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Why the FDA Said No to First In Class Dapagliflozin

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 9 to 6 against recommending the approval of the first in class novel antidiabetic agent dapagliflozin, largely because of fears that the product may cause breast and bladder cancer.

The EMDAC panel was also concerned about a lack of pharmacokinetic data in the sponsors’ presentation.

Dapagliflozin is a first-in-class medication that treats hyperglycemia through inhibition of the sodium glucose cotransporter-2 (SGLT-2) in the proximal renal tubules, where it is responsible for the reabsorption of approximately 90% of glucose filtered through the nephron.

See more SGLT-2 Resources

The drug’s glucose-lowering ability is related to the renal excretion of glucose. The effect is dependent on the amount of glucose filtered through the glomeruli and is independent of insulin secretion.

This method of action minimizes the risk for hypoglycemia. But it also makes dapagliflozin less effective when glomerular filtration rates decline because of the progression of renal impairment, according to FDA background materials.

Excess cancers seen in patients treated with dapagliflozin were a significant concern for some panel members. Doris B. Strader, MD, from the University of Vermont College of Medicine, Burlington, said she could not dismiss breast and bladder cancers as irrelevant or minor. She did not accept the sponsor’s explanation that the excess cancers in patients receiving dapagliflozin versus placebo were preexisting.

“I was concerned about the 5-fold increase and the inability to explain why these happened,” she said.

Another panel member who voted against recommending dapagliflozin for approval was impressed by the new agent. Edward W. Gregg, PhD, chief, Epidemiology and Statistics Branch in the Division of Diabetes Translation at the Centers for Disease Control and Prevention, Atlanta, Georgia, said that dapagliflozin is “a very encouraging drug from an A1c efficacy standpoint and possibly even effectiveness in cardiovascular disease reduction.” However, for Dr. Gregg, an overriding concern was the increased cancer risk. “There was a lack of clarity about who would not benefit from the drug, but that wasn’t a huge factor in my no vote. The big one for me was the magnitude of the risk ratio for the cancers. We clearly can’t say from the data that this drug caused the cancers. If the risk ratio was 1.5 to 2, I think we would have found ourselves able to dismiss it; but with a risk ratio of 4 and 5, that wasn’t the case,” Dr. Gregg explained.

“It was a little shocking to me that basic information about the drug and the mechanism of action were completely missed,” said panel member Kevin McBryde, MD, program director of pediatric nephrology at the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health in Bethesda, Maryland.

“I was quite interested in the drug because of its novel approach to the treatment of diabetes but coming at it from a nephrology perspective. I’ve learned in my career to have a tremendous amount of respect for the proximal tubule of the kidney. It is packed with mitochondria and it is truly a magnificent structure, and simply saying ‘I’m going to block SGLT-2 and it will have no other effect on the proximal tubule,’ is to give a tremendous discredit to the function of the proximal tubule,” he said.

Dr. McBryde said he was a “little surprised” that the sponsor had not done basic studies to find out the effects of proteinuria on the bioavailability of dapagliflozin. “To me a drug that you know is 91% protein-bound should have never been put into a patient without knowing what’s going to happen in hyperproteinemia and proteinuria. We know from numerous drug studies and experience that proteinuria induces drug resistance,” he noted.

Dr. Strader, was also struck by the absence of pharmacokinetic data. Additionally, she was concerned about a case of hepatotoxicity that was reported in 1 patient. “While I don’t think this 1 case is enough to disqualify the drug, it does raise some issues about the importance of monitoring patients with liver disease,” she said.

Abraham Thomas, MD, MPH, Henry Ford Hospital Whitehouse Chair of Endocrinology, Detroit, Michigan, who chaired the session, was 1 of the 6 committee members who voted to support the approval of dapagliflozin. “This is one of the first examples of a medication that is developed for diabetes that works in a different way. Almost all of the medications we have for diabetes take pathophysiology and try to improve it to normal physiology. This actually is taking physiology and making it into pathology, by increasing glucoseuria,” he said.

This is a strange paradigm for a new medication, he noted. “As a result, there are concerns about the side effects. The liver, bladder, and breast issues are very concerning, but I felt there is no way of knowing the answers unless we study more subjects.” Dr. Thomas said it was not realistic for these concerns to be studied before the drug is marketed.

Another panel member who was in favor of supporting approval was Ed J. Hendricks, MD, medical director of the Center for Weight Management in Sacramento, California. “I voted yes. I believe from the data presented here today that this will be an effective drug in treating diabetes. As a clinician, I like it for 3 reasons: 1, it is an oral drug; 2, it has absolutely nothing to do with insulin, so it doesn’t count on insulin action in any way, and I find that very attractive; and last but not least, it actually produces some weight loss, which is in contradistinction to many of the other diabetes drugs that produce weight gain,” he said. Dr. Hendricks agreed that the safety issues were of some concern, but he said he felt that postmarketing studies would settle some of these concerns.

“There are some things you just can’t learn from clinical trials. There’s a limit to what we can do in order to kick medicine forward and introduce innovative new things. We do have to make decisions that imply some degree of risk,” he said.

FDA panel news release July 20, 2011