ADMIRAL: A Phase 1/2a UK Study Investigating the Safety and Pharmacokinetics (PK) of STK-001, an Antisense Oligonucleotide (ASO), in Children and Adolescents with Dravet Syndrome (DS)
Abstract number :
1.215
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2022
Submission ID :
2204346
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
J Helen Cross, MD – UCL-Great Ormond Street Institute of Child Health; Great Ormond Street Hospital; Archana Desurkar, MD – SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST); Andreas Brunklaus, MD – Royal Hospital for Children; Carrie Condon, NA – Stoke Therapeutics; Javier Avendaño, MD – Stoke Therapeutics; James Stutely, NA – Stoke Therapeutics; Nancy Wyant, NA – Stoke Therapeutics; Meena M, PhD – Stoke Therapeutics; Barry Ticho, MD – Stoke Therapeutics; Kimberly Parkerson, MD – 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: ADMIRAL is an ongoing open-label, multi-center UK study of patients with DS aged 2 to 18 years assessing the safety, tolerability, plasma PK and CSF exposure of intrathecally (IT) administered multiple ascending doses (MAD) of STK-001, up to 70 mg/dose. Eligible patients have disease onset prior to 12 months of age with recurrent seizures and with genetically confirmed SCN1A variant. Patients are grouped by age (2-12 and 13-18 years) and SF is observed 28 days before dosing. On Day 1, patients undergo cerebrospinal fluid (CSF) collection followed by a single IT administration of STK-001; this is repeated on Days 57 and 85 with a 6-month follow-up after the last dose. Adverse events (AEs) are monitored continuously, with plasma and CSF collected for STK-001 exposure at multiple times. At end of study, patients meeting criteria have the option to enter an open-label extension study, LONGWING.
Results: As of February 21, 2022, 4 patients (2 in each age cohort; 50% female) received 3 doses of STK‑001 at the 30-mg dose level. All 4 patients experienced treatment-emergent AEs (TEAEs); all events were mild or moderate in severity. One patient experienced a TEAE (vomiting) related to STK-001, and 1 patient experienced a serious TEAE of status epilepticus, not related to STK-001. Following a single IT 30-mg dose in 4 patients, the PK parameters including mean maximum concentration (Cmax) and Area under the curve (AUCinf) in plasma were similar to the plasma PK parameters in patients from MONARCH study with same dose. The t1/2 was similar for all patients and median Tmax was 5 hours. Additional available safety, STK-001 exposure, and SF data will be reported.
Conclusions: Data to date indicate that multiple doses of 30mg of STK-001 are well-tolerated with no safety concerns related to study drug and support continued development of STK-001 as the first potential disease-modifying approach to treat DS. Together with the US MONARCH (NCT04442295) study, these data will help inform future clinical studies of STK-001.
Funding: Stoke Therapeutics
Clinical Epilepsy