Allison Gandey

December 14, 2010

December 14, 2010 — The US Food and Drug Administration (FDA) has issued a complete response letter that will delay approval for the new antiepileptic drug ezogabine as an adjunctive treatment for refractory partial-onset seizures.

After the FDA decision, Valeant Pharmaceuticals announced December 13 that chair Bill Wells resigned from the board to pursue other interests. Robert Ingram has been named the new chair. Ingram has been on Valeant's board since 2003. He is a former executive of GlaxoSmithKline, which is codeveloping ezogabine with Valeant.

In the letter dated December 1, the FDA cited nonclinical reasons for refusing approval at this time, the companies said. They have not disclosed the specific problems identified by regulators, and the agency does not comment publicly on its reasons for rejecting drug applications.

Effects in ezogabine-treated patients from phase 2 and 3 studies and long-term open-label extensions.

However, nonclinical issues that delay approvals often involve label language or requirements for postmarketing studies and risk evaluation and mitigation strategies.

The companies submitted their new drug application more than a year ago. A standard FDA review takes 10 months, but the agency asked for an evaluation of the risks associated with the drug and later extended its review by another 3 months.

Valeant and GlaxoSmithKline say they plan to satisfy the FDA's concerns and will submit their response "as soon as possible in 2011."

The companies report ezogabine has a unique mechanism of action compared with other antiepileptics. Known as retigabine in Europe, it reportedly activates voltage-gated potassium channels in the brain and may also be an option of other neurologic conditions, such as migraine and neuropathic pain. The companies hope to market the product under the trade name Potiga.

Surprise Decision

The recent FDA response came as a surprise to many after the drug received a unanimous endorsement by the FDA's Peripheral and Central Nervous System Advisory Committee, which voted 11 to 0 with 2 abstentions in favor of approval for ezogabine.

This overwhelmingly positive vote was despite concerns the drug has been linked to toxic effects not usually seen with other antiepileptic drugs. The FDA's chief concern was urinary retention that has been reported with ezogabine. However, the advisory committee concluded this risk could be mitigated with monitoring.

In a new study presented at the American Epilepsy Society 64th Annual Meeting, investigators acknowledged ezogabine can exert a pharmacologic effect on bladder function.

"This is evidenced by voiding dysfunction and urinary retention–related adverse events," concluded the team led by Neil Brickel, MD, from GlaxoSmithKline.

The researchers assessed the renal and urinary effects in 1365 ezogabine-treated patients. Most patients were taking 900 to 1200 mg/day. The median total exposure was 261 days.

"The majority of these adverse events were mild, with most patients able to continue treatment without difficulties," they pointed out at the meeting in San Antonio, Texas. "However, caution should be taken in patients at risk of urinary retention."

'No Game Changer'

The investigators reported serious urinary retention in 4 patients and 5 people required bladder catheterization. Urinary hesitation led to discontinuation of treatment in 1 patient, and 6 stopped therapy because of retention.

"Urinary symptoms generally remitted following discontinuation," Dr. Brickel said, "suggesting reversibility consistent with a pharmacological effect."

The researchers conclude that although ezogabine may affect bladder function, leading to urinary retention in a small number of patients, the data do not suggest an irreversible effect on the bladder.

Andrew Wilner, MD, from Lawrence and Memorial Hospital in New London, Connecticut, who provides commentary and analysis for Medscape Neurology, says this drug, like the other new agents discussed at the meeting, will not likely alter the prescribing landscape.

"No game changers have yet appeared for epilepsy treatment," he said. We hope other agents will "fare better than ezogabine," he noted. "FDA approvals remain elusive."

This study was funded by Valeant Pharmaceuticals and GlaxoSmithKline. Dr. Brickel is an employee of GlaxoSmithKline.

American Epilepsy Society (AES) 64th Annual Meeting: Poster 1.272. Presented December 4, 2010.

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