CB-1 Antagonists for Obesity: R.I.P.

In 2005, Sanofi-Aventis’s obesity drug Acomplia (rimonabant) topped Pharm Exec’s pipeline list of blockbusters with potential annual earnings of $2 billion. Three years later, Acomplia, along with treatments from Merck and Pfizer with the same mechanism of action, have been canned.

Last week, Pfizer and Sanofi-Aventis announced that they had ended all clinical trials for their CB-1 antagonist obesity treatments. The drugs target the cannabinoid type 1 receptor in the brain, basically turning off the pleasure center that causes people to crave food. Both Pfizer’s Phase III drug CP-945,598 and Sanofi-Aventis’s Acomplia (rimonabant) had been universally criticized for causing psychiatric adverse reactions in patients using the drugs.

“While confident in the safety of the compound, we believe that this is the appropriate decision based on all available information regarding this class of agents, as well as recent discussions with regulatory authorities,” stated Martin Mackay, president, Pfizer global research and development. “As part of our ongoing portfolio prioritization, we will refocus research and development resources on high-priority therapeutic areas that address an unmet medical need and have a high probability for success.”

The once-promising obesity treatment hit a huge stumbling block in 2007, when FDA refused to approve Acomplia in the United States. The European Medical Agency approved the drug in 2006, but with the caveat that doctors had to screen out patients with psychiatric disorders, and closely monitor patients taking the drug. In October, a year after Acomplia launched, EMEA declared that the drug’s risks outweighed its benefits, and recommended withdrawal. Merck also had a recent obesity drug failure in taranabant, which was stopped in Phase III in the beginning of October.

Decision Resource analyst Donny Wong told Pharm Exec that he had spoken to many doctors who prescribed the drug and they said it drug worked fairly well when given to the right patients. Some of the primary care trusts (localized health authorities in the EU) reimbursed for rimonabant, and as recently as four months ago some of the trusts actively recommended the treatment for some obese patients.

“We very clearly saw both Merck and Pfizer’s compounds following Acomplia’s path,” Wong said. “We were thinking that since the EU had approved Acomplia originally, that the other drugs would have a chance in Europe. But I think this reflects the growing concern over long term safety for any drug.”

Daniel Ruppar, Industry Manager for Frost & Sullivan's Pharmaceuticals & Biotechnology team told Pharm Exec that the writing had been on the wall for some time. “Anything in this drug class targeting an obesity indication at this point will have some higher safety hurdles from the FDA-pretty much guaranteed,” Ruppar said “Pfizer refocusing/restructuring, their canceling of their Phase III product also makes good sense, as they are probably trying to focus on the best possible compounds in the clinic to invest in.”

Rupar compares the obesity drug debacle to the failure of most of the pulmonary insulin pipeline. “Once a couple of big drugs fall in trials, or the first-to-market drug gets pulled, companies who are following the same pathway get nervous, often get hit with similar problems, or re-evaluate and move on for the good of their overall portfolio,” he said.

So what does the future hold for cannabinoid receptor antagonists? The compound had been being considered for smoking cessation and drug rehabilitation treatments, but those indications also seem to have been put aside.

“This particular drug class is done now,” Wong said. “With three late-stage, high-profile failures, I don’t think anyone is going to try to get into this space now. I think the hurdles are just too high.”