Orexigen’s Contrave among weight-loss drugs that face uncertain future with FDA

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Orexigen’s Contrave, the final anti-obesity agent to be reviewed later this year by the FDA, faces an uncertain future in light of the strict requirement for safety, the fact that the drug has provided modest weight-loss and the general stigma surrounding obesity.

The obesity space has notoriously been plagued with safety issues, perhaps most notably by withdrawal of Fen-phen, which caused heart value problems. Recently, the FDA came to a split decision on whether Abbott’s Meridia should remain on the US market since the drug has also been linked to cardiovascular problems. Earlier this summer, Vivus’ Qnexa failed to receive recommendation for approval despite its efficacy, due to the fact that it was shown to cause depression, memory problems and placed women at risk for birth defects. The FDA will make a final decision on the drug late next month.

Competing company, Arena Pharmaceuticals met a similar fate last week when the FDA voted against the drug Lorqess, touted to be a safer half of Fen-phen, since the drug provided little weight-loss and caused cancer in rats. Shares have since fallen more than 50 percent. The FDA was also looking for more data regarding the safety of the drug in patients at higher risk for heart problems.

Contrave is a combination of two approved drugs (naltrexone and bupropion SR or Wellbutrin). Bupropion has the potential to increase pulse and blood pressure because of the way it works, Dr Frank Greenway, professor and director of outpatient clinical research at Pennington Biomedical Research Center and an investigator for the drug explained to Pharmawire.

One concern is that the drug did not reduce patient’s blood pressure as much as those given placebo despite that fact that they did lose weight in clinical trials. Typically, weight-loss is associated with an improvement in blood pressure among other heart related measurements.

The FDA wants to be sure that markers of heart function like blood pressure do not get worse when using any weight-loss drug, said Greenway. Companies may need to run studies to prove that their drug does not increase patient’s risk for side effects such as a heart attack, which could take years to complete, Dr Edward Saltzman, chair of the department of nutrition sciences at the Friedman School of Nutrition Science and policy associate professor of nutrition and medicine at Tufts University explained. However, it is unclear how long safety studies should be since Fen-phen was so unpredictable, he said.

In light of the issues with Meridia, the FDA may be worried about this signal, said Dr Caroline Apovian, director of the Nutrition and Weight Management Center at Boston University Medical Center and a Contrave investigator. However, the drug has been shown to work and both agents are currently approved, so it is unlikely to stop the FDA from approving the agent, she said.

But while patients taking Contrave lost more weight than those given placebo, effects were modest and similar to those seen Meridia, said Dr Lee Kaplan, director of the weight center at Massachusetts General Hospital.

The key question is whether obesity is serious enough to treat and whether these side effects are worth the trade-off, said Kaplan.

Bupropion also carries a risk for seizures. According to Apovian, Wellbutrin has been used as a first-line antidepressant for obese patients, but she agreed that there may be more seizures associated with Contrave since any weight-loss drug is likely to be widely prescribed.

This large demand for an anti-obesity agent had decreased the FDA’s tolerance for any side effects that could potentially affect millions of patients. Even if a drug were limited to certain patients, the FDA is concerned that doctors would prescribe it to patients that were not included on the label, said Dr Patrick O’Neil, professor in the department of psychiatry and behavioral sciences at the Medical University of South Carolina and vice president of the Obesity Society.

Further complicating approval for a weight-loss drug is the general notion that obesity is not a disease, said Dr Timothy Garvey, Butterworth Professor and chair of the department of nutrition sciences at the University of Alabama at Birmingham. A regulatory consultant also noted that some European experts are beginning to think that the weight-loss provided with a drug does not provide the same benefits as those that come with diet and exercise.

However, lifestyle intervention is not available to most patients and the introduction of a new anti-obesity drug could provide an additional tool for clinicians, Garvey said.

Dr Robin Blackstone, a surgeon at the Scottsdale Healthcare Bariatric Center and Secretary/Treasurer elect to the Executive Council of the American Society of Metabolic and Bariatric Surgery noted that obesity is a complex chronic disease that cannot be addressed with one tool, but will require drugs in addition to other methods such as surgery and diet and exercise.

According to the CDC, The latest estimates find that approximately 34 percent of U.S. adults aged 20 and over and 17 percent of children/teens aged 2-19 are obese.

A panel of experts will review Contrave on 7 December, 2010 and the FDA will make a final decision regarding approval by 31 January 2011.

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