30 April 2021
- Approval is the most significant advancement in the treatment of chronic kidney disease in more than 20 years
- In DAPA-CKD Phase III trial, Farxiga demonstrated unprecedented reduction in the risk of the composite of worsening of renal function, end-stage kidney disease and cardiovascular or renal death
AstraZeneca’s Farxiga (dapagliflozin), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been approved in the US to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease (ESKD), cardiovascular (CV) death and hospitalisation for heart failure (hHF) in adults with chronic kidney disease (CKD) at risk of progression.
The approval by the Food and Drug Administration (FDA) was based on positive results from the DAPA-CKD Phase III trial. The decision follows the Priority Review designation granted by the FDA earlier this year.
CKD, a condition defined by decreased kidney function, is often associated with a heightened risk of heart disease or stroke, or the need for dialysis or kidney transplant.1-3 CKD is expected to become the fifth leading cause of mortality globally by 2040.4 Currently in the US, 37 million people are estimated to have CKD.1
The co-chair of the DAPA-CKD trial and its executive committee, Prof. Hiddo L. Heerspink, University Medical Center Groningen, the Netherlands, said: “Based on the unprecedented results of the DAPA-CKD trial, dapagliflozin is now the first SGLT2 inhibitor approved for the treatment of chronic kidney disease regardless of diabetes status. This transformational milestone provides patients and physicians with a new and effective treatment option for this often debilitating and life-threatening disease.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “Today’s approval is the most significant advancement in the treatment of chronic kidney disease in more than 20 years. We’ve shown impressive efficacy for Farxiga in type-2 diabetes, heart failure with reduced ejection fraction and, most recently, chronic kidney disease and we are thrilled to be able to bring this medicine to millions of patients in the US.”
The DAPA-CKD trial demonstrated that Farxiga, on top of standard-of-care treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, reduced the relative risk of worsening of renal function, onset of ESKD, or risk of CV or renal death by 39%, the primary composite endpoint, compared to placebo (p<0.0001) in patients with CKD Stages 2-4 and elevated urinary albumin excretion. The absolute risk reduction (ARR) was 5.3% over the median time in study of 2.4 years. Farxiga also significantly reduced the relative risk of death from any cause by 31% (ARR=2.1%, p=0.0035) compared to placebo.5
Exploratory analyses of the DECLARE-TIMI 58 Phase III trial, a randomised, double-blind, placebo-controlled trial, conducted to determine the effect of Farxiga on CV outcomes support the conclusion that Farxiga is also likely to be effective in patients with less advanced CKD. Farxiga is not recommended for the treatment of CKD in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease, since it is not expected to be effective in these populations.
In both trials, the safety and tolerability of Farxiga were consistent with the well-established safety profile of the medicine.
In the US, Farxiga is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type-2 diabetes (T2D), and to reduce the risk of hHF in adults with T2D and established CV disease or multiple CV risk factors. Farxiga is also indicated to reduce the risk of CV death and hHF in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without T2D.
