HMN 2026: How First gene regulation clinical trials for epilepsy show promising results

A Phase I/IIa clinical trials co-led by Linda Laux, MD, from Ann & Robert H. Lurie Children’s Hospital of Chicago, show that the first gene regulation treatment for epilepsy is safe and well tolerated by patients with Dravet syndrome for whom antiseizure medications are not effective.

Results, published in the New England Journal of Medicine, include significant seizure reduction and improvement in other symptoms of Dravet syndrome, such as language, motor, and behavior issues. Researchers also report sustained treatment benefits in ongoing open-label extension studies.

“Our results are highly promising, especially since currently there are no approved treatments that address the underlying cause of Dravet syndrome,” said Dr. Laux, Head of the Epilepsy Center and Associate Division Head of Neurology at Lurie Children’s, as well as Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine.

“Since this gene regulation product targets the actual root cause of Dravet syndrome, we observed improvements in other developmental and cognitive symptoms, in addition to seizure control. This is unprecedented.”

Understanding Dravet syndrome and its cause

Dravet syndrome includes a spectrum of symptoms that emerge in infancy and evolve. Most patients experience cognitive deficits, communication and behavioral impairments, motor dysfunction, growth delays, and autistic traits. Difficulties with feeding, poor appetite, and weight loss are also common.

As Dr. Laux explained, patients with Dravet syndrome have a mutation on one SCN1A (sodium channel receptor) gene with one normal SCN1A gene. The mutation causes haploinsufficiency (only half of the amount of the alpha 1 sodium receptor subunit is made). This causes seizures, as well as cognitive and motor issues.

How zorevunersen targets the condition

The study medication (zorevunersen) acts on the normal SCN1A gene to make it work harder and overcome the deficit caused by the mutated SCN1A gene. Zorevunersen is injected into the spinal fluid by a lumber puncture.

The two open-label, multicenter studies (one in the U.S. and the other in the U.K.) enrolled 81 patients with Dravet syndrome aged 2–18 years on standard antiseizure medications.

Patients who received two to three doses of 70 mg zorevunersen had a reduction in motor seizures of nearly 85% at three months and 73% at six months from dosing.

Longer-term benefits and safety profile

Eligible patients rolled over to the open-label extension studies. These patients were given 45 mg of zorevunersen every four months, and they continued to have significant seizure reduction ranging from 58% to 90% over the first 20 months. For patients in the extension studies for more than 36 months, expressive and receptive communication were significantly improved.

While nearly all patients had a treatment-emergent adverse event (TEAE), most of these were mild to moderate. The most common TEAE in the Phase I/IIa trials was post-lumbar puncture syndrome (nearly 25%) while the most common event in the extension studies was cerebrospinal fluid (CSF) protein increase (45%). However, none of the patients with CSF protein increase had increased intracranial pressure or hydrocephalus. Of the serious TEAE, only one was considered treatment related.

“Our data support zorevunersen safety and tolerability, as well as improvement in overall clinical status, quality of life, and adaptive behavior following continued dosing in the extension studies,” said Dr. Laux.

A Phase III, double-blind, placebo-controlled trial of zorevunersen for Dravet syndrome is currently underway.

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