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SEC Filings

OREXIGEN THERAPEUTICS, INC. filed this Form S-1/A on 02/16/2007
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A subset of subjects participating in our Phase IIb study for Contrave also participated in a study assessing the effects of Contrave therapy on visceral fat. Visceral fat is the fat that surrounds the organs in the abdomen, and is particularly worrisome as it is associated with increased risk for cardiovascular disease, insulin resistance and other metabolic syndromes. In this substudy, patients from all study arms (Contrave at three different naltrexone dosages, bupropion monotherapy, naltrexone monotherapy and placebo) received body scans to measure body composition at the start of treatment and six months after the start of treatment. These measurements enabled determination of patients’ total and visceral fat and lean tissue composition at the beginning of treatment and at the six month point. Of the patients analyzed, the three Contrave-treated groups experienced a mean decrease in total body fat at six months of between 12.2% and 16.0%, compared to a 3.2% to 4.1% mean decrease for patients receiving either of the monotherapies or placebo. Patients in the three Contrave therapy groups experienced a mean decrease in visceral body fat at six months of between 13.7% and 16.7%, compared to a 0.1% to 4.6% mean decrease for patients receiving either of the monotherapies or placebo. These results suggest that weight loss associated with Contrave therapy results primarily from fat tissue loss, including loss of visceral fat that is associated with significant health risks.
Future Contrave Clinical Development Plans
In April 2006, we met with the FDA to discuss the remaining clinical trial requirements for submission of NDA filings for both Contrave and Excalia. Based on feedback from the FDA, we intend to conduct clinical development programs to provide active drug exposure among 1,500 patients for one year, under double-blind, placebo-controlled conditions for each product candidate. We believe that this clinical development program will provide the basis of an NDA submission for Contrave in the second half of 2009.
For Contrave, we intend to conduct at least four Phase III clinical trials. We believe these studies will provide required efficacy, safety and exposure data required by the FDA. In recent correspondence with the FDA, the agency agreed that based on the results of our Phase IIb clinical trial for Contrave, future clinical trials will need to evaluate the safety and efficacy of Contrave relative to placebo only, and will not need to compare Contrave to the individual constituent drugs. We also submitted the protocol for the first of our planned Phase III clinical trials. We expect that we will initiate our Phase III clinical trials in the first half of 2007. The dosages to be used in these trials will be determined based on our review of the 48 week data from the extension portion of our ongoing Phase IIb study. The primary endpoint for these studies will be percent change in body weight one year after the start of treatment. One of these trials will examine the benefit of Contrave plus an intensive program of behavior modification therapy versus behavior modification therapy alone. We also intend to evaluate Contrave in obese patients with related health conditions, such as diabetes. We expect to receive the results from these Phase III trials beginning in the second half of 2008.
We believe that our clinical trial experience with Contrave has demonstrated and replicated the validity of our naltrexone hypothesis, specifically, that the addition of naltrexone to bupropion permits greater weight loss than bupropion alone and sustains weight loss beyond 24 weeks. Moreover, in our clinical trials, Contrave has demonstrated significantly greater weight loss than naltrexone alone as well as placebo. The rate of response (greater than 5% and 10% reduction in body weight from baseline) has also favored Contrave and provides additional support for our belief that Contrave will provide a clinically relevant alternative for clinicians and obese patients.
While Contrave has generally been well tolerated, the principal adverse event across our trials to date has been nausea. Nausea is typically seen early upon initiating treatment and appears to be transient in most cases. Subjects have generally rated their nausea as mild and, on occasion, moderate in severity. Clinical results from our studies suggest that the incidence of nausea has generally been related to the dose of IR naltrexone, particularly at dosages of 48mg or higher. The pharmacology of naltrexone suggests that nausea is related to both gastrointestinal motility and a dose-related CNS effect. There are a number of ways in which we can attempt to address this issue, including lowering the dose, titrating the drug more slowly and adjusting the formulation to release the drug more gradually. Concerning the latter, we hypothesized that, if the drug could be released beyond the stomach, such as in the small bowel, and the Cmax lowered, the incidence and/or intensity of nausea and other adverse events may be reduced.