Even after FDA rejected the advice of its advisory committee and requested a cardiovascular outcomes trial of Orexigen Inc.'s Contrave bupropion/naltrexone to treat obesity, companies with earlier stage programs remain hopeful they will be able to avoid the issues that have now prevented three late stage compounds from reaching the market.
There are no other obesity compounds under review or in Phase III testing in the U.S. or Europe. But there are more than 50 obesity candidates against at least a dozen targets in preclinical through Phase II development (see "Obesity Opportunities," A3).
Early stage obesity companies contacted by BioCentury believe their focus on novel targets, combined with the availability of more sensitive preclinical assays capable of identifying safety concerns earlier in development, will allow them to win approval.
Based on the length of time it took Orexigen, Vivus Inc. and Arena Pharmaceuticals Inc. to run their Phase III obesity programs - three, three and four years, respectively - it is unlikely anyone new could file before 2014.
If randomized, controlled CV outcomes studies become a requirement before a drug can be approved for the indication, that timeline will extend even further. In briefing documents prepared for a December 2010 meeting of FDA's Endocrinologic and Metabolic Drugs Advisory Committee, Orexigen outlined a potential postmarket cardiovascular outcomes study that would take a minimum of four years to run.
The biotech did not specify if the timeline applied to an observational or a randomized trial.
FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 13-7 in December that Contrave's benefit-risk profile supported approval as a long-term treatment for obesity. The panel also voted 11-8 that a cardiovascular outcomes trial to assess Contrave's risks could be conducted after approval rather than before (see BioCentury, Dec. 13, 2010).
Of the three obesity therapeutics the panel reviewed in 2010, only Contrave received a positive vote.
But last week, the agency issued a complete response letter asking Orexigen to complete a randomized, placebo-controlled CV outcomes study of "sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with Contrave does not adversely affect the drug's benefit-risk profile."
The SCOUT results no doubt influenced FDA's request.
That trial showed patients taking the norepinephrine and serotonin reuptake inhibitor Meridia had a 16% greater risk of experiencing a major cardiovascular event than patients following diet and exercise regimens (see BioCentury, Sept. 20, 2010).
According to FDA's medical review of Meridia, there were signals of an effect on blood pressure and heart rate in preclinical animal toxicology tests, but the results were