When the FDA issued a complete response letter last month for the Arena Pharmaceutical diet pill, the agency cited a few reasons: pending results of a trial in 604 patients with diabetes, concerns that the pill may cause tumors in rats and efficacy was marginal (look here). There was no mention, however, of another issue that two months ago prompted an FDA advisory panel to reject the drug in a 9-to-5 vote: valvulopathy, which is heart-valve disease (see this).

Now, though, that issue might just be revisited. This morning, Arena issued the results of the awaited trial for its Lorqess pill and valvulopathy cropped up again. After 52 weeks, 2.9 percent of the people on the diet drug developed valvulopathy, compared with just 0.5 percent on a placebo. Arena, however, says the trial was not powered to detect “meaningful differences” in the incidence of valvulopathy and heart problems have not emerged as an issue in previous trials.

The trial did offer some good news for Arena: 37.5 percent of patients taking Lorqess twice a day lost at least 5 percent of their weight, more than double the 16.1 percent of those on a placebo. And those on the drug had a mean weight loss of 4.5 percent versus 1.5 percent on placebo. This meets one of two FDA criteria for diet drugs: at least 35 percent of the patients must lose at least 5 percent of their weight and their weight loss must be double the percentage of patients on a placebo. And hemoglobin glycation for Lorqess patients was 0.9 percent compared to 0.4 percent on from placebo. There were also improvements in fasting glucose, HDL cholesterol and triglycerides.

Just the same, valvulopathy could become a factor for one simple reason: the mechanism in Lorqess is similar to the mechanism in fenfluramine. Both are designed to block appetite signals in the brain. And this was the half of the fen-phen weight-loss cocktail that Pfizer’s Wyeth recalled in 1997 - along with a chemically similar pill called Redux - due to a fatal lung disease and heart-valve problems.

Some analysts and many investors are confident the FDA will eventually approve Lorqess. But given the increasing emphasis on safety issues at the agency, the results suggest that it would not be surprising if Arena encounters yet another delay. As Hapoalim Securities analyst Jon LeCroy writes in an investor note: “In our view, any valvulopathy signal is extremely concerning as numerically increased valvulopathy rates were not seen” in previous trials called Bloom or Blossom.

On the other hand, Leerink Swann analyst Steve Yoo writes that the safety profile looks okay and adds that “the FDA did not raise concerns about valvulopathy in the complete response letter. so this is unlikely to become an issue.” Even if the pill is approved, data showing heart-valve disease will likely be one more reason third-party payers will balk at coverage, which will make it harder to grow revenue.

pic thx to alan cleaver on flickr