Four months after receiving a complete response letter from the FDA for its Contrave diet pill, Orexigen Therapeutics has now put further development on hold after receiving an “unprecedented” request for a pre-approval clinical trial that the aspiring drug developer believes “would generate significantly more information than is necessary or feasible.” As a result, Orexigen plans an appeal this month.

At issue are concerns over cardiovascular risks that prompted the FDA to request a randomized, double-blind, placebo-controlled trial. In fact, the FDA told Orexigen execs that the agency plans to hold an advisory committee meeting early next year to assess cardiovascular issues with diet drugs, in general. This is only the latest indication the FDA is raising a high bar for diet drugs; in the past year, the agency has nixed pills from Vivus and Arena Pharmaceuticals (see this).

As for Orexigen, last December, an FDA advisory panel recommended approval for Contrave, but also that a cardiovascular trial should be required, although after approval. However, the FDA made clear in its complete response letter than a pre-approval trial would be requested. At the time, Orexigen ceo Michael Narachi reacted by saying he was “surprised and extremely disappointed.”

In a conference call this morning, Orexigen execs say the FDA trial would require between 60,000 to 100,000 patients, a number they say is difficult to achieve. They also expressed frustration that the FDA would not consider approving Contrave for a narrow indication for patients with lower CV risk, and that they may be dealing with a moving target. That’s because of the advisory committee meeting the FDA’s Division of Metabolic and Endocrinologic Products plans to a hold next year.

“We have serious concerns about broader implications these actions may have in the obesity space,” Narachi told analysts.

Meanwhile, Orexigen is putting further development on hold in the US until its stand-off with the FDA is resolved and will look for opportunities outside the US. You may recall, since receiving the complete response letter earlier this year, Orexigen slimmed down by dismissing roughly 40 percent of its staff (see this).

Narachi added that he has been in touch with Takeda Pharmaceuticals, which struck a marketing deal with Orexigen but does not contribute to pre-approval cardiovascular study costs. Contrave, by the way, combines the Wellbutrin antidepressant and a sustained release form of naltrexone, an opioid blocker used to treat addictions to alcohol and painkillers.

scale pic thx to alan cleaver on flickr