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FDA Approves Two New Treatments for Patients with Uncontrolled Seizures

Fitzgerald, Susan

doi: 10.1097/01.NT.0000442695.45447.75
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The Food and Drug Administration approved two new therapies for partial-onset seizures — an implantable device that can identify activity in the brain and instantly respond with electrical stimulation that is undetectable to the patient and an adjunctive drug that has the same mechanism of action as two other antiepileptic drugs, but shows promise of producing fewer side effects.

Neurologists have two new treatment options for patients with refractory epilepsy — a novel implantable neurostimulation system that is designed to respond to seizure activity as it happens, and an antiepileptic drug (AED) that is chemically related to some medications already on the market but may cause fewer side effects.

The federal Food and Drug Administration in November cleared the way for marketing of the NeuroPace RNS System, an implantable device that can identify activity in the brain and instantly respond with electrical stimulation that is undetectable to the patient. The device, which was approved for patients whose partial-onset seizures are not controlled by two or more AEDs, is not a replacement for resection surgery for patients who are good surgical candidates.

The new drug, eslicarbazepine acetate, was approved for use as an adjuvant treatment for partial-onset seizures after it was tested in patients whose seizures were inadequately controlled by one to three concomitant AEDs. The drug has the same mechanism of action as two other AEDs, carbamazepine and oxcarbazepine, but shows promise of producing fewer side effects. Eslicarbazepine acetate will be marketed in the US under the brand name Aptiom, and is already in use in Europe.

Epilepsy specialists interviewed by Neurology Today said that the new therapies provide more options for the sizable number of patients who have failed different regimens.

“We have 30 to 40 percent of patients whose disabling seizures are not well controlled,” said Gregory Bergey, MD, professor of neurology and director of the Johns Hopkins Epilepsy Center, one of 32 sites where the NeuroPace system was tested. He served as principal investigator at his center.

The new neurostimulation system is expected to offer some advantages over vagus nerve stimulation (VNS), which indirectly delivers electrical stimulation to the brain at timed intervals. The new device, developed by NeuroPace Inc., of Mountain View, CA, “consists of a cranially implanted programmable neurostimulator that senses and records brain activity through electrode-containing leads that are placed at the patient's seizure focus,” according to the company's description. If abnormal electrical activity is detected, the system delivers electrical stimulation.

Dr. Bergey said the device can “within a second or two deliver brief stimuli to the brain near the seizure focus that will possibly alter or prevent a seizure from evolving further into a disabling seizure that otherwise would last many seconds.”

To test the efficacy and safety of the device, researchers implanted it in 191 patients, half of whom then received electrical stimulation as needed and half of whom received a sham treatment. The patients, on average, were 35 years old, had epilepsy more than 20 years, and had 34.2 disabling seizures a month. Half of them had previously been treated with VNS, epilepsy surgery with resection, or both, according to information the company provided to the FDA.

“There was a statistically significant decline in seizure activity,” said Robert E. Gross, MD, PhD, professor of neurology at Emory University who served as principal investigator for the study. During three months of blinded follow-up, there was a 37.9-percent reduction in seizure activity in the group receiving neurostimulation compared with a 17.3-percent reduction in those who got the sham treatment. Dr. Gross said the benefits improved as time went by.

Two years out there's been “a 50 percent reduction in seizures in more than 50 percent of patients,” Dr. Gross said.

“Patients have no idea this thing is going off,” he said. “It is really well tolerated by patients.” He said adverse events experienced by patients included soreness at the incision site and headache.

“This is something that provides an alternative for patients who are not good candidates for resective surgery,” Dr. Gross said.

The company is continuing to follow patients who received the device to see how they fare over time. A spokesperson for NeuroPace said the company expects the first commercial implants to be available by the end of this year. The purchase cost of the system is expected to be in the range of $35,000 to $40,000.

Carl W. Bazil, MD, professor of neurology and director of the Division of Epilepsy and Sleep at Columbia University, said the NeuroPace system is “a very elegant device that does real-time recording of brain activity 24 hours a day.” He said the information collected on seizure activity might help doctors better tailor treatments for their patients.

