US FDA panel rejects BMS/AstraZeneca diabetes drug on cancer, liver injury concerns
This article was originally published in Scrip
Bristol-Myers Squibb's and AstraZeneca's chances of being the first to the US market with a sodium glucose co-transporter-2 (SGLT-2) inhibitor may be in jeopardy after a US FDA advisory panel was unwilling to back the firms' investigational Type II diabetes drug dapagliflozin.
The Endocrinologic and Metabolic Drugs Advisory Committee voted 9 to 6 that the efficacy and safety data failed to provide substantial evidence to support approval of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with Type II diabetes.
"We are lowering our probability of success for dapa from 55% to 20%," said ISI Group analyst Dr Mark Schoenebaum.
Although dapagliflozin at the 5mg and 10mg doses demonstrated statistically significant reductions in HbA1c as a monotherapy and add-on treatment, ranging from -0.4% to -0.8%, versus 0% to -0.4% in the placebo groups, the panel voiced concern about the higher-than-expected rates of breast and bladder cancers in study participants treated with the drug. The committee also expressed worry about one study participant deemed by the FDA as having met the criteria of Hy's law for drug-induced liver injury (DILI) (scripintelligence, 18 July 2011).
"There was just too many unknowns about the safety of the drug," said panelist Dr Kevin McBryde, director of pediatric nephrology at the US National Institute of Diabetes and Digestive and Kidney Diseases.
Dapagliflozin lowers blood glucose levels by blocking reabsorption by the kidneys, causing large amounts of glucose and its associated calories to be excreted with urine, explained Dr Elisabeth Svanberg, vice president of development for dapagliflozin at BMS.
That loss of calories from urinary excretion of glucose also resulted in a "modest" reduction in weight in study participants, which was largely attributed to a decrease in body fat mass, said Dr Shamik Parikh, executive director of clinical development for cardiovascular and gastrointestinal at London-based AstraZeneca.
Dr John Buse, director of diabetes care at the University of North Carolina, noted that most diabetes drugs are associated with weight gain.
The added benefit of weight loss, coupled with the good efficacy in lowering A1c, plus the fact that dapagliflozin can be taken irrespective of means "addresses the unmet need nicely" for Type II diabetes, a disease that affects about 26 million Americans, or 8% of the US population, costing the nation about $174 billion per year, Dr Buse said.
But many on the FDA's panel could not get past the nine breast and nine bladder cancers in dapagliflozin-treated patients in BMS' and AstraZeneca's studies, which the FDA said "exceeded the expected number of cases" in the general Type II diabetes population.
"The breast and bladder cancers I can't dismiss as being irrelevant or minor," said panelist Dr Doris Strader, associate professor of medicine at the University of Vermont College of Medicine in Burlington.
But while the breast and bladder cancer signals were a "credible concern," panelist Dr Sanjay Kaul, director of cardiology at Cedars-Sinai Medical Center in Los Angeles, argued those safety issues could be mitigated through the addition of a black-box warning in the labeling for dapagliflozin, if the FDA permits it to be marketed in the US, "until we have resolved the uncertainty around it, if it can be done".
He joined other panelists in declaring that it would be nearly "impossible" for BMS and AstraZeneca to conduct a premarket trial large enough to rule out the risk of cancer, with many on the committee insisting that such a study would need to involve at least 30,000 patients, if not up to 100,000.
Dr Kaul also was joined by a handful of panelists who contended there may have been some "detection bias" involved with identifying the cancers, arguing that women in the trials may have been more likely to discover breast cancer after losing weight from taking dapagliflozin and the nine bladder cancers may have been more easily detected because of the increased testing for urinary tract infections – a adverse effect of the drug – resulting in the identification of blood in the urine, or hematuria, a symptom of the disease.
"Although there is a scare factor to the word cancer, seeing patients with diabetes, that is a devastating disease. I don't feel we have enough treatments available in our armamentarium," insisted panelist Dr Ellen Seely, a professor of medicine at Harvard Medical School.
Even though panelist Dr Erica Brittain, a statistician at the National Institute of Allergy and Infectious Diseases, said she thought the evidence linking dapagliflozin to cancer in BMS' and AstraZeneca's trials was "fairly weak," it was the "uncertainty" that persuaded her to vote against approval of the drug.
Dr Brittain said, however, that she was "on the fence" about whether the FDA should require more data before or after dapagliflozin enters the US market.
"What is important is that you get more information," she told regulators.
But Dr Strader said she would be "very uncomfortable about subjecting the diabetic population to potential risks in postmarketing studies".
She insisted that studies done before a drug is approved are completed "for a reason".
"And when we find issues that are concerning we should not ignore them but try to find thoughtful ways of being able to balance the benefit of the drug with the potential patient risk," Dr Strader said.
But panelist Dr Ed Hendricks, medical director of the Center for Weight Management in Sacramento, California, argued that "there are some things you just can't learn from clinical trials".
While he said he was "concerned" about the cancer and liver injury signals in the dapagliflozin studies, "I'm satisfied postmarketing studies will settle some of those issues".
"To introduce innovative new things, we do have to make decisions that imply some degree of risk," Dr Hendricks added.
While Dr Strader said she was concerned about the potential for hepatoxicity with dapagliflozin, she said the one "probable" case of DILI may not be "enough to disqualify the drug".
Dr Leonard Seeff, hepatology consultant for the FDA's Office of Surveillance and Epidemiology, explained that there is "no way of making a definitive diagnosis of drug-induced liver injury" with a new drug that has no marketing history.
"All you can do is exclude every other known cause," he said, noting that the National Institutes of Health has defined "probable" DILI as having 51% to 74% certainty.
"We struggle with this all the time," Dr Seeff said.
Dr Strader urged the FDA to develop better guidelines for trial investigators to determine what steps to take when a case of DILI is suspected so they can more clearly determine the causality.
Several members of the FDA's committee said they were disappointed that BMS and AstraZeneca included so few patients over 75 years in the dapagliflozin trials, with less than 3% of the patients in that age group getting the drug, while only about 20% were over 65 years.
The studies also included few African American patients, only about 3.4%.
"We need more information of efficacy in the subgroups that have the burden of diabetes on them," said panelist Dr Ida Spruill, an assistant professor at the Medical University of South Carolina in Charleston.
Dr Kaul, who insisted the panel "agonized" over the 19 July vote, told the FDA that any follow-up studies of dapagliflozin should have at least half the population consisting of patients over 65 years, with more than a quarter over 75. Those trials also should include more patients with moderate renal insufficiency, with at least half also having a prior history of cardiovascular disease.
The FDA is expected to make a decision on dapagliflozin by 28 October, the drug's Prescription Drug User Fee Act action date.