Phase 3 Double-Blind Study of Zorevunersen Sodium in Reducing Major Motor Seizure Frequency in Dravet Syndrome Patients

Trial ID: 2024-519555-28-00
Protocol: STK-001-DS-301
Sponsor: Stoke Therapeutics Inc.

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Diseases & Conditions

Severe myoclonic epilepsy of infancy

Objectives

The primary objective of this study is to evaluate the effect of **zorevunersen** in reducing the frequency of major motor seizures in patients with **Dravet syndrome**. Major motor seizures include hemiclonic, focal with motor signs, focal to bilateral tonic-clonic, generalized tonic-clonic, tonic, tonic/atonic (drop attacks with fall or risk of fall), and bilateral clonic seizures. This objective is clinically relevant as it addresses a critical aspect of Dravet syndrome, which is characterized by frequent and severe seizures that significantly impact patient quality of life.

Secondary objectives include:

Assessing the durability of zorevunersen in reducing the frequency of major motor seizures in patients with Dravet syndrome.
Evaluating the effect of zorevunersen on a multi-component measure of key comorbidities associated with Dravet syndrome.
Assessing the effect of zorevunersen on measures of key comorbidities associated with Dravet syndrome.

Participants

The clinical trial involves a total of **94 participants** diagnosed with **Dravet syndrome**. The study population includes both male and female subjects, aged between 2 and 18 years. Participants were selected based on specific criteria, including a confirmed clinical diagnosis of Dravet syndrome, onset of seizures before 12 months of age, and a documented variant in the SCN1A gene. The trial population is characterized by individuals who have experienced a requisite number of major motor seizures during a 6-week observation period and have previously used at least two interventions for seizure management, such as anti-seizure medications, ketogenic diet, or vagus nerve stimulation. All participants are required to be on at least one anti-seizure medication, with stable maintenance therapies during the baseline period. The study includes a vulnerable population, given the age range and health condition of the participants.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, sham-controlled, parallel group, Phase 3 study to evaluate the efficacy, safety, and tolerability of **zorevunersen sodium** (STK-001) in patients diagnosed with **Dravet syndrome**. The primary objective is to assess the effect of zorevunersen in reducing the frequency of major motor seizures. The trial is expected to commence recruitment on September 15, 2025, and conclude by August 31, 2027, with a maximum treatment period of 52 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, clinical diagnosis, and genetic testing results. Following the screening, eligible participants will enter a baseline period to establish seizure frequency. The treatment phase will involve regular administration of the investigational product via **intrathecal use**. Follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events, with assessments conducted at specified intervals throughout the study duration. The end-of-study visit will occur after the final treatment dose, where comprehensive evaluations will be performed to gather data on the primary and secondary endpoints.

Participant involvement is expected to last up to 52 weeks, with conditions for early termination including non-compliance with protocol requirements, withdrawal of consent, or any adverse events that may compromise participant safety. The primary endpoint focuses on the percent change from baseline in major motor seizure frequency from Week 16 to Week 28, while secondary endpoints extend this assessment to Week 52 and include changes in Vineland-3 Outcome Scores. The trial aims to provide robust data on the potential benefits of zorevunersen for individuals with Dravet syndrome, contributing to the understanding of its therapeutic profile.

Treatment

The clinical trial involves the administration of **zorevunersen sodium**, an experimental medication, under the product name STK-001. This medication is formulated as a **solution for injection** and is administered via **intrathecal use**. The active substance, zorevunersen sodium, is a nucleic acid-based compound, specifically an 18-mer antisense oligonucleotide complementary to SCN1A mRNA, provided as a sodium salt. The trial includes two dosing regimens: one with a maximum daily dose of 45 mg and a total maximum dose of 90 mg, and another with a maximum daily dose of 70 mg and a total maximum dose of 140 mg. The treatment period for both regimens is up to 52 weeks. The medication is not a pediatric formulation and has been designated as an orphan drug.

In addition to the experimental treatment, the study employs a sham-controlled design, which serves as the comparator treatment. This involves a procedure that mimics the administration of the experimental drug without delivering the active substance, ensuring the study remains double-blind. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The primary objective of the trial is to evaluate the efficacy, safety, and tolerability of zorevunersen in reducing the frequency of major motor seizures in patients with Dravet Syndrome.

