After more than two years of regulatory struggles, Orexigen Therapeutics Inc. and marketing partner Takeda Pharmaceutical Co. Ltd. have finally gained clearance for the obesity treatment Contrave – but at least they have arrived with a label that presents few obstacles.

FDA gave the green light to Contrave (naltrexone/bupropion extended-release) late on Sept. 10, approving the combination drug for the treatment of chronic weight management in adults who are obese (body mass index over 30 kg/m²) or are overweight (BMI greater than 27 kg/m²) with a comorbidity such as high cholesterol, type 2 diabetes or hypertension. The treatment is meant as an adjunct to a reduced-calorie diet and increased physical activity Also see "Orexigen Thinks Contrave On The Verge Of Approval, Again" - Pink Sheet, 7 August, 2014..

All said, the label is largely in line with the competition – Arena Pharmaceuticals Inc. /Eisai Co. Ltd.’s Belviq (lorcaserin) and Vivus Inc.’s Qsymia (phentermine/topiramate), as Credit Suisse analyst Koon Ching said in a Sept. 11 note to investors. “Overall, there were no major surprises in the label,” Ching said.

All three drugs have similar labels, with the same indications, limitations of use, and virtually identical adverse events sections. Qsymia’s label, like that for Contrave, is largely in line for the individual components that made up the drug. Meanwhile, Belviq, which is a new molecular entity as opposed to a combination of already generic drugs, has warnings for serotonin syndrome and valvular heart disease, but is also in line with the other two labels.

As with the other drugs, Contrave’s label calls on physicians to check on patients after 12 weeks of use. Patients are encouraged to discontinue use of Contrave at that time if they have not lost at least 5% of their body weight, as the drug is unlikely to be effective in that case. Contrave requires a three-week dose escalation, with one tablet daily during week 1, two tablets daily during week 2, three tablets daily during week 3, and ultimately four tablets daily (2 at night and two in the morning) for the remainder of use.

“We like the profile of the drug as described in the label and we believe Contrave will be an important new therapeutic option for patients struggling with obesity,” Orexigen CEO Mike Narachi said during a Sept. 11 conference call on the approval. “Most of what's in the label was expected and predicted many years ago, because lot of the information on safety is related to what's in the label for the constituent drugs, bupropion and naltrexone,” he added.

Contrave is a combination of two generic drugs, the antidepressant bupropion plus naltrexone, a treatment for alcohol and opioid dependence. While Orexigen has long maintained that doctors are comfortable with prescribing the two drugs, FDA added a boxed warning to Contrave’s label due to the inclusion of bupropion. The box warns against suicidal thoughts and neuropsychiatric reactions that are typical of antidepressants, and requires physicians to monitor patients for any signs of either of these conditions.

The approval – which has been denied multiple times over the last two years due to regulatory concerns about cardiovascular effects – was based on four double-blind, placebo-controlled Phase III studies, as well as interim data from a large cardiovascular outcomes study. The four 56-week Phase III studies included 4,536 patients, including one trial that enrolled patients with the comorbidity of type 2 diabetes.

All of the studies included three weeks of dose escalation followed by one year of continuous use. Patients in two of the studies were given behavioral counseling, a reduced-calorie diet plan and an exercise regimen. For the four trials, the mean age was 46 years; 83% of those participating were female, 77% were Caucasian, 18% were black and 5% were other races. The studies measured percent change in body weight from baseline and the number of patients to achieve a weight loss of at least 5% of their body weight. A greater percentage of patients on Contrave achieved the endpoints as compared to those on placebo in all four of the studies.

The most common adverse events during the trial were nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea.

Limitations Of Use

The drug is contraindicated for those patients with a seizure disorder, those recovering from addiction to alcohol or other drugs and patients who have recently been treated with an MAOI.

Other limitations to its usage include that it has not been approved in pediatric patients. Orexigen and marketing partner Takeda are required to conduct two post-marketing studies in pediatric patients – one in those aged 12-17 and another in patients 7-11, as well as a juvenile animal toxicity study focusing on issues of growth, development, learning, behavior and memory.

The drug has also not been established to be safe and effective when used in combination with other weight loss agents. The company has been prepping to combine Contrave with phentermine (one of the components in competing drug Qsymia and a well-known obesity agent). FDA is requiring a post-marketing study to evaluate Contrave in combination with other drugs.

Due to the naltrexone component, the drug is contraindicated during pregnancy, falling into the pregnancy X category as it poses potential harm to the fetus.

The label also notes that the drug’s effect on cardiovascular morbidity and mortality has not been established. The marketing partners are required to undertake a new cardiovascular outcomes study to address these concerns. Orexigen management said during a conference call with analysts that the study will include 5,000 patients and a protocol is expected by April 2015, with results from the study by 2022.

Orexigen and Takeda are currently conducting a large cardiovascular outcomes study dubbed the Light study. An interim analysis is expected to occur early next year and the study is ongoing, but FDA and the companies determined that there would not be enough on-drug events in the study to satisfy the cardiovascular outcomes requirement. FDA has also expressed concerns about potential bias from data that has been released from the study – this most recent regulatory decision on Contrave was delayed three months due to arguments regarding this requirement Also see "Orexigen’s Big Plans On Hold As FDA Hashes Out Post-Marketing Requirements" - Pink Sheet, 11 June, 2014..

“In the case of the Light Study, the agency expressed concern that the existing disclosures of the interim results while made under strict obligation to confidentiality could eventually result in widespread public knowledge of those findings, and that may bias future conduct by sites or by patients themselves,” Orexigen’s head of global development Preston Klassen said during the conference call ([A#00140623008]).

The Skinny On Labeling For Orexigen’s Contrave

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