On Tuesday, July 19, 2011, Bristol-Myers Squibb Company (BMY) will present their case before the FDA Advisory Committee for dapagliflozin for the treatment of diabetes. This drug is the front runner in a new class of diabetes drugs called SGLT2-inhibitors which reportedly enhances excretion of glucose via the kidneys. With such a unique mechanism of action, attention naturally focuses on intact kidney function for a reliable drug effect. Herein lies my first issue. BMY enrolled over 6000 patients in the trials with over 4000 on dapagliflozin. They included a full range of patients with kidney disease – normal, mild, moderate and severe. As would be expected, those with severe kidney failure didn’t do well on the drug. What is surprising is the response of the patients with moderate kidney failure. Using a post hoc analysis, they split the “normal” moderate range of roughly 30-60 mL/min/1.73m2 in half and showed, as would be expected, those with better kidney function performed better. The question is not so much the post hoc analysis (everyone does it to a certain degree) but rather, is it a reasonable to redefine “moderate” kidney function to gain drug approval? If not, they will have to abandon all of the moderate kidney function patients and label the drug for normal and mild kidney function patients. Is this a risk the FDA wants to take?
The efficacy of the drug in these normal and mild kidney function patients seems adequate, so we don’t have to dwell on it. But, we do have to look at the other safety signals that the FDA wants the Advisory Committee to address. While the FDA agrees that there is no CV risk, they curiously state that “a CV outcomes trial is necessary to better charaterize CV safety…”. There is at least one case of dapagliflozin induced liver injury cited by the FDA reviewer. There are 9 cases of bladder cancer on drug compared to 1 on control, and 9 cases of breast cancer on drug compared to 1 on control.
The FDA has only asked 2 basic questions to help them get at the benefit risk determination. Is it an effective glucose lowering agent? The answer to that is probably yes, in patients with normal or mild kidney disease. Does the efficacy outweigh the risk? The answer to this is, we probably don’t know. The bottom line for the Advisory Committee should be there is an unknown benefit/risk ratio associated with this drug. These unknowns about CV safety, liver injury, bladder cancer and breast cancer, not to mention the issues associated with patients with moderate kidney disease should be addressed before the drug is added to all of the other drugs that effectively treat diabetes today.