AstraZeneca Announces FDA Approval of Dapagliflozin for Chronic Kidney Disease in the U.S.

SHANGHAI, May 1, 2021 /PRNewswire/ -- AstraZeneca announced that Farxiga (generic name: dapagliflozin, a sodium-glucose cotransporter-2 [SGLT2] inhibitor) has been officially approved in the United States for the treatment of adult patients with chronic kidney disease (CKD) at risk of disease progression. The approval is based on its ability to reduce the risk of sustained decline in estimated glomerular filtration rate (eGFR), progression to end-stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for heart failure (hHF).

This approval is based on the positive results from the Phase III DAPA-CKD trial. Earlier this year, the U.S. FDA granted priority review status to the DAPA-CKD application.

Chronic kidney disease is a condition characterized by progressive decline in renal function, typically associated with an increased risk of heart disease or stroke, and may require dialysis or kidney transplantation in its end-stage.^[1]-[3]。By 2040, chronic kidney disease is projected to become the fifth leading cause of death globally.^[4]. Currently, approximately 37 million people in the United States are affected by chronic kidney disease.^[1]。

Professor Hiddo L. Heerspink, Co-Chair of the DAPA-CKD Trial Executive Committee and from the University Medical Center Groningen in the Netherlands, stated: “The results of the DAPA-CKD trial are groundbreaking. Based on these findings, dapagliflozin has become the first SGLT2 inhibitor approved for the treatment of patients with chronic kidney disease, regardless of their diabetes status. This approval represents a transformative and significant milestone, providing patients and physicians with a novel and effective therapeutic option to address this life-threatening debilitating condition.”

Mene Pangalos, Executive Vice President of AstraZeneca’s Biopharmaceuticals R&D, stated:“This approval marks a significant advancement in the treatment of chronic kidney disease over the past two decades. We have demonstrated that dapagliflozin delivers significant efficacy across three therapeutic areas—type 2 diabetes mellitus and heart failure with reduced ejection fraction、as well as the latest developments in the field of chronic kidney disease. We are thrilled that this medication will benefit millions more patients in the United States.”

The DAPA-CKD trial demonstrated that, in patients with stage 2–4 chronic kidney disease (CKD) and elevated urinary albumin excretion, dapagliflozin, compared with placebo, reduced the primary composite endpoint (including worsening of renal function) when added to standard therapy (i.e., angiotensin-converting enzyme inhibitors or angiotensin receptor blockers).、Occurrence of End-Stage Renal Disease、cardiovascular or renal death) by 39% (p<0.0001), with an absolute risk reduction (ARR) of 5.3% over a median follow-up of 2.4 years. Compared with placebo, dapagliflozin significantly reduced the relative risk of all-cause mortality by 31% in patients with chronic kidney disease (ARR = 2.1%, p = 0.0035).^[5]。

The DECLARE-TIMI 58 trial is a randomized, double-blind, placebo-controlled Phase III clinical study evaluating the impact of dapagliflozin on cardiovascular outcomes. Exploratory analyses of this study indicated that dapagliflozin may also be effective in patients with early-stage chronic kidney disease. Dapagliflozin is not recommended for patients with polycystic kidney disease or those with kidney disease who are currently receiving or have recently received immunosuppressive therapy.

The safety and tolerability of dapagliflozin observed in the above two clinical studies were consistent with the known safety profile of the drug.

In the United States, dapagliflozin has been approved to improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise, and to reduce the risk of hospitalization for heart failure (hHF) in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors. Dapagliflozin is also indicated for adults with heart failure with reduced ejection fraction (HFrEF, NYHA class II–IV), regardless of the presence of type 2 diabetes mellitus, to reduce the risk of cardiovascular death and hospitalization for heart failure (hHF).

# About Chronic Kidney Disease

Chronic Kidney Disease (CKD) is a serious condition characterized by progressive decline in kidney function, defined as reduced estimated glomerular filtration rate (eGFR), kidney damage, or both, persisting for more than three months.^[3], affecting nearly 840 million people worldwide, with many patients remaining undiagnosed^[6]. The most common causes of CKD are diabetes, hypertension, and glomerulonephritis.^[7]Patients with chronic kidney disease (CKD) face a significantly increased risk of complications and cardiovascular events, such as heart failure and premature death. Once patients progress to the most severe stage of CKD, namely end-stage kidney disease (ESKD), their kidneys are severely damaged and renal function deteriorates progressively, necessitating dialysis or kidney transplantation for life sustenance.^[1], most patients with chronic kidney disease die from cardiovascular disease before progressing to end-stage chronic kidney disease^[8]。

AboutDAPA-CKDResearch

DAPA-CKD was an international, multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial that enrolled 4,304 patients with chronic kidney disease (CKD) stages 2–4 and elevated albuminuria, with or without type 2 diabetes mellitus, to evaluate the efficacy of adding dapagliflozin 10 mg once daily to standard care. Dapagliflozin was administered once daily in addition to standard therapy. The primary composite endpoint was the risk of worsening renal function or death, defined as a sustained decline in estimated glomerular filtration rate (eGFR) of ≥50%, progression to end-stage renal disease (ESRD), or death from cardiovascular or renal causes. Secondary endpoints included time to first occurrence of a renal composite endpoint (sustained eGFR decline of ≥50%, progression to ESRD, or death from renal causes), a composite of cardiovascular death or hospitalization for heart failure, and all-cause mortality. The study was conducted across 21 countries, and the results have been published in the New England Journal of Medicine.^[9]。

