by Joyce Cramer, President, Epilepsy Therapy Project

(Edited by Robert Fisher for epilepsy.com)

The biennial conference devoted to clinical trials on antiepileptic drugs: "Antiepileptic Drugs-10," was held in Coral Gables, FL, on April 15-17, 2009. The conference gathered physicians, researchers, industry representatives, venture funders and FDA personnel with interests in epilepsy. The goal was to review the current state of affairs of epilepsy drugs and devices and to see what is coming down the pipeline.

Epilepsy experts discussed everything from animal models to how to predict whether drugs would stop seizures, to patient recruitment for clinical trials. The conference was a lively review of review of mechanisms of action, types of preclinical and proof-of-principle drug testing, and of thorny issues related to later stage clinical trials for regulatory approval.

Preclinical Development

The increasing number of animal models with good resemblance to human epilepsy is bringing us to models that apply to human disease. Longstanding evidence that head injury creates a high risk for development of epilepsy has led to a recent surge of interest in preventive treatment for post-traumatic seizures. Approaches to protecting the brain and preventing epilepsy after head injury are high priorities for epilepsy researchers.

Clinical Trial Endpoints

The conference discussed the best endpoint for documenting that a new seizure drug is working. Currently, most trials either count numbers of seizures and look at the mean (average), median (the point for which numbers of seizures are half are above and half below) or number of patients whose seizures are cut in half or better (responder rate). A new method was discussed as being better in some circumstances, namely measuring the time to the 1st, 2nd, 3rd, etc. seizure. Among other advantages, it allows quick discovery of ineffectiveness for trial participants, so they can exit the trial and try something else.

Device Trials

Many of the estimated one million people in the USA with treatment-resistant epilepsy may benefit from devices that stimulate the brain to prevent or abort seizures. The only currently approved device to reduce seizure frequency is the vagus nerve stimulator (Cyberonics), which stimulates a nerve in the neck. Several experimental brain stimulation devices, some in advanced stages of testing, were discussed. The FDA device reviewer provided the FDA perspective on devices. She noted that future devices that combine drugs or biologics with devices will require thoughtful evaluation to determine the efficacy and safety of all components.

Special populations

What pediatric syndromes should be studied? The child neurologists’ view of epilepsy often is based on age of onset. Historically, pediatric studies have focused on infantile spasms, Lennox-Gastaut syndrome and childhood absence epilepsy. Recent evidence that vigabatrin is useful for infantile spasms as a new treatment to ACTH for this disorder. Several drugs have been tested for efficacy in Lennox-Gastaut Syndrome, the most recent being rufinamide (Banzel). An NIH study comparing valproate (Depakote), lamotrigine (Lamictal) and ethosuximide (Zarontin) surprised many clinicians by showing superiority of ethosuximide. Unfortunately, the mixture of many different types of seizures in pediatric syndromes such as Lennox-Gastaut makes trials for specific seizure types harder to interpret.

Formulations and delivery systems

Although neurologists and professional organizations have spoken out against mandatory substitution of generic for branded epilepsy treatments, the laws in many states allow pharmacists to make these changes without physician approval. The problem is that generic drug suppliers change, and one generic may not be as well absorbed into the bloodstream as another. Frequent changing from one to another generic drug can lead to inadequate blood levels, resulting in breakthrough seizures.

Acute repetitive seizures (ARS) are clusters of seizures experienced by some patients. These events are less urgent than is status epilepticus, but ARS still require quick therapy. The benzodiazepines (lorazepam=Ativan, diazepam=Valium, midazolam=Versed) are classic treatments for rapid seizure control but usually are delivered by injection into a vein or muscle. A new concept is the use of nasal sprays to deliver a benzodiazepine. It is assumed that this approach would be more acceptable to patients than is the currently available rectal diazepam administration (Diastat, Valeant). Studies of ARS are complicated by the need to find the uncommon patients who experience sufficient clusters.

Patient recruitment in clinical trials

The number of patients appropriate for a typical clinical trial (having a minimum of four seizures per month) is decreasing for a variety of reasons. More patients may be controlled by the current medications or fewer patients are willing to enroll in trials. Altered inclusion criteria might increase the number of people eligible for a trial. Another approach is to perform studies globally, although this requires extensive assessment and training all investigators and coordinators all over the world.

Epilepsy pipeline review

The pipeline review was divided into sections based on stage of assessments, starting with the most advanced treatments (phase 3) and concluding with those in preclinical testing. Extensive information is available elsewhere about the efficacy and adverse effect profiles for the following antiepileptic drugs now in phase 3 testing (preparation for submission to FDA):

• Brivaracetam is similar in structure and mechanism to levetiracetam (Keppra). It may have fewer adverse effects than does Keppra.
• Carisbamate probably has multiple mechanisms of action. Its tolerability and adverse effect profile are good. Clinical trials are continuing to define efficacy against partial-onset seizures at the optimal dose.
• Eslicarbazepine is similar in structure to carbamazepine (Tegretol) and oxcarbazepine (Trileptal). Efficacy against partial-onset seizures and tolerability is good, likely without the safety concern of low blood sodium (hyponatremia) seen with related drugs. The drug has been approved for use in Europe.

The epilepsy field is entering an exciting time, when multiple new medications and probably several new devices, will become available. None is the “magic bullet” that we all want, but each will be something new to try, for people not experiencing satisfactory results with current therapy. The Epilepsy Therapy Project continues to strive to develop new treatments for epilepsy and to communicate the current state of knowledge to people who care about epilepsy. If you are among them, please support the cause by contributing at http://www.epilepsy.com/etp/donation.

You can register at http://professionals.epilepsy.com/page/mailinglist_signup.php to receive notices about other epilepsy conferences and scientific news.

Listen to an interview of Epilepsy Therapy Project (ETP) Chairman and Co-founder Warren Lammert, ETP President Joyce Cramer and Dr. Jacqueline French on the highlights of Pipeline Day at the conference.

Submitted April 29, 2009