AstraZeneca's Onglyza 'mortality' risks noted by FDA reviewers

For several years, the FDA has been supercautious about the heart risks of diabetes treatments. Now, FDA staff reviewers have raised serious concerns about the safety of AstraZeneca's ($AZN) Onglyza ahead of an advisory committee review Tuesday, which could result in a recommendation of a label change for Onglyza as well as other drugs in the DPP4 inhibitor class. Their conclusion after a closer look: Study data suggests patients who took Onglyza may have had "a significantly increased risk of all-cause mortality."

The observations are in the FDA staff review posted online Friday. The FDA reviewers said that while there was not a statistically significant increase in the death rate of patients during clinical trials, when they ran the data on just those patients taking Onglyza, the risk appeared evident. They acknowledged that some patients had a number of serious medical conditions and that the causes of death were often "multifactorial." Still, reviewers said, they were not reassured by that, and "we do not necessarily view this pattern of variable causes as evidence the mortality signal is due to chance."

AstraZeneca had no comment ahead of the advisory committee meeting Tuesday. That meeting is to go over data from the SAVOR outcomes trial, a study of 16,492 patients with type 2 diabetes mellitus with established cardiovascular disease or at high risk of cardiovascular disease. The study originally suggested that Onglyza patients were more likely to be hospitalized with heart failure, with 27% of them hospitalized for that condition, compared with patients in the control arm. The report said there were 798 deaths of patients in the study.

But the meeting has potential implications for all of the companies who make the so-called DPP-4 inhibitor drugs, the class to which Onglyza belongs--as does Takeda's Nesina, as well as Merck & Co.'s ($MRK) blockbuster Januvia franchise. In addition to the Onglyza data, panelists Tuesday will discuss results of an outcomes trial on Nesina. Results from a trial focusing on the heart risks of Merck's drugs, however, have yet to be released.

Bernstein analyst Tim Anderson

Bernstein analyst Tim Anderson said the FDA briefing materials released Friday "are neutral, balanced and factual without expressing a clear editorial opinion on the significance (or lack thereof)" of the safety signals in the Onglyza trial. "FDA says it views the [heart failure] signal as credible ... yet it also acknowledges it could be a false positive, since it was not a pre-specified endpoint in either trial," Anderson wrote in a Friday note to investors. "FDA slices and dices the data in various ways, as expected, yet none of the analyses seem conclusive."

The FDA asks its panelists to comment on their "level of concern" about the data, Anderson points out. The reviewers also say the advisory committee should assess whether there is a "class effect" to be considered, something analysts have said could have a significant impact on sales in the category if warnings are added.

But not all of the drugs in the class work the same and the FDA noted that as well, saying the possibility that each drug in the class may have different heart risks, based on "their particular characteristics (e.g., potency, selectivity for DPP enzymes)cannot be ruled out based on the currently available data." Anderson has observed in previous investor notes that if the TECOS study of Merck drug finds no statistically significant heart risks then Onglyza and Nesina might get label changes, without requiring the same for the rest of the class.

Of course the committee may come to different conclusions and have its own recommendation for the FDA, which in turn is not required to follow whatever the committee suggests. So it will not be known for awhile what this closer look at the DPP4 inhibitor drugs will mean for the top lines of those who make them.

- here's the FDA briefing material

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