Eighth Eilat Conference on New Antiepileptic Drugs

Epilepsy Therapy Project (Epilepsy Therapy Project) Scientific Advisory Board members Jacqueline French, MD and Steven C. Schachter, MD, along with Warren Lammert, Co-Founder and Chairman, Epilepsy Therapy Project and Bill Braunlich, President, Epilepsy Therapy Project, and Epilepsy Therapy Project’s David Fischer attended the Eighth Eilat Conference on New Antiepileptic Drugs in Sitges, Spain last September 2006. At this year’s conference, as Dr. Schachter noted, a significant and unique event took place: “We heard from the voice of people affected by epilepsy. Warren gave opening remarks on the first day on behalf of himself and his family, as well as Epilepsy Therapy Project. This was a really important and significant moment. Now, at this important meeting, taking their rightful place side by side with the scientists and clinicians, regulators and industry, was the perspective of those affected by epilepsy. Hopefully this will be continued.”

As in the past, the conference program provided an in-depth progress report on new antiepileptic treatments in different stages of development. It also presented new findings on treatments that are already in use. Sessions were devoted to:

  • An update on status epilepticus (SE)
  • An overview of medications in development
  • A review of new studies on drugs that are being used clinically
  • A discussion of neurostimulation as well as evidence-based treatment guidelines

Day One was a discussion of SE trials and therapies from animal models to clinical treatment trials. A key question asked was: What makes studying SE so difficult? Presentations focused on key problem areas, including the limitations of animal studies, the clinical definition of SE, the wide variety of underlying causes of SE in patients, and the impact of SE on patients, hospitals and the healthcare system.

J. French: In the clinical research world we probably do not give SE as much attention as it deserves relative to other aspects of epilepsy. There are available drugs that seem to help terminate SE in animal models or reduce the amount of injury that the animal suffers. However, there has been difficulty translating those findings into clinical trials, partly because these trials are extremely difficult to run. For example, patients themselves are in an urgent situation and cannot give consent for a study. In addition, there are many regulatory roadblocks and challenges to deciding which drugs to study in clinical trials.

S. Schachter: Since time appears to be of the essence in starting therapy, there is also a logistical problem; namely the time it takes from the onset of the first seizure that constitutes the beginning of SE to the point in time that the patient enrolls in a treatment trial. Hopefully the discussions at the Eilat meeting will lead to trials that in time will inform evidence-based practice as it relates to SE.

Day Two was an overview of drugs that are currently in development, from drugs that are just starting to be tested in humans to drugs that are relatively close to being approved by the FDA. Some were presented at previous conferences, and others were discussed for the first time.

J. French: It was encouraging to hear about these new drugs. Many of these investigational drugs undergo a very similar development process. They are generally tested in patients with refractory partial epilepsy and compared to a placebo as add-on treatment. However, there are populations of patients with epilepsy that are not typically studied, including children with devastating epilepsy syndromes, patients with idiopathic generalized epilepsy, and patients with SE.

S. Schachter: I agree entirely. Epilepsy drugs in development are tested in a very stereotyped way that is consistent with FDA requirements. So it is understandable, but regrettable, that they are not being explored for other patient populations while they are still in development.

J. French: We did, however, hear about notable exceptions in terms of the pediatric population. One was a drug called stiripentol, which is available in Canada and France, but not in the United States. A pediatric epileptologist from France discussed how this drug has been extremely useful in a very small group of children with devastating epilepsy called Severe Myoclonic Epilepsy of Infancy. This drug has made a very important difference in many children’s lives. Likewise, another drug that is before the FDA, rufinamide, has been specifically tested in children and adults with the Lennox-Gastaut Syndrome, another underserved population.

In fact, a special symposium was held regarding rufinamide for this population. The take away messages for me were that we need to 1) continue to refine the definition of Lennox-Gastaut and what EEG characteristics define it; 2) take a comprehensive approach to the care of children with Lennox-Gastaut, bringing in the pediatrician and the adult epileptologist as the child gets older, as well as therapists, speech therapists, and social workers; and 3) determine better outcome measures to evaluate effectiveness of therapies and tradeoffs.

S. Schachter: Some of the drugs in development that were discussed represent chemical modifications of existing drugs, for example fluorofelbamate and briveracetam. These new drugs represent the next generation of existing marketed drugs, and whether or not they will have advantages over their predecessors remains for clinical research to demonstrate.

Day Three was a review of new studies of drugs that are already being used clinically. In addition, there was discussion of vagus nerve stimulation.

S. Schachter: One of the interesting presentations concerned vigabatrin, which is available in other countries, but not yet in the U.S. A company intends to apply to the FDA for approval of vigabatrin under an Orphan Drug designation for infantile spasms.

J. French: There is a risk-benefit to this drug. It produces irreversible loss of peripheral vision in some patients who take it for more than six months. In adults, this would be a serious issue in terms of driving; however, it does not appear to otherwise impair quality of life. We’re very concerned, though, when the drug is being given to children who have developmental delays or who are too young to be tested formally for visual changes.

We heard about a test that is reasonably sensitive and specific when given which indicates whether or not the drug should be discontinued. Unfortunately, it is not an easy test to administer to very young children, but it is possible. Even so, it is very important to note that to date even the most severe case of peripheral vision loss did not interfere with being able to see straight ahead, read, and do other functions, so if driving is not an issue, the vision loss is of less concern.

S. Schachter: The dilemma for physicians as well as parents is to avoid treatment with vigabatrin any longer than is necessary. On the other hand, if discontinued too soon, it may not be effective again if the infantile spasms recur. As such, there is this balancing act that pediatric epileptologists spoke about at the meeting, and each speaker seemed to take a somewhat different approach to this problem.

Day Four started with a broad discussion about brain stimulation – “neurostimulation”, and concluded with an update on evidence-based guidelines for the treatment of epilepsy.

J. French: Neurostimulation mechanisms that are currently being studied include deep brain stimulation, primarily using thalamic stimulators. It was very important to see that people are thinking about how stimulation should be performed. There are many different ways that a stimulator can be used in terms of the intensity, the frequency, and pulse width. There are so many different combinations of these things that in human beings it would be almost impossible to test which is optimal.

A second type of stimulation discussed was the Responsive Neurostimulator. This is a “smart device,” able to detect the onset of a seizure, at which time the neurostimulator gives counter-stimulation in the area where the seizure is beginning, assuming that the simulating electrodes are placed properly in that region. This is currently undergoing trials that look promising. Because these are in randomized trials, we won’t know the results for another year or two to be able to say how useful these therapies will be.

S. Schachter: With regard to evidence-based treatment for patients with epilepsy, efforts are being made to synthesize the relevant published literature into guidelines. These efforts represent a very intense commitment of time by committee members to read the literature, extract details, and synthesize material in a way that could be as helpful to clinicians as published literature can be.

J. French: The issue that was raised is very important -- not everything can be studied in a randomized controlled trial. And not everything that can be studied has been studied. The absence of evidence does not mean evidence of absence, meaning that just because something has not been studied in a methodologically definitive way and therefore has not been published, does not mean that that therapy should not be used in a given situation.

Clinical decision-making still has to play a role here, but physicians should continue to be aware of areas where a therapy has been proven and areas where we need to gather more evidence through rigorous clinical trials.

S. Schachter: I agree; it is particularly important that issues encountered in daily practice or decisions that come up requiring therapeutic decisions in clinical practice are explored.

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