The cardiovascular results reported in the Declare-Timi trial – that Astrazeneca's Farxiga can prevent heart failure hospitalisations, but does not prevent heart attacks or strokes – will present a challenging commercial and regulatory case for the diabetes pill.
Astra’s message will be that, since heart failure is one of the earlier cardiovascular complications of diabetes, Farxiga is as every bit as good as Jardiance, which showed a benefit across a broader number of endpoints. Adding to the complexity of the analysis is Declare-Timi’s inclusion of both low and high-risk patients, a decision that could test regulators’ willingness to approve the use of subgroup data on the label.
In purely scientific terms Declare-Timi is a success. It showed Farxiga to be non-inferior to placebo on a three-point composite cardiovascular endpoint incorporating cardiovascular death, myocardial infarction or stroke. Numerically fewer patients taking the SGLT2 pill experienced any of these events, but Farxiga failed to show a statistically significant benefit.
However, Astra included a second co-primary composite endpoint, cardiovascular death or hospitalisation for heart failure, on which Farxiga performed better than placebo statistically. Heart failure is thought to drive the cardiovascular benefit across this class, as the SGLT2s have a mild diuretic effect.
Detailed data are being held until the American Heart Association meeting in November. Nevertheless, Astra was keen to celebrate the win on heart failure. “When you look at it, heart failure is one of the earliest and biggest complications of diabetes,” Ludovic Helfgott, Astra’s global vice-president for cardiovascular, renal and metabolic drugs, told Vantage.
At 17,000 patients, Declare-Timi was larger than Jardiance’s outcomes trial Empa-Reg Outcome, which enrolled 7,000. This decision allowed Astra to test Farxiga’s cardiovascular benefit in lower-risk patients; it included 7,000 diabetics with established cardiovascular disease and 10,000 with multiple risk factors such as elevated cholesterol or high blood pressure.
Empa-Reg Outcome subjects were higher risk in that they had established disease, such as a history of myocardial infarction or revasculariation, or significant coronary blood vessel blockage. As such, any benefit would likely be magnified in that population.
Mr Helfgott said Astra should be able to present the data on its high-risk subgroup when the final analysis is revealed at AHA. Cardiologists and diabetes specialists will no doubt be eager to see a significant benefit across cardiovascular endpoints, not just heart failure hospitalisations.
As it tries to boost Farxiga sales, Astra will also hope that the US FDA is willing to permit the data in the high-risk population, if these are indeed positive, to be included on the label. Lilly and Boehringer Ingelheim’s US Jardiance advertising campaign has gone strongly on the prevention of cardiovascular death in patients with heart disease, something Astra cannot counter for now.
Payers, of course, know that lowering hospital costs of heart failure patients is as worthy a goal as preventing cardiovascular death, and will be eager to see the magnitude of benefit in the broad diabetic population. In this sense, Declare-Timi might have given Astra the justification to argue for a higher price, or at least resist deeper rebates.
The trial cannot be said to be a victory just yet, but does give signs that Farxiga will not fall further behind Jardiance.