An FDA advisory panel voted 13-7 to recommend approval of Orexigen’s Contrave (buproprion/altrexone). approving bupropion/naltrexone (Contrave), a weight-loss drug developed by San Diegoâ€™s Orexigen Therapeutics for the U.S. market.
Below is an excerpt from MedMarket Diligence‘s December 2010 Report #S835, “Products, Technologies and Markets Worldwide for the Clinical Management of Obesity, 2011-2019”:
Orexigen Therapeutics, Inc. is a biopharmaceutical company focused on the treatment of obesity. Its lead combination product candidates targeted for obesity are ContraveÂ® (naltrexone SR/bupropion SR), which has completed Phase 3 clinical trials and has submitted an NDA for FDA review, and Empaticâ„¢ (zonisamide SR/bupropion SR), which has completed Phase 2 clinical development. The company is located in La Jolla, California.
Orexigenâ€™s approach involves taking advantage of the synergy between established products, combined with the companyâ€™s novel science, resulting in unique mechanisms of action that act on the central nervous system. Its drug combinations are designed to initiate and sustain weight loss by reducing appetite and increasing metabolism. According to the company, Contrave is the first treatment for obesity to address the reward system in the brain that causes food cravings.
The US FDA held a Division of Metabolic and Endocrine Drug Products Advisory Committee meeting on December 7, 2010. The committee voted 13 to 7 to recommend approval of Contrave. The company still has to have final approval when the Prescription Drug User Fee Act (PDUFA) meets on January 31, 2011. The PDUFA usually, but not always, follows the advisory committeeâ€™s recommendation.
Contrave is a combination of two well-established drugs, naltrexone and bupropion, in a sustained release formulation (SR). The drug is 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.
Orexigen says that Contrave demonstrates favorable efficacy, safety and tolerability, and they put forth several arguments supporting this stance. The active ingredients of Contrave have been safely used in millions of patients for nearly 20 years. Bupropion (Wellbutrin) is a widely-prescribed antidepressant and smoking cessation medication, while naltrexone is a treatment for alcohol and opioid addiction. Clinical research demonstrates that bupropion helps initiate weight loss while naltrexone may potentially sustain weight loss by preventing the bodyâ€™s natural tendency to counteract efforts to lose weight. According to Orexigen, this unique combination holds the potential to improve symptoms of co-morbid depression, which occurs in approximately 20% of obese patients. The company further states that in trials, Contrave has been well tolerated with a side effect profile consistent with similar medications, including nausea, headache and dizziness.
In August, 2010, Orexigen published results of the COR-BMOD study in the journal Obesity. Orexigen said that the benefit of adding specific pharmacotherapies to a rigorous behavior modification (BMOD) program had not been extensively evaluated. The COR-BMOD clinical trial was designed to test this hypothesis by evaluating Contrave in a setting conducive to maximizing weight loss. The COR-BMOD trial evaluated intensive BMOD plus Contrave32 (32mg naltrexone sustained release (SR)/360mg bupropion SR) compared to BMOD plus placebo, in 793 overweight or obese patients. Patients used the medication as part of a broader weight-loss effort. Participants in both groups received diet and exercise counseling during 28 small group sessions with one or two professionals, each lasting 90 minutes, over the course of the year-long trial. Results showed that adding Contrave to intensive BMOD was associated with significantly greater improvements in markers of cardio metabolic risk, including waist circumference, triglycerides, high density lipoprotein (HDL) cholesterol and fasting insulin. Results showed that patients taking Contrave lost 9.3% of their body weight compared to 5.1% for patients on placebo (p< 0.001), on an intent-to-treat basis. For those who completed 56 weeks of treatment, patients taking Contrave plus BMOD lost 11.5% of their body weight compared to 7.3% for those taking placebo (p<0.001).
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 cardio metabolic 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 prescribed by physicians for several years.