FARXIGA DAPA-CKD Phase III Trial Reduced Worsening of Kidney Function, Risk of Cardiovascular or Renal Death in Patients With Chronic Kidney Disease Irrespective of Underlying Cause

WILMINGTON, Del.–(BUSINESS WIRE)–A new subgroup analysis from the ground-breaking DAPA-CKD Phase III trial showed that AstraZeneca’s FARXIGA^® (dapagliflozin), on top of standard of care, reduced the composite of worsening of kidney function or risk of cardiovascular (CV) or renal death in patients with chronic kidney disease (CKD), irrespective of the underlying cause of the disease.¹

CKD is a serious, progressive condition defined by decreased kidney function. It is estimated it affects nearly 700 million people worldwide, many of them still undiagnosed.^2–5 The main causes of CKD are diabetes (38%), high blood pressure (26%), and glomerulonephritis (kidney inflammation, 16%).⁶

In the subgroup analysis, compared to placebo, FARXIGA showed a relative risk reduction (RRR) of 37% for patients whose CKD was primarily driven by diabetic kidney disease; (absolute risk reduction [ARR] = −5.8%), 25% for high blood pressure; (ARR = −2.2%), 57% for glomerulonephritis; (ARR = −7.5%), and 42% for CKD of other or unknown causes. (p−interaction for RRR 0.53). Similarly, FARXIGA showed a reduction in all-cause mortality, a secondary outcome, compared to placebo, regardless of underlying CKD cause (p-interaction 0.55).⁷

The safety and tolerability of FARXIGA was consistent with the well-established safety profile of the medicine.

Prof. Hiddo L. Heerspink, Co-chair of the DAPA-CKD trial and its Executive Committee, University Medical Center Groningen, the Netherlands, said: “These results reinforce the potential of FARXIGA to change the standard of care for a wide range of patients with chronic kidney disease, regardless of the root cause of their disease. This could open up enormous possibilities for the millions of patients living with chronic kidney disease worldwide.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The DAPA-CKD trial showed the potential of FARXIGA as the first SGLT2 inhibitor to significantly prolong survival in a renal outcomes trial in patients with chronic kidney disease with and without type 2 diabetes. The new data presented further demonstrate FARXIGA’s consistent and clinically meaningful benefit across a diverse group of patients with chronic kidney disease, a population in urgent need of new treatment options to slow the progression of their disease.”

The data were presented at the American Society of Nephrology (ASN) Kidney Week Reimagined 2020.

Earlier this month, FARXIGA was granted Breakthrough Therapy Designation by the US Food and Drug Administration (FDA) for patients with CKD, with and without T2D. Additionally, in May 2020, FARXIGA was approved in the US to reduce the risk of CV death and hospitalization for heart failure (hHF) in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without T2D.

In the US, FARXIGA is also indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D and to reduce the risk of hospitalization for heart failure in patients with T2D and established CV disease or multiple CV risk factors. FARXIGA is not indicated to reduce the worsening of renal function or death in patients with CKD.

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 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

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION for FARXIGA^® (dapagliflozin) 5 mg and 10 mg tablets

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) being treated for glycemic control without established CV disease or multiple CV risk factors
• Patients on dialysis

Warnings and Precautions

• 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
• Ketoacidosis in Diabetes Mellitus has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. 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
• 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 in patients with T2D, the recommended starting dose of FARXIGA is 5 mg orally once daily, taken in the morning. In patients tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily
• To reduce the risk of hospitalization for heart failure in patients with T2D and established CV disease or multiple CV risk factors, the recommended dose of FARXIGA is 10 mg orally once daily
• To reduce the risk of CV death and hospitalization for heart failure in patients with HFrEF, the recommended dose of FARXIGA is 10 mg orally once daily

Please see accompanying US Full Prescribing Information and Medication Guide for FARXIGA.

Chronic kidney disease

CKD is a serious, progressive condition defined by decreased kidney function (shown by reduced estimated glomerular filtration rate [eGFR] or markers of kidney damage, or both, for at least three months).^2–5 In its most severe form, known as end stage kidney disease (ESKD), kidney damage and deterioration of kidney function have progressed to the stage where dialysis or kidney transplantation are required.⁸ The majority of patients with CKD will die from CV causes before reaching ESKD.⁹

DAPA-CKD

DAPA-CKD is an international, multi-center, randomized, double-blinded trial in 4,304 patients designed to evaluate the efficacy of FARXIGA 10 mg, 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. Detailed results shared at the European Society of Cardiology Meeting in August 2020 and published in The New England Journal of Medicine showed FARXIGA reduced the primary composite endpoint of worsening of renal function (defined as a composite of a sustained ≥50% eGFR decline, onset of ESKD and death from CV or renal cause) or renal or CV death by 39% compared to placebo (p<0.0001). The results were consistent in patients both with and without T2D. FARXIGA also met all secondary endpoints including the time to first occurrence of the renal composite (sustained ≥50% eGFR decline, ESKD and renal death), the composite of CV death or hHF, and death from any cause by 31% (ARR = 2.1%, p=0.0035). Median duration of the study was 2.4 years.

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 to protect organs and improve 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.

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

1. Wheeler D. Effects of dapagliflozin on kidney function, cardiovascular events and all-cause mortality according to cause of kidney disease in the DAPA-CKD trial. (presented at the American Society of Nephrology – Kidney Week 2020 Reimagined. 22-25 October 2020).
2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplement. 2013;(3):1–150.
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. The Lancet. 2020; 395(10225):709–33.
4. Hirst JA et al. Prevalence of chronic kidney disease in the community using data from OxRen: A UK population-based cohort study. Br J Gen Pract. 2020;70(693):e285-e293.
5. National Kidney Foundation. Kidney Disease: The Basics; 2020 [cited 23 September 2020]. Available from: URL: https://www.kidney.org/news/newsroom/factsheets/KidneyDiseaseBasics.
6. National Kidney Foundation. Kidney Disease: Causes; 2015 [cited 23 September 2020]. Available from: URL: https://www.kidney.org/atoz/content/kidneydiscauses.
7. Heerspink HJL et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446.
8. Centers for Disease Control and Prevention (CDC). Chronic Kidney Disease in the United States, 2019; 2019 [cited 31 March 2020]. Available from: URL: https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html
9. Briasoulis A, Bakris GL. Chronic Kidney Disease as a Coronary Artery Disease Risk Equivalent. Current Cardiology Reports. 2013;15(3):340.

US-46365 Last Updated 10/20