A major task confronting Arena as it pursues approval of Lorqess is to provide FDA with an explanation that shows the neoplasms found in rats during animal studies of the obesity drug are not a predictor of cancer risk in humans.

Concerns about potential carcinogencity contributed to a 9 to 5 vote against approval of Lorqess (lorcaserin) by FDA's Endocrinologic and Metabolic Drugs Advisory Committee Sept. 17, as members confessed to an inability to determine what the animal findings mean for the drug's impact on people.

"I have absolutely no idea how to translate animals to people so I feel particularly lost on this one," said Michael Proschan, a statistician at NIH.

Advisory Committee Vote

Panel voted 5-9 that the available data demonstrate the potential benefits of lorcaserin outweigh the potential risks when the drug is used long-term in a population of overweight and obese individuals

The occurrence of mammary neoplasms in female rats at low doses was the focus of the carcinogenicity discussion at the meeting, with FDA in search of a reason why it should not be a cause for concern.

"Right now we don't feel like we know how it works, and that's scarier than knowing how it works," Todd Bourcier, pharmacology team leader at the Division of Metabolism and Endocrinology Products, said. But, he added, "I think there is a path forward."

The discovery of mammary tumors in female rats during a two-year lifetime exposure study was at all doses, even the lowest and thus closest to human exposure levels, which meant there is no margin to provide comfort on the safety signal, FDA pharm/tox reviewer Fred Alavi reported. The preclinical study also found lorcaserin caused multiple types of tumors, including mammary neoplasms, in male rats at higher doses that represent a five-fold safety margin over clinical exposure.

Arena contends there is an explanation, and one that shows it is not a cause for concern in humans: the mammary tumors are due to lorcaserin-related increased production of prolactin, which does not have the same effect in humans as in rats.

Prolactin is not established as a factor in human breast neoplasia, company consultant Gary Williams, New York Medical College, said, noting that other drugs that increase prolactin and mammary neoplasia in rats have not been associated with breast cancer in humans.

As Bourcier alluded, if the explanation behind the mammary tumors in rats is related to prolactin, then that should be an explanation that FDA can work with.

Because of the rat findings, Arena evaluated chronic prolactin release during its Phase III program, finding that lorcaserin did not result in robust or sustained elevation in serum prolactin. While FDA – which had been aware of the preclinical finding and determined the clinical trials should proceed as planned – agreed with that finding, it noted that the studies do not rule out rare lorcaserin-related increases.

Arena also conducted mechanistic studies in female rats, but Alvari said those do not adequately support a role for prolactin in lorcaserin's tumorigenic mode of action, so "the relevance of lorcaserin-related mammary tumors in rodents to the obese patient population cannot be dismissed."

FDA understands the argument about prolactin, Bourcier said. "We just don't feel that the data supports that sufficiently."

If the prolactin explanation can be proven, then FDA has experience with constructing labeling.

If experiments can be designed "to clarify how does this happen … and we're able to define it a little better, then I think we're in a much better place," he noted.

If prolactin turns out to be the explanation and FDA understands how it is involved, then it can draw on experience with other drugs, such as antipsychotics, that cause mammary tumors in rodents and have been approved, he said. "There's experience there and we have some basis for it."

Arena's focus right now is on discussing options with the agency, CEO Jack Lief said during a Sept. 18 conference call. "We continue to believe that the findings are not relevant to humans."

Limited Patient Population Taints Efficacy Results

Even if the cancer issue can be cleared up, a request for a new clinical trial is not out of the question as FDA considers the advisory committee's efficacy concerns, a large part of which were based on the absence of diabetics and other high-risk patients from lorcaserin's two Phase III trials.

The Lorqess studies "used a very select group, a population that is not indicative of people that are going to use the drug," commented Lamont Weide, an endocrinologist at University of Missouri. Trial participants should include a significant proportion of diabetics, as well as people with other problems, such as high blood pressure and thyroid conditions, he contended.

A study of Lorqess in 600 diabetics has been completed and Arena expects the results to be available by the end of the year. But a study that small "is not going to give us what we need," Weide said.

Noting that there were 42 exclusionary criteria in one Phase III study and 35 in the second one, Sanjay Kaul, a cardiologist at Cedar Sinai Medical Center in Los Angeles, contended that "we have no idea what the benefit/risk is" in the population that will use Lorqess.

"If you use such a selective patient population where you filter out patients that are less likely to respond in terms of weight loss, and are less likely to experience an adverse outcome, you overestimate efficacy and you underestimate risk," he concluded.

By using a highly selective patient population, Arena's trials may have overestimated efficacy and underestimated risk, Kaul said.

Acting Chairman Abraham Thomas, Henry Ford Hospital, also pointed out that the clinical trial results are "probably the best that you're going to get." The likelihood of achieving the same results in clinical practice "is much smaller."

During the pivotal trials, about 47% of patients receiving the proposed lorcaserin dosage of 10 mg BID lost at least 5% of their baseline body weight during year one, compared to about 23% of placebo patients. This only slightly met the criterion for the proportion of drug-treated patients achieving that goal to be twice that of the proportion in the placebo group, which is one of the two efficacy standards laid out in FDA's 2007 draft guidance on obesity drugs.

Lorcaserin's ability to meet only one of the guidance's criteria also was a concern for panel members. The difference in the adjusted mean percentage change in weight from baseline between the 10 mg BID and placebo arms was 3.7% in one trial and 3% in the other. Both these figures failed FDA's other efficacy criterion – at least a 5% difference between weight loss in the active-product and placebo-treated groups.

If Arena does have to conduct another clinical trial, it will have Eisai to help foot the bill. With fortuitous timing for the San Diego-based firm, the Japanese company acquired U.S. marketing rights to the weight management drug July 1. As part of that deal, Easai agreed to split regulatory costs evenly up to U.S. approval ("Arena Scores Hefty Obesity Drug Deal With Eisai Ahead of PDUFA Date," "The Pink Sheet," July 2, 2010).

Even without lorcaserin approval this year, Lief said Arena expects to end the year with $142 million to $152 million in cash, as predicted in earlier projections.

Arena is seeking approval for Lorqess for weight loss and maintenance of weight loss for obese patients (a BMI equal to or greater than 30 kg/m) or overweight patients (a BMI equal to or greater than 27 kg/m) with at least one weight-related co-morbidity. FDA's user fee deadline for action on the application is Oct. 22.

By Cathy Dombrowski

Arena Must Deal With Rat Neoplasms To Move Forward With Lorqess

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