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NEW STUDY REPORTS LACOSAMIDE IS EFFECTIVE AS ADD-ON THERAPY FOR EPILEPSY

ARTICLE IN BRIEF

✓ In a placebo-controlled trial, 41 percent of patients taking 400 mg of lacosamide experienced a 50 percent reduction in seizures, a statistically significant finding.

SAN DIEGO—The ideal therapy for epilepsy silences seizures without unbearable side effects.

“We have done that for most people with epilepsy, but 15- to 25-percent of people with epilepsy still need more than we can offer,” said Gregory Barkley, MD, clinical vice chairman of the department of neurology at Henry Ford Health System in Detroit.

“That's why we keep looking for more drugs that can do the job better, and fortunately there are several candidates in the pharmaceutical pipeline,” he said here at the first North American Regional Epilepsy Congress in December. The conference was jointly sponsored by the American Epilepsy Society, the Canadian League Against Epilepsy, and the Jamaica chapter of the International League Against Epilepsy.

“The furthest along the pipeline as far as new drugs are concerned is lacosamide,” said Martin Brodie, MD, professor of medicine and clinical pharmacology at the Western Infirmary at the University of Glasgow in Scotland.

Lacosamide has been developed by Schwarz Biosciences of Raleigh, NC, as a treatment for epilepsy and the neuropathic pain of diabetes patients.

STUDY PROTOCOLS

One study highlighted here at a special session indicated that lacosamide was effective as an add-on agent in reducing the frequency of seizures. The trial included patients from 12 European countries and Australia. Peter Halasz, MD, PhD, professor of neurology at the National Institute of Psychiatry and Neurology in Budapest, Hungary, enrolled 477 adults with partial seizures uncontrolled by their current medication. The researchers assigned 159 patients to placebo, 160 patients to lacosamide 200 mg/day, and 158 patients to lacosamide 400 mg/day.

After 28 days, a 50 percent reduction in seizures was reported for 25 percent of controls; 35 percent of patients on 200 mg; and 41 percent of patients on 400 mg lacosamide. The difference between the highest dose of lacosamide and placebo reached statistical significance at the p<.01 level, Dr. Halasz said.

“Being seizure-free is of tremendous importance to patients,” said Dr. Barkley, who was not involved with the trial. “In Michigan, if you have one seizure, you can't drive an automobile for six months. That has a terrific impact on a person's quality of life. That's why reducing the number of seizures-while important to the patient's health - is still far from being seizure-free.”

SIDE EFFECTS

Diplopia and vomiting were the most frequent adverse events that led patients to drop out of the trial, including five percent of the placebo group, 6 percent on lacosamide 200 mg, and 16 percent on the 400 mg dose.

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Dr. Gregory Krauss said that lacosamide is being developed for oral and intravenous administration, so that patients who cannot swallow because of an acute seizure or for other reasons have an alternative therapy.

“However, no clinically relevant influence of lacosamide on laboratory values, vital signs, or body weight were observed,” Dr. Halasz said. “No clinically relevant influence of lacosamide on the electrocardiogram was observed, either.”

Another author of the paper, Felix Rosenow, MD, professor of neurology at the University of Marburg in Germany, noted that lacosamide was given to patients who had uncontrolled seizures despite trying numerous other anti-epileptic medications.

Dr. Rosenow said the exact mechanism for lacosamide in seizure relief “is not really well understood.” Preclinical work conducted by Schwarz Pharma suggests a duel mode of action for lacosamide, however.

Unlike traditional anticonvulsants that affect sodium channel fast-inactivation, lacosamide is believed to selectively enhance slow-inactivation, reducing abnormal neuronal transmission in the brain. Lacosamide may reduce pathological hyperactivity of neurons without disrupting normal physiological activity.

In addition, investigators speculate that lacosamide acts on collapsing-response mediator protein 2 (CRMP-2), a protein involved in axonal growth and neuronal plasticity. The interaction of lacosamide with CRMP-2 may prevent the formation of abnormal neuronal connections in the brain. This interaction could have a possible effect on the underlying disease.

“The reason we need more antiepileptic drugs,” Dr. Brodie explained, “is because when a drug doesn't work or stops working for one reason or another, all the other drugs that work in the same fashion tend not to work in that patient either. This is why there is so much excitement about lacosamide and some other drugs that have novel mechanisms. We think these drugs will become useful in patients for whom we have nothing to offer right now.”

ORAL AND INTRAVENOUS ADMINISTRATION

Lacosamide is being developed for oral and intravenous administration, so that patients who cannot swallow because of an acute seizure or for other reasons have an alternative therapy.

Gregory Krauss, MD, associate professor of neurology at Johns Hopkins University in Baltimore, led a research team that enrolled people who were taking the oral form of lacosamide and were then switched to an intravenous preparation.

“The switch from oral to intravenous form for patients in the hospital was seamless,” said Dr. Krauss.

He enrolled 160 patients who were receiving oral lacosamide and switched them to the intravenous form of the drug in either a 30-minute infusion tested by 40 patients; a 15-minute infusion tested by 100 patients; or a 10-minute infusion tested by 20 patients.

The only serious adverse side effect in the trial was an episode of bradycardia in one patient on the second 15-minute infusion. The arrhythmia resolved after four minutes, but the patient was discontinued from the study.

Two patients in the 10-minute infusion reported upper abdominal pain. That complaint was not reported in the 15-minute infusion patients or in the 40-minute infusion patients.

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Dr. Gregory Barkley: “In Michigan, if you have one seizure, you cant drive an automobile for six months. That has a terrific impact on a persons quality of life. Thats why reducing the number of seizures — while important to the patients health — is still far from being seizure-free.”

“Lacosamide solution for Intravenous infusion at 10 mg/mL is being developed as short-term replacement for oral lacosamide,” Dr. Krauss said.

“In this trial the safety profile for lacosamide solution for intravenous infusion was comparable to oral lacosamide tablets based on analysis of adverse events, electrocardiograms, viral signs, laboratory results, and seizure counts,” Dr. Krauss said. He said likely candidates for the short course of the intravenous treatment would be in-hospital patients who suddenly begin to have seizures or those who come to the emergency department.

Dr. Rosenow said that some of his patients responded dramatically to lacosamide. “I had two patients who were not being helped by anything,” he said. “They were having as many as 40 seizures a day. When we put them on lacosamide their seizures decreased to less than one a day.”

“We have all seen patients,” said Dr. Barkley, “who could not control seizures despite numerous medicines and then when we gave them the right medication, it was like flicking a switch.”

The researchers said they expect that lacosamide could become available some time in 2007 or 2008, depending on company and regulatory hurdles.

“Assuming lacosamide is approved by the FDA, I would anticipate using it in my practice,” Dr. Barkley said.