AED IX - Highlights of Day One: New Drugs in the Future for Persons with Epilepsy

The Ninth Antiepileptic Drug Trials Conference, sponsored by the University of Pennsylvania Medical Center and the Epilepsy Therapy Development Project, was held in Sunny Isles, Florida, March 21 – 23, 2007. The meetings explored:

• Development of new drugs to prevent epilepsy and treat epilepsy, and how to test drugs and devices – Day One.
• Special populations, formulations, and secondary endpoints – Day Two.
• Drugs in the pipeline – Day Three.

For persons with epilepsy, the Antiepileptic Drug Trials conference, which occurs every two years, is considered to be one of the most important and comprehensive meetings on this topic held in the United States. AED IX was a gathering of physicians from around the world, corporate leaders, and Food and Drug Administration officials. Participants shared a single goal – making new therapies for epilepsy available to patients, or to put it differently, bringing these therapies to market. With more than 30 percent of patients with epilepsy still experiencing seizures that are uncontrolled by drugs, new therapies are desperately needed.

The opening presentations on Day One set the stage for the conference talks:

• Preclinical – development of new antiepileptic drugs (AEDs) and new drugs to prevent epilepsy in people who have not yet had a seizure but are at high risk of developing epilepsy
• Proof of Principle
• Monotherapy
• Device Trials

Development of new AEDs and drugs to prevent epilepsy focused on new animal models, models of epileptogenesis available for drug screening, biomarkers in epileptogenesis, human dose prediction from animal studies, and why/when epilepsy drugs fail during pre-clinical development.

Marc A. Dichter, MD, PhD, Professor of Neurology and Pharmacology at the University of Pennsylvania School of Medicine (UPenn), moderated the first segment and talked with epilepsy.com. Dr. Dichter, co-director of the conference, pointed out the need for new AEDs for “those 30 – 40 percent of patients for whom seizures are not controlled by medication. Of all the new drugs that have been discovered recently and approved – that number remains intact. Therefore we need to look at new animal models for screening new compounds.”

Dr. Dichter noted that the process of developing new treatments is very time consuming. “For the sake of our patients, we need new clinical trial methods to test these therapies more efficiently,” he said. Proposed new clinical trial methods included: Relevance of the photosensitivity model; Proof of principle for epileptogenesis; and Time to the Nth seizure.

New Clinical Trial Methods

The photosensitivity model was presented by Dorothee Kasteleijn-Nolst Trenite, MD, PhD, MPH, from the Universita Di Roma “La Sapienza” II, Department of Neurology, Rome, and the University of Utrecht, the Netherlands. In this model, patients are given a drug to see if it blocks the development of specific abnormalities on their EEG when they are exposed to a flashing strobe light. She said that “to date, AEDs effective in the photosensitivity model have also been effective in epilepsy patients in general” and added that “the results of photosensitivity studies provide some guidance as to the choice of the potential dose in further Phase II and Phase III trials.”

Another new approach was discussed by Susan Herman, MD, Director of the Epilepsy Monitoring Unit and Neurodiagnostics Laboratory at UPenn. She said that the development of seizures in particular patients may be preventable, and that new clinical trial methods are needed to test treatments in these patients. She said, “For example, we can anticipate that some patients who have had a traumatic brain injury (TBI) will eventually develop seizures.” Therefore, she proposed a model in which scientists find biomarkers which predict who will develop epilepsy, so that therapy can be targeted to those at highest risk.

Dr. Dichter commented: “Dr. Herman is setting a stage for the new model. My own feeling is that epilepsy has been almost unique in the field of medicine. We treat the symptoms (seizures) after they have developed rather than working to eliminate the cause. It is like telling smokers ‘Don’t worry about what happens when you smoke. If you get lung cancer, we will see what we can do.”

Reinforcing Dr. Herman’s new model, he added, “We need to begin to focus on people at risk for developing epilepsy and do something to prevent it – biomarkers are a way to do this – to intervene.”

