Zorevunersen’s Additive Efficacy in Patients on Established Antiseizure Medications

In this two-part NeurologyLive® Special Report, epilepsy experts Scott Perry, MD, and Joseph Sullivan, MD, provide clinical insights into zorevunersen, an investigational antisense oligonucleotide therapy in development for Dravet syndrome. Across both discussions, they explore the rationale behind targeting the SCN1A gene, review emerging efficacy and safety data, and highlight how gene-directed approaches may complement or go beyond current anti-seizure medications.

In this latest installment, Sullivan, director of the Pediatric Epilepsy Center at UCSF, discussed the 36-month data presented at IEC 2025, including long-term seizure reduction, Vineland-3 outcomes, and safety observations from the open-label extension. He also breaks down the design of the ongoing phase 3 EMPEROR trial and reflects on how zorevunersen continues to demonstrate additive benefit, even in patients already receiving highly effective therapies.

Many participants in the early-phase program entered the trial on modern, FDA-approved therapies such as fenfluramine, yet still experienced further gains with zorevunersen. Sullivan attributes this additive benefit to the drug’s disease-modifying mechanism—up-regulating SCN1A messenger RNA and restoring Nav1.1 sodium-channel function rather than simply suppressing seizures. He describes how this mechanistic precision may enable broader developmental benefits that go beyond symptomatic seizure control.

Transcript edited for clarity.

Joseph Sullivan, MD: This aspect of the data is really important—the fact that many of the patients enrolled were already on highly effective antiseizure therapies. Drugs like fenfluramine have made a big difference for individuals with Dravet syndrome, and some of my own patients on those medications have shown modest cognitive or behavioral improvements. But at the end of the day, those are still antiseizure drugs. They treat the symptoms; they don’t address the underlying cause of the disorder.

What stands out about zorevunersen is that it adds to what these existing drugs are already doing. Its mechanism—up-regulating the amount of productive SCN1A messenger RNA, which in turn increases Nav1.1 sodium-channel expression—means that it’s potentially correcting part of the disease biology. That’s fundamentally different from simply reducing seizure activity through symptomatic modulation.

Roughly half of the patients in the phase 1/2a studies were already on fenfluramine, yet when zorevunersen was added, we still saw additional seizure reduction and improvements in neurodevelopmental measures like communication and adaptive functioning. To me, that speaks volumes about the drug’s potential.

Some critics might argue that if you reduce seizures by 75 %, of course development will improve—that’s true to some extent. But I think this goes beyond that. The natural-history data were key here: many of those patients were also receiving current standard-of-care drugs, and yet they didn’t show the same level of improvement we’re now observing. That tells us we’re seeing more than just the downstream effect of seizure reduction.

Because of its precision mechanism, zorevunersen may be providing an additive or synergistic benefit that reaches the neurodevelopmental core of the syndrome itself. That’s what makes these findings so compelling and why I’m optimistic that this could represent a genuine disease-modifying step forward for Dravet syndrome.