Adjunctive cenobamate reduces seizure frequency in patients with uncontrolled focal seizures.
A phase 2 randomised controlled trial of cenobomate at daily doses of 100 mg, 200 mg and 400 mg involved 437 patients from 107 epilepsy and neurology centres across 16 countries including Australia.
Patients had a median age of 40 years, a seizure history of more than 20 years and had previously tried three anti-epileptic drugs (AEDs).
The most commonly used concomitant AEDs were levatiracetam, lamotrigine, valproate and carbamazepine.
The study included an eight-week prospective baseline assessment, a six-week titration phase then a 12-week maintenance period.
It found the median percentage change in focal seizure frequency was -24% with placebo, -35.5% with 100 mg cenobamate and -55.0% for both the 200 mg and 400 mg doses.
The responder rate, defined as a 50% or more reduction in seizure frequency, was 25% in controls, 40% at 100mg, 56% at 200 mg and 64% at 400 mg cenobamate.
In particular, 21% of patients treated with 400 mg cenobamate and 11% of those treated with 200 mg cenobamate had no seizures at all during the maintenance phase of the study.
The study noted high levels of treatment-emergent adverse events – 70% in controls, 65-90% with cenobamate – such as somnolence, dizziness, headache, fatigue and diplopia.
There were also three hypersensitivity reactions in the 200 mg dose group.
Rate of discontinuation due to adverse events such as ataxia, dizziness, somnolence, nystagmus and vertigo were recorded in 5% of controls versus 10% with 100 mg, 13% with 200 mg and 20% with 400 mg cenobamate.
An exploratory post-hoc analysis calculated the number needed to treat to achieve seizure freedom was 10 in the cenobamate 200 mg group and five in the 400 mg group.
“Efficacy with cenobamate occurred in a dose-related manner and treatment was generally well tolerated. High rates of seizure freedom were observed with doses of 200 mg and 400 mg,” the study concluded.
A Comment article in Lancet Neurology, by Dr Stephan Arnold of Germany’s Schon Klinic, said cenobamate appeared to be a promising anticonvulsant drug and that the seizure freedom rate of >20% was unheard of.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks.”
“Even when seizures are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The mechanism of action of the drug was still under investigation but was believed to be via inhibition of excitatory sodium-channel currents and enhancing inhibition by modulation of GABAA receptors.
He added that the accepted new drug application for the sale and marketing of cenobamate by the FDA in February 2019, might make this treatment option available for all patients soon.