About a year after receiving an approvable letter, Neurocrine Biosciences Inc. resubmitted its new drug application for 5-mg and 10-mg capsules of immediate-release indiplon in adult and elderly insomnia.

Neurocrine President and CEO Gary Lyons told BioWorld Today he expects the review to take about six months and does not anticipate a panel meeting. If approved, indiplon could be launched in early 2008. San Diego-based Neurocrine is in the process of finding a partner to support such a launch, and Lyons said the company has had "preliminary discussions with a number of interested parties."

Aaron Reames, analyst with A.G. Edwards & Sons Inc., said starting from an approvable letter "certainly increases the odds" of getting an approval, but cautioned that no one knows exactly what the FDA's concerns were. He added that most people thought indiplon would be approved the first time around, given that the drug had hit its primary endpoint in 72 studies and was partnered with Pfizer Inc.

Instead, the FDA delivered an approvable letter for the indiplon 5-mg and 10-mg immediate-release capsules and a non-approvable letter for the 15-mg modified-release tablet formulation. The unexpected setback shaved 62 percent from Neurocrine's market cap and prompted Pfizer to abandon the partnership. (See BioWorld Today, May 17, 2006, and June 26, 2006.)

"There is clearly something we don't know that the FDA sees in the data," Reames said.

The approvable letter for the immediate-release capsules requested a reanalysis of 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 and a revised display of the adverse-event table. Earlier this year, Neurocrine announced that additional trials would not be required to address those issues. The NDA resubmission instead relies on analyses discussed with consultants and in Neurocrine's interactions with the FDA. (See BioWorld Today, Jan. 24, 2007.)

The non-approvable letter for the modified-release tablets was more complex, requesting a reanalysis of certain safety and efficacy data, a longer-term sleep lab study and the identification of an elderly patient dose. Reames projected that approval could take several more years and noted the "vast majority of the market opportunity" is in the modified-release formulation, which could be indicated for sleep maintenance. (See BioWorld Today, June 19, 2006.)

Indiplon selectively acts at a subtype of the GABA-A receptor, which Lyons said allows the drug to be "a lot more potent" while causing fewer side effects. If approved, it will compete against other GABA-modulating drugs like Lunesta (eszopiclone, Sepracor Inc.). Ambien CR (zolpidem tartrate extended-release, Sanofi-aventis Group) also targets a specific area of the GABA receptor, as does a Phase II insomnia drug from Neurogen Corp. Evotec AG also has a Phase II GABA modulator in development.

Reames said the main difference between the various GABA drugs is their half-life. For example, Lunesta has a six-and-a-half-hour half-life, while immediate-release indiplon's half-life is one and a half hours, he said. That makes indiplon less applicable to sleep maintenance but more applicable for those who need middle-of-the-night dosing, similar to Sonata (zaleplon, King Pharmaceuticals Inc.).

Beyond the GABA modulators, several biotechs are developing insomnia drugs that target serotonin receptors. MediciNova Inc. is in Phase II with a 5-HT1A agonist, while Arena Pharmaceuticals Inc. is in Phase II with a 5-HT2A antagonist and Acadia Pharmaceuticals Inc. has completed a proof-of-concept study with a 5-HT2A inverse agonist. Hypnion Inc., recently acquired by Eli Lilly and Co., had completed a Phase II trial with its drug targeting histamine H1 and serotonin 5-HT2A.

Also in the insomnia space is Vanda Pharmaceuticals Inc., which reported positive Phase III data with the melatonin agonist VEC-162 late last year.

Although indiplon tends to get most of the attention, it isn't the only drug in Neurocrine's pipeline. The company expects to complete enrollment in a Phase IIb endometriosis trial with NBI-56418, its small molecule Gonadotropin-Releasing Hormone (GnRH) receptor antagonist, in the third quarter of 2007, with data due in the first quarter of 2008. A Phase II trial in congestive heart failure with an extended infusion of NBI-69734, which mimics urocortin-2, is slated to begin around the end of the year. And Phase I data in neuropathic pain with a Selective Norepinephrine Reuptake Inhibitor (sNRI) are due next month.

Neurocrine and partner GlaxoSmithKline plc also are conducting multiple Phase II trials in irritable bowel syndrome and social anxiety disorder with a Corticotropin-Releasing Factor receptor (CRF-R) antagonist. Data from those trials should begin trickling in late this year and early next. An additional lead compound from the program is in Phase I studies.

Neurocrine reported $166.8 million in cash, equivalents and investments as of March 31. Lyons said the company expects to burn about $80 million in 2007, but potential partnerships and the refinancing of a building could be expected to "replenish" that cash burned.

Shares of Neurocrine (NASDAQ:NBIX) dipped 19 cents on Wednesday to close at $12.43.