FDA fails to endorse new wt. loss drug

From MedScape: http://www.medscape.com/viewarticle/728705

A US Food and Drug Administration (FDA) panel today has refused to endorse the weight loss drug lorcaserin (Arena Pharmaceuticals, Inc), voting 5 to 9 against approval.

The vote, by the Endocrinologic and Metabolic Drugs Advisory Committee, was an arduous one. Many panel members said they hoped the drug would eventually be approved because they believed it had potential to help obese individuals achieve their weight loss goals.

Arena was seeking approval of its novel 5HT2c receptor agonist to be given in a dose of 10 mg twice daily as an adjunct to diet and exercise for the treatment of obesity in patients with a body mass index of 30 kg/m2 or more, or 27 kg/m2or more if the patient also had obesity-related comorbidities.

Major safety concerns with lorcaserin included the increased cancer risk, particularly brain and breast tumors, seen in animal studies and the potential for lorcaserin-induced valvular heart disease.

Speaking for the sponsor, Gary Williams, MD, from New York Medical College, New York City, and an expert in the relevance of preclinical studies to human studies, told the FDA and the Endocrinologic and Metabolic Drugs Advisory Committee that neoplasms in rats are not predictive of human risk and insisted that lorcaserin does not pose a threat to humans at the recommended dose.

The panel did not appear to be too concerned about lorcaserin's potential for valvular disease and spent a brief time discussing whether adequate evidence had been provided to assess the potential risk. A few committee members ventured an opinion. One was Heidi M. Connolly, MD, professor of medicine, Mayo Clinic, Rochester, Minnesota. Dr. Connolly said she thought there was evidence for some degree of valvular regurgitation and suggested follow-up echocardiograms would be reasonable to do if the drug were marketed.

"I think this is a promising drug. I thought the weight loss, although not great, was acceptable, and the profile of risk factor benefits was encouraging, and there wasn't any clear evidence that this was a dangerous drug," commented Edward W. Gregg, PhD, from the Centers for Disease Control and Prevention, Atlanta, Georgia.

Despite this, he voted against approval. "There was enough doubt raised about some of the risks that forced me to take a harder look at what I saw as the crux of the benefit. On balance, I think the drug is promising, but it's not quite there yet in terms of showing the evidence."

One panel member who voted yes, Jodie B. Siegel, MD, MPH, from Johns Hopkins University, Baltimore, Maryland, said she thought the sponsor met the efficacy requirements but agreed that the cancer risk "feels a little unsettled." She suggested that the postapproval period would need very active surveillance to look for possible brain and breast cancer development in patients taking the drug.

Allison B. Goldfine, MD, from Harvard Medical School and the Joslin Diabetes Clinic, Boston, Massachusetts, also voted yes. "I found this a very hard decision to make. The drug showed a very small magnitude of weight loss, but I think that that can be clinically quite important." She added that, should the drug be approved, patients using it should be counseled about the potential risk for breast cancer.

Another thing that bothered the panel was the exclusion of patients with other comorbidities, including patients with diabetes, from the studies under consideration.

Panel members complained that there were not enough data on patients with diabetes, hyperlipidemia, and cardiovascular disease. "Because of these low rates of these diseases, we may not have a viable estimate of true efficacy or risk," said Abraham Thomas, MD, MPH, from Henry Ford Hospital, Detroit, Michigan, who was acting chair of the panel.

Dr. Thomas voted yes, and similar to many other panel members, admitted it was a very hard decision to make. "I was vacillating between yes and no for quite a while in preparation for this meeting, and even throughout this day. The reason for that is because the actual efficacy is very small."

He added that his concern was that the efficacy was in a very selected population that was generally healthy for an obese population. "When this is translated into clinical practice, the weight loss is going to be much smaller, and then you wonder: Is it worth taking compared to placebo?"

Similar to others who voted in favor of approval, Dr. Thomas noted that the sponsor met the FDA's criteria for benefit. "I think they did their best to try and assess many of the other risks that [were] concerned with this type of agent, including valvular heart disease."

He also said he was concerned about the tumor issues. "There has to be some type of registry with very significant follow-up if approved to look at these agents, and if there are any animal studies that could be done, they probably should be started now."

In explaining his yes vote, Michael A. Proschan, PhD, statistician at the National Institutes of Health, Bethesda, Maryland, said his decision to vote in the affirmative was a close one, made by a small margin. "I agree that there are doubts stemming from the fact that the population was pretty restricted and from the troubling results in some animals. However, I don't know how to translate that to humans, and the evidence in people did not really raise a huge safety flag in my mind."

Sanjay Kaul, MD, from the Division of Cardiology at Cedar Sinai Medical Center, Los Angeles, California, who voted no, said the evidence was not sufficient to persuade him that a desirable benefit had been demonstrated.

"A highly selected patient population that is not representative of the real world was chosen, and disease conditions that cluster with obesity were either excluded or minimally included," he said. "As a result, in my opinion, the benefit was likely overestimated, and the risk was likely underestimated."