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What BMS, AstraZeneca must show FDA for dapagliflozin in diabetes

With an FDA panel wanting more data on diabetes candidate dapagliflozin from Bristol-Myers Squibb Co. and AstraZeneca plc, the pharmas' best bet is to convince the agency they can address safety concerns with further analyses of existing data and postmarketing studies.

FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 9-6 last week against approving dapagliflozin. During the discussion, all the panelists agreed the sponsors need to show more safety and subpopulation data. They had mixed opinions on whether the data should be generated before or after approval, but that was not a question they were asked to vote on.

Doctors have been hoping to use the sodium-glucose cotransporter 2 (SGLT2) inhibitor as a second-line treatment because it is oral, causes weight loss, has no intrinsic risk of hypoglycemia, has potential to provide cardiovascular benefit and appears to be as efficacious as some second-line diabetes drugs(see BioCentury, July 4).

However, safety signals in clinical trials are likely to delay the drug, particularly a non-significant increase in the incidence of breast and bladder cancers and one case of severe liver injury that was probably caused by dapagliflozin.

Panelists also questioned whether the companies had identified the appropriate patient population. Indeed, they scored the sponsors for failing to prospectively characterize the enrolled patients, which the committee said could have addressed many questions up front.

Bristol-Myers and AstraZeneca declined to discuss the panel's conclusions other than to say they remain committed to the program.

Potential benefits

Dapagliflozin is a first in class compound being reviewed to improve glycemic control in Type II diabetes.

SGLT2 is a transporter protein found exclusively in the kidneys that promotes reabsorption of glucose into the bloodstream. Blocking the protein increases the amount of glucose excreted in urine, thus lowering plasma glucose and reducing hyperglycemia.

Removing about 400 Cal/day of glucose from the blood also causes

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