FDA advisory panel recommends cardiovascular warning label for AstraZeneca's Onglyza, Takeda's Nesina

An FDA advisory panel on Tuesday voted 14-1 recommending that labels of AstraZeneca's diabetes drugs Onglyza (saxagliptin) and Kombiglyze (saxagliptin/metformin) include a warning regarding a potential risk of heart failure and death, while the panel unanimously agreed that a similar warning should be added to the label of Takeda's diabetes treatment Nesina (alogliptin). Meanwhile, the panellists voted 13-1 and 16-0 that AstraZeneca's therapies and Nesina, respectively, carried an acceptable heart safety profile.

The panel vote for Onglyza and Kombiglyze was based on the findings of the 16 000-patient SAVOR heart study, which did not show an increased risk of heart attack associated with Onglyza versus placebo. However AstraZeneca's trial results suggested the therapy was linked to a higher rate of heart failure. Last week, agency reviewers concluded that the drug appears to be associated with an elevated risk of death.

The advisory committee noted that confounding factors made it difficult to determine whether the increased risk of death observed in the study is real or a statistical fluke. Some panellists recommended additional studies, as the SAVOR trial was not designed to assess heart failure and the study included patients already predisposed to heart problems.

Separately, a preliminary FDA review of Nesina identified a numerical increase in hospitalisations for heart failure in association with the therapy versus placebo, although the difference was not significant. However, Deutsche Bank analyst Richard Parkes commented "we believe the FDA will likely view the risk [of heart failure] as likely to be a class effect and apply changes to all approved drugs in the [DDP-4 inhibitor] class."

In 2013, study data published in the NEJM suggested that the DDP-4 inhibitor class, which also includes Merck & Co.'s Januvia (sitagliptin) and Eli Lilly and Boehringer Ingelheim's Tradjenta (linagliptin), may be linked to an elevated risk of heart failure. Subsequently, the FDA commissioned a review of the heart failure risk associated with Onglyza, while Merck is expected to release data from the TECOS study assessing the cardiovascular risk associated with Januvia later this year.

Leerink Swann analyst Seamus Fernandez predicted that if Merck's study identifies no heart risk associated with Januvia, sales of AstraZeneca's products could be depressed by 50 percent. Conversely, Fernandez stated "given the absence of a serious safety issue for either Onglyza or [Nesina] suggests that, barring an overtly negative signal in TECOS, growth of the DPP-4 class is likely to continue without a meaningful change in current prescribing trends." The analyst projected peak sales of $1.8 billion for Onglyza and Kombiglyze.

Onglyza was co-developed as part of a joint venture between AstraZeneca and Bristol-Myers Squibb, which the former drugmaker acquired for $4.3 billion in 2014. The therapy, which was cleared by the FDA for the treatment of type 2 diabetes in 2009, amassed $820 million in sales last year.

Meanwhile, Nesina was approved by the FDA in 2013 for the treatment of type 2 diabetes as an adjunct to diet and exercise. The drug generated $403 million in sales during the 2014 fiscal year.

For further analysis, see ViewPoints: Handicapping potential outcomes from Tuesday’s FDA meeting to discuss safety of DPP-IV inhibitors. See also ViewPoints: Possible heart failure signal may begin to weigh on DPP-IV class of diabetes drugs.

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