The FDA is concerned that two AstraZeneca (AZ) drugs based on its DPP-4 inhibitor saxagliptin for diabetes may pose and increased risk of death.
The regulator makes its views known in a briefing document published ahead of an advisory committee due to be held tomorrow (April 14) that will review data from the 16,500-patient SAVOR trial, which raised some concerns about the safety of the drug.
AZ’s Onglyza (saxagliptin) and Kombiglyze (saxagliptin plus metformin) will come under scrutiny at the meeting along with a similar drug Nesina (alogliptin) from Takeda.
Last year, the FDA requested additional data from AZ to investigate a possible association between use of saxagliptin and heart failure, and also started looking into the safety of Nesina after the drug was associated with a trend towards an increased risk of heart failure in the EXAMINE trial.
The published results of SAVOR – which appeared in the New England Journal of Medicine (NEJM) in 2013 – indicated a 27% higher rate of hospitalisation for heart failure in patients treated with Onglyza or Kombiglyze compared to placebo. The trial did not find any increased risk of death or other major cardiovascular events such as heart attack or stroke.
The briefing document from the FDA suggests however that the agency’s reviewers have found the same hospitalisation trend and – potentially more seriously – have also uncovered a “significant increased risk of all-cause mortality” in the data that is “not necessarily … due to chance”.
AZ has always maintained the SAVOR data indicate no difference between saxagliptin or placebo on major adverse cardiac events (MACE) and hospitalisations for unstable angina, heart failure or coronary revascularisation.
The company has acknowledged that SAVOR showed a higher risk for hospitalisation for heart failure in a subgroup of patients at increased risk – such as those with a history of heart failure or renal impairment – but suggests this can be handled by a change to the drug’s labelling. It maintains the increase in all-cause mortality is down to chance, not the drug.
The FDA document also suggests that there does not appear to be any causal link between Nesina and heart failure from the EXAMINE data.
The probe into saxagliptin is part of a broader investigation by the FDSA into the cardiovascular safety of drugs used to treat diabetes, and there is considerable interest in the outcome of Merck & Co’s TECOS cardiovascular outcomes trial, which involves its $6bn-a-year DPP-4 inhibitor Januvia (sitagliptin).
TECOS results are due to be presented at the American Diabetes Association (ADA) meeting in June and should give important additional new data on the safety of DPP-4 inhibitors.
If Januvia is given a clean bill of health it suggests there is no class effect for DPP-4 inhibitors on cardiovascular risk. On the other hand, if a safety signal is uncovered it will be a major cause for concern.
AZ was obliged to carry out SAVOR after the publication of FDA guidelines in 2008 that required all new diabetes drugs to be tested in cardiovascular outcome studies.
The requirement was introduced in the build-up to the withdrawal of GlaxoSmithKline’s Avandia (rosiglitazone) from the European market – as well as the imposition of prescribing restrictions in the US – on concerns of cardiovascular toxicity.