AstraZeneca's Farxiga (Dapagliflozin) Approved in China for Heart Failure with Reduced Ejection Fraction

Shanghai, February 4, 2021 /PRNewswire/ -- AstraZeneca's Forxiga^®(Generic name: dapagliflozin) has been officially approved in China for the treatment of adult patients with heart failure with reduced ejection fraction (HFrEF, NYHA class II–IV), reducing the risk of cardiovascular death and hospitalization for heart failure (hHF).

Chronic heart failure is a life-threatening condition that can lead to reduced cardiac pumping function, making it difficult to meet the body's needs.^[1]. At least half of the patients have heart failure with reduced ejection fraction (HFrEF).^[2], typically manifesting as inadequate contraction of the left ventricular myocardium, thereby reducing blood supply to the circulation and peripheral tissues^[3-5]。

The approval of dapagliflozin for the indication of heart failure in China is based onThe New England Journal of Medicinethe positive results from the landmark Phase III DAPA-HF clinical trial published in . In May 2020, the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) included the DAPA-HF study in its priority review program.

Ge Junbo, Academician of the Chinese Academy of Sciences, Director of the Department of Cardiology at Zhongshan Hospital Affiliated to Fudan University, and Principal Investigator of the DAPA-HF China Clinical StudyThe professor stated, “Cardiovascular disease mortality in China far exceeds that of cancer and other diseases, making it the leading cause of death among residents. The DAPA-HF study enrolled patients across 30 research centers in China, and its findings strongly support the approval of dapagliflozin in China as a new standard of care, benefiting tens of millions of Chinese patients with heart failure.”

Mene Pangalos, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, stated, “Apart from heart transplantation, there are currently no known cures for chronic heart failure; therefore, patients urgently need novel therapies that can alleviate symptoms and prolong survival. With tens of millions of heart failure patients worldwide, our overarching ambition is to identify treatment regimens that can improve their prognosis. Hence, this approval is of significant importance.”

Mr. Wang Lei, Executive Vice President of AstraZeneca and President of International Operations and China, stated, “The approval of dapagliflozin will provide a new treatment option for heart failure patients in China, further underscoring its significant role in the management of both diabetes and heart failure. AstraZeneca will continue to prioritize patient needs by accelerating the research, development, and introduction of innovative medicines to address the unmet needs of patients with chronic diseases.”

Dr. He Jing, President of the AstraZeneca Global R&D China Center, stated: “AstraZeneca is committed to continuously pushing the frontiers of science and exploring potential connections across different disease areas. Dapagliflozin is the first SGLT2 inhibitor officially approved in China for the indication of heart failure, capable of significantly reducing the incidence of cardiovascular death and worsening heart failure events. This approval will redefine current treatment standards and bring new hope to tens of millions of heart failure patients in China.”

The DAPA-HF Phase III clinical trial demonstrated that adding dapagliflozin to standard therapy (including ACE inhibitors or ARBs) reduced the risk of the composite endpoint of cardiovascular death or worsening heart failure events (including hospitalization for heart failure [hHF]) by 26% compared with placebo, and both components of the primary composite endpoint contributed to the overall treatment benefit.^[6]Dapagliflozin is the first SGLT2 inhibitor to achieve this efficacy. The safety profile observed in the Phase III DAPA-HF clinical trial was consistent with the known safety profile of the drug. During the trial, one cardiovascular death, heart failure hospitalization, or heart failure-related urgent visit was prevented for every 21 patients treated.^[6]。

Dapagliflozin has been approved in the United States, Europe, Japan, and many other countries and regions worldwide for the treatment of heart failure with reduced ejection fraction in adults.

Scientific research continues to uncover close interconnections among the heart, kidneys, and pancreas, while AstraZeneca’s investigations into dapagliflozin for the prevention of cardiorenal events are steadily advancing. DAPA-HF is part of the comprehensive DapaCare clinical research program, which aims to evaluate the potential of dapagliflozin in delivering cardiovascular and renal benefits. This program also explores the performance of dapagliflozin in the field of chronic kidney disease (CKD). In August 2020, the complete results of the Phase III DAPA-CKD trial were released, demonstrating that dapagliflozin met all primary and secondary endpoints, including a reduction in all-cause mortality. Furthermore, in the Phase III DELIVER trial, dapagliflozin is currently being studied in patients with heart failure with preserved ejection fraction (HFpEF), with data expected to be announced in the second half of 2021. Another ongoing study, the Phase III DAPA-MI clinical trial, focuses on patients with acute myocardial infarction (MI) or heart attack who do not have type 2 diabetes. This study is the first randomized controlled trial based on indication-specific registry research within its class.

