Groundbreaking Phase 1/2a 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."
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 a 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. 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.
Owen – a Lurie Children's patient who participated in the clinical trial and now continues in the open label extension study – is a 12-year-old boy with Dravet syndrome, whose seizures were not controlled by medications. He also had intellectual disability and gait abnormalities. With zorevunersen, Owen's seizures are significantly reduced and he has had marked improvement in language and behavior, according to Dr. Laux.
"He is able to make friends, which is kind of a new development," said Owen's mother Austin. "His quality of life has increased substantially so that he's able to enjoy more activities with neurotypical peers."
The two Phase 1/2a, 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 reduction of motor seizures of nearly 85% at three months and 73% at six months from dosing.
Eligible patients, like Owen, 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 1/2a 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 3, double-blind, placebo-controlled trial of zorevunersen for Dravet syndrome is currently underway.
Funding was provided by Stoke Therapeutics.
Dr. Laux holds the Lorna S. and James P. Langdon Chair in Pediatric Neurology at Lurie Children's.
Ann & Robert H. Lurie Children's Hospital of Chicago is a nonprofit organization committed to providing access to exceptional care for every child. It is the only independent, research-driven children's hospital in Illinois and one of less than 35 nationally. This is where the top doctors go to train, practice pediatric medicine, teach, advocate, research and stay up to date on the latest treatments. Exclusively focused on children, all Lurie Children's resources are devoted to serving their needs. Research at Lurie Children's is conducted through Stanley Manne Children's Research Institute, which is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children's is the pediatric training ground for Northwestern University Feinberg School of Medicine. It is ranked as one of the nation's top children's hospitals by U.S. News & World Report.
