the additional observed reductions in seizures quite meaningful. 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," Joseph Sullivan, MD, professor of neurology and pediatrics, and director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco, said in a statement.
Throughout MONARCH and ADMIRAL, investigators performed multiple analyses, including a "through” analysis that incorporates data from a period of time during and after dosing and an “at” analysis that captured data at a specific time point after dosing was complete. At day 29 through 3 months after the last dose, the 30 mg, 45 mg, and 70 mg groups showed median seizure reductions of 28% (n = 17), 18% (n = 16), and 42% (n = 8), respectively. At day 29 through 6 months after the last dose, investigators observed reductions of 24% (n = 16), 26% (n = 14), and 42% (n = 6) in the respective groups.
The safety analysis for the phase 1/2a studies included 74 patients who were treated with single or multiple doses of STK-001 (10 mg, 20 mg, 30 mg, 45 mg, 70 mg) and followed for up to 6 months after their last dose. All told, the antisense oligonucleotide was generally well-tolerated, with no discontinuations related to the study drug. Treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 32% and 20% of treated patients, respectively. Of note, one patient who received multiple doses of 70 mg in the ADMIRAL study experienced suspected unexpected serious adverse reactions that were attributed by the investigator to STK-001. That patient went on to the complete the study.
"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, chief executive officer at Stroke Therapeutics, said in a statement. "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. 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."
Across the 2 studies, a dose-dependent increase in the plasma pharmacokinectic profile of STK-001 was observed. Drug levels increased in the cerebrospinal fluid (CSF) following 3 doses of 30 mg and 45 mg, suggesting STK-001 accumulation in central nervous system tissues. Exposure in CSF was measurable up to 6 months following multiple intrathecal doses of STK-001, indicating sustained exposure of STK-001 in the brain.
Following treatment in the MONARCH study, patients who met study criteria were eligible to continue treatment in the SWALLOWTAIL open-label extension. This included only those who received a cumulative total dose of at least 30 mg of STK-001 in MONARCH and continued treatment with 30 mg or 45 mg doses every 4 months in SWALLOWTAIL. Among a cohort of 26 individuals, investigators not only observed reductions in convulsive seizure frequency, but substantial improvements in expressive and receptive communication, as measured by the Vineland Adaptive Behavior Scale-III, after 12 months.
Sullivan added, "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."
Additional data from SWALLOWTAIL showed improvements in gross motor skills, as well as executive function, measured using the Behavior Rating Inventory of Executive Function-Preschool version. STK-001-treated patients also saw enhanced scores on Global Impression of Change as reported by caregivers and clinicians. In comparison, using Stroke Therapeutic’s BUTTERFLY natural history study, those patients showed little to no changes in these assessments using typical antiseizure medications.