Overviewing Early-Stage Efficacy, Safety Data of Zorevunersen

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 Monarch (U.S.; NCT004442295) and Admiral (U.K.) studies explored ascending doses of zorevunersen, showing up to 75–80% reductions in seizure frequency at the 70 mg dose. In addition, patients who continued into open-label extensions maintained long-term seizure control with 45 mg maintenance doses for up to 36 months. In this episode, Perry provides a brief highlight of these studies, while overviewing the therapy’s favorable safety profile and the significance of monitoring protein elevations in cerebrospinal fluid, a known class effect of antisense oligonucleotide therapies.

Transcript edited for clarity.

Scott Perry, MD: The Monarch trial in the U.S. and the Admiral trial in the U.K. were early-phase studies evaluating single and multiple ascending doses of zorevunersen, up to a maximum of 70 mg. Each of these studies rolled into an open-label extension—Swallowtail in the U.S. and Longwing in the U.K.

Across the studies, we found that multiple 70 mg doses produced the most rapid and robust seizure reduction—about a 75% to 80% average decrease. In the open-label extensions, patients continued on maintenance doses of 45 mg and maintained this reduction long term, now out to about 36 months.

The drug was well tolerated overall. The most common effects were procedural vomiting, which is expected after lumbar puncture, and mild elevations in cerebrospinal fluid protein. While around 86% of patients had elevated protein levels, none showed clinical symptoms, and only one withdrew due to that finding. It’s something we continue to monitor closely, but so far, it hasn’t been clinically significant.