Staff Writer

Neurocrine Biosciences Inc. reported positive results from the latest of its battery of Phase III trials of indiplon, its investigational insomnia therapeutic.

Data showed that the study of an immediate-release formulation of the drug achieved statistically significant results in primary and secondary endpoints of sleep initiation over about a month. Also, there was no evidence of next-day effects in the 200 chronic primary insomnia adult patients.

"This is our second Phase III and eighth positive study in a row," Neurocrine President and CEO Gary Lyons told BioWorld Today. "In all previous Phase II and Phase III trials, we have shown that the drug is very effective in putting people to sleep, but these have been one- or two-night treatment periods. This was the first longer-term trial we have done, and it showed that the sleep-initiation effect persisted and tolerance was not induced - a concern of people continuing to take medication."

The randomized, double-blind, placebo-controlled, parallel-group, multicenter study measured the safety and efficacy of 10-mg or 20-mg immediate-release indiplon capsules. Throughout the 35-day study, indiplon demonstrated a statistically significant improvement in the primary endpoint of latency to persistent sleep at both dose levels relative to placebo. Specifically, the 10-mg dose induced sleep 9.2 minutes quicker than placebo on the first two nights after dosing, as well as 9.5 minutes quicker on the 15th and 16th nights and 10.9 minutes quicker the 29th and 30th nights (p<0.01). The 20-mg dose induced sleep 9.8 minutes quicker than placebo on the first two nights after dosing, as well as 11.2 minutes quicker on the 15th and 16th nights (p<0.05) and 15.2 minutes quicker the 29th and 30th nights (p<0.01).

Both doses were well tolerated. In addition, side effects for the indiplon groups were no different from placebo and there were no statistically significant differences in next-day residual sedation detected by any of three validated measurements - visual analogue scale, symbol copy test and digital symbol substitution test - as compared with placebo.

Though the data, which stem from the second of eight planned Phase III studies of the drug, do not trigger a milestone payment from Neurocrine's development partner, Pfizer Inc., Neurocrine plans to file a new drug application early next year.

"We don't need to finish all eight, though we would like to," Lyons said. "But there are some trials that are not necessary for filing."

The San Diego-based company plans to file for approval of both immediate- and modified-release formulations of indiplon in a range of sleep disorder indications - sleep initiation, sleep maintenance, long-term treatment and middle-of-the-night dosing in adult and elderly patients (65 or older).

Licensed from Fort Lee, N.J.-based DOV Pharmaceuticals Inc. more than four years ago, the non-benzodiazepine acts on a specific site of the GABA-A receptor. (See BioWorld Today, July 10, 1998.)

The immediate-release formulation is part of a five-trial program, with two now complete. The remainder includes a one-year safety trial studying its long-term treatment in more than 500 chronic insomnia patients, a safety and efficacy study of two dose levels in about 600 chronic insomnia patients and a safety and efficacy study of two dose levels in about 360 elderly chronic insomnia patients. Results from the first two are expected in the third quarter, while findings from the latter are expected in the fourth quarter.

Three Phase III trials in a program studying a modified-release formulation of indiplon got under way last year. The modified-release program is focused on broadening the differentiation strategy for the indiplon franchise to include total sleep maintenance, with the studies including more than 1,300 adult and elderly sleep maintenance insomnia patients in a variety of settings.

"We have a three- to six-month efficacy trial with the immediate-release and a similar trial with the modified-release," Lyons said. "Those trials are intended to enable us to get a label that does not restrict the drug to short-term treatment. By showing efficacy out to three months, we believe we can get that claim."

Late last year, Neurocrine entered a potential $400 million global agreement for the exclusive worldwide development and commercialization rights to indiplon. New York-based Pfizer, which is funding the drug's ongoing development, will create a sales force at Neurocrine that eventually will sell indiplon and Pfizer's antidepressant drug Zoloft.

The deal carried with it a $100 million up-front payment to Neurocrine, followed by milestone payments worth up to $300 million, as well as undisclosed royalties on worldwide sales and co-promotion fees in the U.S. Milestones are based on clinical trial successes, as well as filings and approvals in the U.S. and other markets such as Europe and Japan. Pfizer will hold an exclusive license to develop and market indiplon abroad. (See BioWorld Today, Dec. 20, 2002.)

Just a month earlier Neurocrine released results from the first of the Phase III trial series, showing that an immediate-release formulation of the drug demonstrated a statistically significant improvement in its primary endpoint of latency to persistent sleep at dose levels of 10 mg and 20 mg relative to placebo (p<0.0001). (See BioWorld Today, Nov. 15, 2002.)

Outside of indiplon, Neurocrine's drug development efforts include a pair of Phase II products. A 190-patient study of its Type I diabetes candidate is expected to complete enrollment by the end of the year, and patient recruitment will begin this quarter for a 150-patient multiple sclerosis study.

Neurocrine's gonadotropin-releasing hormone small-molecule antagonist program for endometriosis, fibroids and prostate cancer includes a drug that recently completed a second Phase I study, while additional clinical candidates are expected to enter Phase I studies in July and November. Lyons said Neurocrine plans to select the most effective compound for Phase II development to begin next year.

The company also continues to develop a dopamine-selective agonist compound acquired from Peapack, N.J.-based Pharmacia Corp., which recently merged with Pfizer. Lyons said Neurocrine maintains full rights to the potential Phase II compound for erectile dysfunction.

A corticotropin-releasing factor collaboration continues with London-based GlaxoSmithKline plc with a Phase I compound that has completed two Phase I trials and additional preclinical candidates. Neurocrine also expects to license out a glioblastoma candidate from its interleukin-4 program ready for Phase III development.

The company's stock (NASDAQ:NBIX) ticked up 48 cents Tuesday to close at $43.65.