FDA staff suggest AstraZeneca's diabetes drug Onglyza linked to higher rate of death

In documents released Friday ahead of an FDA advisory committee meeting on April 14, agency staff said that AstraZeneca's diabetes drug Onglyza (saxagliptin) appears to be linked with an increased rate of death. The meeting will also review Takeda's similar DPP-4 inhibitor Nesina (alogliptin), which FDA reviewers noted wasn't associated with a raised risk of death. Shares in AstraZeneca dropped as much as 3.3 percent on the news.

The FDA staff noted that while primary results from the SAVOR trial of Onglyza did not show a statistically significant increase in the rate of death, further analyses that included only deaths occurring while patients were exposed to treatment suggested a "significant or near-significant increases in all-cause mortality" associated with the drug. The regulator indicated that the causes of death were "multifactorial," adding that some patients may have had several serious medical conditions in the period preceding death. However, the agency noted that it "is not reassured that the observation that causes of death span multiple disparate aetiologies, and we do not necessarily view this pattern of variable causes as evidence the mortality signal is due to chance."

The SAVOR trial was conducted by AstraZeneca after the FDA issued guidance in 2008 requiring companies to undertake studies to show that new diabetes drugs do not increase cardiovascular risk compared with current treatments. According to AstraZeneca, the study met the objective of showing that patients taking Onglyza were not at greater risk as measured by a composite benchmark comprising cardiovascular death, non-fatal heart attack and non-fatal ischaemic stroke. "AstraZeneca is committed to ensuring patient safety and will continue to work closely with the FDA to support further review of the data," the company added.

Agency staff stated that patients treated with Onglyza may have a 27 percent higher risk of hospitalisation for heart failure compared to placebo-treated patients. "The baseline characteristics of the patients suggests those on Onglyza were sicker and older, making solid conclusions difficult," commented Bloomberg Intelligence analyst Sam Fazeli. "The panel may ask AstraZeneca to conduct a specific trial to assess this risk," he added.

Studies published in the NEJM in 2013 suggested that the DDP-4 inhibitor class, which also includes Merck & Co.'s Januvia (sitagliptin), may be associated with an increased risk of heart failure. Following this finding, the FDA announced a review of the heart failure risk associated with saxagliptin, which is also marketed in combination with metformin under the name Kombiglyze XR. Results from a study assessing the cardiovascular risk of Januvia are expected to be presented later this year at the American Diabetes Association annual meeting.

Onglyza was co-developed by AstraZeneca and Bristol-Myers Squibb as part of a joint venture, which the UK drugmaker purchased last year for $4.3 billion. The therapy was approved by the FDA for the treatment of type 2 diabetes in adults in 2009, amassing sales of $820 million last year. Meanwhile, Nesina generated revenue of $403 million for fiscal 2014, with Januvia recording sales of $3.9 billion last year.

Leerink Partners Seamus Fernandez said that the FDA's concerns over all-cause mortality associated with Onglyza were unexpected and could lead to a cut of up to 50 percent in his $1.8 billion peak annual sales estimate, if Januvia does not show similar problems. Fernandez estimates that if the FDA concludes that the DDP-4 inhibitor class increased cardiovascular risk, sales of the drugs could be depressed by 5 percent to 15 percent in the short term. "But ultimately, we believe it should not fundamentally alter the utility of these drugs," Fernandez remarked.

For related analysis, see ViewPoints: Possible heart failure signal may begin to weigh on DPP-IV class of diabetes drugs.

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