FARXIGA Granted Breakthrough Therapy Designation in US for Chronic Kidney Disease

Designation follows DAPA-CKD Phase III trial results in which FARXIGA demonstrated unprecedented reduction in the risk of kidney failure and cardiovascular or renal death in patients with chronic kidney disease

WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca’s FARXIGA^® (dapagliflozin) has been granted Breakthrough Therapy Designation (BTD) in the US for patients with chronic kidney disease (CKD), with and without type 2 diabetes (T2D).

CKD is a serious, progressive condition defined by decreased kidney function and is often associated with an increased risk of heart disease or stroke. In the US, 37 million people are estimated to have CKD.¹

The Food and Drug Administration (FDA)'s BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need. The new medicine needs to have shown encouraging early clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “There is a serious, unmet need for better and earlier treatment options for patients with chronic kidney disease. Following the ground-breaking DAPA-CKD results, the Breakthrough Therapy Designation is further testament to FARXIGA’s potential to slow the progression of chronic kidney disease. We look forward to working with the FDA to make FARXIGA available to patients in the US as quickly as possible.”

The FDA granted BTD based on clinical evidence from the DAPA-CKD trial. The detailed results presented in August demonstrated that FARXIGA on top of standard of care reduced the composite measure of worsening of renal function or risk of cardiovascular (CV) or renal death by 39% compared to placebo (absolute risk reduction [ARR] = 5.3%, p<0.0001) in patients with CKD while also significantly reducing death from any cause by 31% (ARR = 2.1%, p=0.0035) compared to placebo.

In the US, FARXIGA is 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. In May, FARXIGA was approved in the US to reduce the risk of CV death and hospitalization for heart failure (hHF) in adults with heart failure (HF) (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without T2D. 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) affecting nearly 700 million people worldwide, many of them still undiagnosed.^2,3 The most common causes of CKD are diabetes, hypertension and glomerulonephritis.⁴ CKD is associated with significant patient morbidity and an increased risk of CV events,³ such as HF and premature death.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.¹ The majority of patients with CKD will die from CV causes before reaching ESKD.⁶

DAPA-CKD

DAPA-CKD is an international, multi-center, randomized, double-blinded 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 is given once daily in addition to standard of care. The primary composite endpoint is worsening of renal function or risk of death (defined as a composite of an eGFR decline ≥50%, onset of ESKD and death from CV or renal cause). The secondary endpoints included 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. The trial was conducted in 21 countries and high-level results were announced in July 2020.

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.

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

1. Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2019 [cited 01.05.20]. Available from URL: https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html.
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. National Kidney Foundation. Kidney Disease: Causes, 2017; [cited 2020 May 01]. Available from URL: https://www.kidney.org/atoz/content/kidneydiscauses.
5. Segall L et al. Heart failure in patients with chronic kidney disease: A systematic integrative review. Biomed Res Int 2014; 2014:937398.
6. Briasoulis A, Bakris GL. Chronic Kidney Disease as a Coronary Artery Disease Risk Equivalent. Cur Cardiol Rep 2013; 15(3):340.

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