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 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 studyassociated 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.
• Patient must experience 6 or more major motor seizures during the 6-week Observation Period and must not be free of major motor seizures for more than 21 consecutive days during the Observation Period. Patients may not be randomized if they experience an average of more than 10 major motor seizures per day 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 ASMs, ketogenic diet and/or 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.
• Patient must have a negative pregnancy test at Baseline (Day -1) if female of childbearing potential.
• Anticoagulants (including but not limited to heparins, warfarin, dabigatran, and rivaroxaban) and antiplatelets (including but not limited to aspirin and non-steroidal anti-inflammatory drugs) must be discontinued per standard of care prior to and after the lumbar puncture dosing/sham procedure at Visit 1 (Day 1).

Exclusion Criteria:

• Patient has documented variant in the SCN1A gene associated with gain-of-function including but not limited to: Thr162Ile, Arg1636Gln Thr226Met, Ile236Val, Leu263Val, A420Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Ileu1483Met, Gln1489Lys, Ile1498Thr, Ile1498Met, Phe1499Leu, Met1500Val, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1636Gln, Arg1648Cys, Leu1649Gln, Phe1661Leu, Leu1670Trp, Gly1674Arg, Phe1774Ser, or Asp1866Tyr.
• Patient has a pathogenic or likely pathogenic variant in a gene other than SCN1A on the epilepsy gene screening panel (the pathogenic or likely pathogenic variant must be homozygous in cases of known recessive disease).
• 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 clinically relevant symptoms or a clinically significant illness (in the judgement of the Investigator) during the Observation Period, other than epilepsy. This includes the presence of an active infection requiring systemic antiviral or antimicrobial therapy.
• 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 history of CNS disease (other than epilepsy or DS), including history of bacterial or viral meningitis or brain malformation.
• 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.
• Patient has clinically significant (in the judgment of the Investigator) abnormal laboratory values at Screening Visit B (Week -6). Testing may be repeated once during the Baseline Period if initial values are clinically significant, at the discretion of the Investigator.
• Patient has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5-fold upper limit of normal (ULN), eGFR 3-fold but ≤5-fold ULN or eGFR ≥30 mL/min/1.73 m2 but <60 mL/min/1.73 m2 at Screening Visit B or on repeat, must also undergo testing at Baseline (Day -1) with results that meet this criterion. ALT, AST, serum creatinine to calculate eGFR and/or platelet tests may be repeated once at each timepoint, if initial results do not meet this criterion, at the discretion of the Investigator.
• Patient has clinically significant abnormalities, based on the judgement of the Investigator, in the 12-lead ECG measured at Screening Visit B (Week -6).
• Patient is a female of childbearing potential, or patient is a fertile male with female partner(s) of childbearing potential, unless willing to ensure that they and their partners use highly effective contraception throughout the duration of the study and for at least 6 months after their last dose of zorevunersen
• Patient is a female who is lactating or planning pregnancy during the duration of the study and for at least 6 months after their last dose of zorevunersen.
• Patient has a positive response on the Baseline/Screening C-SSRS at Screening Visit B (Week -6) or on the Since last Visit C-SSRS at Baseline (Day -1), or is considered at risk of suicide or self-harm based on the clinical judgement of the Investigator. A positive response is defined as a “Yes” response on Suicidal Ideation Questions 4 and/or 5 and/or on any Suicidal Behavior Questions with the exception of self-injurious behavior.
• Patient is currently taking part in or has been part of a clinical study involving an IMP within 2 months (or 5 half-lives, whichever is longer) prior to Screening Visit A, or is currently taking part in an observational study, unless AEs are not collected per protocol or will not be collected during the duration of enrollment in this study.
• Patient has been part of an interventional clinical study in which an investigational gene therapy or in which zorevunersen was administered.
• Patient has any other disease or disorder, including a clinically significant unstable medical condition, in which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study including consideration of sedation procedures, may influence the results of the study, or may affect the patient’s ability to participate in the study.
• Patient has known hypersensitivity to the excipients of the IMP.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 03/11/2025. Questions regarding updates should be directed to the study team contact.