Orexigen® Therapeutics Announces Publication of COR-I Phase 3 Study of Contrave in Lancet

SAN DIEGO, July 29 /PRNewswire-FirstCall/ -- Orexigen® Therapeutics, Inc. (Nasdaq: OREX) announced that results from its COR-I trial of Contrave® were published online today in the journal Lancet. COR-I was the largest of the four, 56-week, Phase 3 trials supporting the New Drug Application for Contrave, currently under review by the U.S. Food and Drug Administration. Results show that patients taking Contrave were two to three times more likely to lose at least 5% or 10% of their body weight compared to those taking placebo, on both an intent-to-treat (ITT) and completers basis.

Many patients with obesity are at higher risk for diabetes and cardiovascular disease, so evaluating the impact of weight loss on markers of cardiovascular and metabolic risk was a key objective of the COR (Contrave Obesity Research) Phase 3 program. Results from COR-I showed that treatment with Contrave resulted in significant improvements over placebo in waist circumference, insulin resistance, HDL cholesterol, triglycerides, and hsCRP, which are well-known and accepted measures of cardiometabolic risk. Patients taking Contrave also showed significant improvements in patient-reported control of eating, including reduced food cravings and reduced difficulty resisting food cravings.

"The secondary health benefits of weight loss are critical to understanding the potential role of pharmacotherapy in managing overweight and obese patients," said Frank Greenway, M.D., Medical Director at the Pennington Center Outpatient Research Clinic and lead investigator for the study. "This study showed that treatment with Contrave has meaningful impact on markers of cardiometabolic risk, demonstrating its potential to be an important new approach to the treatment of obesity."

Additional findings from patients on Contrave32 (32mg naltrexone sustained release (SR)/360mg bupropion SR):

• 34% of patients completing the study lost at least 10% of their body weight as compared to 11% on placebo (p<0.0001).
• Patients taking Contrave showed significant improvements in important secondary endpoints: waist circumference (-6.2 cm on Contrave32 vs. -2.5 cm on placebo), insulin resistance (-20.2% vs. -5.9%), HDL cholesterol (+8.0% vs. +0.8%), triglycerides (-12.7% vs. -3.1%) and hsCRP (-29.0% vs. -16.7%) compared to patients taking placebo on an ITT basis.

The most frequently observed treatment-emergent adverse events in COR-I included nausea, headache, constipation and upper respiratory tract infection. Adverse events in the Contrave groups were generally mild to moderate in intensity, transient, and did not result in discontinuation for most patients. Mean systolic blood pressure decreased from baseline to endpoint by 1.6 mmHg for patients taking Contrave32 and 2.8 mmHg for patients on placebo. As expected, greater weight loss was associated with greater reductions in blood pressure.

"As a clinician, I was comforted to see that the safety findings from the largest of the Phase 3 studies of Contrave were consistent with the known effects of its constituent components," said Ken Fujioka, M.D., Director of Nutrition and Metabolic Research at Scripps Clinic and investigator in this study. "When studying a combination therapy, a primary goal is making sure that the combination does not result in a different safety profile from what is already known about the constituent components. Contrave achieved that goal: the adverse event profile was consistent with the 20-year history of use of these products."

Study Design

COR-I was a 56-week placebo-controlled, double-blind randomized trial enrolling patients whose body-mass index (BMI) was between 30-45 kg/m(2) for patients with uncomplicated obesity, or BMI 27-45 kg/m(2) with controlled hypertension or dyslipidemia, or both. 1742 patients were randomized to receive either Contrave32, Contrave16 (16mg naltrexone SR/360mg bupropion SR), or placebo in a 1:1:1 ratio. Thirty-four sites in the United States participated in the study.

About Contrave

Contrave is an investigational combination therapy believed to address both physiological and behavioral drivers of obesity. The two components of this combination therapy act in a complementary manner in the central nervous system. The central pathways targeted by this treatment are involved in controlling the balance of food intake and metabolism, and regulating reward-based eating behavior. In clinical trials, Contrave was shown to help obese patients initiate and sustain significant weight loss, improve important markers of cardiometabolic risk and increase ability to control eating. The U.S. Food and Drug Administration (FDA) has tentatively scheduled a Division of Metabolic and Endocrine Drug Products Advisory Committee meeting on December 7, 2010 and the Prescription Drug User Fee Act (PDUFA) action date has been set for January 31, 2011.

About the Contrave Clinical Development Program

All four trials in the COR Phase 3 program (COR-I, COR-II, COR-BMOD and COR-Diabetes) were randomized, double-blind, placebo-controlled trials. The co-primary endpoints were the proportion of patients achieving at least 5% weight loss and percent change in body weight compared to placebo. Secondary endpoints included multiple measures of cardiometabolic risk, quality of life, control of eating, and glycemic control. Contrave was generally well tolerated. The safety and tolerability profile of Contrave in the clinical development program was consistent with the safety profile of the constituent components, which have been in use for other indications for over 20 years. The most frequent treatment-emergent adverse events in patients treated with Contrave were nausea, constipation, headache, vomiting, and dizziness. Treatment with Contrave was not associated with increases in adverse event reports of depression or suicidal ideation compared to placebo. Mean blood pressure with Contrave was generally unchanged from baseline to endpoint. Placebo patients experienced decreases in blood pressure from baseline to endpoint of approximately 2mmHg. Greater weight loss correlated with greater reductions in blood pressure in both Contrave and placebo patients, suggesting that the expected relationship between weight loss and blood pressure was maintained. Importantly, normal circadian blood pressure patterns were preserved with Contrave. There was an increase in pulse of about one beat per minute in patients taking Contrave. Serious events were reported infrequently and included events of cholecystitis (Contrave 0.2%, PBO <0.1%), seizure (<0.1%, 0%) and major cardiovascular events (<0.1%, <0.1%).

About Orexigen Therapeutics

Orexigen Therapeutics, Inc. is a biopharmaceutical company focused on the treatment of obesity. Further information about the Company can be found at www.orexigen.com.

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 anticipated action date for the FDA to complete its review of the Contrave NDA, the potential for, and timing of, approval for Contrave and the Company's belief that this product candidate may be an important therapeutic option in the treatment of obesity. 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 uncertainty of the FDA approval process and other regulatory requirements; the therapeutic and commercial value of Contrave; reliance on third parties to assist with the development of Contrave; the potential for adverse safety findings relating to Contrave; 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. Further information regarding these and other risks is included under the heading "Risk Factors" in the Company's Quarterly Report on Form 10-Q, which was filed with the Securities Exchange Commission on May 10, 2010 and is available from the SEC's website (www.sec.gov) and on our website (www.orexigen.com) under the heading "Investor Relations". 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.

SOURCE Orexigen Therapeutics, Inc.