ARTICLE IN BRIEF
✓ A new study reports a 50-percent reduction in the monthly frequency of partial seizures for participants taking retigabine at 600 mg (23.2 percent), 900 mg (31.6 percent), and 1,200 mg (33 percent), compared to 15.6 percent among control patients.
The first controlled study of retigabine for partial-onset seizures produced a strong dose-response curve, cutting monthly seizure frequency significantly more than placebo.
In the April 10 Neurology (2007;68:1197–1204), researchers reported that the median-percent change in monthly partial seizure frequency was −23.4 percent at 600 mg, −29.3 percent at 900 mg, and −35.2 percent at 1,200 mg. The rate for placebo was −13.1 percent (p = <0.001) for the overall differences in all treatment groups.
The patients had partial seizures ranging from eight to 10 per month on formerly prescribed medications. [See “Seizure Types.”]
The new drug was tested in a prospective, multicenter, randomized, double-blind, placebo-controlled trial of 396 treatment-resistant patients. The study included an eight-week baseline phase, followed by an eight-week titration phase, and eight-week maintenance phase.
Among trial participants, 86.9 percent had complex partial seizures and 14.9 percent had simple partial seizures with motor signs. All patients continued to take their other prescribed antiepileptic medications.
After the baseline phase, patients were randomized into four groups: a placebo arm, which included routine medications; and groups in which patients were titrated up to maintenance doses of 600, 900, or 1,200 mg per day of retigabine. Patients were titrated at 150 mg per day at weekly intervals.
In the 16-week treatment phase, there was a 50-percent reduction in the monthly frequency of partial seizures for participants taking retigabine at 600 mg (23.2 percent), 900 mg (31.6 percent), and 1,200 mg (33 percent), compared to 15.6 percent among control patients.
“These data demonstrate that retigabine, in its first controlled efficacy trial, has substantial efficacy for hard-to-treat partial seizures,” wrote Roger J. Porter, MD, and colleagues at Wyeth Research, which developed the drug.
[Dr. Porter was a vice president at Wyeth when he led the study and is now a consultant to Wyeth Research and Valeant Research and Development, which has two phase-3 studies in progress, including 800 to 900 patients. He is also an adjunct professor of neurology at the University of Pennsylvania.]
The study was not designed to determine which subgroups of treatment-resistant partial-seizure patients might do best on the drug, Dr. Porter told Neurology Today.
MECHANISM OF ACTION
“What we do know is that this drug has a brand new mechanism of action,” Dr. Porter said. “There are no other potassium channel openers on the market. For that reason, it may be an effective drug for patients with refractory epilepsy.”
Other antiepileptic drugs are sodium-channel blockers; they restrain cellular excitability by blocking the influx of sodium into the cells, Dr. Porter explained. Retigabine is the first drug that restrains cell excitability by opening voltage-gated potassium channels, he said, allowing for the outflow of potassium from cells.
The story behind retigabine dates back to the 1980s, when Dr. Porter was at the NIH studying flupertine, which was marketed for at least a couple of decades in Germany as an analgesic. He had studied the drug but found it ineffective as a possible antiepileptic.
Ultimately, German medicinal chemists rearranged the drug's molecular structure to see if the changes might boost its antiepileptic potency. The result was retigabine, which proved more effective in animal models of epilepsy than the old flupertine. But at that time, researchers didn't know about the new drug's unique mechanism.
Dr. Porter continued to work on retigabine at Wyeth Research from 1994 to 2000, taking it through to completion of phase 2 studies. During the early human studies, researchers discovered its novel mode of action, he said.
“Getting a dose response in the first (controlled) study tells people that we have a powerful drug for patients with epilepsy,” Dr. Porter said.
He added that the response rates were similar to two relatively new drugs — levetiracetam and zonisamide — that were tested using a similar study design to the retigabine trial.
Most adverse effects occurred during the titration phase, and CNS-related adverse effects were the most common. These included somnolence, dizziness, confusion, vertigo, tremor, amnesia, abnormal gait, and paresthesia (p < 0.05).
“The incidence of CNS-related symptoms seemed to be dose-related,” the authors wrote.
