FARXIGA Granted Priority Review in the US for the Treatment of Patients With Chronic Kidney Disease

The Food and Drug Administration (FDA) grants Priority Review to regulatory submissions for medicines that offer significant advances over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance. The Prescription Drug User Fee Action date, the day the FDA targets for their regulatory decision, will be during the second quarter of 2021.

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. CKD is expected to become the world’s fifth leading cause of mortality by 2040. Currently in the US, 37 million people are estimated to have CKD.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “This decision brings us a step closer to delivering this new treatment option for the millions of patients living with chronic kidney disease in the US. FARXIGA has the potential to be a truly transformational medicine across a breadth of diseases, including type 2 diabetes, heart failure with reduced ejection fraction and, if approved, chronic kidney disease.”

The acceptance of the regulatory submission by the FDA and the granting of Priority Review was based on clinical evidence from the DAPA-CKD Phase III trial showing that FARXIGA, on top of standard of care consisting of an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), reduced the risk of the composite of worsening of renal function or risk of cardiovascular (CV) or renal death by 39%, the primary endpoint, compared to placebo (absolute risk reduction [ARR] 5.3%, p<0.0001) in patients with CKD Stages 2-4 and elevated urinary albumin excretion. It also significantly reduced the risk of death from any cause by 31% (ARR 2.1%, p=0.0035) compared to placebo. The safety and tolerability of FARXIGA were consistent with the well-established safety profile of the medicine.

In March 2020, an independent Data Monitoring Committee recommended the trial be stopped early, based on its determination of overwhelming efficacy. Detailed results from the DAPA-CKD trial were shared in August 2020 and published in The New England Journal of Medicine.

In October 2020, FARXIGA received Breakthrough Therapy Designation in the US for patients with CKD with and without T2D. 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 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. 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. The most common causes of CKD are diabetes, hypertension and glomerulonephritis. 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 end-stage kidney disease (ESKD), kidney damage and deterioration of kidney function have progressed to the stage where dialysis or kidney transplantation are required. The majority of patients with CKD will die from CV causes before reaching ESKD.

DAPA-CKD
DAPA-CKD was an international, multi-center, randomized, double-blinded trial in 4,304 patients designed to evaluate the efficacy of dapagliflozin 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 consisting of an ACEi or an ARB. 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 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.

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.

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