Naltrexone
Bupropion
As many of you know, this blog has been covering the review of preregistration antiobesity drugs by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and by the FDA itself. 2010 was supposed to be the year in which one or more new obesity drugs would be approved by the FDA and reach the market. Three new drugs developed by small California companies–Vivus Pharmaceuticals’ Qnexa, Orexigen Therapeutics’ Contrave, and Arena Therapeutics’ lorcaserin, were up for FDA review this year. This follows a long hiatus, since the FDA has approved no antiobesity drug since 1999.
So far, the Advisory Committee–and later the FDA itself–has rejected approval of two of these drugs–Qnexa and lorcaserin. At the same time, the marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request.
The third preregistration antiobesity drug, Orexigen’s Contrave, was scheduled for review by the Endocrinologic and Metabolic Drugs Advisory Committee in December 2010, and the review was held on December 7th. Most industry experts expected that the Advisory Committee would reject Contrave as well. But, surprisingly, the Committee recommended that the FDA approve Contrave (naltrexone sustained release [SR]/bupropion SR), by a vote of 13-7, for long-term use by certain obese and overweight patients.
The FDA usually follows the advice of its advisory panels, but does not always do so.
Contrave is a combination of long-acting formulations of two FDA-approved drugs–naltrexone and bupropion. Orexigen designed Contrave to have a dual effect on pathways within the hypothalamus of the brain that control energy balance–increasing anorexia and inhibiting the reward effects of food. The company also believes that Contrave may block the body’s compensation for weight loss–i.e., decreased energy use and increased feeding. For additional details, see our 2008 book-length obesity report, published by Cambridge Healthtech Institute.
The Advisory Committee, although they voted positively, did not do so with much enthusiasm, since Contrave just barely met the FDA’s criteria for efficacy. The drug enabled a majority of patients to lose about 5% of their body weight. Despite the drug’s minimal efficacy, a 5% loss in body weight can have significant health effects, such as helping patients to prevent diabetes and heart disease and to control their blood pressure. Some panelists were concerned that there is no data on the drug’s efficacy or safety beyond one year of treatment. Obesity is a long-term condition, and most patients would probably require long-term treatment with Contrave if it is approved.
However, as in the previous reviews by the Advisory Committee of Qnexa and lorcaserin, the main emphasis of the discussion was on safety. Clinical trials indicate that Contrave treatment can result in elevated blood pressure in some patients. Some panelists were also concerned about the risk of seizures, which have been seen with one of the components of Contrave, bupropion. Especially because of the adverse effect on blood pressure, some panelists expressed concern that Contrave, once approved, might suffer the same fate as Meridia, which at the time of its approval was also known to cause elevated blood pressure in some patients. The reason for this year’s withdrawal of Meridia was its increased risk of cardiovascular events.
As a result of these safety discussions, the panel voted 11-8 to require Orexigen to conduct a long-term study of the effects of Contrave on cardiovascular health. However, they concluded that that study could be done post-marketing rather than requiring the company to conduct the study in order to gain approval.
Overall, the Advisory Committee concluded that physicians and patients need additional options to treat obesity, and that the risk-to-benefit ratio for Contrave falls on the side of benefits. Although that was the general conclusion of the panel, some members did not agree.
When the FDA conducts its own review of Contrave, it not only must decide on whether to approve the drug, but also on the drug’s label and on requirements for post-marketing studies. FDA action is expected by the end of January 2011.
As we discussed in a previous blog post, Takeda is Orexigen’s commercialization partner for Contrave. Under their agreement, Orexigen granted Takeda North American (U.S, Mexico, and Canada) marketing rights for Contrave; Orexigen retains copromotion rights in the United States. Takeda paid Orexigen $50 million upfront, and will pay (upon FDA approval) tiered double-digit royalties (starting at 20% and increasing to 35%) on any net sales of Contrave. The deal is estimated to be worth a potential $1 billion. Takeda will also share the costs of further development of these drugs, presumably including any post-marketing studies.
As we also discussed in the same article, Takeda also has an agreement with Amylin to develop earlier-stage antiobesity drugs, with the potential for greater efficacy than drugs that address appetite-control pathways in the CNS that involve common neurotransmitters.
The approval of Contrave (if the FDA goes along with its Advisory Committee’s recommendations) may affect the strategy of Vivus and Arena as they work with the FDA to obtain reconsideration for approval of Qnexa and lorcaserin, respectively. And it might restart research on early-stage antiobesity drugs, which has been largely on hold as the pharmaceutical/biotechnology industry and the medical and financial communities awaited approval of one or more of the three drugs being reviewed by the FDA in 2010. And–by lifting the “pall of gloom” over the antiobesity drug field–it might improve funding and partnering prospects for such early-stage obesity specialist companies as Zafgen and Energesis, which we discussed in an earlier blog post.
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