Everolimus: A Novel Treatment for Seizures?

August 06, 2013

The immunosuppressant/anticancer agent everolimus was associated with a dramatic reduction in seizures in patients with tuberous sclerosis complex in whom treatment with many other antiepileptic drugs had failed, according to a new study.

The study, published online in the Annals of Neurology, was conducted by a team led by Darcy A. Krueger, MD, University of Cincinnati College of Medicine, Ohio.

"We think our results could have huge ramifications," Dr. Krueger commented to Medscape Medical News. "This drug could represent a novel treatment strategy for epilepsy, and possibly even for autism and cognitive impairment."

Reduction in Seizure Frequency, Duration

Everolimus inhibits the mammalian target of rapamycin (mTOR) protein, which is unregulated in tuberous sclerosis and drives the disease process, Dr. Krueger explained. "mTOR also seems to drive epilepsy in these patients, so there was a strong molecular basis for this study. There was also strong preclinical and building clinical evidence with some pilot studies having reported an improvement in seizures in tuberous sclerosis patients taking everolimus."

Everolimus is not considered an antiepileptic drug, and he said he is not aware of any other treatments for epilepsy that target this pathway. "It could benefit other patients with epilepsy — especially those with epilepsy due to traumatic brain injury, brain tumors, temporal lobe epilepsy, and possibly absence seizures — as mTOR might be involved in these conditions too," he added.

Dr. Krueger noted that epilepsy, autism, and cognitive impairment are all manifestations of tuberous sclerosis. "These conditions are all representative of the brain not acting normally and in tuberous sclerosis they share the same underlying mechanism related to mTOR. There are anecdotal reports of improvements in autism and cognition in tuberous sclerosis patients taking everolimus. These processes may also be active in non–tuberous sclerosis patients with autism and cognitive impairment, and there is some evidence that mTOR is also active in Parkinson's and Alzheimer's."

For the current study, 20 patients with tuberous sclerosis and refractory epilepsy were treated with everolimus for a total of 12 weeks. Seizure frequency was reduced in 17 patients and was reduced by 50% or more in 12. Seizure frequency was also reduced during 23-hour electroencephalographic monitoring. Seizure duration decreased significantly, and behavior and quality of life also improved. Adverse effects were common but were said to be mild or moderate in severity.

Dr. Krueger noted that epilepsy is a major problem for patients with tuberous sclerosis, affecting about 90% of individuals, many of whom do not respond to traditional antiepileptic drugs.

"We saw a very large effect — much larger than would be expected with traditional antiepileptic drugs," he added.

He suggested this may have occurred because everolimus is acting by a completely novel mechanism or because it is particularly suitable for seizures in patients with tuberous sclerosis. A third possibility is that the study just happened to recruit a group of good responders, but he thinks this is unlikely.

"We recruited patients who had not responded well to other therapies," he pointed out. "The majority were having seizures every day on multiple antiepileptic medications and had failed 6 to 10 seizure medications in the past, and some had also had surgery, so they were a very difficult population to treat, but we are now conducting a larger trial in hundreds of patients to address this further."

In the current study, some patients showed benefit right away, but in others the benefit appeared after a couple of months of treatment. An extension phase has now been completed and improvement continues as time goes by, Dr. Krueger reported. He attributes this to the time taken for the brain to remodel itself.

"When having frequent seizures, the brain is in an abnormal state," he noted. "With successful treatment the brain can develop as it would have done if it was normal but this takes time."

Dr. Krueger said people should not be put off because everolimus is used as an anticancer drug. "That may cause some hesitancy because of concern about side effects, but only among those who were inexperienced with this drug as it has far fewer adverse effects than most other anticancer drugs."

Funding for this study was provided by Novartis Pharmaceuticals and the Clack Foundation.

Ann Neurol. Published online. Abstract

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