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Dravet Syndrome Agent STK-001 Continues to Exemplify Disease-Modifying Effects in Open-Label SWALLOWTAIL and LONGWING Extensions
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STK-001 (zorevunersen), an investigational therapy, shows promising results in reducing seizures and improving cognition in patients with Dravet syndrome, offering potential beyond current anti-seizure medications.
Andreas Brunklaus, MD
New data from the phase 1/2 SWALLOWTAIL and LONGWING extension studies revealed that treatment with STK-001, an investigational antiseizure oligonucleotide (ASO), was safe and led to substantial and durable reductions in seizure frequency among patients with Dravet syndrome (DS). These 12-month data, which expand upon the phase 1/2 MONARCH and ADMIRAL studies, further support the potential of STK-001 as the first disease-modifying therapy for DS.1-3
Presented at the 15th European Epilepsy Congress (EEC), 94.7% (54 of 57) and 84.2% (14 of 17) of patients who completed MONARCH (NCT04740476) and ADMIRAL (NCT04442295), respectively, were enrolled in SWALLOWTAIL and LONGWING as of November 1, 2023, with 15 patients having been treated for at least 2 years and having received up to 10 doses total. In these open-label extension (OLE) studies, nearly half (49%; 33 of 68) of patients were concomitantly on fenfluramine (Fintepla; UCB Pharma), a previously approved therapy for DS.2
In terms of dosing, patients received STK-001, also known as zorevunersen, as an intrathecal slow bolus injection every 16 weeks, with patients currently receiving 45 mg per dose. Overall, results revealed that reductions in convulsive seizure frequency were sustained throughout week 48 of the OLEs. More substantial reductions were observed in the initial 3 patients who received multiple doses of 70 mg STK-001 in the phase 1/2 studies followed by a single dose of 45 mg in the OLE.
Led by Andreas Brunklaus, MD, a pediatric neurologist at the Royal Hospital for Children, Glasgow, the therapy was well tolerated across patients in both OLEs, with the most commonly reported treatment-emergent adverse events (TEAE) being cerebrospinal fluid protein (CSF) increased, pyrexia, and COVID-19. CSF protein elevation was observed in 74% (50 of 68) of patients, and was considered the only drug-related TEAE that resulted in the study’s only withdrawal.
By month 12 of the OLEs, results revealed substantial improvements in cognition and behavior, indicated by changes in the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). In addition, patients treated with STK-001 showed substantial improvements in Clinician and Caregiver Global Impression of Change for Cognition that greatly differed to the estimated change on the BUTTERFLY natural history study.
Stoke also presented a 24-month analysis of BUTTERFLY, with results further supporting the urgent need for disease-modifying therapies in DS. BUTTERFLY was a multicenter, US-based, longitudinal, prospective, observational study that primarily observed neurodevelopmental status of patients with DS, as well as the number of countable convulsive seizures per 4-week period before visits; change from baseline in overall clinical status, locomotor skills, and executive function.3
Despite receiving the best available antiseizure medications, this patient population experienced an average of 14.3 seizures/28 days. Patients reported a mean of 3.5 (0-7) ongoing seizure therapies at baseline, which included clobazam (69.4%), fenfluramine (44.4%), stiripentol (38.9%), valproic acid (38.9%), cannabidiol (33.3%), and levetiracetam (22.2%). After 24 months, patients with DS demonstrated no improvements in Expressive Communication, Personal Skills, Gross Motor, or Fine Motor outcomes in subdomains of the Vineland-3.
Overall, the only statistically significant improvements in neurodevelopmental assessments came in Receptive Communication (P = .0189; n = 32) and Coping Skills (P = .0114; n = 32). Using disease progression modeling, patients with DS on antiseizure medications still had no significant change in convulsive seizure frequency through month 24 (P = .6280; n = 23), as well as no significant changes in locomotor skills or executive functioning. Mean CaGI-C and CGI-C scores at the end of month 24 were 3.26 and 2.90, respectively, indicating “slightly improved.”
Barry Ticho, MD, PhD
"The two-year natural history data provide clear evidence that current anti-seizure medicines are insufficient because even with the best available medicines patients still suffer from continued high rates of seizures and, as these children age, their development falls further behind their neurotypical peers," Barry Ticho, MD, PhD, chief medical officer at Stoke, said in a statement. “Data from our clinical studies of zorevunersen provide a glimpse into the future of treatment for patients with Dravet syndrome."
He added, "The data from our studies suggest that by restoring protein expression with zorevunersen, we may be able to substantially reduce seizures beyond any benefit patients are currently receiving from anti-seizure medicines. Even more promising is the potential to improve cognition and behavior, which has never before been demonstrated in a clinical study of Dravet syndrome. These data provide confidence in our plans for a Phase 3 registrational study, including the dose regimen and clinical endpoints."
Zorevunersen, a proprietary ASO, is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. To date, the agent has been granted orphan drug designation by the FDA and EMA, and rare pediatric disease designation by the FDA as a potential new treatment for DS.
