Results of a randomized, placebo-controlled, phase 3 trial showed that everolimus (Afinitor, Novartis) — an oral agent developed as a cancer drug — significantly reduced seizure frequency in patients with treatment-resistant tuberous sclerosis complex (TSC).
A rare genetic disorder caused by overactivation of the mammalian target of rapamycin (mTOR) pathway that promotes cell growth, TSC leads to seizures, cortical malformations, and neuronal hyperexcitability. A common feature is subependymal giant cell astrocytomas (SEGAs).
The results, though, may have much broader implications for the treatment of epilepsy.
"I have to emphasize to you what a big leap this is," Jacqueline French, MD, professor, neurology and co-director, epilepsy research and epilepsy clinical trials, NYU Comprehensive Epilepsy Center, New York, told Medscape Medical News.
"Up until now, we have not treated anybody for their epilepsy; we have only treated them for their seizures. We have given them drugs that suppress their seizures, but we have not fundamentally changed the mechanism underlying that, which caused the epilepsy."
Everolimus is proving to be successful in TSC, but it might also be useful for some cortical dysplasias and other types of epilepsy, she said.
"This might be a first step," said Dr French, who was the global principal investigator for EXIST-3 (EXamining everolimus In a Study of TSC).
She presented the results here during the American Academy of Neurology (AAN) 2016 Annual Meeting. EXIST-3 was sponsored by Novartis Pharmaceuticals.
The study included 366 patients with TSC with a median age of 10 years (range, 2 - 65 years). They had to have had at least 16 treatment-resistant seizures and were receiving 1 to 3 antiepileptic drugs (AEDs) at stable doses. In about half of the patients, 6 or more AEDs had failed before enrollment.
Many patients had also tried other treatment approaches, including the high-fat, low-carbohydrate ketogenic diet and vagus nerve stimulation.
The overall median baseline seizure frequency per 28 days was 37.5. The study didn't restrict the type of seizures, so patients had tonic-clinic, atonic, clonic, myoclonic, and several other seizure types.
After an 8-week baseline phase, patients were randomly assigned to receive, in addition to their AEDs, placebo, lower-dose everolimus (3 - 7 ng/mL), or higher-dose everolimus (9 - 15 ng/mL)...
The study showed that 15.1% of the placebo group, 28.2% of the low-dose everolimus (P = .008 vs placebo), and 40% of the high dose everolimus group (P < .001 vs placebo) attained the primary endpoint of a 50% responder rate.
The treatment also came out on top for the other primary endpoint, percentage reduction in seizure frequency: 14.9% for placebo, 29.3% for low dose (P = .003 vs placebo) and 39.6% for the high dose (P < .001 vs placebo).
"Whether looking at one or the other primary outcome, the results were statistically significant, and there was a dose-response relationship," said Dr French...
"It was very unlikely that placebo would render patients seizure-free," commented Dr French. Total seizure freedom was achieved by 0.8% of the placebo, compared with 5.1% for the low-dose and 3.8% for the high-dose treatment groups.
When asked whether the higher seizure freedom rate in the lower dose was important, Dr French said she didn't think it was "a real difference" and might change during the later extension phase.
The three study groups had a similar safety profile. Adverse events (AEs) were consistent with known risks associated with the drug. The most common ones were stomatitis, diarrhea, mouth ulceration, nasopharyngitis, and upper respiratory tract infection.
"This is not a new drug; it's been around a long time and these are the expected AEs," commented Dr French.
Perhaps the "most problematic" side effects were the ulcers in the mucus membrane of mouth, said Dr French. "But there are ways to treat those and they come and go, so it's not like you have one forever."
And the fact that there were so few dropouts "suggests that they were manageable and tolerable."
Hematologic and biochemical AEs included neutropenia, hypercholesterolemia, elevated alanine aminotransferase levels, and hypertriglyceridemia.
"These are things you don't usually see with AEDs," noted Dr French. "We have to be looking out for these when we use everolimus for this indication."...
Although this is still to be analyzed and verified, Dr French said "there is a hint" that the earlier that patients start the drug, the more benefits they get. It's possible, she said, that earlier initiation may help ward off sometimes severe developmental delays.
"The ideal would be to treat as early as possible, before you had the burden of cognitive dysfunction," said Dr French. "But again, it's very early days. The first thing we had to do was say that it works."
And the fact that this new study shows that it does work is "very exciting," said Dr French.
"In the epilepsy world, it's a big deal because it's where we want to go with epilepsy therapy in general — you don't want to be masking or suppressing the seizures; you want to be treating the epilepsy, and it's something we never have been able to do."
It's possible that other types of epilepsy are related to abnormalities of the mTOR pathway, including some focal cortical dysplasias.