A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome

Zorevunersen is an investigational new medicine for the treatment of Dravet syndrome. It is an antisense oligonucleotide (ASO) that is intended to increase the level of productive SCN1A messenger RNA (mRNA) and consequently increase the expression of the sodium channel Nav1.1 protein. This RNA-based approach is not gene therapy, but rather RNA modulation, as it does not manipulate nor insert genetic deoxyribonucleic acid (DNA).

Zorevunersen is designed to upregulate Nav1.1 protein expression from the nonmutant (wild-type) copy of the SCN1A gene to restore physiological Nav1.1 levels. Nav1.1 levels are reduced in people with Dravet syndrome.

This is a global, multicenter, randomized, double-blind, sham-controlled, parallel group Phase 3 study to assess the efficacy, safety, and tolerability of zorevunersen in patients with Dravet syndrome. The study duration and endpoints are designed to evaluate the potential of zorevunersen for disease modification. The study consists of two parts, Treatment Period 1 and Treatment Period 2. The primary and secondary endpoints will be assessed at the conclusion of Treatment Period 1. These endpoints will be assessed again at the end of Treatment Period 2. The primary endpoint is the change from baseline in major motor seizure frequency. Secondary endpoints include the change in behavior and cognition, clinical status, and health-related quality of life in patients with Dravet syndrome.

Patients will have the opportunity to enroll in an open label extension study and receive zorevunersen if they meet eligibility criteria at the end of the study.

• zorevunersen (Drug): Treatment Period 1: Zorevunersen group will receive study drug by intrathecal (IT) administration on Day 1 (after the 8-week Baseline Period), Day 57 (Week 8), Day 169 (Week 24), and Day 281 (Week 40) at a dose level of 70 mg on Day 1 and Day 57, and 45 mg on Day 169 and Day 281. Treatment Period 2: Group assigned to zorevunersen in Treatment Period 1 will receive 45 mg of zorevunersen on Day 393 (Week 56), Day 477 (Week 68), and Day 589 (Week 84).
• Sham Comparator (Other): Treatment Period 1: Sham group will not have drug administered. Sham group will have a procedure intended to mimic the drug administration. Treatment Period 2: Group assigned to sham in Treatment Period 1 will receive 70 mg of zorevunersen on Day 393 (Week 56) and on Day 477 (Week 68), and 45 mg of zorevunersen Day 589 (Week 84).

Primary outcomes

• Measurement of Seizure Change [Week 28]: Measured by daily seizure diary

Secondary outcomes

• Measurement of Seizure Change [Week 52]: Measured by daily seizure diary
• Multi-component Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Outcome Score [Week 52]: Measurement of change from baseline for multi-component score. Scoring is non-parametric and based on rank between treatment and sham groups. Individual items are scored on a scale of 0, 1, or 2, indicating never, sometimes, or usually or often, or on a scale of 0 or 2, indicating no or yes, with higher scores indicating greater performance
• Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Subdomain Score [Week 52]: Measurement of change from baseline for individual subdomains. Scoring is point-based on a scale that varies, depending on subdomain, Individual items are scored on a scale of 0, 1, or 2, indicating never, sometimes, or usually or often, or on a scale of 0 or 2, indicating no or yes, with higher scores indicating greater performance.

Sex: All, ages: 2 Years to 17 Years

Key Inclusion Criteria:

1. Patients must be ≥2 and <18 years of age.
2. Patients must have a clinical diagnosis of DS confirmed by the Epilepsy Study Consortium, Inc. (ESCI) and as defined by:

   Onset, prior to 12 months (inclusive, <13 months), of age, of recurrent focal with motor signs, hemiclonic, or generalized tonic-clonic seizures. No other known etiology causing clinical DS manifestations..
3. 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.
4. Patient must experience the required number of major motor seizures during the 6-week Observation Period. Major motor seizure types included are 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.
5. 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.
6. 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.
7. Patients' 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.

Key Exclusion Criteria:

1. Patient has documented variant in the SCN1A gene associated with gain-of-function
2. 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.
3. Patient is currently treated with neuromodulation techniques (e.g., responsive neurostimulation, deep brain stimulation, or transcranial magnetic stimulation), with the exception of VNS.
4. 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.