In December 2013, Orexigen Therapeutics resubmitted the NDA for its weight loss drug Contrave (naltrexone SR/bupropion SR) to the FDA. This is their second attempt; the drug was rejected in 2011 because the company could not provide sufficient data supporting the cardiovascular (CV) safety of Contrave. Hence, Contrave is being tested in an ongoing CV outcomes study (the LIGHT study) involving approximately 8,900 patients. Orexigen announced positive interim results, which made them confident that Contrave will win FDA approval on its PDUFA date: Wednesday, June 11, 2014. However, the FDA decided to extend its review of the resubmitted NDA for Contrave due to the need to reach an agreement on postmarketing obligation for further CV safety data, shifting the new PDUFA date back to September, 11 2014. In their conference call about the delayed PDUFA date, Orexigen made clear that the issue is the need for post-marketing CV outcomes data, and not related to any data or safety signals in the LIGHT study. Although they gave no information about future plans for additional CV outcome trials, they remain confident about a quick agreement with the FDA in terms of postmarketing obligations.

Assuming it is approved in the United States, Contrave's direct competitors will include Arena's Belviq (lorcaserin) and Vivus's Qsymia (phentermine/topiramate extended-release). Unlike Contrave, neither product has positive CV outcomes data yet, although the FDA approved Qsymia and also Belviq with postmarketing requirements to conduct a long-term CV outcomes trial. Qsymia and Belviq have been rejected by the EMA for use in Europe, which seems to be a tough market for weight-loss drugs to gain a foothold. However, Orexigen did obtain positive feedback from the EMA about Contrave in February this year. If approved, it would give obese patients and their doctors in Europe a boost, as the only have prescription weight loss medication available there is orlistat (Roche's Xenical, generics). Orexigen is confident Contrave will gain approval in the EU, but is awaiting further feedback from the EMA.

In previous studies, Contrave helped patients to lose 5 percent or more of their body weight in 53 percent of cases, compared to 21 percent placebo over the 12 month trial duration. Additionally, in the Contrave Obesity Research (COR) program, 34-48 percent of patients lost at least 10 percent of their baseline body weight after 56 weeks of Contrave therapy. Improvements in cholesterol levels and blood sugar control were also observed in many patients. This suggests that Contrave may be more efficacious that Belviq, but less so than Qsymia.

On the other hand, one disadvantage of Contrave is its dosing schedule. The maintenance dosing regimen is two tablets in the morning and another two in the evening. Thought leaders caution that high pill burdens can lead to poor compliance for patients. Another potential issue is that bupropion has a black box warning for suicidality, which may put off some physicians. The question remains whether or not Contrave's weight loss efficacy and CVOT data will make up for these disadvantages. Furthermore, future uptake of Contrave will be highly dependent on Orexigen's pricing strategy, as weight-loss agents often struggle to receive favorable reimbursement. Patients are likely to have to pay at least part of the treatment out of their own pocket, which many will not be willing to do.

In my opinion, Contrave will launch in the United States, and more importantly in Europe, giving patients there new hope in the treatment of obesity.  Although Qsymia may offer greater efficacy, and Belviq more convenient dosing, Contrave's risk-benefit profile will give it an advantage over these competitors, and is likely to convince a good number of physicians, especially in the EU, to prescribe it once it finally gets approved.

Stefanie Hoffart, M.Sc., is a data analyst in the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

In-depth analysis of obesity, with accompanying epidemiology driven sales forecast models, are presented in Decision Resources Group's Obesity Pharmacor, available here.

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