AstraZeneca's Farxiga Demonstrates Landmark Phase III Success in Reducing Heart Failure Worsening and Cardiovascular Death Regardless of Background Therapy

March 29, 2020 News /BioValleyBIOON/ ---AstraZeneca(AstraZeneca) recently announced new data from a subgroup analysis of the landmark Phase III DAPA-HF study of its glucose-lowering drug Farxiga (Chinese brand name: Andatang; generic name: dapagliflozin). The results showed that in patients with heart failure with reduced ejection fraction (HFrEF), regardless of their background therapy (i.e., other medications used to treat heart failure), compared with placebo,Farxiga significantly reduced the incidence of the primary composite endpoint of heart failure (HF) worsening or cardiovascular (CV) death (16.3% vs 21.2%; HR=0.74 [95% CI: 0.65–0.85], p<0.0001).

Farxiga was evaluated in patients with HFrEF receiving extensive pharmacological therapy, device therapy, and cardiac resynchronization therapy.Reduced consistency in the primary outcome was observed across all these treatment subgroups (HR range for the primary endpoint: 0.57–0.86).These results were presented at the virtual American College of Cardiology Annual Scientific Session/World Congress of Cardiology (ACC.20/WCC Virtual) held recently and published in the European Heart Journal. The article is titled:Effects of dapagliflozin in DAPA-HF according to background heart failure therapy。

Mene Pangalos, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, stated: “These new data from the DAPA-HF trial further reinforce Farxiga’s role inDiabetesclinical benefits beyond these. By reducing the risk of heart failure worsening, regardless of background therapy, Farxiga has the potential to improve the current standard of care and alleviate the disease burden among heart failure patients worldwide.”

Farxiga is a first-in-class, once-daily oral selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. The approved indications for this drug are: (1) as monotherapy and as part of combination therapy for type 2DiabetesAdult patients, improve glycemic control. (2) For the presence of type 2Diabetes, reduce the risk of heart failure hospitalization in patients with cardiovascular disease or multiple CV risk factors.

In January 2020, the U.S. FDA accepted a supplemental new drug application (sNDA) for Farxiga and is conducting a priority review: to use Farxiga in patients with or without type 2 diabetesDiabetesadult patients with HFrEF, reducing the risk of cardiovascular death or worsening heart failure. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target date for this sNDA in the second quarter of 2020. In September 2019,FDAFarxiga was granted Fast Track Designation (FTD) for reducing the risk of cardiovascular death or worsening heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). In August 2019, the FDA granted Farxiga another FTD for delaying the progression to renal failure and preventing cardiovascular and renal death in patients with chronic kidney disease (CKD), with or without type 2 diabetes.

Farxiga has excellent applications in the treatment of type 2 diabetes,FDAThe priority review of the supplemental new drug application for Farxiga in the treatment of HFrEF indicates that the drug also has the potential to deliver positive outcomes for patients with heart failure. Heart failure affects approximately 64 million people worldwide, and about half of them die within five years of diagnosis. If approved, Farxiga will become the first SGLT2 inhibitor indicated for the treatment of heart failure.

This sNDA is based on the results of the landmark Phase III DAPA-HF trial. The study results were published in the New England Journal of Medicine (NEJM) in September 2019 and presented at the 2019 European Society of Cardiology (ESC) Congress. The results demonstrated that, in patients with heart failure with reduced ejection fraction (HFrEF), with or without type 2 diabetes mellitus, Farxiga, when added to standard of care, reduced the incidence of the composite endpoint of cardiovascular death or worsening heart failure compared with placebo.

