Sept. 16, 2011 -- Companies developing three different weight-loss pills that were rejected by the U.S. Food and Drug Administration still believe they can eventually bring the products to market, though the firms are taking different approaches to winning over the agency.
Vivus Inc., which is developing an oral combination of the drugs topiramate and phentermine called Qnexa, said Thursday that it planned to submit a revised application for the product this October, sooner than it had first expected, after discussions with FDA staff.
The developer of lorcaserin hydrochloride (Lorqess), Arena Pharmaceuticals, recently announced that it had obtained encouraging results from new studies intended to answer the FDA's concerns, which centered on cancer risk and unimpressive efficacy.
Meanwhile, the company that is pursuing a combination of the drugs bupropion and naltrexone (Contrave) is mounting more of a frontal assault on the FDA. Orexigen Therapeutics said it was appealing the agency's demand for a new clinical trial through its dispute resolution process, and would focus on gaining approvals elsewhere in the world if it fails to change the FDA's mind.
The emergence of serious post-marketing safety problems with previous weight-loss drugs -- notably the combination of fenfluamine and phentermine known popularly as Fen-Phen -- has led the FDA to take a harder line on new products, insisting on detailed data for evaluating the balance of risks and benefits.
Vivus, Arena, and Orexigen received so-called complete response letters on their products during a three-month span from October 2010 to January 2011.
Qnexa's Way Forward
For Qnexa, the FDA had identified increased risk of psychiatric problems, cardiovascular effects, and, in women taking the drug during pregnancy, birth defects. These issues are believed to result mainly from the topiramate half of the combination, although psychosis is a recognized risk of phentermine as well.
Vivus said its new development plan calls for an initial application that would list "child-bearing potential" as a contraindication for the drug in obese women. It is currently conducting a retrospective analysis of electronic health records for some 2,500 children of women who took topiramate during pregnancy.
If results of that study exonerate topiramate, Vivus would then seek broader approval in all obese women as well as men. The company also has conducted other retrospective analyses showing minimal risk of birth defects associated with topiramate.
The company has not indicated how it plans to address the FDA's concerns about psychiatric or cardiovascular risks associated with the product, although new clinical trials do not appear to be on its agenda.
No New Contrave Trial
The agency told Orexigen in late January that it needed to conduct "a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug's benefit-risk profile."
In June, the company said such a trial would be "unprecedented and would generate significantly more information than is necessary or feasible."
It also expressed frustration that the FDA refused to consider approving the product for a restricted population without the additional cardiovascular safety data.
Orexigen has since been mum on further progress, other than to say last month that it was continuing with the dispute resolution process.
New Look at Crucial Lorcaserin Rat Study
Arena's lorcaserin was tripped up by data showing an increase in rat mammary tumors coupled with clinical efficacy results showing a mean average weight loss of 5 percent, the poorest of the three products. The FDA indicated that the drug's tepid efficacy failed to offset the safety risks.
The company has now produced a reanalysis of the two-year rat study, commissioning a group of independent pathologists to take another look at the tumor diagnoses.
The result: "Adenocarcinomas were no longer numerically higher than the control group in the lorcaserin low- and mid-dose groups," Arena said in a statement.
Another potential cancer risk mentioned by the FDA was astrocytoma, also seen in rat studies, though not in the drug's clinical trials. Arena has addressed this problem indirectly, with pharmacokinetic data indicating that the drug penetrates into the human brain at far lower rates than in rats.
As a result, the company suggested, lorcaserin concentrations in the human brain are probably much lower than rats at equivalent doses.
On the other hand, recently reported efficacy data for lorcaserin have confirmed that it seldom produces large weight loss. For example, a meta-analysis of three phase III trials reported in June, based on intention to treat, found that more than one-third of patients failed to lose 5 percent of body weight after one year and only about one-fifth lost 10 percent or more.
Arena has not said when it plans to ask the FDA to reconsider approving the drug.