Chronic kidney disease
CKD is a serious, progressive condition defined by decreased kidney function (shown by reduced eGFR or markers of kidney damage, or both, for at least three months) 3 affecting 840 million people worldwide, many of them still undiagnosed.6 The most common causes of CKD are diabetes, hypertension and glomerulonephritis.7 CKD is associated with significant patient morbidity and an increased risk of CV events, such as heart failure (HF) and premature death. In its most severe form, known as ESKD, kidney damage and deterioration of kidney function have progressed to the stage where dialysis or kidney transplantation are required.1 The majority of patients with CKD will die from CV causes before reaching ESKD.8
DAPA-CKD was an international, multi-centre, randomised, double-blinded Phase III trial in 4,304 patients designed to evaluate the efficacy of Farxiga 10mg, compared with placebo, in patients with CKD Stages 2-4 and elevated urinary albumin excretion, with and without T2D. Farxiga was given once daily in addition to standard of care. The primary composite endpoint was worsening of renal function or risk of death (defined as a composite of an eGFR decline ≥50%, onset of ESKD or death from CV or renal cause). The secondary endpoints included the time to first occurrence of the renal composite (sustained ≥50% eGFR decline, ESKD or renal death), the composite of CV death or hHF, and death from any cause. The trial was conducted in 21 countries.9 Detailed results from the trial were published in The New England Journal of Medicine.9
DECLARE-TIMI 58 was an AstraZeneca-sponsored, randomised, double-blinded, multi-centre Phase III 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, and also assessed key renal exploratory endpoints. The trial included more than 17,000 patients across 882 sites in 33 countries and was independently conducted in collaboration with academic investigators from the TIMI study group (Boston, US) and the Hadassah Hebrew University Medical Center (Jerusalem, Israel). Results from the trial were published in The Lancet.10
Farxiga (dapagliflozin) is a first-in-class, oral, once-daily SGLT2 inhibitor. The research for Farxiga is advancing from cardiorenal effects to prevention and organ protection as science continues to identify the underlying links between the heart, kidneys and pancreas. Damage to one of these organs can cause the other organs to fail – contributing to leading causes of death worldwide, including T2D, HF and CKD.
For nearly a decade Farxiga has been an effective monotherapy and part of combination therapy as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. Following results from the landmark DECLARE-TIMI 58 Phase III CV outcomes trial, it is approved in adults with T2D to reduce the risk of hHF or CV death when added to standard of care.11 Farxiga is also the first SGLT2 inhibitor approved for the treatment of HFrEF in adults with and without T2D.
In August 2020, results from the DAPA-CKD Phase III trial demonstrated that Farxiga achieved unprecedented reduction in the composite risk of kidney failure and CV or renal death in patients with CKD with and without T2D versus placebo.9 It is now the first SGLT2 inhibitor shown to significantly improve overall survival in a renal outcomes trial for this patient population and provide organ protection.
DapaCare is a robust programme of clinical trials to evaluate the potential CV, renal and organ protection benefits of Farxiga. It includes more than 35 completed and ongoing Phase IIb/III trials in more than 35,000 patients, as well as more than 2.5 million patient-years’ experience. It is currently being assessed in patients with HF with preserved ejection fraction in the DELIVER Phase III trial. Farxiga is also being tested in patients without T2D following an acute myocardial infarction (MI) or heart attack in the DAPA-MI Phase III trial – a first of its kind, indication-seeking registry-based randomised controlled trial.
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three therapy areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines in Oncology and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.
Posted: April 2021
- Farxiga Approved in the US for the Treatment of Heart Failure in Patients with Heart Failure with Reduced Ejection Fraction – May 6, 2020
- FDA Approves Farxiga (dapagliflozin) to Reduce the Risk of Hospitalization for Heart Failure in Patients with Type 2 Diabetes – October 21, 2019
- FDA Approves Farxiga to Treat Type 2 Diabetes – January 8, 2014
- FDA Advisory Committee Recommends the Investigational SGLT2 Inhibitor Dapagliflozin for Treatment of Type 2 Diabetes in Adults – December 12, 2013
- AstraZeneca and Bristol-Myers Squibb resubmit Dapagliflozin New Drug Application for the treatment of type 2 diabetes in the U.S – July 25, 2013
- Bristol-Myers Squibb and AstraZeneca Receive Complete Response Letter from U.S. Food and Drug Administration for Dapagliflozin – January 19, 2012
- U.S. Food and Drug Administration Extends Action Date for Dapagliflozin by Three Months – October 27, 2011
- FDA Advisory Committee Makes Recommendation on Investigational Compound Dapagliflozin – July 20, 2011
- FDA Accepts New Drug Application for Investigational Compound Dapagliflozin for the Treatment of Type 2 Diabetes – March 8, 2011
Farxiga (dapagliflozin) FDA Approval History
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