Washington Editor

WASHINGTON – Investors were relieved Monday after FDA reviewers said Valeant Pharmaceuticals International Inc.'s experimental epilepsy drug Potiga (ezogabine/retigabine) was effective as an adjunctive treatment for partial onset seizures.

Shares of the Aliso Viejo, Calif.-based specialty drugmaker (NYSE:VRX), which is developing Potiga under a 2008 deal with London-based GlaxoSmithKline plc, gained $2.27, to close at $59.38. (See BioWorld Today, Aug. 29, 2008.)

Shares of Biovail Corp. (NYSE:BVF), which reported in June that it was merging with Valeant, also benefited from the mostly positive review of Potiga, with the Toronto-based company's stock closing at $23.09, a gain of 68 cents.

Potiga also is known under the scientific name retigabine, which was changed in the U.S. earlier this year to ezogabine after the FDA raised concerns about its orthographic and phonetic similarity to UCB SA's Parkinson's disease drug rotigotine, whose trade name is Neupro.

While Potiga's efficacy looked good, the FDA reviewers raised concerns about urinary retention, or the inability to urinate, which regulators called a "significant safety issue."

The urinary tract was noted to have been the site of Potiga-induced toxicity in rodent studies, with some of the animals developing distended bladders, while others developed renal lesions thought to be secondary to urinary retention, said Russell Katz, director of the FDA's Division of Neurology Products.

Those findings were considered to have been the result of the pharmacologic action of Potiga on potassium channels, and therefore, specific monitoring of urinary function was undertaken in clinical trials of the drug, Katz noted in briefing documents released Monday ahead of Wednesday's meeting of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee.

In Potiga's controlled trials, there were five serious adverse events (SAEs) in four patients treated with the drug related to the urinary system, compared with one in the placebo group.

The five Potiga urinary system-related SAEs included renal colic, urinary retention, atonic bladder, renal failure and urinary incontinence.

The patient with renal failure, who withdrew from Valeant's study, was a 53-year-old woman whose symptoms of myalgia, cough, polydipsia and sweats began on the 23rd day of taking Potiga 600 mg/day, FDA reviewers noted.

After the drug was discontinued, however, her laboratory values returned to normal several days later, regulators said.

The other patient who withdrew from Valeant's study, a 34-year-old woman who experienced atonic urinary bladder on day 21 of Potiga 600 mg/day and urinary incontinence on day 63, also had normal bladder sensation after discontinuing the drug, the FDA's documents showed.

Katz noted that four other patients withdrew from treatment for signs and symptoms attributed to the urinary system, with one of those cases related to urinary retention.

Urinary retention made up 1.9 percent of the adverse urinary system events in the Potiga Phase II and III studies, with others events consisting of urinary tract infection (7.7 percent), urinary hesitation (3.1 percent), abnormal urinalysis (2.6 percent), dysuria (2.4 percent), hematuria (1.8 percent), chromaturia (1.7 percent), polyuria 1.6 percent and residual urine volume (1.1 percent).

"The data clearly establish ezogabine's capacity to produce urinary retention that in most, though not all, cases was shown to be reversible," Katz said.

He said regulators were particularly interested in the committee's view of that safety signal and whether Valeant and GSK have identified means to monitor for urinary retention so that it can either be prevented or, if it occurs, kept from becoming irreversible.

Katz noted that the firms have insisted the risk of urinary retention could be mitigated with monitoring and through the use of a medication guide that would alert patients to the signs and symptoms of the condition.

"We will be interested in the committee's view of the adequacy of the sponsor's overall program to mitigate the risk of urinary retention," Katz said.

Other potential safety concerns noted in the FDA's review included arrhythmias, especially atrial fibrillation – which seemed to be most prominent in a trial of patients with post-herpetic neuralgia – and QT prolongation.

FDA's reviewers found no evidence of a signal for increased suicidality in the Potiga-treated patients – a risk that has been noted with other epilepsy drugs.

There was an apparent relationship between the incidence and randomized dose of Potiga for overall adverse cognitive events, confusion and memory-related events, in addition to adverse events related to speech, the FDA's scientists said.

But they said there was "substantial" evidence of Potiga's effectiveness demonstrated in the firm's "adequate and well-controlled clinical trials."

Partial onset seizures are the most common type of seizure in adult patients with epilepsy.

While there are many epilepsy drugs approved on the U.S. market, Valeant argued that many patients are "not adequately treated with currently available options," estimating that nearly one-third of patients have either intractable or uncontrolled seizures or have significant adverse events secondary to medication, limiting their ability to appropriately control their epilepsy with current therapies.

"The high empiric failure rate with existing drugs due to lack of efficacy, adverse events and drug interactions supports the need for new treatment options for patients with epilepsy," the company said in separate documents released Monday.

Valeant, which filed its new drug application with the FDA last October, with a safety update submitted in February, noted that Potiga's pharmacological profile is different from currently approved epilepsy drugs.

Potiga's primary mode of action is at the KCNQ, or Kv7, ion channels.

While neuronal potassium-gated channels play a major role in the control of neuronal excitability, currently marketed epilepsy therapies have minimal to no effects on those channels, Valeant claimed, adding that its drug is the first neuronal potassium channel opener developed for the treatment of epilepsy.