For families of children with Dravet syndrome who have exhausted conventional treatment options, new hope is emerging.
A first‑ever gene‑regulation therapy tested in early‑phase clinical trials co‑led by Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago's Dr. Linda Laux has proven safe. The drug, called zorevunersen, delivered striking improvements in seizure frequency, language, motor skills and behavior, the study found, marking a potential turning point for patients whose conditions have long resisted standard treatment.
Additionally, after the main trial ended, some participants continued receiving the treatment in follow‑up studies (known as an ongoing open-label extension studies) in which all parties knew which treatment they were receiving, and the benefits still held up, the scientists said.
The results were published last week in the New England Journal of Medicine.
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.
"Our results are highly promising, especially since currently there are no approved treatments that address the underlying cause of Dravet syndrome," said Laux, head of the Epilepsy Center, an associate professor of pediatrics at Feinberg and the associate division head of neurology at Lurie Children's. "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."
Patients with Dravet syndrome have a mutation on one SCN1A (sodium channel receptor) gene with one normal SCN1A gene, Laux said. 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. 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 lumbar puncture.
Meet Owen
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, Laux said. Read Owen's patient story here.
"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."
How the study worked
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, transitioned to 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," Laux said.
A Phase 3, double-blind, placebo-controlled trial of zorevunersen for Dravet syndrome is currently underway.
Funding was provided by Stoke Therapeutics.
