VANCOUVER—Adjunctive treatment with everolimus significantly reduces seizure frequency in patients with treatment-resistant seizures associated with tuberous sclerosis complex (TSC), according to a trial described at the 68th Annual Meeting of the American Academy of Neurology. The drug appears not to be associated with unexpected adverse events in this indication.
“Results from this [study] … suggest that one can use everolimus as an antiepilepsy therapy, which treats the underlying cause of seizures,” said Jacqueline A. French, MD, Professor of Neurology at NYU Langone Comprehensive Epilepsy Center in New York City. “Whether it in fact is also disease-modifying for epilepsy and [whether] continued therapy will produce a continued improvement remain to be seen.”
Comparing Two Drug Concentrations With Placebo
She and her colleagues conducted a randomized, double-blind, placebo-controlled trial of everolimus in patients with TSC. Eligible participants were between ages 2 and 65 and had at least 16 treatment-resistant seizures in the eight-week baseline phase. Participants also had to be taking one to three antiepileptic drugs at stable concentrations for four weeks before enrollment, as well as through the study’s eight-week baseline phase.
Participants were randomized to adjunctive treatment with placebo, a low serum concentration of everolimus (ie, 3 to 7 ng/mL), or a high serum concentration of everolimus (ie, 9 to 15 ng/mL). Concentrations were titrated during the first eight weeks to achieve stable serum concentrations of treatment. A 12-week maintenance phase followed. Seizures were counted during the titration and maintenance phases. At the end of the maintenance phase, patients had the option of continuing in the extension phase of the trial, which is ongoing. The primary end points were percentage seizure reduction and 50% responder rate.
In all, 119 patients received placebo, 117 received low-concentration everolimus, and 130 received high-concentration everolimus. The treatment arms were evenly matched, in terms of age and gender. Approximately half of participants were female. Five patients in the placebo arm discontinued the study, compared with seven in the low-concentration group and eight in the high-concentration group. Five discontinuations in the low-concentration group resulted from adverse events, including stomatitis, anxiety, immunodeficiency, and pyrexia. Four discontinuations in the high-concentration group resulted from adverse events, including mouth ulceration, neutropenia, pneumonia, and stomatitis. Most patients chose to enter the extension phase.
The study population was highly resistant to treatment. Approximately half of participants had failed more than six antiepileptic drugs before enrollment, and about half were taking three antiepileptic drugs at enrollment. Median baseline seizure frequency per 28 days was higher than the requirement for enrollment. Several participants were receiving treatment with vagus nerve stimulation or the ketogenic diet. Patients had various seizure types and syndromes.
Treatment Yielded Clinically Meaningful Improvement
The median percent seizure reduction was significantly greater with low-concentration everolimus (29.3%) and high-concentration everolimus (39.6%), compared with placebo (14.9%). The 50% responder rate also was significantly greater with low-concentration everolimus (28.2%) and high-concentration everolimus (40%), compared with placebo (15.1%).
Approximately 5% of participants in the low-concentration group became seizure-free, along with 3.8% of participants in the high-concentration group versus 0.8% for placebo. Patients receiving placebo had a greater likelihood of seizure worsening, compared with patients receiving everolimus. Participants who received everolimus were more likely to improve, compared with controls. Approximately 15% of the patients in the high-concentration group had a 75% to 100% improvement in seizures.
Approximately 17% of participants in the low-concentration group and 23% of participants in the high-concentration group had severe or life-threatening adverse events versus 10.9% on placebo. The most common adverse events were stomatitis, diarrhea, mouth ulceration, nasal pharyngitis, and upper respiratory tract infection.
“This study demonstrated a statistically significant and clinically meaningful reduction in seizure frequency in patients with treatment-resistant seizures associated with TSC,” said Dr. French. “As we learn more, we find that there are more causes of epilepsy that relate to abnormalities in the mTOR pathway, including … some focal cortical dysplasias,” she continued. Although Dr. French was discussing a cohort of patients with tuberous sclerosis, “it could be that this pathway and interventions in this pathway will be very important for other common forms of epilepsy as well.”