Inside the EMPEROR Trial: Evaluating Zorevunersen’s Efficacy and Safety

Zorevunersen is an investigational antisense oligonucleotide therapy being studied for Dravet syndrome, a developmental and epileptic encephalopathy caused primarily by pathogenic variants in the SCN1A gene. By modulating RNA splicing to enhance production of functional sodium channel protein, zorevunersen is designed to target the underlying genetic mechanism of the disorder. Early clinical studies have suggested reductions in seizure frequency and signals of improvement across adaptive behavior measures, warranting further investigation in phase 3 evaluation.

In this NeurologyLive^® Special Report mini-series, Scott Perry, MD, Co-Director of the Jane and John Justin Neurosciences Center at Cook Children’s Hospital, reviews the available evidence and ongoing research surrounding zorevunersen. Across five focused episodes, Perry discusses its molecular rationale, early-phase trial findings, clinical outcomes beyond seizure control, the design of the ongoing EMPEROR trial, and what these developments may mean for the future management of Dravet syndrome.

The ongoing phase 3 EMPEROR study (NCT06872125) is a randomized, sham-controlled, registrational trial designed to rigorously assess zorevunersen’s efficacy in patients with Dravet syndrome. In the trial, participants receive either the active drug via intrathecal administration or a sham procedure, ensuring blinding for investigators and families. For this next segment, Perry provides insights on the design of the study, detailing the dosing strategy and crossover to open-label extension. Above all, he underscored the trial’s importance as a potential registrational pathway.

Transcript edited for clarity.

Scott Perry, MD: The EMPEROR trial differs from earlier studies in that it’s a randomized, sham-controlled design. Some participants undergo the same spinal tap and cerebrospinal fluid collection but receive no active medication, while others receive zorevunersen. Investigators, caregivers, and patients are all blinded to the assignment.

The dosing protocol includes two loading doses of 70 mg given eight weeks apart, followed by maintenance doses of 45 mg every four months. After 52 weeks, participants can transition into the open-label extension, where those initially receiving sham will start active treatment.

This design allows us to confirm efficacy and safety in a controlled setting while ensuring all participants eventually have access to the therapy. We’re optimistic and look forward to seeing results when they become available in early 2027.