Promising results from the first ever gene regulation trials in epilepsy have been released in the New England Journal of Medicine.
The MONARCH and ADMIRAL studies revealed promising safety profiles and initial clinical improvements with the investigational antisense oligonucleotide zorevunersen for the genetic disorder Dravet syndrome.
This inherited condition can result in dozens of treatment-resistant seizures each day and is most often caused by a mutated copy of the SCN1A gene, which impacts the function of sodium ion channels in the brain.
The mutation causes only half the regular amount of the alpha 1 sodium receptor subunit to be made, affecting the generation and transmission of electrical signals. This causes seizures along with cognitive, communication, behavioral and motor challenges.
There are currently no genetic treatments for Dravet syndrome approved by the U.S. Food and Drug Administration.
“The findings of this study show that zorevunersen, a compound that targets the underlying cause of Dravet syndrome, is well-tolerated with a good safety profile,” lead investigator Linda Laux, MD, from Lurie Children’s Hospital of Chicago, told Inside Precision Medicine.
“The Phase I/IIa studies and subsequent open-label extension studies also showed significant reduction of seizures in addition to improvements in overall clinical state and development.
“Further evaluation of zorevunersen in a Phase III double-blind, placebo-controlled study is underway.”
The current standard of care for Dravet syndrome includes antiseizure medications, diet, neuromodulation aimed at controlling seizures. But this does not affect seizures for most patients and has only minimal impact on nonseizure symptoms.
Instead of attempting to suppress seizures, zorevunersen is a disease-modifying therapy that acts on the underlying process causing them, targeting the channelopathy and boosting protein production from the healthy SCN1A gene.
The open-label, multicenter studies investigated the effects of zorevunersen in patients with Dravet syndrome, one conducted in the U.S. and the other in the U.K.
The 81 participants, all aged two to 18 years, were on standard antiseizure medications. Participants received the investigational drug through injection into spinal fluid every four months under anesthesia.
Results showed that seizures among those who received two or three doses of 70 mg zorevunersen reduced by almost 85% at three months and 73% at six months.
Eligible patients who were rolled over into the open-label extension studies SWALLOWTAIL and LONGWING then received 45 mg zorevunersen every four months, and experienced seizure reductions of between 58% and 90% in the first 20 months.
Expressive and receptive communication also significantly improved among those in extension studies for more than three years.
Nearly all patients had a treatment-emergent adverse event (TEAE), but most were classed as mild or moderate. Post-lumbar puncture syndrome most common in the initial trials and affected nearly a quarter of participants.
In the extension studies, 45% of patients experienced increases in cerebrospinal fluid protein, although this never resulted in intracranial pressure of hydrocephalus.
Only one of the serious TEAEs was considered treatment related.
The researchers concluded: “The results reported here support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome.”