Dr. Bazil was involved at different points in developing and testing of the device, and said it should be particularly useful for persons with bitemporal epilepsy and others with refractory epilepsy who cannot be helped by resection surgery.





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Study results that were used to gain FDA approval for eslicarbazepine acetate were presented at the American Epilepsy Society (AES) annual meeting in December in Washington, DC. The drug was tested in three randomized, double-blind placebo-controlled trials involving more than 1,400 patients whose seizures were not controlled by one to three medications, including carbamazepine, lamotrigine, valproic acid, and levetiracetam. Patients were on average 38 years old, had epilepsy for about 21 years and had at least four partial-onset seizures a month. Half the patients had eslicarbazepine acetate added to their regimen and the other half received a placebo pill.

A pooled analysis of the study results found that at the end of a 12-week fixed-dose maintenance phase, the median change in standardized seizure frequency (SSF) was 22.6 percent for patients getting a 400 mg dose of the drug, 31.2 percent for those on 800 mg, and 33.3 percent for those on 1,200 mg. That compares with a 16.7-percent reduction in SSF in patients taking the placebo. A seizure reduction rate of at least 50 percent was realized in 40.9 percent of the group taking 1,200 mg of the drug, compared with 20.9 percent of the placebo group, according to an abstract submitted for the AES meeting.

Fred Grossman, DO, senior vice president for clinical development and medical affairs for Sunovion Pharmaceuticals Inc., of Marlborough, MA, which will market the drug, said the medication has a well-established safety profile. Among the most frequent side effects are dizziness, nausea, and headache. The rate of discontinuation because of a side effect was 14 percent for the 800 mg group and 25 percent for the 1,200 mg group, compared with 7 percent for the placebo group, according to the abstract.

Dr. Grossman said the drug's safety profile will not include a black box warning. Also, eslicarbazepine will not be classified as a controlled substance, and thus will not be subject to controlled substance protocol, prescribing, and storage, he said. Sunovion hopes to have eslicarbazepine on the US market early in 2014.

“The most important thing is that eslicarbazepine when used adjunctively to antiepileptic medications offers sustained seizure reduction with convenient once daily dosing and simple titration for people living with partial-onset seizures who have not been adequately controlled by their existing seizure medications,” Dr. Grossman said. “Patients now have another option to help control seizures.”

While the drug won FDA approval as an adjuvant therapy, Sunovion announced in September that two completed phase 3 trials of eslicarbazepine acetate as a monotherapy treatment met their primary endpoints. Data from those trials will be presented at upcoming scientific meetings, Dr. Grossman said.

Dr. Bazil said that it remains to be seen whether eslicarbazepine acetate offers any advantage over carbamazepine and oxcarbazepine. “The theory is it is a better version of those, but in reality we don't know yet,” he said.

Greg Krauss, MD, professor of neurology at Johns Hopkins, said eslicarbazepine acetate might be better tolerated by patients, but he said it might still be problematic at higher doses. Also, he said it's not clear how much more effective it will be than other drugs already available. Dr. Krauss said there is an increasing awareness that optimal epilepsy treatment does not just involve stopping seizures, but also minimizing side effects that can keep patients from leading a full life.

“When you do quality-of-life inventories, quality of life is correlated with whether there are drug toxicities,” he said. So this consideration should be factored into treatment decisions, he added.

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•. AES abstract: Eslicarbazepine acetate as adjunctive therapy in patients with refractory partial-onset seizures: Safety results of a 12-week randomized placebo-controlled study:
    •. AES abstract: Adverse event profile of eslicarbazepine acetate during dose titration in phase III controlled studies of patients with refractory partial-onset seizures:
      •. AES abstract: Eslicarbazepine acetate as adjunctive treatment for refractory partial-onset seizures: Pooled analysis of safety data from three phase III controlled trials:
        •. AES abstract: Efficacy of eslicarbazepine acetate in patients with refractory partial onset seizures: A pooled analysis of three phase III controlled studies:
          © 2014 American Academy of Neurology