Washington Editor

Fresh out of its post-IPO quiet period, Orexigen Therapeutics Inc. has a lot to say about its obesity drug Contrave, a fixed-dose product that combines sustained-release formulations of bupropion and naltrexone. The San Diego biopharmaceutical company, which last month completed an $84 million initial public offering, has just moved Contrave into the second of four Phase III studies in hopes of eventually entering a developing landscape of medicines to address the growing problem.

"The market's size, the level of dissatisfaction and a significant consumer insight and interest in therapeutic alternatives," said Orexigen President and CEO Gary Tollefson, "all speak to why there is so much commercial interest in products in the obesity space."

The company's approach involves managing obesity through the central nervous system, specifically through sites in the hypothalamus that regulate appetite and energy use, while simultaneously avoiding unintended consequences. Failing to account for compensatory pathways when hitting one point in the brain's circuitry can spell doom, Tollefson explained, offsetting initial weight loss benefits by causing plateaus between 12 weeks and 16 weeks after treatment begins.

Contrave has been developed to overcome such a pitfall in the way its ingredients act to not only initiate weight loss but also sustain it. Bupropion, which is approved for depression and smoking cessation, stimulates neurons to reduce appetite and increase energy use. Naltrexone, which is approved for opioid addiction and alcohol addiction, prevents endogenous opioids from turning off the same neurons bupropion is stimulating through a natural feedback loop.

Tollefson said such a dual effect would lead "to a long, progressive reduction in weight," and do so safely, given the ingredients' long-known side-effect profiles and improvements in their formulations made by Orexigen.

He told BioWorld Today that the company expects to file for Contrave's approval in the second half of 2009. The registration program is evaluating a variety of obesity-related outcome measures, with the percent of weight loss from baseline to one year the four studies' primary endpoint plus secondary measures related to the metabolic cascade such as blood pressure and blood lipids, and behavioral aspects associated with obesity.

That newest Phase III trial will take 56 weeks to assess Contrave's safety and efficacy compared to placebo in a co-morbidity setting of about 525 obese Type II diabetics. They are being enrolled at 40 sites around the country to evaluate both weight loss as well as several factors related to glucose metabolism such as insulin sensitivity, blood sugar and hemoglobin A1c levels.

The first Phase III study of Contrave, which began in April, is looking at its weight loss potential alone or when combined with intense diet, exercise and behavior modification, compared to placebo, over the course of a year's treatment. About 800 subjects are being enrolled.

The third study, which has yet to begin, would seek to examine multiple Contrave doses against placebo to measure weight loss and impact on behaviors like mood and food cravings. Tollefson said the company has determined that a twice-daily tablet of 360 mg bupropion and 32 mg naltrexone is Contrave's optimal dose, but would like an alternative strength available to account for patient variability. A fourth study would seek to identify new dosing strategies in nonresponders and patients in whom benefits taper off to improve weight loss and keep it off.

In a previous Phase IIb trial, Contrave demonstrated statistically significant weight loss after 48 weeks of treatment compared to sustained-release bupropion, immediate-release naltrexone alone and placebo.

Further development efforts at Orexigen also are targeted at obesity, namely a Phase IIb product called Empatic. Formerly known as Excalia, it combines sustained-release bupropion and sustained-release zonisamide, a drug approved for treating epilepsy that inhibits certain neurons from increasing appetite and conserving energy.

According to the Centers for Disease Control and Prevention, about a third of Americans are obese and another third are classified as overweight, and both categories are growing. There is an association between obesity and increased risk of cardiovascular disease, diabetes, orthopedic problems, breathing issues and sleep loss, among others.

"There's a litany cascade of secondary medical complications," Tollefson said, and an accompanying "intense" interest in developing optimal solutions.

Multiple pharmaceutical options are marketed for weight loss, including versions of the lipase inhibitor orlistat sold as Xenical by Basel, Switzerland-based F. Hoffmann-La Roche Ltd. and Alli by London-based GlaxoSmithKline plc, as well as Abbott Park, Ill.-based Abbott Laboratories' monoamine re-uptake inhibitor Meridia (sibutramine). Paris-based Sanofi-Aventis Group's Acomplia (rimonabant) is under FDA review, and certainly countless others remain in various stages of development.

But Tollefson does not regard the market as overcrowded, given the belief that existing drugs leave patients underserved. He said they want better options, adding that the market "clearly can handle more than one therapeutic option." And given the heterogenous nature of obesity, "there's not going to be a silver bullet" singular approach to treating everyone.

Orexigen, which has all rights to Contrave and Empatic, might consider partnering the products down the road, but Tollefson said the company would "keep our options open as long as we can."

The company sold 7 million shares at $12 apiece in its IPO, and as of Tuesday, its stock (NASDAQ:OREX) continued to trade above that benchmark, tacking on $2.13 to close at $18.10.

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