SILVER SPRING, Md. – In a unanimous vote, a federal advisory panel on Aug. 11 agreed that the antiepileptic drug ezogabine had been shown to be effective as adjunctive therapy for partial onset seizures, but recommended that treated patients be closely monitored for the development of urinary retention.
At a meeting the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee also voted 11 to 0, with 2 abstentions, that they agreed that the risk of urinary retention could be mitigated by monitoring patients, pointing out the importance of educating clinicians in how to properly evaluate patients for changes in urinary symptoms. But none of the panel members thought that the urologic or other safety issues associated with ezogabine should preclude the approval of the drug for the proposed indication, as an adjunctive treatment of patients aged 18 and older with partial onset seizures with or without secondary generalization.
The panel was not asked to vote specifically on whether to recommend approval. The recommended starting dose is 300 mg per day, increasing at weekly intervals by a maximum of 150 mg/day, to a maximum dose ranging from 600 mg to 1,200 mg per day (daily dose is divided into three divided doses per day).
If approved, ezogabine would be the first neuronal potassium channel opener for treating epilepsy, according to the manufacturer, Valeant Pharmaceuticals Inc. Neuronal potassium channels “play a major role in the control of neuronal excitability,” according to the company’s background materials.
The three pivotal trials were international, randomized, 24-26 week studies comparing ezogabine (600 mg/day, 900 mg/day and/or 1200 mg/day, in three divided doses) to placebo, as add-on therapy, in about 1,200 patients, aged 16-75 years (their mean age was 35-38 years), who experienced at least four seizures over a 28-day period, with or without secondary generalization, despite treatment with one to three AEDs. (About 800 patients were on ezogabine and 75% were on two or more AEDs.)
In the studies, the primary end point – the percent reduction from baseline in partial seizure frequency over 28 days – was significantly greater among those on ezogabine, compared with placebo. Reductions in the frequency of seizures ranged from 35% to 44% among those on the 1,200 mg dose, 29%-40% among those on 900 mg/day, and 23%-28% among those on the 600 mg dose, compared with 13%-18% among those on placebo.
As with other AEDs, central nervous system-related side effects were the most common adverse events in the pivotal trials, and included dizziness and somnolence; they were generally related to dose, affected patients early in treatment and were the most common cause of discontinuation of the drug. Discontinuation rates in the study were high, which the company attributed to the forced titration design of the study.
Urinary effects, which were observed in animal studies and are attributed to the drug’s inhibition of the contractility of bladder smooth muscle, were more common among treated patients. In the phase III studies, voiding dysfunction and urinary retention were reported in 5% of patients on all doses, compared with 3% of those on placebo, but there was no association with urinary tract infections, according to the company. Among the 1,365 patients who received the drug in phase II/III trials, there were four cases of urinary retention that required catheterization in treated patients, (compared with 1 patient on placebo) in phase II/III studies, all resolved once treatment stopped, except for one patient who required intermittent catheterization.
Other adverse events that were more common in treated patients included hallucinations and psychosis, and abnormal liver function tests, which were infrequent. There was a slight, transient QT prolonging effect of the drug seen in healthy volunteers titrated to 1,200 mg/day, but there was no clinical evidence of QT prolongation in clinical studies.
Valeant plans to study real-world safety in a prospective postmarketing study in the United States and has proposed a risk management plan to address the potential risks of the drug, which includes instructions to clinicians to “consider the potential effects in the bladder when deciding for whom the drug is appropriate” and a medication guide for patients explaining the potential risks associated with treatment, including how to recognize signs of urinary retention.
The FDA is expected to make a decision on approval by Aug. 30.
If approved, Valeant plans to market ezogabine as Potiga. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.