Stoke STK-001-DS-102 Phase 1/2a
Research type
Research Study
Full title
An Open-Label Study to Investigate the Safety and Pharmacokinetics of Multiple Ascending Doses of Antisense Oligonucleotide STK-001 in Children and Adolescents with Dravet Syndrome
IRAS ID
295734
Contact name
Shamim Ruff
Contact email
Sponsor organisation
Stoke Therapeutics, Inc
Eudract number
2020-006016-24
ISRCTN Number
ISRCTN99651026
Duration of Study in the UK
3 years, 4 months, 12 days
Research summary
Research Summary
This study will look at how an investigational drug, called STK-001, works and how safe it is in different doses in children and adolescents with Dravet Syndrome (DS). DS is a rare infantile-onset drug resistant developmental and epileptic encephalopathy which has a poor long-term prognosis on . DS is among the most drug-resistant forms of epilepsy, with more than 90% of patients continuing to have uncontrolled seizures despite treatment with multiple antiepileptic drugs (AEDs), putting them at high risk for injury or death. The primary goal of therapy for DS is to reduce seizure frequency and severity; however, there remains a significant need for additional therapies for these patients that address the other comorbidities of DS.
DS is most commonly caused by a mutation in the sodium voltage-gated channel type 1 alpha subunit (SCN1A) gene which most often lead to loss of function of the protein and results in reduced levels of the protein. STK-001 is intended to increase the expression of the protein using an RNA based approach.
This is a Phase 1/2a open-label study which will consist of 3 dose cohorts (1, 2 and 3), with the option to include 2 additional cohorts. The proposed dose levels are 30mg, 45mg and 70mg per drug administration but the dose may be adjusted based on safety review, additional preclinical and/or clinical data/and or regulatory authorities’ recommendation.
The study will have the following main periods:
• Screening and observation period (about 4 weeks, but can last up to 12 weeks)
• Baseline visit
• Treatment period (about 12 weeks or 3 months)
• Follow-up period (about 24 weeks or 6 months)Up to 60 patients are anticipated to be enrolled in approximately 5-10 centres across the UK. Duration participation is expected to last 40 weeks. If the observation period is extended, the duration could be up to 48 weeks.
Summary of Results
Study STK-001-DS-102 (Admiral) Results Lay Summary:
Title: A trial of an investigational drug called STK-001 (also called zorevunersen), a genetic-based research treatment for patients with Dravet syndrome.
This was an "open-label" trial, meaning that both patients and researchers knew that all of the patients were taking zorevunersen.
Objective: For patients living with Dravet syndrome, the main goal of this study was to find out if the zorevunersen is safe for people to take and to see how the drug behaves in the body (pharmacokinetics). Potential side effects (adverse events) were assessed to learn about safety, and the amount of zorevunersen in plasma (liquid part of your blood) and in cerebrospinal fluid (CSF; fluid around the brain and spinal cord) was analyzed to see how the drug behaves in the body. Another goal of the study was to find out if taking zorevunersen on top of the patients' existing standard seizure control medicines could reduce the number of seizures in patients with Dravet syndrome.
Results Summary: The trial enrolled 19 patients with Dravet syndrome aged 3-17 years old. Patients were given two or three doses of zorevunersen on Day 1, Day 57, and Day 85 at 30 mg, 45 mg, or 70 mg.
Multiple dose levels at either 30, 45, or 70 mg of zorevunersen were generally well-tolerated when taken on top of standard seizure control medicines. All 19 patients were taking at least 1 other seizure control medicine and 14 patients (73.7%) were taking 3 or 4 seizure control medicines when they started the study. All 19 patients had at least one adverse event while on the study. Most adverse events were mild or moderate (16/19 patients, 84.2%). Adverse events were considered related to zorevunersen in 8/19 patients (42.1%). The most common adverse events related to zorevunersen were vomiting because of the intrathecal administration (injection into the CSF) procedure, and protein increase in the CSF. One patient (5.3%) had serious adverse events (severe health problems that required medical attention) considered related to zorevunersen. No patients stopped zorevunersen during the administration procedure or stopped zorevunersen treatment because of adverse events. All patients completed the study.
The amount of zorevunersen in the plasma increased with increase in dose levels from 30 mg to 70 mg. For the majority of patients, zorevunersen was found in plasma for up to 6 months after the last dose of multiple doses equal to or higher than 30 mg.
Following multiple dose administrations (at 30 mg, 45 mg, and 70 mg), an upward trend in average CSF zorevunersen concentrations was observed on Day 57 and Day 169, suggesting zorevunersen accumulation in CSF after repeat dosing.
Although this wasn't the main goal of the study, the number of convulsive seizures went down in the group of patients who received higher doses of zorevunersen. Patients who were given doses of 70 mg zorevunersen had the greatest reduction in the number of seizures. About 3 months after last dose of zorevunersen, the reduction in the number of seizures was 89.47% (n=5) and about 6 months after last dose it was 81.17% (n=4) for patients who received 3 doses of 70 mg.
A phase 3 study is planned to further investigate zorevunersen in patients with Dravet syndrome.
REC name
Wales REC 3
REC reference
21/WA/0107
Date of REC Opinion
2 Jun 2021
REC opinion
Further Information Favourable Opinion