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FDA Panel Votes 9-6 Against Dapagliflozin

http://online.wsj.com/article/SB10001424052702303795304576456540086097846.html

›JULY 20, 2011
By JENNIFER CORBETT DOOREN

A federal advisory panel voted against a new type of diabetes drug being developed by Bristol-Myers Squibb Co. and AstraZeneca PLC and said more information is needed to address certain safety concerns before the drug should be marketed.

The panel voted 9 to 6 against a question that asked if the efficacy, or effectiveness, and safety data submitted by the companies in support of the drug, dapagliflozin, provided substantial evidence to support approval. The vote amounts to a recommendation that the FDA not approve the drug without more data. The deadline for an FDA decision is Oct. 28.

Several of the panel members who voted against the drug said they struggled with their decisions, but were concerned about safety signals seen in clinical studies of the drug that included breast and bladder cancer.

Panel members who voted in support of dapagliflozin said they were also concerned with the potential cancer and other risks, but said that more information on those risks could only be discovered in large registries and post-marketing studies that could be set up after the product is approved. Studies conducted in support of a drug approval aren't usually designed to be large or long enough to fully address certain safety issues like cancer takes years to develop.

Mary Parks, the director of FDA's endocrinology division, suggested the agency will pay more attention to the panel's discussion rather than the actual vote, telling panel members after the vote, "you have highlighted the difficulty of the benefit-risk decision."

One panel member, Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, recommended the agency approve dapagliflozin with the strongest boxed warning discussing cancer risks until more data could be collected.

Dapagliflozin is the most advanced candidate in a new class of drugs known as sodium-glucose co-transporter-2 (SGLT2) inhibitors. Such drugs are designed to lower blood glucose levels in patients with diabetes by increasing the amount of glucose excreted in the urine. The SGLT2 system is used by the kidneys to filter and reabsorb glucose circulating in the blood. Other companies developing SGLT2 inhibitors include Johnson & Johnson, Boehringer Ingelheim GmbH and Astellas Pharma Inc.

In materials prepared for Tuesday's meeting the FDA said dapagliflozin was effective at lowering blood sugar levels but had several "unexpected" safety issues.

The agency said some of the safety issues included an imbalance in breast and bladder cancers as well as one possible case of liver injury that might be drug-related. However, the agency also said the product didn't appear to be associated with "excess cardiovascular" risk that have been seen with some other diabetes drugs like Avandia.

In a safety update released last month, the companies said there were nine bladder cancers seen in 5,478 patients being treated with dapagliflozin compared to one seen among 3,156 patients who were in control groups and not being treated with the drug. Nine breast cancers were reported among 2,223 women in the dapagliflozin groups, compared to one among 1,053 women not receiving the drug. The safety update included an additional study that was not part of the original drug application submitted to FDA.

Most of the cancers were diagnosed in the first year of the studies, which the companies said makes it unlikely the drug played a role as cancers usually take a long time to develop [#msg-64636960]. Company officials said they would continue studying the safety issues in clinical studies and a surveillance system that would be set up to track drug side effects after approval.

Diabetes affects about 26 million Americans and is characterized by high blood-glucose levels caused by the body's inability to either make or properly use insulin. Type 2 diabetes is the most common form of the disease and is often associated with weight gain and older age. Type 1 is an autoimmune disease often diagnosed in children in which the body's immune system destroys pancreatic beta cells that produce insulin.‹