Stoke Therapeutics’ Dravet Syndrome ASO STK-001 Demonstrates Ability to Reduce Seizure Frequency on Top of SOC

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The data comes from 2 phase 1/2a clinical trials and their respective open-label extension studies.

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
Credit: UCSF

Stoke Therapeutics’ STK-00, an investigational antisense oligonucleotide (ASO), has demonstrated the ability to reduce seizure frequency in patients with Dravet syndrome in data from several clinical trials and open-label extension (OLE) studies.1 Notably, the seizure reductions occurred on top of reductions already observed from standard of care (SOC) antiseizure medications the patients had been taking.

The data comes from the phase 1/2a MONARCH clinical trial and its OLE SWALLOWTAIL and the phase 1/2a ADMIRAL clinical trial and its OLE LONGWING. Data from 19 patients treated in MONARCH and ADMIRAL with 1-3 doses of STK-001 at 70mg per dose was combined for analysis. It was found that at 3 months posttreatment, the 8 patients who received a single 70mg dose showed a mean 43% reduction from baseline in convulsive seizure frequency and the 10 patients (1 patient’s data was excluded because of a change in background antiseizure medication) who received 2 or 3 70mg doses showed a mean 85% reduction from baseline in convulsive seizure frequency. At 6 months posttreatment, 7 of the patients who received a single 70mg dose (1 patient’s data was excluded because more than 50% of the seizure diary was missing) showed a mean 57% reduction from baseline in convulsive seizure frequency and 9 of the patients who received 2-3 70mg doses (an additional patient’s data was excluded because of a change in background antiseizure medication) showed a mean 74% reduction from baseline in convulsive seizure frequency. It was noted that participants in MONARCH and ADMIRAL were highly refractory to SOC treatment and were taking the best available antiseizure medications, with 85% of participants taking 3 or more medications for seizure control and 54% of participants taking 4 or more medications for seizure control. Fenfluramine was being taken by half of the participants.

SWALLOWTAIL and LONGWING included 68 patients, and 57 of these patients remained on-study at the time data from them were analyzed. Among patients who received at least 30mg of STK-001 in MONARCH and ADMIRAL and continued to receive 30mg or 45mg doses in the OLEs every 4 months, durable reductions in convulsive seizure frequency were observed through 12 months from initiation of treatment. Furthermore, clinically meaningful improvements from baseline in measures of cognition and behavior were reported, with improvements in multiple subdomains of the Vineland Adaptive Behavior Scale specifically noted to have occurred through the 12-month timeframe.

“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, th CEO of 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 antiseizure medicines, which confirms our highly differentiated mechanism of action and approach to treating this disease. 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.”

In terms of safety, STK-001 was reported to be generally well-tolerated across the 2 trials and 2 OLE studies. In MONARCH and ADMIRAL specifically, it was noted that 24 of the 81 (30%) treated patients had cases of adverse events (AEs) deemed related to STK-001, with the most common being cerebrospinal fluid (CSF) protein elevations and procedural vomiting. Serious treatment-emergent serious AEs were experienced by 18 of the patients (22%); however, excepting 1 patient who experienced suspected unexpected serious adverse reactions, all serious AEs were deemed unrelated to STK-001. In the OLEs, CSF protein elevations were more common than in MONARCH and ADMIRAL, with 50 of 68 patients (74%) in the OLEs showing at least 1 CSF protein elevation to higher than 50 mg/dL. Although, no clinical manifestations were reported for them. One patient discontinued treatment in an OLE in relation to CSF protein elevation, however.

“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, added to the 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. 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.”

STK-001 is not the only advanced therapeutic being evaluated for the treatment of Dravet syndrome. Recently, in February 2024, Encoded Therapeutics received clearance from the FDA and the Australia Therapeutic Goods Administration for 2 separate clinical trials intended to evaluate ETX101, an investigational adeno-associated virus vector-based gene therapy, for the treatment of SCN1A+ Dravet syndrome.2 ETX101 consists of a transgene encoding a GABAergic regulatory element and an engineered transcription factor that is delivered via a nonreplicating, recombinant AAV9 vector. The engineered transcription factor is intended to upregulate expression of the disease-targeted SCN1A gene, with the expectation that it will lead to increased production of NaV1.1 protein sodium channels in clinically relevant neurons. The phase 1/2 US clinical trial is referred to as ENDEAVOR (NCT05419492) and the phase 1/2 Australia clinical trial is referred to as WAYFINDER (NCT06112275).

REFERENCES
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. Stoke Therapeutics, Inc. March 25, 2024. Accessed April 11, 2024. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-landmark-new-data-support-potential
2. Encoded Therapeutics Announces US IND Clearance and Australian CTA Approval for Dravet Syndrome Gene Therapy Candidate ETX101. News release. Encoded Therapeutics Inc. February 6, 2024. Accessed February 6, 2024. https://encoded.com/press-releases/encoded-therapeutics-announces-us-ind-clearance-and-australian-cta-approval-for-dravet-syndrome-gene-therapy-candidate-etx101/
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