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FDA advisory committee: Saxagliptin has no unacceptable CV risk
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The agent is under review for treatment of type 2 diabetes.
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 10-2 that evidence of cardiovascular safety with saxagliptin is sufficient to rule out unacceptable, excess cardiovascular risk with the drug.
The committee met to evaluate whether saxagliptin (Bristol-Myers Squibb) met recommendations from an FDA guidance released in December 2008, which recommended manufacturers developing new type 2 diabetes drugs provide evidence that the therapy will not increase risk for CV events.
Since saxagliptin trials were completed prior to the new guidance, post-hoc evaluation of CV events was performed on randomized, controlled periods for completed phase-2 and -3 trials.
The FDA requested cardiovascular analyses using two endpoints: Standardised MedDRA Queries for MI and Central Nervous System Hemorrhages and Cerebrovascular Accidents (SMQ MACE) and Custom MACE, a subset of SMQ MACE.
“Saxagliptin was caught in the interregnum between the former cardiovascular requirements and the new publication of guidelines in December 2008, and any effort to assess data in such a study will intrinsically have flaws. We have taken those into account the best way we can,” said Kenneth Burman, MD, who voted in favor of the ruling. Burman is chief of the Endocrine Section in the Department of Medicine at Washington Hospital Center in Washington D.C.
However, Kathleen Wyne, MD, PhD, who voted against the ruling, said that “the numbers of events are too low to provide an adequate assessment. It is a restricted population, so it does not give us a good overall assessment of cardiovascular safety.”
Wyne is assistant professor in the Division of Endocrinology and Metabolism at the University of Texas Southwestern Medical School in Dallas.
Although the majority of the committee voted that prospective review of findings from saxagliptin trials demonstrated cardiovascular event safety, all voted “no” in response to whether data were adequate to deem post-marketing CV trials unnecessary.
Data presented included 11 CV events in 24-week, short-term study periods and 40 CV events from short-term and long-term study periods with a median 62-week exposure. Based on these data, the committee felt further long-term, post-marketing studies including higher-risk patients were necessary.
“I worry about approving a drug and not requiring any longer-term trial, regardless of the drug,” Michael Proschan, PhD, mathematical statistician in the Office of Biostatistical Research, National Heart, Lung, and Blood Institute, said during the committee meeting.
“There is enough uncertainty for a longer-term trial and perhaps enrollment of people with coronary disease, so we can obtain further evidence,” he added. – by Christen Haigh