The first of a highly anticipated class of diabetes drugs assessed by the US Food and Drug Administration (FDA) got the thumbs-down from the agency’s Endocrinologic and Metabolic Drugs Advisory Committee yesterday. The FDA panel rejected dapagliflozin, developed by Bristol-Myers Squibb and AstraZeneca, by a 9–6 margin.
Unlike current type 2 diabetes medicines, which modulate insulin activity to affect sugar levels in the bloodstream, dapagliflozin regulates blood sugar independently of insulin by preventing the protein sodium-dependent glucose cotransporter 2 (SGLT2) from reabsorbing glucose into the kidney. Usually, this simple sugar is dumped back into the bloodstream, inducing a symptom known as hyperglycemia. But dapagliflozin and similar drugs in development cause the kidney to excrete the excess glucose into the urine.
These SGLT2 inhibitors excite researchers and doctors because they provide “a new option for patients with diabetes with a totally different mechanism of action,” says Steven Shoelson, head of pathophysiology and molecular pharmacology at the Joslin Diabetes Center in Boston who is not involved in the development of these drugs.
In phase 3 trials, dapagliflozin proved to regulate blood sugar and even caused weight loss in many of study subjects. However, the FDA panel voted down the drug because of safety issues. Notably, patients taking dapagliflozin had higher rates of breast and bladder cancer compared to those in the control arms of the trials.
Looking ahead, other drugmakers developing experimental SGLT2 inhibitors will have to “be very careful to make sure that they do sufficient numbers of people to test [cancer incidence] adequately,” says Shoelson. Johnson & Johnson have a drug called canagliflozin in phase 3 trials, and Boehringer Ingelheim and Lexicon Pharmaceuticals have a related agent in phase 2 testing.
The FDA doesn’t have to follow the recommendations of its advisory panels, but it usually does. A final decision is due 28 October.
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