CAMBRIDGE, U.K.—Sept. 24 saw positive news—though with a significant caveat—on the cardiovascular and diabetes fronts with news from AstraZeneca of positive results from its Phase 3 DECLARE-TIMI 58 cardiovascular outcomes clinical trial of Farxiga (dapagliflozin). The drug, which is used to treat diabetes, was being evaluated compared to placebo for its effects on cardiovascular outcomes, or major adverse cardiovascular events (MACE). The trial evaluated more than 17,000 patients across 882 sites in 33 countries and compared the effect of Farxiga compared to placebo on cardiovascular outcomes in adults with type 2 diabetes (T2D) at risk of cardiovascular events.
The DECLARE cardiovascular outcomes trial (CVOT) for Farxiga is reportedly the broadest SGLT2 inhibitor CVOT conducted thus far, and AstraZeneca focused on the fact that the therapeutic met its primary safety endpoint of non-inferiority for MACE, achieving a statistically-significant reduction in the composite endpoint of hospitalization for heart failure (hHF) or cardiovascular (CV) death, one of the two primary efficacy endpoints.
However, the news was not entirely rosy. While fewer MACE events were observed with Farxiga—the other primary efficacy endpoint—this results did not reach statistical significance.
Again, pushing the positive aspects, the company noted that “Data from DECLARE-TIMI 58 confirmed the well-established safety profile of Farxiga.”
As a Reuters article notes, “The failure to achieve a more convincing reduction in CV events—such as heart attacks and strokes—may be seen as disappointing. But Ludovic Helfgott, AstraZeneca’s head of CV and metabolic diseases, believes the overall data suggests Farxiga could win expanded approval as a diabetes drug with proven heart benefits in a wide range of patients.”
“Farxiga has achieved a statistically significant and clinically-important reduction in hospitalization for heart failure or CV death in a broad range of patients with type 2 diabetes and cardiovascular risk. The results from this landmark trial are especially important since heart failure is an early and frequent complication of diabetes, and associated with hospitalizations that result in a considerable societal and economic burden,” noted Elisabeth Björk—an AstraZeneca vice president and head of the company’s Cardiovascular, Renal and Metabolism, Global Medicines Development division—in the company’s news release about the outcomes.
Dr. Stephen Wiviott of Brigham and Women’s Hospital and Harvard Medical School, a senior investigator with the Thrombolysis in Myocardial Infarction study group and co-principal investigator of the trial, added: “The DECLARE-TIMI 58 results offer compelling evidence that dapagliflozin helps to address an important medical need among a diverse group of patients with type 2 diabetes by reducing the composite of hospitalization for heart failure or CV death, with a safety profile supportive of broad use.”
Detailed trial results will be presented Nov. 10 at the American Heart Association Scientific Sessions 2018 in Chicago.
DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58 is an AstraZeneca-sponsored, randomized, double-blinded, placebo-controlled, multicenter trial designed to evaluate the effect of Farxiga compared with placebo on CV outcomes in adults with T2D at risk of CV events, including patients with multiple CV risk factors or established CV disease. DECLARE is part of the extensive DapaCare clinical program for Farxiga, which will enroll patients in randomized clinical trials, including a wide range of mechanistic studies, and is supported by a multinational real-world evidence study (CVD-REAL). The DapaCare clinical program will generate data across a spectrum of people with CV risk factors, established CV disease and varying stages of renal disease, both with and without T2D. DECLARE is paving the way for three other Phase 3 trials: Dapa-HF, DELIVER and Dapa-CKD.
Farxiga is a first-in-class, oral, once-daily selective inhibitor of human sodium-glucose co-transporter 2 (SGLT2) indicated as both monotherapy and as part of combination therapy to improve glycaemic control, with the additional benefits of weight loss and blood pressure reduction, as an adjunct to diet and exercise in adults with T2D. Farxiga is not currently indicated to reduce the risk of CV events, CV death or hHF.
Competitors for Farxiga include Victoza from Novo Nordisk and Jardiance from Eli Lilly and Co. and Boehringer Ingelheim. Both drugs have already shown their ability in trials to improve cardiovascular outcomes—what sets AstraZeneca’s work apart, though, is that the company takes the extra step to try to show that Farxiga helps decrease cardiovascular events in patients that don’t have established cardiovascular disease. This is something that Jack Scannel, an analyst with UBS, wrote in an investor’s note could “provide a degree of commercial differentiation.”
Around the same time as the DECLARE news, AstraZeneca also announced that the Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion on a Type-II variation update for Bydureon (exenatide extended-release), to include in the European label CV data from the EXSCEL (EXenatide Study of Cardiovascular Event Lowering) trial in adults with T2D at a wide range of CV risk.
In EXSCEL, Bydureon did not increase the incidence of MACE, a composite endpoint of CV death, non-fatal heart attack or non-fatal stroke, compared to placebo. Although the primary efficacy objective of a superior reduction in MACE narrowly missed statistical significance (p=0.061), there were fewer CV events observed in the Bydureon arm of the trial. The prespecified secondary analysis on all-cause mortality has also been accepted for inclusion in the European label. Patients on Bydureon had a 14-percent lower incidence of all-cause mortality compared to usual care alone.
“We are pleased with this positive recommendation for Bydureon and what it means for patients with type 2 diabetes with a wide range of cardiovascular risk,” said AstraZeneca’s Björk of the study data, the full results of which have been published in the New England Journal of Medicine. “Our pursuit of this label is based on our strong belief in the clinical value the EXSCEL data brings to physicians and patients.”