DAPA-HF was the first heart failure outcomes study to evaluate an SGLT2 inhibitor in combination with standard-of-care medications (including angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], beta-blockers, mineralocorticoid receptor antagonists [MRAs], and neprilysin inhibitors) for the treatment of adult patients with heart failure with reduced ejection fraction (HFrEF), both with and without type 2 diabetes. This was an international, multicenter, parallel-group, randomized, double-blind study conducted in patients with HFrEF (LVEF ≤40%), including those with and without type 2 diabetes. The study assessed the efficacy and safety of Farxiga 10 mg once daily versus placebo, added to standard-of-care therapy. The primary endpoint was time to first occurrence of worsening heart failure events (hospitalization or an equivalent event, such as an urgent visit for heart failure) or cardiovascular (CV) death.

The results demonstrated that the study met its primary composite endpoint: compared with placebo, Farxiga significantly reduced the risk of the composite endpoint of cardiovascular (CV) death or worsening heart failure by 26% (p < 0.0001), with reductions observed in each individual component of the composite endpoint. Specifically, the risk of first occurrence of worsening heart failure was reduced by 30% (p < 0.0001), and the risk of CV death was reduced by 18% (p = 0.0294). The effect of Farxiga on the primary composite endpoint was generally consistent across key subgroups studied. Furthermore, the results showed significant improvements in patient-reported outcomes as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), and a nominally significant 17% reduction in all-cause mortality (7.9 vs. 9.5 patients with an event per 100 patient-years), favoring Farxiga. In this study, the safety profile of Farxiga was consistent with its established safety profile. The proportions of patients experiencing volume depletion (7.5% vs. 6.8%) and renal adverse events (6.5% vs. 7.2%) were comparable to those in the placebo group; these are events of common concern in the treatment of heart failure. Major hypoglycemic events were rare in both treatment groups (0.2% vs. 0.2%).

Heart failure (HF) is a life-threatening condition in which the heart fails to pump sufficient blood to the body. HF affects approximately 64 million people worldwide (at least half of whom have reduced ejection fraction). It is a chronic, progressive disease, with half of patients dying within five years of diagnosis. Heart failure remains associated with men (prostate cancer and bladder cancer) and women (Breast Cancer) as lethal as the most common cancers. Heart failure is the leading cause of hospitalization among patients aged 65 and older, representing a significant clinical and economic burden.

The active pharmaceutical ingredient of Farxiga is dapagliflozin, a first-in-class, once-daily oral selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved to improve glycemic control in adult patients with type 2 diabetes. The drug acts independently of insulin by selectively inhibiting SGLT2 in the kidneys, thereby helping patients excrete excess glucose through urine. In addition to its glucose-lowering effects, the drug also hasWeight Lossand the additional benefit of lowering blood pressure.

AstraZeneca is advancing a robust clinical development program for dapagliflozin, encompassing more than 35 completed or ongoing Phase IIb/III clinical studies with over 35,000 enrolled patients and more than 2.5 million patient-years of clinical experience.

Notably, in March 2019, Forxiga (the European brand name for dapagliflozin) received approval from the European Union and Japan for a new indication: as an oral adjunct to insulin for the treatment of adult patients with type 1 diabetes (T1D). It was the first SGLT2 inhibitor approved in Europe for the treatment of T1D and the first T1D drug to receive regulatory approval for AstraZeneca. The specific indication is for improving glycemic control in adult patients with T1D who are on insulin therapy but have inadequate glycemic control and have a body mass index (BMI) ≥27 kg/m² (overweight or obese). In the United States, however, its use for treating T1D was halted in July 2019 due to the risk of diabetic ketoacidosis (DKA).FDARejection of Approval.

In China, dapagliflozin (Chinese brand name: Forxiga) was approved in March 2017 as a monotherapy to improve glycemic control in adult patients with type 2 diabetes. This approval made dapagliflozin the first SGLT2 inhibitor approved in the Chinese market. The drug is an oral tablet, with each tablet containing 5 mg or 10 mg of dapagliflozin. The recommended starting dose is 5 mg once daily in the morning. (Bioon.com)

Original Source:Farxiga reduced the incidence of heart failure worsening or cardiovascular death in a sub-analysis from landmark Phase III DAPA-HF trial