A groundbreaking Phase 1/2a clinical trial co-led by Linda Lo, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago, shows that the first gene-modulating treatment for epilepsy is safe and well-tolerated in patients with Dravet syndrome who are unresponsive to antiepileptic drugs.
The result is New England Medical Journalincluding a significant reduction in seizures and improvement in other symptoms of Dravet syndrome, such as speech, motor, and behavior problems. Researchers are also reporting sustained treatment effects in an ongoing open-label extension study.
Our results are very promising, especially since there is currently no approved treatment that addresses the underlying cause of Dravet syndrome. Because this gene regulatory product targets the actual root cause of Dravet syndrome, in addition to seizure control, improvements in other developmental and cognitive symptoms were also observed. This is unprecedented. ”
Dr. Linda Lux, Director of the Epilepsy Center and Associate Director of Neurology, Chicagoan & Robert H. Lurie Children’s Hospital
Dr. Lux is also an associate professor of pediatrics at Northwestern University Feinberg School of Medicine.
Dravet syndrome includes a variety of symptoms that begin in infancy and progress. Most patients experience cognitive impairment, communication and behavioral disorders, motor dysfunction, growth delay, and autistic traits. Eating disorders, anorexia, and weight loss are also common.
As Dr. Lo explained, patients with Dravet syndrome have one normal SCN1A gene and one mutated SCN1A (sodium channel receptor) gene. This mutation causes haploinsufficiency (only half the amount of alpha 1 sodium receptor subunits produced). This causes seizures as well as cognitive and motor problems. The investigational drug (Zolebnersen) acts on the normal SCN1A gene, enhancing its function and overcoming the defects caused by the mutated SCN1A gene. Zorebnersen is injected into the spinal fluid through a lumbar puncture.
Owen, a Lurie pediatric patient who participated in the clinical trial and is currently continuing an open-label extension study, is a 12-year-old boy with Dravet syndrome whose seizures are not controlled by medications. He also had an intellectual disability and a gait abnormality. Lowe said the treatment with zorebnersen significantly reduced Owen’s seizures and markedly improved his speech and behavior.
“He’s been able to make friends, which is kind of a new development,” said Owen’s mother, Austin. “His quality of life has improved significantly and he is now able to enjoy more activities with his neurotypical peers.”
Two phase 1/2a, open-label, multicenter studies (one in the US and one in the UK) enrolled 81 Dravet syndrome patients aged 2 to 18 years taking standard antiepileptic drugs.
Patients who received 2 to 3 doses of 70 mg of zorebnersen experienced a nearly 85% reduction in motor seizures at 3 months and 73% at 6 months.
Eligible patients like Owen were switched to an open-label extension study. These patients received 45 mg of zolebnersen every 4 months and continued to experience significant seizure relief ranging from 58% to 90% over the first 20 months. Patients who participated in extension studies beyond 36 months had significant improvements in expressive and receptive communication.
Almost all patients experienced treatment-emergent adverse events (TEAEs), most of which were mild to moderate. The most common TEAE in the Phase 1/2a trial was post-lumbar puncture syndrome (approximately 25%), whereas the most common event in the extension trial was increased cerebrospinal fluid (CSF) protein (45%). However, none of the patients with increased CSF protein had increased intracranial pressure or hydrocephalus. Only one serious TEAE was considered treatment-related.
“Our data support the safety and tolerability of zolebnersen in an extension study, as well as improvements in overall clinical status, quality of life, and adaptive behavior after continued administration,” said Dr. Laux.
A phase 3, double-blind, placebo-controlled trial of zolevnersen for Dravet syndrome is currently underway.
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Ann & Robert H. Lurie Children’s Hospital of Chicago
