Orexigen Therapeutics, Inc. (Nasdaq: OREX), a biopharmaceutical company focused on the treatment of obesity and other central nervous system-related disorders, today announced that the company reviewed in an oral presentation at the Obesity Society Annual Scientific Meeting that the investigational drug, Empatic™ (zonisamide SR/bupropion SR), demonstrated up to 15% reduction in body weight of healthy obese people who completed 48-weeks of treatment in the absence of diet and exercise.

In a second presentation, Orexigen reviewed Contrave® (naltrexone SR/bupropion SR) data demonstrating a 50% reduction from baseline in the prevalence of metabolic syndrome in obese patients. More than 47 million people have metabolic syndrome, a condition associated with increased risk of developing diabetes or cardiovascular disease.

"The currently available obesity pharmaceuticals have given disappointing weight loss, and have sometimes actually worsened medical problems associated with being obese," said Frank Greenway, M.D., lead investigator for both studies, Pennington Biomedical Research Center. "However, I believe Empatic and Contrave have the potential to improve the magnitude of weight loss and improve the medical conditions associated with insulin resistance with good tolerability profiles through unique mechanisms of action that work in the central nervous system."

Empatic is in the later stages of Phase 2 development. Contrave is the Company's lead product candidate, currently in Phase 3 clinical trials and on track for a late 2009 New Drug Application (NDA) submission to the FDA.

About the Clinical Trials

The primary objective of the Empatic trial was to determine optimal dose ratios of zonisamide SR and bupropion SR. The randomized, double-blinded trial of 623 obese patients included a minimal diet and exercise intervention. Results based on a modified-ITT analysis show:

- Of 87 patients randomized to the Z360/B360 dosage arm, 64 completed 24 weeks and 56 remained on blinded treatment for 48 weeks. These 56 patients averaged 14.0 percent weight loss at week 48, with 37 (66.2 percent) achieving ≥10 percent weight loss.

- Of 85 patients randomized to Z120/B360 dosage arm, 71 completed 24 weeks and 45 remained on blinded treatment for 48 weeks. These 45 patients averaged 12.1 percent weight loss at week 48, with 25 (55.0 percent) achieving ≥10 percent weight loss.

Data from two new post-hoc analyses of the Empatic trial were also presented at the meeting. Results show:

- Empatic is associated with a statistically significant improvement in quality of life compared with placebo, as measured by the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) scale. Improvements in physical function and self esteem were most commonly observed.

- The Z120/B360 and Z360/B360 formulations of Empatic demonstrated promising durability of response in patients who completed the 24-week study. The majority of these patients achieved 5 percent or greater weight loss at week 12 and achieved further weight loss at week 24.

- Early response to treatment with Empatic predicted greater weight loss at 24 weeks.

The Contrave clinical trial showed improvements in risk factors associated with metabolic syndrome including triglycerides, HDL (good) cholesterol, waist circumference, insulin and fasting glucose. The most significant improvements were found in patients with higher levels of baseline insulin or triglycerides. The improvements in these risk factors may suggest that Contrave associated weight loss might improve obesity-related complications such as Type II diabetes and cardiovascular disease.

"Orexigen is the only company currently developing two late-stage product candidates to address the obesity epidemic, which afflicts more than 75 million Americans," said Gary Tollefson, M.D., Ph.D., Orexigen President and CEO. "These studies demonstrate the potential of our obesity franchise and reflect a growing understanding of how the central nervous system regulates appetite and metabolism as well as the mechanisms that limit weight loss over time."

About Orexigen Therapeutics

Orexigen Therapeutics, Inc. is a biopharmaceutical company focused on the treatment of obesity and other central nervous system-related disorders. The Company's lead combination product candidates targeted for obesity are Contrave, which is in Phase 3 clinical trials, and Empatic, which is in the later stages of Phase 2 clinical development. 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. Beyond obesity, Orexigen is developing drug combinations for use in schizophrenia and obsessive-compulsive disorder. Further information about the company can be found at http://www.Orexigen.com.

About Contrave

Contrave is an investigational weight loss medication with a mechanism of action that works at two sites within the central nervous system. The first is a hypothalamic site that controls the balance of food intake and metabolism. We believe that Contrave is possibly the first treatment for obesity to address a second site, the reward system in the brain that controls food preference and food cravings. In clinical trials, Contrave has initiated and sustained significant weight loss over one year of treatment (approximately 8-10.7% in patients completing 48 weeks of therapy) by reducing appetite, increasing metabolism and allowing the body to continue losing weight by offsetting its natural tendency to fight back and slow down the weight loss process. We expect to receive data from the first of our Contrave Phase 3 trials in January of 2009 and the remaining three trials by mid next year.

About Empatic

Empatic is a fixed dose combination of bupropion SR with our proprietary sustained release formulation of zonisamide. Research indicates that zonisamide inhibits AgRP, a system associated with increasing appetite while bupropion increases metabolism. Based on the strength of these results and the unique Empatic mechanism of action, the Company selected this product combination to complement our Contrave clinical development program.

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," "designed" and similar expressions are intended to identify forward-looking statements. These statements are based on the Company's current beliefs and expectations. These forward-looking statements include statements regarding the enrollment, timing, execution and completion of clinical trials of its product candidates, the timing of an NDA submission for Contrave, the potential to obtain regulatory approval for, and effectively treat obesity with, Contrave and Empatic, and the scope and duration of protection of issued patents relating to the Company's product candidates. 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 the Orexigen business, including, without limitation: the progress and timing of the Company's clinical trials; the potential that earlier clinical trials may not be predictive of future results; the ability for Contrave or Empatic to receive regulatory approval on a timely basis or at all; the potential for adverse safety findings relating to Empatic or Contrave to delay or prevent regulatory approval or commercialization, or result in product liability claims; the ability of Orexigen and its licensors to obtain, maintain and successfully enforce adequate patent and other intellectual property protection of its product candidates; and other risks described in the Company's filings with the Securities and Exchange Commission. 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.

Orexigen Therapeutics