About Heart Failure

Heart failure (HF) affects approximately 64 million people worldwide, at least half of whom have heart failure with reduced ejection fraction.^[2,7], including 15 million in the European Union and 6 million in the United States^[8,9]and the 7 million adult heart failure patients treated in China^[10]Heart failure is a chronic disease, with more than half of patients dying within five years after diagnosis.^[11]. Heart failure is classified into two major categories based on ejection fraction (EF: the percentage of stroke volume relative to end-diastolic ventricular volume): heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).^[3]Heart failure with reduced ejection fraction is characterized by inadequate contraction of the left ventricular myocardium, leading to reduced blood supply to the systemic circulation and peripheral tissues.^[4,5]. Heart failure is as lethal as some of the most common cancers in men (prostate cancer and bladder cancer) and women (breast cancer).^[12], it is also a leading cause of hospitalization among patients aged 65 and older, imposing a substantial clinical burden on physicians and a significant economic burden on patients.^[13]。

AboutDAPA-HFResearch

DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was an international, multicenter, parallel-group, randomized, double-blind Phase III clinical trial that enrolled 4,744 patients with heart failure with reduced ejection fraction (LVEF ≤40%), regardless of the presence or absence of type 2 diabetes. The trial aimed to evaluate the efficacy of adding dapagliflozin 10 mg once daily to standard therapy compared with placebo. The primary composite endpoint was the first occurrence of a worsening heart failure event (hospitalization or an equivalent event, such as an emergency department visit for heart failure) or cardiovascular death. The median follow-up duration was 18.2 months.

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 focusing on its cardiorenal benefits to emphasizing the prevention of cardiorenal diseases and organ protection. Damage to a single organ can lead to corresponding failure 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, the efficacy of dapagliflozin has been demonstrated in both monotherapy and combination therapy, improving glycemic control in adults with type 2 diabetes mellitus when used as an adjunct to diet and exercise. The landmark DECLARE-TIMI 58 trial confirmed that adding dapagliflozin to standard care significantly reduces the risk of hospitalization for heart failure (hHF) or cardiovascular death in adults with type 2 diabetes mellitus. Dapagliflozin is also the first SGLT2 inhibitor approved for the treatment of adults with heart failure with reduced ejection fraction (HFrEF), regardless of whether they have concomitant type 2 diabetes mellitus.

In August 2020, the full results of the Phase III DAPA-CKD clinical trial demonstrated that dapagliflozin achieved unprecedented efficacy in reducing the composite risk of kidney failure and cardiovascular or renal death in patients with chronic kidney disease (CKD), compared with placebo. Among renal outcome trials in this patient population, dapagliflozin has become the first SGLT2 inhibitor to significantly prolong patient survival and provide organ protection. Currently, the indication for dapagliflozin in chronic kidney disease has not yet been approved.

DapaCare is a comprehensive clinical trial program designed to evaluate the potential benefits of dapagliflozin in cardiovascular and renal fields. The program includes 35 completed and ongoing Phase IIb/III clinical trials, enrolling more than 35,000 patients and accumulating over 2.5 million patient-years of exposure. Currently, the DELIVER Phase III trial is evaluating patients with heart failure with preserved ejection fraction. In the DAPA-MI Phase III trial, dapagliflozin is being studied in patients with acute myocardial infarction (MI) or heart attack without comorbid type 2 diabetes; this study is the first randomized controlled trial based on indication-specific registry research within its class.

Disclaimer: The content mentioned in this articleDAPA-CKDResearch,DELIVERResearch,DECLARE-TIMI 58Research andDAPA-MIThe indication under investigation is still in the development stage and has not yet been approved in China. AstraZeneca does not recommend any unapproved uses of its medicines.

References

[1]. Mayo Clinic. Heart Failure; 29 May 2020 [cited 5 January 2021]. Available from: URL: https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142.

[2]. Travessa AMR, Menezes Falcão LF de. Treatment of Heart Failure With Reduced Ejection Fraction-Recent Developments. Am J Ther 2016; 23(2):e531-49.

[3]. American Heart Association. Ejection Fraction Heart Failure Measurement; 2017 [cited 2 Nov 2020]. Available from: URL: https://www.heart.org/en/health-topics/heart-failure/diagnosing-heart-failure/ejection-fraction-heart-failure-measurement.

[4]. Ponikowski P et al. 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) Developed with the Special Contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37(27):2129–200.

[5]. National Guideline Centre (UK). Chronic Heart Failure in Adults: Diagnosis and Management. London: National Institute for Health and Care Excellence (UK); 2018 Sep. (NICE Guideline, No. 106.) 13, Glossary.

[6]. McMurray JJV et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019; 381(21):1995–2008.

[7]. Vos T et al. Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 328 Diseases and Injuries for 195 Countries, 1990–2016: A Systematic Analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390(10100):1211–59.

[8]. Dickstein K et al. ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in Collaboration with the Heart Failure Association of the ESC (HFA) and Endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008; 29:2388–442.

[9]. Centers for Disease Control and Prevention. Heart Disease: Heart Failure. 8 September 2020.   https://www.cdc.gov/heartdisease/heart_failure.htm#:~:text=Facts%20About%20Heart%20Failure%20in,estimated%20%2430.7%20billion%20in%202012.

[10]. AstraZeneca. Data on File. February 2020.

[11]. Mozaffarian D et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016; 133(4):e38–360.

[12]. Mamas MA et al. Do Patients Have Worse Outcomes in Heart Failure than in Cancer? A Primary Care-Based Cohort Study with 10-year Follow-up in Scotland. Eur J Heart Fail 2017; 19(9):1095–104.

[13]. Azad N, Lemay G. Management of Chronic Heart Failure in the Older Population. J Geriatr Cardiol 2014; 11(4):329–37.