Takeda Pharmaceuticals U.S.A., Inc. and Orexigen® Therapeutics, Inc. (Nasdaq: OREX) jointly announced today that the U.S. Food and Drug Administration (FDA) has approved Contrave® (naltrexone HCI and bupropion HCI) extended-release tablets as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition.
"Some individuals seeking to manage their weight may require a treatment plan that includes more than lifestyle modification with diet and exercise," said Dr. Ken Fujioka, director, Center for Weight Management, Division of Diabetes and Endocrinology at Scripps Clinic. "Clinical trial data for Contrave demonstrates that this new treatment, when used as an adjunct to a reduced-calorie diet and increased physical activity, is a therapeutic option for some adults who are either overweight with a comorbidity, or obese. In my clinic, I often treat patients who fit these criteria, and now, with the approval of Contrave, I am excited to have a new treatment option to consider for my patients."
Contrave is an important addition to Takeda's portfolio of cardiometabolic products. Takeda is committed to providing patients with obesity with treatment options that help address their needs, and the company is planning to commercially launch Contrave in the fall of 2014.
The effect of Contrave on cardiovascular morbidity and mortality has not been established. In addition, the safety and effectiveness of Contrave in combination with other medications intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.
The exact neurochemical effects of Contrave leading to weight loss are not fully understood. Contrave has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system).
"The FDA approval of Contrave is a significant milestone in Takeda's and Orexigen's commitment to leading innovation in medicine for patients and physicians dealing with chronic conditions and diseases, such as obesity," said Douglas Cole, president, Takeda Pharmaceuticals USA, Inc. "It's important that physicians and appropriate patients have options when discussing weight management, especially when you look at the prevalence of obesity in today's society. We're excited about the addition of Contrave to our Cardiovascular and Metabolic Disease Portfolio."
"We are extremely proud of our team's work and commitment to the research and development efforts that have charted our path to Contrave approval," said Michael Narachi, CEO of Orexigen. "Takeda has been a great, contributing partner throughout this endeavor, and we at Orexigen now look forward to doing everything possible to support them as they bring Contrave to the U.S. market."
According to National Health and Nutrition Examination Survey (NHANES) 2012 estimates, approximately 35 percent, or one out of three, adults age 20 years or older were classified as obese based on a BMI of 30 kg/m2 or greater. Obesity has been recognized by the American Medical Association, as well as other medical and government organizations, as a chronic disease.
Contrave Clinical Trials Program
Four 56-week multicenter, double-blind, placebo-controlled obesity trials (CONTRAVE Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of Contrave in conjunction with lifestyle modification in 4,536 patients randomized to Contrave or placebo. The COR-I, COR-II, and COR-BMOD trials enrolled patients with obesity (BMI 30 kg/m2 or greater) or overweight (BMI 27 kg/m2 or greater) and at least one comorbidity (hypertension or dyslipidemia). The COR-Diabetes trial enrolled patients with BMI greater than 27 kg/m2 with type 2 diabetes with or without hypertension and/or dyslipidemia.
COR I and COR II included a program consisting of a reduced-calorie diet resulting in an approximate 500 kcal/day decrease in caloric intake, behavioral counseling, and increased physical activity. COR-BMOD included an intensive behavioral modification program consisting of 28 group counseling sessions over 56 weeks as well as a prescribed diet and exercise regimen. COR-Diabetes evaluated patients with type 2 diabetes not achieving glycemic goal of a HbA1c less than 7 percent either with oral antidiabetic agents or with diet and exercise alone. Co-primary efficacy endpoints were percent change from baseline in body weight and proportion of participants who achieved a decrease in body weight of 5 percent or more. In these studies, the most common adverse reactions (≥5 percent) seen in patients taking Contrave included nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.
The clinical trial program also includes an ongoing, double-blind, placebo-controlled cardiovascular outcomes trial known as the LIGHT study. The primary objective of this study is to evaluate the occurrence of major adverse cardiovascular events in overweight and obese adults with cardiovascular risk factors receiving Contrave.
As part of the approval of Contrave, Takeda and Orexigen agreed to several post-marketing requirements, including studies to assess the safety and efficacy of Contrave for weight management in obese pediatric patients. There will also be a new randomized double-blind, placebo-controlled study to evaluate the effects of long-term treatment with Contrave on the incidence of major adverse cardiovascular (CV) events in overweight and obese subjects with CV disease or multiple CV risk factors.
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