Epilepsy Agent STK-001 Demonstrates Disease-Modifying Effects in Early Phase Studies of Dravet Syndrome


With data showing significant therapeutic benefit on seizure reduction and other outcomes of cognition and behavior, Stoke will move forward with a new study to assess high doses of 70 mg STK-001 followed by continued dosing at 45 mg.

Joseph Sullivan, MD, FAES, professor of neurology and pediatrics, and director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco

Joseph Sullivan, MD, FAES

New data from 2 open-label phase 1/2 studies and their open-label extensions showed that treatment with STK-001 (Stoke Therapeutics), an investigational antisense oligonucleotide (ASO), resulted in substantial and durable reductions in convulsive seizure frequency among patients with Dravet syndrome (DS). These improvements, coupled with benefits in measures of cognition and behavior, further demonstrate the potential disease-modifying impacts of this agent in DS.1

Stoke reported on data from MONARCH (NCT04740476) and ADMIIRAL (NCT04442295), 2 open-label studies of children and adolescents ages 2 to 18 with DS, confirmed by evidence of a genetic mutation in the SCN1A gene. The new analysis focused on 19 patients treated in the highest dose group (70 mg), with results showing a 43% (n = 8) median reduction in convulsive seizure frequency at 3 months after last dose with 1 dose of STK-001 and 85% (n = 10) reduction in 70 mg patients who received 2 or 3 doses (n = 11).

In addition to the positive data, the company also announced the FDA has cleared it to begin dosing patients at 3 doses of 70 mg followed by continued dosing at 45 mg. Stoke is expected to meet with the agencies to discuss a registrational study that will include this type of dosing regimen.

Stoke noted that the improvements seen in the high dose group were significant considering the patient cohort was highly refractory to treatment and taking high-level antiseizure medications. Specifically, 85% of patients were taking at least 3 and 54% were taking at least 4 therapies to control seizures. Fenfluramine (Fintepla; UCB Pharma), an FDA-approved therapy specific to DS, was being used in half of the cohort.

"For decades, the primary goal of treating Dravet syndrome has been to control the frequency and severity of seizures, but, as we can now see from natural history data, many patients still experience high rates of seizure frequency and fall further and further behind in their neurodevelopment,” Joseph Sullivan, MD, FAES, 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.1 "A 50% reduction in seizures is an important measure of clinical efficacy, so an 80% reduction on top of any benefit patients may already be getting from their baseline anti-seizure regimen is profound."

He added, "The further evidence of improvements in skills like communication, behavior, socialization and movement distinguish this approach from anything we have seen to date and mark our entry into a new era in the treatment of Dravet syndrome."

At 6 months after last dose, the effects of STK-001 remained. Investigators observed a median seizure reduction of 57% (n = 7) in the 70 mg 1-dose group and a reduction of 74% (n = 9) in the 2 or 3 dose group. Of note, seizure data from month 5-6 for 1 patient was excluded because more than 50% of their seizure diary was missing and seizure data was excluded for 2 patients 1 patient prior to 3 month after last dose, 1 prior to 6 month after last dose) following a change in background anti-seizure medications.

READ MORE: Lifting Barriers to Equitable Care in Epilepsy

Following the completion of the phase 1/2 studies, 92% (68 of 74) of eligible patients, which included those with continued dosing at 30 mg and 45 mg had enrolled in the OLEs and 84% (57 of 68) remained in the studies. In addition to seeing durable reductions in convulsive seizure frequency, results showed clinically meaningful improvements in multiple outcomes of cognition and behavior, including different sub-domains of the Vineland Adaptive Behavior Scale, after 12 months since the beginning of treatment.

"The totality of these data provide compelling evidence that support the potential for STK-001 to be a disease-modifying medicine for patients with Dravet syndrome by treating the underlying cause of the disease, rather than just the symptoms,” Edward M. Kaye, MD, chief executive officer, Stoke Therapeutics, said in a statement.1 "STK-001 is the first medicine in development to demonstrate substantial and durable reductions in seizure frequency and improvements in multiple measures of cognition and behavior. These effects were observed in patients who were already taking the best available anti-seizure medicines, which confirms our highly differentiated mechanism of action and approach to treating this disease."

The safety analysis, which included 81 patients treated with the therapy, continued to showcase STK-001’s well-tolerated profile. Treatment-emergent adverse events (TEAEs) related to the study drug were found in 30% of patients, with cerebrospinal fluid (CSF) protein elevations and procedural vomiting as the most common. CSF protein elevations were more frequent in the OLEs, with 74% of patients (50 of 68) having at least 1 CSF protein value above 50 mg/dL. No clinical manifestations were observed in these patients.

Across the phase 1/2 and OLE studies, 1 patient discontinued treatment as a result of elevated CSF protein, which was attributed to STK-001. In total, 22% (n = 18) of patients had a treatment-emergent serious AE, all of which were deemed unrelated to study drug except for a previously reported case of 1 patient who experienced Suspected Unexpected Serious Adverse Reactions (SUSARS).

Kaye added, "We look forward to meeting with regulatory agencies to discuss our plans for a randomized, controlled registrational study and to providing an update coming out of those discussions later in 2024."1

At the 35th International Epilepsy Congress, held September 2-6, 2023, several presentations covered STK-001 and the promise behind ASOs. Sullivan, an expert in the field, sat down with NeurologyLive following the meeting to discuss the advances in research and the shift in how gene therapy approaches are viewed for patients with epileptic encephalopathies. In the link below, he spoke on the mechanism of STK-001 and how it opens the door for future research in this field.

1. Stoke Therapeutics announces landmark new data that support the potential for STK-001 to be the first disease-modifying medicine for the treatment of patients with Dravet syndrome. News release. March 25, 2024. Accessed March 26, 2024. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-landmark-new-data-support-potential
2. Stoke Therapeutics presents data related to the ongoing clinical development of STK-001 for the treatment of Dravet syndrome at the 35th International Epilepsy Congress. News release. September 5, 2023. Accessed March 26, 2024. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-presents-data-related-ongoing-clinical
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