Washington Editor

The long-anticipated sleep drug indiplon probably will need further studies in the wake of recent approvable and not-approvable letters from the FDA.

That was the message delivered Friday by Neurocrine Biosciences Inc., the San Diego company behind the investigational product that plans to amend its financial guidance as a result.

Those admissions drove down its shares (NASDAQ:NBIX) by $4.19 Friday, or 21.6 percent, to $15.18. That represents a 52-week low, and is well off the stock's high value of $73.13 over the past year.

The company has requested a meeting with the FDA to go over the month-old action letters and a briefing document that articulates Neurocrine's understanding of the issues communicated by the agency. President and CEO Gary Lyons said the meeting should "clarify the action letters that we received" and help the company "whittle down" what deficiencies, if any, must be addressed.

An application for immediate-release indiplon capsules of 5 mg and 10 mg received an approvable letter, while a separate submission for a 15-mg dose of extended-release tablets received a not-approvable letter. Those communiqués caused a stock drop of nearly two-thirds that day, from $54.63 to $20.76. (See BioWorld Today, May 17, 2006.)

Since the company believes many of the FDA's concerns can be allayed through a re-examination of existing datasets, the meeting would allow "us to identify and understand any issues that remain," he told BioWorld Today. Neurocrine contacted the agency just days ago, so both parties should likely get together later this summer.

The company conceded that the FDA likely would require additional clinical data on the extended-release tablets, representing a delay of at least two years, industry analysts have said. That's troubling for investors, given that many of those analysts have projected that the lion's share of total indiplon sales would come from that formulation. The agency also might mandate more clinical and/or preclinical safety data for the 5-mg and 10-mg capsules.

Should any additional studies be required, Pfizer Inc. would shoulder those costs, per terms of its partnership with Neurocrine. Lyons noted that the New York pharmaceutical firm has been "very helpful" in dealing with this situation in recent weeks, despite speculation that Pfizer could terminate the arrangement. Lyons said he wouldn't expect any change in the partnership before the FDA meeting, if at all.

For his comapny's part, he said Neurocrine remains "100 percent" committed to indiplon.

The not-approvable letter, which requested that Neurocrine reanalyze certain safety and efficacy data, also questioned the sufficiency of the application's objective sleep maintenance clinical data with the 15-mg tablet given that the majority of studies were conducted with higher doses. The extended-release submission also comprised 20-mg and 30-mg doses, but recommended the 15-mg tablet because its efficacy was on par with the higher doses with a "cleaner safety profile," Lyons said. He added that the FDA has yet to see data from a 100-patient sleep maintenance study conducted in a sleep laboratory. The results, he said, were "highly statistically significant in extending sleep duration."

The approvable letter requested that the company reanalyze data from certain preclinical and clinical studies to support approval for sleep initiation and middle-of-the-night dosing, as well as a re-examination of the safety analysis in the elderly.

Neurocrine said it believes that information included in the original submissions and subsequent amendments filed during the review period have provided responses to a number of the issues raised in the FDA's letters. The amendments include reanalysis of certain data for indiplon capsules and a polysomnographic clinical study with the 15-mg tablets.

The company, whose management expressed surprise upon first receiving the action letters, already notified the FDA that it would amend further both applications to respond to any deficiencies.

Neurocrine began filing its new drug application for immediate-release indiplon a year and a half ago, followed soon after by a separate submission for the extended-release formulation. The product's Phase III program included 16 trials, and its total clinical development involved more than 8,000 patients. (See BioWorld Today, Oct. 20, 2004.)

The drug, a non-benzodiazepine agent, is partnered with Pfizer in an agreement worth up to $400 million. Neurocrine, which received a quarter of that amount at the outset, stood to receive a $30 million milestone payment had the immediate-release capsules been approved and a $75 million milestone payment for the extended-release tablets. (See BioWorld Today, Dec. 20, 2002.)

Indiplon was discovered by Madison, N.J.-based Wyeth, and two years ago Neurocrine paid $95 million in cash and stock to buy out Wyeth's interest. (See BioWorld Today, March 1, 2004.)