They occurred more frequently in the retigabine arms — 46 percent for the daily doses of 600 mg, 900 mg (60 percent), and 1,200 mg (76 percent) — compared with 32 percent in the placebo arm (p = 0.004).
Seventy-nine patients dropped out of the study because of adverse events: 17 patients in the group taking daily doses of 600 mg, 19 patients in the 900 mg group, and 31 patients in the 1200 mg arm, as compared to 12 patients taking a placebo. All but 10 percent of patients who reached the maintenance phase completed the study.
Patients at the maintenance phase who wanted to drop down by 100 mg or 200 mg per day because of adverse effects were permitted to do so, but Dr. Porter said few patients did that.
“We see no problems with the adverse effects. There is no indication that this drug wouldn't be satisfactory for long-term treatment,” said Dr. Porter, who is also an adjunct professor of pharmacology at the Uniformed Services University of the Health Sciences in Bethesda, MD.
“As far as I'm concerned, we hit pay dirt with the first study,” in terms of the positive outcomes and the side-effect profile, said Dr. Porter.
Commenting on the study for Neurology Today, Kimford J. Meador, MD, the Melvin Greer Professor of Neurology at the University of Florida McKnight Brain Institute, said that despite the positive results, “the ultimate impact is uncertain.”
“The novel mechanisms and the broad spectrum in animal models suggest that retigabine might be effective where other antiepileptic [AED] drugs are not,” he said. But he noted that “several AEDs with novel mechanisms have been introduced in the last 15 years, yet they have not had a major impact on the number of patients refractory to AEDs.”
Dr. Meador said that “the efficacy of retigabine in this study is generally similar to randomized clinical trials for other AEDs during development.” He pointed out that there were slightly more dropouts, which may be due to the aggressive titration schedule, and the higher doses were at the “upper end of tolerability.”
“Thus, it remains to be seen how retigabine ultimately compares to other AEDs,” Dr. Meador told Neurology Today.
“The side-effect profile is typical of other AEDs with reported adverse events being primarily CNS-related. Children and the elderly are at greater risk to such side effects,” Dr. Meador said. “However, the incidence of adverse events in the present study may be less with slower titration and longer maintenance therapy.”
“On the other hand,” he continued, “some side effects do not become apparent until many more patients are given a drug. More clinical studies and investigations including formal cognitive assessment will be needed to clarify these issues,” Dr. Meador said.
Also commenting on the study, Orrin Devinsky, MD, professor of neurology, neurosurgery, and psychiatry at New York University Medical Center, said: “Despite many new antiepileptic drugs during the past 15 years, uncontrolled seizures affect approximately 500,000 Americans. For retigabine, as for all new AEDs, the critical question is, will it help patients who were not controlled with other drugs? Because retigabine may have a novel mechanism of action on the K+ channel, it may be a valuable contribution to our therapeutic options.”
Dr. Devinsky agreed the efficacy profile is comparable to other effective AEDs, but added that cognitive and behavioral side effects are a concern. He focused particularly on the two higher-dose groups, where benefits over placebo were strongest, but also where the adverse effects were more common.
He agreed that slower titration could help prevent or minimize this effect. “Additional data on both efficacy and toxicity will be critical in assessing how valuable an agent retigabine may be.”
These preliminary data, though, suggest that retigabine deserves further study in larger clinical trials for patients with refractory partial epilepsy, Dr. Devinsky said.
Simple partial seizures result when the ictal discharge occurs in a limited and often circumscribed area of the cortex, the epileptogenic focus. Observable symptoms might include unilateral sensory disturbances as well as complex emotional, psychoillusory, hallucinatory, or dysmnesic phenomena — for example, feelings of unreality or detachment, déjàvu, and olfactory hallucinations. Patients can interact normally during simple partial seizures except for limitations imposed by the seizure on specific localized brain functions.
Complex partial seizures involve impaired consciousness and imply bilateral spread of the seizure discharge, at least to basal forebrain and limbic areas. Patients with complex partial seizures usually exhibit lip-smacking, repeated swallowing, clumsy perseveration of an ongoing motor task, or other complex motor activities that are undirected and inappropriate.
Source: Merritt's Neurology. 10th edition. pages 812–813.