Efficacy

The efficacy of **zorevunersen** (STK-001) in patients with Dravet Syndrome will be assessed through a series of predefined endpoints. The primary endpoint is the percent change from baseline in major motor seizure frequency, measured as the number of seizures per 28 days, in patients receiving zorevunersen compared to those receiving a sham treatment. This assessment will occur from Week 16 to Week 28 of the trial. Secondary endpoints include the percent change from baseline in major motor seizure frequency from Week 16 to Week 52, as well as changes from baseline in the Vineland-3 Outcome Score and its subdomain scores at Week 52. These efficacy parameters will be collected and analyzed at specified timepoints to evaluate the therapeutic impact of zorevunersen on seizure frequency and overall patient outcomes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient and/or authorized representative must be willing and able to give informed consent/assent and any authorizations required by local law for participation in the study.
Patient and their caregiver must be willing and able (in the Investigator’s opinion) to comply with all protocol requirements.
At signing of consent/assent, patient must be ≥2 and <18 years of age.
Patient must have a clinical diagnosis of DS confirmed by the Epilepsy Study Consortium, Inc. (ESCI) and as defined by: Onset, prior to 12 months of age, of recurrent focal with motor signs, hemiclonic, or generalized tonic-clonic seizures, which are often prolonged and triggered by hyperthermia. No past history of causal magnetic resonance imaging (MRI) lesion (past MRI or study-associated MRI not required to confirm absence of lesion). No other known etiology causing clinical DS manifestations. Normal development at seizure onset.
Patient must have a documented pathogenic, likely pathogenic variant, or variant of uncertain significance in the sodium voltage-gated channel type 1 alpha subunit (SCN1A) gene. Patients who have SCN1A testing results of Negative (no variants identified) cannot be randomized.
Experiences the required number of major motor seizures during the 6-week Observation Period. Seizure types included in counts are Hemiclonic, Focal with Motor Signs, Focal to Bilateral Tonic-Clonic, Generalized Tonic-Clonic, Tonic, Tonic/Atonic (Drop Attacks with fall or risk of fall), and Bilateral Clonic.
Patient must have used at least 2 prior interventions for seizures. These can include anti-seizure medications (ASMs), ketogenic diet and/or vagus nerve stimulation (VNS) with either lack of adequate seizure control or discontinued due to an AE(s). These interventions can be ongoing therapies.
Patient must be taking at least one ASM. Benzodiazepines or ASMs used on a standing basis (i.e., not as needed [PRN]) for any indication will be considered an ASM.
All maintenance ASMs and interventions for seizures (i.e., ketogenic diet or VNS), as well as any marijuana- or cannabinoid-based products, must have been stable (unless adjusted for weight) during the Baseline Period. Felbamate must have been stable (unless adjusted for weight) for at least 6 months prior to Screening Visit A and during the Baseline Period. VNS implantation must have occurred at least 6 months prior to Screening Visit A. Rescue ASMs used on an as needed basis do not need to be stable.

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Exclusion Criteria

Patient has documented variant in the SCN1A gene associated with gain-of-function potentially including but not limited to: Ala23Glu, Thr162Ile, Arg1636Gln, Thr226Met, Ile236Val, Val250Leu, Leu263Val, Thr398Met, Ala420Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Ile1483Met, Gln1489Lys, Ile1498Thr, Ile1498Met, Phe1499Leu, Met1500Val, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1636Gln, Arg1648Cys, Leu1649Gln, Leu1660Ile, Phe1661Leu, Leu1670Trp, Gly1674Arg, Phe1774Ser, or Asp1866Tyr.
Patient has a diagnostic result in a gene other than SCN1A on the epilepsy gene screening panel. For genes associated with dominant inheritance, one heterozygous pathogenic or likely pathogenic variant is exclusionary. For genes associated with recessive inheritance, biallelic pathogenic or likely pathogenic variant(s) are exclusionary. This includes homozygous variants and compound heterozygous variants. Results consistent with carrier status are not exclusionary.
Patient is currently treated with a maintenance ASM acting primarily as a sodium channel blocker, including but not limited to phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, rufinamide, or cenobamate, given the mechanism of action of zorevunersen.
Patient is currently treated with neuromodulation techniques (e.g., responsive neurostimulation, deep brain stimulation, or transcranial magnetic stimulation), with the exception of VNS.
Patient has emergence of a new seizure type or reemergence of a past seizure type (seizure types that last occurred more than 12 months before Screening Visit A) during the Baseline Period, or has more than 1 hospitalization for seizures during the Baseline Period.
Patient has a spinal deformity or other condition that may alter the free flow of CSF or has an implanted CSF drainage shunt. This does not exclude patients with scoliosis or spinal rods if, in the judgement of the Investigator, lumbar puncture can be performed and there is free flow of CSF.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	01 Apr 2026	3
Germany	Not Recruiting	01 Apr 2026	12
Italy	Not Recruiting	01 Apr 2026	2
Poland	Not Recruiting	01 Apr 2026	9
Spain	Not Recruiting	01 Apr 2026	3
Sweden	Not Recruiting	01 Apr 2026	6