There is one possible drawback, Moskowitz says: "As a twice-daily injectable, its growth could be slowed by resistance to the delivery system." There is also competition coming. Novo Nordisk has its own GLP-1 agonist Liraglutide (NN-2211) in Phase II, and Merck and Novartis are working on oral agents with a similar mechanism of action (MOA). An NDA was filed in June and was accepted for review by FDA in September. A decision is anticipated by the end of first quarter 2005.

A treatment for insomnia, a condition that affects 40 percent of US adults, indiplon is a second-generation nonbenzodiazepine sedative hypnotic that functions as a GABA_A receptor agonist. Its mechanism of action is similar to Sanofi-Aventis' best-selling Ambien (zolpidem), Jones Pharma's Sonata (zaleplon), and Sepracor's forthcoming Estorra (eszopiclone). But indiplon, perhaps because of its tendency to bind selectively with the alpha-1 subunit, believed to be the specific subsite responsible for promoting sleep, has shown little, if any, residual hangover effects or evidence of withdrawal or rebound insomnia. In addition to its clean side-effect profile, indiplon's biggest advantage may be Neurocrine Biosciences' choice of marketing partner: Pfizer. The two are collaborating on clinical development and promotion in the United States. Pfizer has exclusive rights to market and develop indiplon elsewhere. An NDA for indiplon IR (immediate release) was filed in October and one for a modified release formulation last month. A decision is likely in the middle of 2005.

One of three carryovers from last year's Pipeline Report—it topped the list—lasofoxifene is a potent, non-steroidal, tissue-selective estrogen receptor modulator (SERM) being tested for the prevention of postmenopausal osteoporosis and breast cancer. Unlike estrogen, which inhibits bone loss but raises the risk of uterine cancer, it shows signs of being an anti-cancer agent. Discovered by Ligand and Pfizer, the drug is being developed by Pfizer under license in accordance with the resolution of a contract dispute.

An NDA was submitted in October for postmenopausal osteoporosis, and a product launch is forecast for 2006-2007. Phase III trials are under way to test its effectiveness in reducing the risk of breast cancer, vertebral fractures, and cardiovascular disease.

Pharmaceutical Executive Pipeline Report

Torcetrapib "inhibits cholesteryl ester transferase protein (CETP), an enzyme responsible for LDL-mediated control of cholesterol synthesis," Samet explains. Now in a massive Phase III study—the largest clinical trial ever—torcetrapib, in combination with Lipitor, boosted HDL by 60-100 percent. But this, Samet points out, "required twice-daily dosing, which may slow the launch of a combination pill." However, he adds, "There are few drugs near the market that can significantly elevate HDL, which provides a unique marketing advantage for Pfizer's franchise." Winton Gibbons, an analyst at William Blair & Co. agrees: "The marketing advantage is all Pfizer's. Roche has no statin with which to package JTT-705, the HDL-raising drug it in-licensed from Japan Tobacco—though it could conceivably make a deal for one." What's more, he says, "Results of Phase II tests showed that Lipitor and torcetrapib had genuine synergy: Patients' lipid profiles were better when the drugs were taken together than when taken alone." Finally, Gibbon says, "Lipitor already has a broad claim to prevent cardiovascular disease in its original label, while Roche will have to earn it at considerable expense and over time." An NDA filing is expected before 2006.