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News from the American Epilepsy Society Annual Meeting: Can an Anti-Inflammatory Inhibit Partial-onset Seizures?

Talan, Jamie

doi: 10.1097/01.NT.0000410756.96941.4f
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Investigators presented preliminary data suggesting a proof of concept that an anti-inflammatory is safe and effective for treating partial-onset seizures.

With increasing evidence that inflammation plays some role in the pathogenesis of seizures, neurologists are embarking on a study of a novel anti-inflammatory agent that inhibits interleukin-1beta (IL-1B) production to see whether it has an impact on reducing refractory partial onset seizures.

The idea for the study was set in motion three years ago at the annual American Epilepsy Society meeting when Annamaria Vezzani, PhD, of the Mario Negri Institute for Pharmacological Research in Milano, Italy, approached Jacqueline A. French, MD, professor of neurology at the New York University Comprehensive Epilepsy Center.

Dr. Vezzani had led the way in describing inflammatory markers on the heels of a seizure in animals. She had been working with transgenic mice — overexpressing proinflammatory cytokines or increasing endogenous pro-inflammatory markers. Among her observations, she had found that inflammation precipitated seizures and inflammatory signals seem to last, apparently contributing to epileptogenesis.

She found that IL-1B significantly exacerbates the seizure activity, and that using an anti-inflammatory drug such as VX-765 could prevent the abnormal electrical activity in the brain.

VX-765 is an IL-1B-converting enzyme/caspase 1 inhibitor that reduces the production and release of IL-1B. She told Dr. French, an editorial advisory board member of Neurology Today, that VX-765, which was being tested for psoriasis, might have some potential in patients with epilepsy. Vertex Pharmaceuticals, of San Diego, provided the drug for a study testing VX-765 as an adjunctive treatment.

At this year's American Epilepsy Society annual meeting, Drs. French and Vezzani presented their preliminary data from a phase 2 trial, which they say, offers a “proof of concept” for the approach.

They enrolled 60 patients — who had had at least six observable partial-onset seizures six weeks between screening and the start of treatment; 48 were randomized to the medication arm of the study and 12 who were on placebo.

The six-weeks of treatment was followed by a six-week observation period. The primary endpoints were safety and tolerability. Even though the study was not powered to look at its effect on seizure reduction, they did a post-hoc analysis to compare seizure frequency during the baseline period and the final two weeks of active treatment.

Over the 12-week study period, the medication appeared safe and well tolerated. The scientists recorded adverse events in 72.9 percent (35/48) of subjects on VX-765 and 83.3 percent (10/12) on placebo. The most common complaint was dizziness. One patient in the active arm of the study developed a rash and was dropped from the study. Three of the 48 patients on the active medicine (6.3 percent) had a serious side effect, including hernia surgery, pain, and acute worsening of complex partial seizures, but most of these were not thought by the investigator to be drug-related, said Dr. French.

The seizure frequency dropped in those patients taking the experimental drug. Dr. French said that the effect was not observable until after the first two weeks of treatment, which is not surprising given that the medication is targeting inflammatory pathways.

The differences in the reduction in seizure rates and 50 percent responder rates were not significant for the placebo and experimental groups. But 12.5 percent of those taking VX-765 were seizure-free during the last two weeks of treatment versus none of the placebo group (p=0.333). During the observation period, there appeared to be a positive trend towards a better 50 percent responder rate (31.3 percent in the VX-765 group compared with 8.3 percent in the placebo group; p=0.153).

This was a proof of concept study, Dr. French noted. “The study showed a trend toward improvement,” she said. “The results were positive enough for us to move forward with a larger double-blind study,” which will aim to enroll 400 patients.

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While there is good scientific and clinical evidence for inflammation in the region of the seizure foci,it is still not entirely clear whether the inflammation causes the seizures or the inflammation is a result of the seizures, or both. Studies are now underway to understand this process.

“If inflammation is important in initiating seizures, it does open up the possibility of new ways to treat epilepsy,” said Howard Goodkin, MD, PhD, the Shure Professor of Neurology and Pediatrics at the University of Virginia. “This inhibitor appears to reduce seizure frequency but we have no idea if it is specific for one type of epilepsy or many of the epilepsies.”

“This study is fascinating because it is looking at epilepsy in an entirely new light,” said Joseph I. Sirven, MD, professor and chairman of the department of neurology at the Mayo Clinic in Scottsdale, AZ. “There is logic in the manner the investigators pursued the concept of an anti-inflammatory approach to chronic epilepsy. Relatively recent literature is replete with many examples of an immune-based etiology of epilepsy.”

Consider, he said, Rasmussen's encephalitis and several of the paraneoplastic syndromes in which an altered pathology results in refractory seizures. “Thus, it makes perfect sense to approach the condition from this angle.”

“The drawback to any anti–inflammatory approach to treatment are the adverse side effects of such a treatment. Take, for example, the world of multiple sclerosis treatment and the side effects of those treatments. This is what the adverse effects are likely to be for this type of treatment. When all is said and done, this is an exciting and seminal development for the treatment of epilepsy should the trials continue to be positive when completed.”

Kimford J. Meador, MD, professor of neurology and director of the Epilepsy Center at Emory University, agrees that such an approach may be useful. “The use of an anti-inflammatory agent, which in this case inhibits interleukin-1 beta, is a very novel approach to the treatment of epilepsy. The animal studies from Dr. Vezzani's lab are most interesting, and the preliminary results from the phase 2 study are promising.”

“This line of investigation is an excellent example of translation of basic science findings to human disease,” he said. “Further, the translation in this case has been rapid, and there are likely to be additional insights from further laboratory investigations and from the clinical studies.”

He added that the approach has potential to address the great need for a preventive treatment for epilepsy. “Although translation from the lab to the clinic is a difficult and long process which could fail for multiple reasons, I look forward to the results of the planned phase 3 study, which will be critical in demonstrating efficacy and safety.”

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Vezzani A, French J, Baram TZ, et al. The role of inflammation in epilepsy. Nat Rev Neurol 2011;7, 31-40.
    Vezzani A, Friedman A. Brain inflammation as a biomarker in epilepsy. Biomark Med 2011;5(5): 607-14.
      Vezzani A, Aronica E, Pittman QJ,et al. Epilepsy and brain inflammation. Exp Neurol 2011;E-pub 2011 Oct. 1.
        Vezzani A, Maroso M, Bartfai T, et al. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun 2011;25(7): 1281-1289.
          ©2012 American Academy of Neurology