Phase 1/2 Studies Support Higher Dose Regimen of STK-001 for Dravet Syndrome Treatment

Helen Cross, PhD, ChB, MB

Results from the phase 1/2 MONARCH (NCT04740476) and ADMIRAL studies (NCT04442295) showed that investigational STK-001 (Stoke Therapeutics) on top of standard of care (SOC) antiseizure medications led to seizure reduction and improvements in cognition and behavior, overall clinical status, and quality of life in patients with Dravet syndrome (DS). All told, the data support a potential 70 mg loading dose regimen in a future registrational study.^1,2

These findings, presented at the 15th European Epilepsy Congress (EEC), are an add-on to previously reported data in early March of this year. Overall, 97 patients were screened, and 81 patients with DS were enrolled across both studies. MONARCH, the US-based trial, included a single-ascending dose (SAD) and multiple ascending dose (MAD) portions, with the primary goal of safety and tolerability. ADMIRAL, based in the UK, comprised of a MAD phase that studied doses of STK-001 up to 70 mg per dose.

Coming into the study, more than 85% of patients were taking 3 or more antiseizure medications, including clobazam, stiripentol, and fenfluramine (Fintepla; Pfizer). Despite being on best available antiseizure medications, baseline median convulsive seizure frequency per 28 days was 17, highlighting the refractory nature of seizures. All told, patients treated with 2 or 3 doses of 70 mg of STK-001 experienced median seizure reductions of 85% (n = 10) at 3 months and 74% (n = 9) at 6 months after last dose, compared with baseline.

"The profound reductions in seizures and improvements in cognition and behavior seen in these studies open the door to a new era in the treatment of Dravet syndrome and provide convincing evidence of the potential for zorevunersen as the first disease-modifying medicine," lead investigator Helen Cross, PhD, ChB, MB, The Prince of Wale’s Chair of Childhood Epilepsy and director of the University College London Great Ormond Street Institute of Child Health, said in a statement.¹ "We are very encouraged by the data from the Phase 1/2a ADMIRAL study that showed substantial reductions in seizures and meaningful improvements in cognition and behavior within the first year of treatment. As patients continue treatment in the open-label extension study we see even greater improvements in their cognition and behavior, which is remarkable."

STK-001, otherwise known as zorevunersen, was considered safe and well tolerated at doses up to 70 mg. During the study, 30% of treated patients experienced a study drug-related treatment-emergent adverse event (TEAE), which mainly consisted of cerebrospinal fluid (CSF) protein elevations and procedural vomiting. Grade 3 and higher TEAEs were observed in 13 patients (16%), and 1 patient experienced a fatal event of presumed sudden death in epilepsy that was considered not related to the study drug. Notably, there were no TEAEs that led to study withdrawal.

READ MORE: Radiprodil Significantly Reduces Seizure Frequency in Phase 1b Honeycomb Study of GRIN-Related Neurodevelopmental Disorder

In the 70 mg SAD cohort of zorevunersen, patients experienced a 43% reduction at 3 months after last dose (n = 8) and a 57% reduction at 6 months after last dose (n = 7). In addition, the data indicated improvements in overall clincial status and quality of life within 36 weeks after treatment with zorevunersen. In the 70 mg SAD and MAD cohorts of MONARCH and ADMIRAL, the predicted rate of improvement was 7.756 on EuroQol 5-dimension questionnaire-youth. In addition, marked improvements in overall clinical status were observed by caregivers and clinicians on Caregiver Global Impression of Change and Clinical Global Impression of Change scales.

After 36 weeks of treatment, all cohorts in ADMIRAL showed improvements in numerous subdomains of the Vineland-3 Adaptive Behavior Scale. These included Receptive Communication (growth scale value change, 5.778), Expressive Communication (GSV, 3.272), Personal Skills (GSV, 2.030), Interpersonal Relationships (GSV, 3.096), Coping Skills (GSV, 0.700), Gross Motor (GSV, 3.517), and Fine Motor (GSV, 1.993).

In terms of pharmacokinetics, zorevunersen was shown to distribute rapidly in central nervous system tissues and to systemic circulation after intrathecal injection. Patients on active drug showed a dose-dependent plasma drug exposure as well. Furthermore, predicted drug exposure-seizure relationship showed a significant negative drug, demonstrating that higher zorevunersen brain exposure leads to higher reduction in seizure frequency.

At the 35th International Epilepsy Congress, held September 2-6, 2024, several presentations covered STK-001 as a potential treatment for patients with DS. At the time, epilepsy expert Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at UCSF, sat down to discuss the potential of STK-001, an antisense oligonucleotide, to treat rare epilepsies like DS. In the clip below, he spoke on the promise of the treatment, its mechanism of action, and how it opens the door for future research in this field.

REFERENCES
1. Stoke Therapeutics Presents Zorevunersen Data Showing Substantial Reductions in Seizures and Improvements in Multiple Measures of Cognition and Behavior That Support the Potential for Disease Modification in Dravet Syndrome. News release. Stoke Therapeutics. September 10, 2024. Accessed September 11, 2024. https://finance.yahoo.com/news/stoke-therapeutics-presents-zorevunersen-data-110000795.html
2. Cross HJ, Laux L, Sullivan J, et al. MONARCH and ADMIRAL: Open-label, Phase 1/2a studies in USA and UK investigating safety, drug exposure, and clinical effect of zorevunersen (STK-001), an antisense oligonucleotide, in children and adolescents with Dravet syndrome. Presented at: EEC