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Orexigen Therapeutics Reports Preclinical Results Showing Contrave Acts on Specific Pathways in the Brain to Reduce Food Intake

SAN DIEGO--(BUSINESS WIRE)--Oct 23, 2007 - Orexigen(TM) Therapeutics, Inc. (NASDAQ: OREX), a biopharmaceutical company focused on the treatment of central nervous system (CNS) disorders including obesity, today presented the results of a preclinical study that further supports the Company's understanding of an aspect of the mechanism of action of Contrave(TM), one of its two late-stage obesity drug candidates. The findings showed:

-- The combination of bupropion and naltrexone resulted in a 94% reduction of food intake in obese mice, greater than either drug alone;

-- The drugs act in a part of the brain where food reward pathways are located;

-- The combination directly increased firing of neurons associated with reduction in food intake and satiety.

The data were disseminated in a poster presentation* at The Obesity Society's Annual Scientific Meeting (NAASO) being held in New Orleans, October 20-24, 2007.

"We originally theorized that the combination of bupropion and naltrexone, the components of Contrave, would stimulate proopiomelanocortin (POMC) neuronal firing which would lead to sustained weight loss. These new findings indicate that Contrave may also modulate food cravings through its effect on reward pathways," said Orexigen founder and Chief Scientific Officer, Michael Cowley, Ph.D. "We believe this aspect of Contrave's mechanism of action may have the potential to differentiate it from other pharmaceutical therapies available or in development for the treatment of obesity."

One study examined the effects of bupropion, naltrexone and the combination of bupropion plus naltrexone in both lean and obese mice. In lean mice, treatment with bupropion, naltrexone or the combination resulted in a 34%, 67% and 77% reduction of food intake, respectively. In obese mice, treatment with bupropion, naltrexone or the combination resulted in a 27%, 49% and 94% reduction of food intake, respectively. The interaction between bupropion and naltrexone appeared more potent in obese mice than in lean mice.

A separate study examined the effects of bupropion, naltrexone or the combination of bupropion plus naltrexone when they were selectively administered to the ventral tegmental area (VTA), a part of the brain that is often described as the center of "the reward pathway". This is the region of the brain that determines whether an environmental stimulus is rewarding or aversive. The combination of bupropion plus naltrexone in the VTA caused a statistically significant, synergistic reduction of food intake suggesting a possible connection to the behavioral aspects of obesity.

Contrave employs a proprietary formulation of two CNS molecules, bupropion and naltrexone, that have been independently approved by the US Food and Drug Administration in other indications. Orexigen chose these two constituent drugs based on the results of a proprietary screening model and the Company's understanding of circuitries in the brain that regulate appetite and energy balance. The unique combination of these molecules is designed to provide more clinically meaningful weight loss for patients by both initiating weight loss and sustaining it over a longer period of time.

About Orexigen Therapeutics

Orexigen Therapeutics, Inc. is a biopharmaceutical company focused on the development of pharmaceutical product candidates for the treatment of central nervous system disorders including obesity. Orexigen's lead combination product candidates targeted for obesity are Contrave(TM), which is in Phase III clinical trials, and Empatic(TM), which is in the later stages of Phase II development. Both product candidates are designed to take advantage of the Company's understanding of how the brain appears to regulate appetite and energy expenditure, as well as the mechanisms that come into play to limit weight loss over time. Each product candidate is designed to act on a specific group of neurons in the central nervous system with the goal of achieving appetite suppression and sustained weight loss. Further information about the Company can be found at

Forward-Looking Statements

Orexigen cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "indicates," "will," "intends," "potential," "suggests," "assuming" and similar expressions are intended to identify forward-looking statements. These statements are based on Orexigen's current beliefs and expectations. These forward-looking statements include statements regarding the science of the mechanism of action of Contrave and the potential to effectively treat obesity with Contrave. The inclusion of forward-looking statements should not be regarded as a representation by Orexigen that any of its plans will be achieved. Actual results may differ from those set forth in this release due to the risk and uncertainties inherent in Orexigen's business, including, without limitation: the potential that earlier preclinical studies and clinical trials may not be predictive of future results; the potential for adverse safety findings relating to Contrave to delay or prevent regulatory approval or commercialization, or result in product liability claims; Orexigen and its licensors may not be able to obtain, maintain and successfully enforce adequate patent and other intellectual property protection of its product candidates; and other risks described in Orexigen's filings with the Securities and Exchange Commission (SEC), including those detailed under the heading "Risk Factors" in Orexigen's Quarterly Report on Form 10-Q for the quarter ended June 30, 2007 filed with the SEC on August 10, 2007. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Orexigen undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.

* 567-P Bupropion and Naltrexone interact synergistically to decrease food intake in mice



Graham Cooper, 858-436-8600
Stephen Gendel, 212-918-4650
Jason Spark, 619-849-6005

Posted: October 2007