Zorevunersen (STK-001) Demonstrates Potential for Disease Modification Including Reductions in Seizures and Improvements in Cognition and Behavior in Children and Adolescents with Dravet Syndrome (DS)
Abstract number :
2.379
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
683
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Linda Laux, MD – Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
J. Helen Cross, MBChB, PhD – UCL-Great Ormond Street Institute of Child Health; Great Ormond Street Hospital
Archana Desurkar, MD – SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Children’s Hospital Colorado
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES – LeBonheur Children’s Hospital
Colin Roberts, MD – Oregon Health & Science University
John Schreiber, MD – Children’s National Hospital, George Washington University School of Medicine & Health Sciences, Washington, DC
M. Scott Perry, MD – Jane and John Justin Institute for Mind Health, Neurosciences Center, Cook Children's Medical Center
Orrin Devinsky, MD – NYU Grossman School of Medicine
Matt Lallas, MD – Nicklaus Childrens Hospital
Elaine Wirrell, MD – Mayo Clinic
Charlene Brathwaite, BA – Stoke Therapeutics
Carolyn Condon, MPH – Stoke Therapeutics, Massachusetts, United States of America
Jessie Lynch, BA – Stoke Therapeutics
James Stutely, BA – Stoke Therapeutics
Fei Wang, PhD – Stoke Therapeutics, Massachusetts, United States of America
Meena Meena, PhD – Stoke Therapeutics
Kimberly Parkerson, MD – Stoke Therapeutics, Massachusetts, United States of America
Barry Ticho, MD, PHD – Stoke Therapeutics
Rationale: DS is a severe and progressive genetic developmental and epileptic encephalopathy that typically begins in the first year of life. Approximately 85% of cases are caused by heterozygous, loss-of-function mutations in the SCN1A gene, which encodes the Nav1.1 protein. DS is characterized by high seizure frequency (SF) and severity and intellectual disability. STK-001 is an investigational ASO treatment designed to upregulate Nav1.1 protein expression by leveraging the wild-type (non-mutant) copy of SCN1A to restore physiological Nav1.1 levels, with the potential for disease modification by addressing the underlying genetic cause of DS.
Methods: MONARCH (NCT04442295) and ADMIRAL (2020-006016-24) were open-label studies of patients with DS aged 2-18y assessing safety, tolerability, pharmacokinetics, and clinical effect of intrathecally administered ascending doses of STK-001. Patients had disease onset at < 12m with recurrent seizures and confirmed SCN1A variant. SF was observed for 28 days before dosing and followed for 6 months after the last dose. Adverse events (AEs) were monitored continuously, with plasma and CSF collected for STK-001 exposure at multiple timepoints. Longer-term open-label extension study are reported separately from these data.
Results: 81 patients received ≥1 dose of STK-001 across all dose levels (10-70mg). Patients were highly refractory to available treatments with 85% taking ≥3 and 54% taking ≥4 concomitant anti-seizure medications, including 49% taking fenfluramine. Median baseline convulsive SF was 17 per 28 days in clinically evaluable patients. Reductions in convulsive SF were observed among patients treated with multiple STK-001 doses of 30, 45, or 70mg (Fig 1), with most substantial and sustained reductions observed in the 70mg group (median reduction from baseline of 85% at 3 months and 74% reduction at 6 months after last dose). Among patients receiving multiple doses of 70mg, 80.0% and 77.8% experienced ≥50% reduction in convulsive SF at 3 and 6 months after their final dose, respectively. Data indicate improvements across adaptive behavior (Vineland-3), overall clinical status (CGI-C and CaGI-C), and quality of life (EQ-VAS) within the first 9 months of treatment. STK-001 was generally well-tolerated, with 29.6% of patients experiencing a TEAE related to study drug. CSF protein elevations (13.6% of patients) and procedural vomiting (4.9% of patients) were the most common treatment-related TEAEs. No patients discontinued treatment due to TEAEs. One patient (reported Cross et al, 2023) who received 3 70mg doses experienced Suspected Unexpected Serious Adverse Reactions (SUSARs) but completed the study.
Conclusions: STK-001 benefit-risk profile appears favorable in single and multiple doses up to 70mg/dose, supporting continued development as the first potential disease-modifying medicine to treat DS. The fact that these effects are on top of the best available anti-seizure medicines support the highly differentiated mechanism of action for STK-001. We are currently planning a global registrational study of STK-001 in patients with DS.
Funding: Stoke Therapeutics
Anti-seizure Medications