WILMINGTON, Del.--(BUSINESS WIRE)--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 hospitalization 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 randomized, 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 glycemic 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.

INDICATIONS AND LIMITATIONS OF USE for FARXIGA^??(dapagliflozin)

FARXIGA is indicated:

• as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
• to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular (CV) disease or multiple CV risk factors
• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction
• to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression

FARXIGA is not recommended for patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.

FARXIGA is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m². FARXIGA is likely to be ineffective in this setting based upon its mechanism of action.

FARXIGA is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. FARXIGA is not expected to be effective in these populations.

IMPORTANT SAFETY INFORMATION for FARXIGA

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Patients on dialysis

Warnings and Precautions

• Ketoacidosis in Diabetes Mellitus?has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
• Volume Depletion:?FARXIGA can cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine. Acute kidney injury requiring hospitalization and dialysis has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors, including FARXIGA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating FARXIGA in these patients, assess volume status and renal function. After initiating therapy, monitor for signs and symptoms of hypotension and renal function
• Urosepsis and Pyelonephritis:?SGLT2 inhibitors increase the risk for urinary tract infections (UTIs) and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
• Hypoglycemia:?FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
• Necrotizing Fasciitis of the Perineum (Fournier?s Gangrene):?Rare but serious, life-threatening cases have been reported in patients with diabetes mellitus receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue FARXIGA
• Genital Mycotic Infections:?FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse reactions (=5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

• Pregnancy:?Advise females of potential risk to a fetus especially during the second and third trimesters
• Lactation:?FARXIGA is not recommended when breastfeeding

DOSING

To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control.

For all other indications, the recommended dose is 10 mg orally once daily.

Please see?link?to US Full Prescribing Information for FARXIGA.

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

DAPA-CKD was an international, multi-center, randomized, 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

DECLARE-TIMI 58 was an AstraZeneca-sponsored, randomized, double-blinded, multi-center 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

AstraZeneca in CV, Renal & Metabolism (CVMD)

CV, renal and metabolism together form one of AstraZeneca?s main therapy areas and 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 improving outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of CVMD diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit?www.astrazeneca-us.com?and follow us on Twitter?@AstraZenecaUS.

References

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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.