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New Advancements in Drugs and Devices for Treatment-Resistant Epilepsy


 

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Several new antiepileptic drugs and devices aimed at suppressing or preventing seizures are on their way to approval for clinical use.

SAN DIEGO—“Evolutionary and revolutionary” antiepileptic drugs (AEDs) and neurostimulation devices are among the recent developments in therapies for treatment-resistant epilepsy, Jacqueline A. French, MD, reported at the 136th Annual Meeting of the American Neurological Association.

Dr. French, Professor of Neurology and Codirector of Epilepsy Clinical Trials at the New York University Comprehensive Epilepsy Center in New York City, reviewed results of clinical trials for novel evolutionary AEDs that alter the structure of existing compounds, as well as new compounds that are awaiting FDA approval. She also discussed new devices, including implantable neurostimulators, which are undergoing human trials.

“The past few years have been extremely rich in bringing new therapies forward to treat epilepsy,” Dr. French stated. “Recent assessments have indicated that about one-third of patients were treatment-resistant or not responding to AEDs … but I think our patients are better treated now, with fewer side effects.”

New AEDs in Development
“New AEDs are moving forward in development in both the evolutionary and revolutionary categories,” Dr. French stated. Evolutionary drugs are those that use the same mechanism that an existing compound does, but they alter the compound’s structure to hopefully enhance the drug’s safety, tolerability, or potency. “Since many of the difficulties with available AEDs relate to side effects and pharmacokinetic issues,” Dr. French noted, “it makes sense that evolution might produce new drugs with substantial benefits over old.”

Clobazam, a derivative of benzodiazepine that recently received FDA approval, was found to be efficacious in clinical trials involving patients with Lennox-Gastaut syndrome, and also seemed to produce less tachyphylaxis than other drugs in its class, Dr. French reported. Eslicarbazepine, a third-generation version of carbamazepine, also has an improved side-effect profile compared with its parent drug and is awaiting approval by the FDA.

Brivaracetam is an evolutionary AED derived from levetiracetam—an AED that “seems to be very efficacious and produces a lot of seizure reduction,” Dr. French noted, but “can cause irritability and depression.” Brivaracetam, however, showed “extremely promising” results and low rates of adverse events in one clinical trial, but the drug failed in a second study; a third FDA trial is under way.

New Mechanisms in Revolutionary AEDs
“We’ve actually made enormous leaps by taking older drugs that have good mechanisms and finding ways to make them more potent,” Dr. French stated. “Fortunately, several revolutionary compounds—those with entirely novel mechanisms—are also in development or recently approved.”

Ezogabine, a novel potassium channel blocker that selectively activates the KCNQ channel “resulting in the stabilization of hyperexcitable neuronal cells,” was among the revolutionary AEDs that Dr. French discussed. The drug has been tested in patients with partial-onset seizures and showed no plateau of efficacy, but side effects caused a substantial portion of study participants to discontinue.

VX-765, another revolutionary AED submitted for approval, was originally developed for psoriasis and other inflammatory disorders. “The drug works by modulation of proinflammatory cytokines and inhibition of interleukin-converting enzymes,” Dr. French explained. One human proof-of-concept trial has been completed, and further studies to evaluate this mechanism’s efficacy in suppressing seizures are planned.

“[Perampanel is] the first late-stage drug that works on excitatory mechanisms,” Dr. French said, “but it has also only been tried on partial-onset seizures, so we have a whole world of other syndromes to look at.” She also noted that the long-term effects of impacting excitatory mechanisms have yet to be determined.

“So far in the clinic, there doesn’t seem to be a huge difference in the efficacy or the ability to suppress seizures according to whether a drug is evolutionary or revolutionary, but certainly we have high hopes for the revolutionary drugs,” Dr. French said.

Neurostimulation Devices for Epilepsy Treatment
“There are a couple of devices under study that are very close to the clinic—the deep brain stimulator and the responsive neurostimulator,” Dr. French said. The deep brain stimulator (Medtronic, Inc; Minneapolis) produces shocks at regular, timed intervals following implantation in the thalamus. In studies, both treated and sham device groups experienced an immediate reduction in seizure frequency, but efficacy improved compared with time in the treated group, and it is believed to be most efficacious after two years of treatment. “It is not a smart device,” Dr. French noted, but patients can self-trigger when they feel a seizure coming on.

The responsive neurostimulator system (NeuroPace, Inc; Mountain View, California) is an example of a smart device that can detect when a seizure begins and delivers a countercharge to the epileptic focus to suppress the seizure. Immediate results in the trial were limited, Dr. French said, “but if you look at what happens in the long-term, the results get better and better.”

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