Dr. Dichter anticipates a sharp rise in new cases of epilepsy with soldiers returning from Afghanistan and Iraq who have suffered head injuries. He said, “The kinds of wounds we are seeing are more related to explosions, especially from improvised explosive devices, rather than bullet wounds. Head injuries are very common and soldiers with moderate and severe head injuries are being saved because of the excellent medical care they are receiving very quickly. We need to be able to protect these injured soldiers from a possibly high incidence of post-traumatic epilepsy.”

Out-of-the-Box Thinking

Another alternative clinical trial model, “Time to Nth Seizure”, was presented by Jacqueline French, MD, who served as symposium director. Dr. French is Professor of Neurology, University of Pennsylvania School of Medicine, and Director of the Penn Epilepsy Center. She asked: “Would you be happy with a trial design that was based on out-of-the-box thinking?” She suggested that “"Time to the Nth" would eliminate the need for baseline, markedly improve recruitment, allow patients to exit after only 4-9 seizures, allow enrollment of patients with rare seizures, and also allow minimal placebo exposure in children.”

She said, “With such a trial, you would start by picking a dose and seeing if it works. If it doesn’t work, people drop out of the study, but there is always a base because the group that remains is still able to be counted. Non-responders drop out quickly in both groups,” she said, “thus allowing super-responders (the ones you really want on the drug) to remain behind.”

This may be a useful alternative endpoint for clinical trials to demonstrate an AED’s treatment effect. She said, “One of the potential advantages of this model will be in reducing clinical trial duration from 16 weeks to 6 weeks.”

In commenting on the “Time to the Nth seizure” model, Dr. Dichter said: “If I were in charge of everything, and had enough resources available to me, I would look for compounds that worked against animal models of refractory epilepsy and test them in a more stringent manner. We would need a consortium of 10 centers, with a large number of potential patients with refractory epilepsy. We would try the first drug and the placebo with a "Time to the Nth" seizure trial. Once a set number of subjects dropped out of the trial, we would move to the second drug. The advantage is that we would be able to test drugs sequentially, get an answer relatively quickly for each agent with minimal exposure to ineffective medications and be able to accumulate a large control group quickly. Since the trial would continue in a consistent manner, the control group for each study could be cumulative.”

Dr. Dichter discussed what he called his science fantasy approach. “In my science fantasy approach I would rethink how much it costs to get a drug from the laboratory in Phase I. It is about $5 million per compound. For $100 million we could be testing 20 drugs using the new models.”

Monotherapy and Device Trials

Other major issues discussed included monotherapy and device trials. With regard to monotherapy, talks focused on: Options for approval of AEDs as monotherapy in the US and Europe; Active control trials; and How to approach monotherapy.

A heated discussion followed with Martin J. Brodie, MD, Professor of Medicine and Clinical Pharmacology, University of Glasgow, at the helm. This segment – and all segments -- will be available for viewing on www.epilepsytdp.org in the coming weeks.

Device trial discussions focused on the perspectives of both the investigator and the Food and Drug Administration (FDA) and ended with a review of difficulties in recruitment of subjects for device trials.

Acceptability of New Approaches

Russell Katz, MD, from the FDA, seemed to agree with the need for a new design and said that “"Time to the Nth" seizure appears to be possible and doable, but will require more consideration.” Dr. Katz is Director of the Division of Neurology Products, Center for Drug Evaluation and Research, FDA. He added, “Some trials are uninterpretable. However, this design is designed to show a difference, which is interpretable.”

In talking with epilepsy.com Dr. Katz said, “This conference gives me information that I can take back with me to the FDA. And it is important to learn what is happening in the epilepsy community. There is a lot we can learn. And being here gives me the opportunity to go back to my colleagues at the FDA and say, ‘I was there. I saw this. I heard this. Let’s put our heads together.’ We do this because we are all working towards the same goal,” he concluded.

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