Consistent Effects of FARXIGA in Heart Failure Patients With Reduced Ejection Fraction Shown in New Analyses From Landmark Phase III DAPA-HF Trial

AstraZeneca today announced new data from five additional analyses of the landmark Phase III DAPA-HF trial, which showed that FARXIGA (dapagliflozin) reduced the risk of the primary composite outcome of worsening heart failure (HF), defined as hospitalization or an urgent visit, or death from cardiovascular (CV) causes versus placebo, when added to standard of care.

DAPA-HF is the first outcomes trial with an SGLT2 inhibitor investigating the treatment of HF in patients with reduced ejection fraction (HFrEF), with and without type 2 diabetes (T2D). The new analyses showed the consistency of these results across patient subgroups with and without T2D, an early onset of effects, and improvement in patient-reported outcomes of HF-related health status.

These data were presented at the American Heart Association (AHA) Scientific Sessions in Philadelphia.

Elisabeth Björk, Senior Vice President, Head of Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, said: "Heart failure affects approximately 64 million people around the world and about half of those patients will die within five years of diagnosis. These new analyses from the DAPA-HF trial reinforce the science behind FARXIGA as clinically significant across heart failure patient populations and suggest the potential to improve the current standard of care for millions of these patients."

Across all five analyses, FARXIGA showed improvements versus placebo in the worsening or progression of the disease and improved patient-reported symptoms and quality of life.

The Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure Trial (DAPA-HF): Results in Nondiabetic Patients subgroup analysis showed that FARXIGA reduced the risk of the primary composite endpoint compared to placebo in patients with HFrEF without T2D. This analysis evaluated the primary composite and its components and secondary endpoints in a subgroup of patients without T2D. With FARXIGA, the relative risk of the composite of worsening of HF or CV death was reduced by 27% among participants without diabetes (absolute risks 9.2% vs 12.7%, n=2605; HR 0.73 [95% CI 0.60, 0.88]) and by 25% in patients with diabetes (14.6% vs 19.4%, n=2139; HR 0.75 [95% CI 0.63, 0.90]). All components contributed to the overall result. The data suggest that FARXIGA has the potential to be a treatment for patients with HFrEF both with and without T2D.

Another pre-specified analysis presented, Effect of Treatment on the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF), examined the effects of FARXIGA on HF related health status (symptoms, physical limitations and quality of life) in HFrEF, assessed using the KCCQ. An improvement in the KCCQ total score for dapagliflozin compared to placebo was seen at 4 months, and the magnitude of the improvement was amplified at 8 months. Furthermore, fewer patients treated with FARXIGA had significant deterioration (?5 points), and more experienced small (?5 points), moderate (?10 points) and large (?15 points) clinically meaningful improvements in total KCCQ score. The total symptom score on the KCCQ range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with HF and a change of 5 or more points considered to be clinically meaningful.

The Timing of Onset of Clinical Benefit with Dapagliflozin in Patients with Heart Failure: An Analysis from the Dapagliflozin And Prevention of Adverse-outcomes In Heart Failure Trial (DAPA-HF) post-hoc analysis explored the timing of onset of clinical benefit with FARXIGA in patients with HFrEF compared to placebo. Reduction in the risk of the composite of worsening HF or CV death versus placebo was shown as soon as 4 weeks. These exploratory data reinforce that FARXIGA provided crucial early benefit for patients with HF.

The Effect of Treatment According to Age in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF) subgroup analysis suggested that FARXIGA may benefit outcomes in patients with HFrEF, regardless of age. There was no apparent effect of age on the occurrence of adverse events or treatment discontinuation of dapagliflozin versus placebo.

The Influence of Ejection Fraction on the Effect of Treatment in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF) subgroup analysis indicated that the treatment effects of dapagliflozin versus placebo were consistent over a broad spectrum of left ventricular ejection fraction (LVEF) (P interaction = 0.205 for primary composite outcome). LVEF is a predictor of mortality and hospitalization related to HF.

These positive FARXIGA results build on the DAPA-HF detailed results announced in September 2019. FARXIGA is currently being studied in patients with HF with preserved ejection fraction (HFpEF) in the DELIVER and DETERMINE (HFrEF and HFpEF) trials.

Additionally, in September 2019, the US Food and Drug Administration (FDA) granted Fast Track designation for FARXIGA to reduce the risk of CV death, or the worsening of HF in adults with HFrEF or HFpEF based on the Phase III DAPA-HF and DELIVER trials. The FDA also recently updated the FARXIGA label to add an indication to reduce the risk of hospitalization for HF (hHF) in adults with T2D and established CV disease or multiple CV risk factors. The approval was based on results from the landmark DECLARE-TIMI 58 CV outcomes trial (CVOT), the largest SGLT2 inhibitors CVOT conducted to date. FARXIGA is not indicated to reduce the risk of hHF in patients without diabetes, or to reduce the risk of CV death.

Indication and Limitations of Use for FARXIGA^® (dapagliflozin) tablets

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 disease or multiple cardiovascular risk factors

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

Important Safety Information for FARXIGA^® (dapagliflozin) tablets

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: FARXIGA causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating FARXIGA in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension
• Ketoacidosis 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
• Acute Kidney Injury: FARXIGA causes intravascular volume contraction and can cause acute kidney injury. Reports of acute kidney injury requiring hospitalization and dialysis have occurred with FARXIGA. If acute kidney injury occurs, discontinue and promptly treat

Increases in serum creatinine and decreases in eGFR may be observed with initiation of FARXIGA. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses

Before initiating FARXIGA, evaluate renal function and monitor periodically. FARXIGA is not recommended when the eGFR is <45 mL/min/1.73 m²

• 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 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.

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

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NOTES TO EDITORS

About DAPA-HF

DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction (LVEF ? 40%), with and without T2D, designed to evaluate the effect of FARXIGA 10mg, compared with placebo, given once daily in addition to standard of care. The primary composite outcome was time to a worsening heart failure event (hospitalization or equivalent event; i.e. an urgent heart failure visit), or cardiovascular death.

The full results of the DAPA-HF trial were published in The New England Journal of Medicine in September 2019.

About 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. 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.

US-34678 Last Updated 11/19