Authors :
Presenting Author: Archana Desurkar, MD – SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST
Scott Perry, MD – Cook Children's Hospital; Joseph Sullivan, MD – UCSF; Linda Laux, MD – Ann & Robert H. Lurie Children's Hospital of Chicago; J Helen Cross, MD – UCL Queen Square Institute of Neurology; Orrin Devinsky, MD – NYU; Kelly Knupp, MD – Children's Hospital Colorado; Matt Lallas, MD – NeuroNetwork Partners; Steven Phillips, MD – Mary Bridge Children's; John Schreiber, MD – Children's National Hospital; Colin Roberts, MD – OHSU; Javier Avendaño, MD – Stoke Therapeutics; Charlene Brathwaite, BS – Stoke Therapeutics; Jessie Lynch, BS – Stoke Therapeutics; Meena M, PhD – Stoke Therapeutics; Fei Wang, PhD – Stoke Therapeutics; James Stutely, BS – Stoke Therapeutics; Kimberly Parkerson, MD – Stoke Therapeutics; Barry Ticho, MD – 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,
de novo mutations in the
SCN1A gene, which encodes the voltage-gated sodium channel type 1 α subunit (Na
v1.1) 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 Na
v1.1 protein expression in the brain by leveraging the wild-type (non-mutant) copy of SCN1A to restore physiological Na
v1.1 levels, thereby potentially reducing both SF and non-seizure comorbidities.
Methods: SWALLOWTAIL (NCT04740476; US) and LONGWING (2021-005626-14; UK) are ongoing multi-center OLE studies, assessing the long-term safety, tolerability, plasma, and CSF exposure and clinical effect of STK-001 repeat doses administered every four months by intrathecal (IT) injection in patients who completed STK-001 Phase 1/2a studies, MONARCH (NCT04442295; US) or ADMIRAL (2020-006016-24; UK), respectively. Adverse events (AEs) are monitored continuously, and plasma and CSF samples are collected for STK-001 exposure at each visit. Clinical assessments including SF, neurodevelopmental status, gait, and executive functioning are evaluated.
Results:
As of March 24, 2023 (SWALLOWTAIL) and February 22, 2023 (LONGWING), 51 (96.2%) patients who completed MONARCH or ADMIRAL enrolled in SWALLOWTAIL or LONGWING. Patients have received up to a total of 7 STK-001 doses given every four months (10-45 mg/dose) in the OLE studies. All patients are currently receiving 30 mg/dose in SWALLOWTAIL and 45 mg/dose in LONGWING. Safety findings are in the table. On Day One, prior to dosing in SWALLOWTAIL, STK-001,plasma levels were close to lower limit of quantitation, and mean CSF STK-001 levels were lower in MONARCH SAD patients than MAD patients. Following repeat dosing every four months in SWALLOWTAIL, an increase in STK-001 levels was observed suggesting accumulation in the CNS. LONGWING plasma and CSF exposure data are not available at the time of abstract submission but will be included in the presentation. Previously presented data from SWALLOWTAIL showed durable reductions in seizure frequency and an early trend toward improvement in non-seizure comorbidities (BRIEF-P). New data will be shared from the analyses of seizure and non-seizure endpoints.
Conclusions:
Data support continued STK-001 development as the first potential disease-modifying approach to treat DS. SWALLOWTAIL and LONGWING will inform on the long-term safety and tolerability of repeat administration and will help inform future STK-001 clinical studies.
Funding: Stoke Therapeutics