Worries are emerging about the safety of new diabetes medicines Januvia and Galvus, drugs expected to be big sellers for makers Merck and Novartis. But it is unclear if the concerns are justified or just the result of a hair-trigger tendency concerning drug safety on the part of doctors and regulators.
On Monday, Novartis said the U.S. Food and Drug Administration wants it to run a new safety study of Galvus. Analysts say that could take another year; the pill has already been delayed for three months.
That follows a Feb. 1 article in The New England Journal of Medicine that questioned the safety data available for these drugs. David M. Nathan, a Harvard Medical School endocrinologist, wrote that it is "surprising" that the FDA decided to clear Januvia at all, given the "paucity of published data from long-term clinical trials on its safety and efficacy." Nathan, who is a consultant for Novartis and other drug makers but not Merck , did not return requests for comment.
The concerns represent a delicate situation for Merck, which has undergone a resurgence under Chief Executive Richard Clark. It rushed Januvia to market, pulling past Novartis after a late start. Now it will reap profits from Novartis' delay, booking an additional $130 million this year and $300 million next year, according to Timothy Anderson of Prudential Equity Group. Wednesday morning, Merck boosted its earning forecasts for the year by 4%, based on strong performance of its drugs. It also unveiled promising late-stage data on an AIDS drug that is expected to hit the market this year.
But the withdrawn pain pill Vioxx, for which Merck is still facing thousands of lawsuits, is a reminder that problems with one company's drug can hurt rivals as well. When Merck yanked Vioxx, investors at first thought Pfizer, which made rival drugs Celebrex and Bextra, would profit. Instead, Bextra wound up off the market as well, and Celebrex struggled for years before regaining its footing.
"We continue to actively monitor the safety of Januvia, as we do for all of our products,” Merck said in a statement. “The labeling for Januvia accurately reflects the safety profile of the product."
Januvia and Galvus are the leaders of a new class of medicines called DPP-4 inhibitors, which block an enzyme (dipeptyl peptidase 4). This enzyme normally breaks down a peptide, called GLP-1, that helps the body break down blood sugar. DPP-IV drugs are supposed to help patients control their diabetes with fewer side effects than older medicines. Nobody is pointing to an actual problem with these drugs, but some worry that potential problems have not been ruled out.
Merck's Januvia was approved after studies in 2,700 patients. James Underberg, a cardiologist at the New York University Medical Center who participated in trials of Januvia, says that the concern that the drug has been studied in only a limited number of patients is real, and that doctors should be cautious with new drugs. But he says Januvia is an important option for diabetes patients who cannot tolerate existing medicines because of side effects like diarrhea, weight gain and swelling.
"A lot of the medicines we currently have are difficult for people to take," Underberg says. "No one is saying this should be a first-line drug, but if you're a diabetic who is spiraling downward, you are grasping at straws." Underberg is a paid speaker for Novartis.
There are several potential concerns about DPP-4 drugs, clear evidence of them has not turned up in clinical trials so far. In theory, the medicines could affect the immune system, because a receptor on immune cells is very similar to DPP-4. In studies of monkeys, Galvus and another DPP-4 inhibitor being developed by Bristol-Myers Squibb and AstraZeneca have caused skin lesions. Merck says that its studies have not turned up this side effect, and that Januvia was designed to bind only to the DPP-4 enzyme, reducing the chances of these side effects.
Merck says its tests of DPP-4 inhibitors that also hit related enzymes turned up the side effect in monkeys where its own experiments did not. The company says that this research is continuing and that it is carefully monitoring the results.
It is not entirely clear how these safety worries relate to the clinical trial Novartis must conduct. On a conference call, James Shannon, the drug giant's head of clinical research, said the FDA wants more data studying Galvus in patients with impaired kidneys. It had been thought that Galvus might eke a marketing advantage over the fact that it is not processed by the kidneys, while Januvia is. But another molecule created when the body metabolizes Galvus does build up in the kidney.
Even if the trial is not specifically designed to look at either skin or immune system side effects, it is likely to turn them up if they exist. Patients with impaired kidneys have more of the drug in their bloodstream and would be more likely to experience side effects.
In a conference call with financial analysts, Shannon noted that the FDA division that is handling the Januvia application has been hit by a series of safety scandals.
Seven years ago, Rezulin, a Pfizer diabetes drug, was pulled from the market. In the past several months, studies of Actos and Avandia, from Takeda Pharmaceutical and GlaxoSmithKline, have failed to alleviate safety concerns with those drugs. A letter was recently sent to physicians involving Avandia's tendency to lead to osteoporosis. Then came Nathan's piece in the New England Journal. Two weeks ago, members of this division appeared in front of Congress to defend their handling of a failed diabetes drug developed by Bristol and Merck.