FDA Advisory Committee Votes 9 to 6 Not to Approve Dapagliflozin
Alan J. Garber, MD, PhD, FACE
On July 19, 2011, the US Food and Drug Administration (FDA) conducted a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to evaluate the new drug application dapagliflozin, manufactured by Bristol-Myers Squibb and AstraZeneca. The Advisory Committee voted 9 to 6 not to approve dapagliflozin.
The presentation by the sponsor relied on the BMS and AZ personnel together with a large number of outside consultants. John B. Buse, MD, PhD, CDE, gave the initial presentation, noting that the “safety concerns with dapagliflozin seem modest and on par with other accepted agents.” The presentations closed with James R. Gavin, III, MD, PhD providing comment on the risk benefit of dapagliflozin and his belief that it was safe and effective. The A1c was non-inferior to sulfonylureas and metformin, and a weight loss of 2 kg greater than the placebo was noted.
During the meeting, it became apparent that the data were insufficient in a number of areas, including the effects in patients with proteinuria and decreased GFR. The trials used metformin renal criteria so very few had a GFR <60 ml/min. Dapagliflozin had little effect in patients over age 65, perhaps because of decreased renal function. The A1c reduction with GFR <60 was 0.1%. Dapagliflozin had a diuretic effect and decreased blood pressure, but increased hematocrit.
The FDA presentation to the Advisory Committee indicated that there are large concerns regarding dapagliflozin and increased risk of breast and bladder cancer. It was noted that there were clear imbalances with an increased risk of 4-5 fold but not statistically significant. Other concerns included the doubling of genitourinary infections and urinary tract infections, but not pyelonephritis. In addition, the bone evaluation displayed calcuria and a DXA scan was used to assess bone changes at one year, but no changes were noted. There may have been an increase in PTH levels at one year. It was also concerning to the committee that the liver evaluations had five possible and one probable cases of liver toxicity, one of which met the criteria for Hy’s law regarding drug induced liver toxicity.
The Advisory Committee’s presentation criticized the “durability study” given that patient completion was 21-43% of enrollees at 104 weeks, which is a very poor retention rate. Additionally, there was one failed study in the reduced creatinine clearance (30-50 ml/min) group. The FDA estimate for malignancy was a 4-5 fold increase over comparator arms.
Public speakers at the meeting included Kelly Close, President of Close Concerns, Diane Zuckerman, PhD, President of the National Research Center for Women & Families, and Sidney Wolfe, MD, Director of Health Research Group. Ms. Close expressed a positive outlook on dapagliflozin, while Dr. Zuckerman and Dr. Wolfe indicated a negative perspective on the drug.
During the discussion by the Advisory Committee it was noted that BMS and AZ may need to conduct a randomized control trial of 30,000 patients to define the cancer risk, or at least 100,000 patients if using an epidemiologic approach. The Advisory Committee indicated dapagliflozin will need further long-term evaluations of the concerns regarding infections and the bone. There was significant discussion on how to approach these problems. The Advisory Committee seemed to like the idea of a new drug, especially an option with weight loss and minimal hypoglycemia, but was very concerned about the undefined risks of dapagliflozin. BMS-AZ was criticized for a lack of obvious studies, such as kidney-related and bone issues.
Mary Parks, MD, Director of FDA's Division of Metabolic and Endocrine Drug Products, indicated that the FDA will consider the committee’s concerns and reevaluate dapagliflozin and weigh the risks of this agent as opposed to its therapeutic potential.