AboutDECLARE-TIMI 58Research

The DECLARE-TIMI 58 study was a randomized, double-blind, multicenter Phase III clinical trial initiated by AstraZeneca, designed to evaluate the cardiovascular outcomes of dapagliflozin versus placebo in adult patients with type 2 diabetes (T2D) at risk for cardiovascular events (including multiple cardiovascular risk factors or established cardiovascular disease), while also assessing key exploratory renal endpoints. The study enrolled more than 17,000 patients from 882 centers across 33 countries and was conducted independently by the TIMI Study Group (Boston, USA) in collaboration with the Hadassah Hebrew University Medical Center (Jerusalem, Israel). The renal endpoint results of this study have been published in The Lancet.

About Dapagliflozin

Dapagliflozin is the first-in-class sodium-glucose cotransporter-2 (SGLT2) inhibitor, administered orally once daily. As scientific research continues to uncover the potential interrelationships among the heart, kidneys, and pancreas, studies on dapagliflozin have evolved from examining its cardiorenal benefits to focusing on the prevention of cardiorenal diseases and organ protection. Impairment of a single organ can lead to dysfunction in other organs, which constitutes a major cause of death worldwide, including in patients with type 2 diabetes, heart failure, and chronic kidney disease.

Over the past decade, dapagliflozin has been used as monotherapy and in combination with other agents, in addition to diet and exercise, to improve glycemic control in adults with type 2 diabetes. The landmark DECLARE-TIMI 58 Phase III cardiovascular outcomes trial confirmed^[5], adding dapagliflozin to standard therapy can effectively reduce the risk of hospitalization for heart failure (hHF) or cardiovascular death in adult patients with type 2 diabetes. Dapagliflozin is also the first SGLT2 inhibitor approved for adult patients with heart failure with reduced ejection fraction, regardless of whether they have comorbid type 2 diabetes.

In August 2020, the full results of the Phase III DAPA-CKD clinical trial demonstrated that dapagliflozin reduced the composite risk of kidney failure and cardiovascular or renal death in patients with chronic kidney disease, with or without type 2 diabetes mellitus (T2DM), to an unprecedented extent compared with the placebo group.^[6]. In renal outcome trials among patients with this disease, dapagliflozin has become the first SGLT2 inhibitor to significantly improve survival in patients with chronic kidney disease (CKD) and provide organ protection.

DapaCare is a comprehensive clinical trial program designed to evaluate the potential benefits of dapagliflozin in cardiovascular and renal outcomes, as well as organ protection. The program comprises 35 completed and ongoing Phase IIb/III clinical trials involving more than 35,000 patients, alongside accumulated real-world experience from over 2.5 million patients annually. The currently ongoing DELIVER Phase III trial is assessing the efficacy of dapagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). In the DAPA-MI Phase III trial, dapagliflozin is being studied in patients with acute myocardial infarction (MI) or heart attack who do not have type 2 diabetes; this represents the first randomized controlled trial of its kind designed to support indication-based registration.

Disclaimer: TheDAPA-CKDThe study has not yet been approved in China, and the mentionedDELIVERResearch andDAPA-MIThe indications under investigation are still in the development phase and have not yet been approved in China. AstraZeneca does not recommend any unapproved uses of its medicines.

References

1. Centers for Disease Control and Prevention (CDC). Chronic kidney disease in the United States, 2019. [cited 2021 Apr 29]. Available from: URL: https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html.

2. Segall L, et al. Heart failure in patients with chronic kidney disease: a systematic integrative review. Biomed Res Int. 2014;2014:937398.

3. Bikbov B, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709-733.

4. Foreman KJ, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories. Lancet. 2018;392(10159):2052-2090.

5. Heerspink H. DAPA-CKD - Dapagliflozin in Patients with Chronic Kidney Disease. Presented at: ESC Congress 2020 - The Digital Experience, 2020 August 29 - September 01.

6. Jager KJ, et al. A single number for advocacy and communication—worldwide more than 850 million individuals have kidney diseases. Nephrol Dial Transplant. 2019;34(11):1803-1805.

7. National Kidney Foundation. Kidney Disease: Causes; 2015 [cited 2021 Apr 29]. Available from: URL: https://www.kidney.org/atoz/content/kidneydiscauses.

8. Briasoulis A, Bakris GL. Chronic kidney disease as a coronary artery disease risk equivalent. Curr Cardiol Rep. 2013;15(3):340.

9. Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446.

10. Mosenzon O, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 Randomised Trial. Lancet. 2019;7(8):606-617.

11. Wiviott SD, et al, for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes [article and supplementary appendix]. N Engl J Med. 2019:380:347-357.