MONARCH Interim Analyses: A Phase 1/2a US Study Investigating Safety and Drug Exposure of STK-001, an Antisense Oligonucleotide (ASO), in Children and Adolescents with Dravet Syndrome (DS)
Abstract number :
1.227
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2022
Submission ID :
2204323
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Linda Laux, MD – Ann & Robert H. Lurie Children's Hospital of Chicago; Joseph Sullivan, MD – University of California San Francisco; Colin Roberts, MD – OHSU; John Schreiber, MD – Children's National Hospital; Scott Perry, MD – Cook Children's Hospital; Orrin Devinsky, MD – NYU; Matt Lallas, MD – NeuroNetwork Partners; Steven Phillips, MD – Mary Bridge Children's; Charlene Brathwaite, NA – STOKE Therapeutics; Javier Avendaño, MD – Stoke Therapeutics; James Stutely, NA – Stoke Therapeutics; Nancy Wyant, NA – Stoke Therapeutics; Meena M, PhD – Stoke Therapeutics; Kimberly Parkerson, MD – Stoke Therapeutics; Barry Ticho, MD, PhD – Stoke Therapeutics
Rationale: Dravet syndrome (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, de novo mutations in the SCN1A gene, which encodes the voltage-gated sodium channel type 1 α subunit (Nav1.1) protein. DS is characterized by high seizure frequency (SF) and severity, intellectual disability, ataxia/motor abnormalities, and a high risk of sudden unexplained death in epilepsy. STK-001 is an investigational ASO treatment designed to upregulate Nav1.1 protein expression in the brain by leveraging the wild-type (non-mutant) copy of SCN1A to restore physiological Nav1.1 levels, thereby potentially reducing both SF and non-seizure comorbidities.
Methods: MONARCH (NCT04442295) is an ongoing, open-label, multi-center study in the US of patients with DS aged 2-18 years assessing the safety, tolerability, plasma PK and CSF exposure of intrathecally (IT) administered single (SAD) and multiple ascending (MAD) doses of STK-001, up to 45 mg/dose. Eligible patients have disease onset prior to 12 months of age with recurrent seizures and a genetically confirmed SCN1A variant. Patients are grouped by age (2-12 and 13-18 years) and SF is observed for 28 days before dosing. STK-001 is administered on Day 1 as a single dose, or on Day 1, Week 4, and Week 8 as MAD with a 6-month follow-up after last dose. Adverse events (AEs) are monitored continuously, with plasma and CSF collected for STK-001 exposure at multiple time points. At end of study, patients meeting criteria have the option to enter an open-label extension study, SWALLOWTAIL (NCT04740476).
Results: As of February 21, 2022, 29 patients received at least 1 dose of STK-001 at the 10, 20 or 30mg dose levels. Demographics and AEs are shown in the table. Plasma PK parameters were determined following a single dose (in SAD) and the first dose in MAD. STK-001 exposure was evaluated in CSF samples collected 3 months and 6 months post single dose in SAD and prior to the second and thirddose in MAD. Additional available safety, plasma and CSF exposure, and SF data will be reported.
Conclusions: Data to date indicate that SAD and MAD doses of STK-001 up to 30 mg are well-tolerated with no safety concerns related to study drug. Dose-dependent increases in plasma exposure have been observed. STK-001 was detected in CSF samples up to 6 months post single dose at all dose levels indicating sustained STK-001 exposure in brain. A previous interim analysis that included 17 patients with DS treated with STK-001 demonstrated a trend toward reduction in median percent change from baseline in convulsive SF. These data support continued development of STK-001 as the first potential disease-modifying approach to treat DS. Together with the US SWALLOWTAIL and UK ADMIRAL studies, these data will help inform future clinical studies on use of STK-001.
Funding: Stoke Therapeutics
Clinical Epilepsy