Eyeing a sliver of light at the end of the drug development tunnel, Neurocrine Biosciences Inc. submitted a new drug application for indiplon immediate-release capsules for insomnia.

The submission marks the first FDA filing in the history of the San Diego-based company, and also begins the final process in moving the long-studied product toward the market.

Neurocrine has tested immediate-release indiplon in seven Phase III trials, results from which are included in the NDA. Such safety and efficacy findings stem from studies conducted in adult and elderly patients with transient and chronic insomnia. The company, which also is developing a modified-release tablet formulation, expects to submit a second NDA for that version next month.

But the first NDA contains the lion's share of material, including preclinical, clinical and manufacturing information that is common to both applications. It has been submitted in electronic common technical document format and includes data from a safety and efficacy evaluation of about 3,000 subjects.

"This is something we always expected to happen, and the fact that it's happened on time and the volume and extent of this NDA is substantial," Neurocrine President and CEO Gary Lyons told BioWorld Today. "It's certainly a landmark, and I think given the quality of it, the regulatory risk is minimal."

The FDA has 60 days to acknowledge the submission, after which the agency will have eight months to make its decision on a timeline established by the Prescription Drug User Fee Act.

Neurocrine said the condition of insomnia includes various types of sleep difficulties and symptoms, such as trouble falling asleep, trouble staying asleep or waking up frequently during the night. Studies have shown that indiplon capsules and tablets have demonstrated efficacy and safety in more than 70 clinical evaluations measuring those multiple parameters of sleep difficulties in about 8,000 patients.

That kind of success drew the interest of Pfizer Inc., which two years ago signed a deal with Neurocrine to market the drug, a non-benzodiazapine agent that acts on a specific site of the GABA-A receptor.

"Our real focus is on [market] growth in marketing this with Pfizer," Lyons said. "Pfizer is one of the better companies in developing markets, and this is a market we think is significantly underdeveloped."

He noted that of 85 million insomniacs diagnosed annually, only about 5 million receive non-benzodiazapine drugs such as the market leader Ambien (zolpidem, from Sanofi-Synthelabo SA, now Sanofi-Aventis Group). Others are treated through off-label use of antidepressants and anti-anxiety medications.

"We think that through patient awareness, direct-to-consumer advertising and physician education," Lyons added, "we can really develop the market through improved penetration and improved duration of therapy."

Longer term, he said the drug would be targeted to ease sleep-problem symptoms that arise as a secondary condition in patients with pain, anxiety, depression, menopause and rheumatoid arthritis.

The product, discovered by Madison, N.J.-based Wyeth, initially was the subject of a 1998 licensing agreement with DOV Pharmaceutical Inc., of Hackensack, N.J. DOV later licensed indiplon to Neurocrine, which eventually entered a $400 million deal with New York-based Pfizer to take it to market. (See BioWorld Today, July 10, 1998, and Dec. 20, 2002.)

Earlier this year, Neurocrine paid $95 million in cash and stock to buy out Wyeth's indiplon interest. Should indiplon reach the market, DOV would receive a royalty of 3.5 percent. (See BioWorld Today, March 1, 2004.)

Indiplon capsules have been shown to help patients fall asleep faster and have improved sleep quality and sleep duration. Phase III trials have shown that indiplon capsules can be taken during the night for patients who suffer from nighttime awakenings and have been shown to be safe and effective for long-term use. Data from two long-term Phase III studies proved that indiplon remains effective for at least three months and is associated with quality-of-life improvements for its users. (See BioWorld Today, March 25, 2004.)

The tablets are designed for sleep initiation, sleep maintenance and long-term use.

Given Neurocrine's parallel development of both formulations, Lyons said he believes the company has established one product that can be used to treat certain patients' needs while the other version is tailored for the requirements of others. Studies in various patient populations, each with different sleep problems, are expected to lead to a broad label.

"That was the reason this was such an extensive program," Lyons said. "If we had just tried to get the drug approved, it would have been a much quicker and simpler process."

Together the capsules and tablets have been tested in 14 Phase III studies, 13 of which have been completed. The remaining study, which is not required for approval, is testing a lower dose of the product.

Beyond indiplon, Neurocrine features a pipeline with eight products in clinical studies. Leading the pack are NBI-5788, a multiple sclerosis product enrolling a second Phase II study, and NBI-6024, a product for Type I diabetes that has completed Phase II enrollment. Data from both are expected by the end of next year, Lyons said.

Stepped slightly lower in the portfolio is NBI-428, a gonadotropin-releasing hormone antagonist entering Phase II to evaluate its ability to suppress estrogen and testosterone to treat endometriosis or benign prostatic hyperplasia. Urocortin is in Phase I development for congestive heart failure. A CRF1 receptor antagonist for depression, partnered with London-based GlaxoSmithKline plc, is about to enter Phase I.

On Tuesday, Neurocrine's shares (NASDAQ:NBIX) lost $1.34 to close at $45.82.

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