Patients with Dravet Syndrome in Open-label Extension Studies of Zorevunersen (STK-001) Have Durable Reductions in Seizure Frequency and Clinically Meaningful Improvements in Cognition and Behavior
Abstract number :
2.364
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
1022
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
M. Scott Perry, MD – Jane and John Justin Institute for Mind Health, Neurosciences Center, Cook Children's Medical Center
Andreas Brunklaus, MD – Royal Hospital for Children
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
Linda Laux, MD – Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
John Schreiber, MD – Children’s National Hospital, George Washington University School of Medicine & Health Sciences, Washington, DC
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Children’s Hospital Colorado
Charlene Brathwaite, BA – Stoke Therapeutics
Carolyn Condon, MPH – Stoke Therapeutics, Massachusetts, United States of America
Ann Dandurand, MD – 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: Eligible patients who completed treatment in the Phase 1/2a studies were given the option to continue treatment with STK-001 in one of two OLEs [SWALLOWTAIL (US, NCT04740476) and LONGWING (UK, 2021-005626-14)] assessing longer-term safety, tolerability, pharmacokinetics, and clinical effect of intrathecally administered repeat doses of STK-001. At the time of the datacut (01Nov2023), 92% (68/74) of patients had enrolled in the OLEs, and 84% (57/68) of the enrolled patients remained in the studies. Patients have received up to a total of 9 STK-001 doses given every four months (10-45 mg/dose) in the OLE studies. All patients are currently receiving 45 mg/dose every 4 months. Adverse events (AEs) are monitored continuously, and plasma and CSF are collected for STK-001 exposure at multiple timepoints.
Results: STK-001-treated patients in the OLE studies had durable reductions in convulsive SF (Fig 1) and clinically meaningful improvements in multiple measures of cognition and behavior, including in multiple subdomains of the Vineland-3 (Fig 2) over 12 months. These results are in contrast to the natural history for patients with DS who have little change in SF or cognition and behavior over time. This analysis included patients who received a loading dose of STK-001 ranging from 30mg to 70mg as either a single dose or multiple loading doses (max 70mg with 3 loading doses) in the Phase 1/2a studies and then received STK-001 at a dose of either 30mg or 45mg every 4 months in the OLEs. STK-001 was generally well-tolerated across the OLE studies. A greater incidence of CSF protein elevation was observed in the OLEs versus the Phase 1/2a studies. 74% (50/68) of patients in the OLEs had ≥1 CSF protein value >50 mg/dL. No clinical manifestations have been observed in patients with elevated CSF protein levels.
Conclusions: In summary, clinically meaningful improvements in multiple measures of cognition and behavior over 12 months were observed as well as a consistency across caregiver and clinician assessments of improvements. Overall, the data from patients treated with 30mg or 45mg of STK-001 every 4 months support plans for maintenance dosing as part of a pivotal study regimen. STK-001 has the potential to be the first disease-modifying medicine addressing the underlying pathogenic mechanism of DS.
Funding: Stoke Therapeutics
Anti-seizure Medications