Investigational Dravet Syndrome Agent STK-001 Demonstrates Safety in Phase 1/2a


In addition to a well-tolerated safety profile, investigators observed a dose proportional increase in plasma pharmacodynamics in the MONARCH study cohort of 21 children and adolescents.

Barry Ticho, MD, PhD

Barry Ticho, MD, PhD

Recently announced data from the phase 1/2a MONARCH study of STK-001 (Stoke Therapeutics), an investigational agent for the treatment of Dravet syndrome (DS), found that single doses of the drug up to 30 mg and multiple doses up to 20 mg to be well-tolerated, with no safety concerns in children and adolescents with the disease.

Barry Ticho, MD, PhD, chief medical officer of Stoke Therapeutics said in a statement that the initial data is "highly encouraging," and that they now "have greater clarity on the dose levels that are likely to be pharmacologically active in patients." The company plans to share additional data from MONARCH at the upcoming 2021 American Epilepsy Society annual meeting, December 3-7, as well as clinical data on multiple doses of 30-mg STK-001 in the second half of 2022.

STK-001, a proprietary antisense oligonucleotide, is designed to upregulate NaV1.1 protein expression by leveraging the nonmutant copy of the SCN1A gene to restore physiological NaV1.1 levels. Through this, it reduces the occurrence of seizures and significant nonseizure comorbidities, which has been shown in preclinical studies.

This interim analysis was based on data from 21 children and adolescents, aged 2 to 18 years old, who were treated with either 10-mg (n = 5), 20-mg (n = 4), or 30-mg (n = 6) single doses of STK-001. The study also included 6 patients who were on multiple ascending doses of 20 mg, most of whom had received 3 monthly doses of the investigational drug. Demographically, the cohort represented had high seizure burden, with patients having a median of 17 convulsive seizures during the 4-week screening period prior to first dose of STK-001.

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Treatment emergent adverse events (TEAEs) related to the study drug were found in 3 of the 21 patients (14%), none of which were in the 30-mg single dose or 20-mg multiple dose groups. Among the entire cohort, headache, irritability, vomiting, seizure, and back pain were among the most common TEAEs. Furthermore, all serious treatment-emergent AEs (SAEs), recorded in 4 patients (19%), were not related to STK-001.

Ticho added, "Although based on an open-label study of a small number of patients, we saw an early trend toward a reduction in convulsive seizure frequency, which is remarkable considering the amount of concomitant medicines used and the relatively low single dose levels of STK-001 evaluated."

Although only 11 patients from the single ascending dose (SAD) cohorts had seizure data available, 8 demonstrated a reduction in convulsive seizure frequency. Using seizure diaries, investigators also observed a trend toward reduction in median percent change from baseline in the frequency of these seizures in the single dose cohorts. Patients aged 2 to 12 years old showed the most evident change.

There were no discontinuations of study treatment, and investigators were able to measure cerebrospinal fluid (CSF) at 6 months following a single intrathecal dose, indicating a sustained exposure of the study drug in the brain. Notably, there was a dose-proportional increase in CSF concentration in the 20 to 30 mg groups and a dose proportional increase in study drug exposure in plasma pharmacokinetics (PK). PK model findings further showed a correlation between treatment with STK-001 and levels in plasma and CSF. An estimated 95% of patients were predicted to have pharmacologically active STK-001 brain cells following 3 doses of 30 mg administered 1 month apart. Notably, half of all the patients were anticipated to remain at therapeutic levels for approximately 3 months after the last dose.

All patients included in the SAD portions of MONARCH proceeded to SWALLOWTAIL, an open-label extension study assessing long-term safety and tolerability of repeat doses of STK-001. The company is currently evaluating the agent in doses of up to 70 mg in the phase 1/2a ADMIRAL study, which had first patients dosed in September 2021.

Ticho also stated, "We look forward to continuing our 2 ongoing studies as we work to identify a dose level that has the potential to maximize efficacy while minimizing treatment frequency for patients with Dravet syndrome."

Stroke Therapeutics announces positive interim safety, PK and CSF exposure data from the phase 1/2a MONARCH study of STK-001 in children and adolescents with Dravet syndrome. News release. Stroke Therapeutics. September 21, 2021. Accessed November 29, 2021.
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