ESC19: AstraZeneca LBCT DAPA-HF Study Shows Farxiga Reduced CV Death and Worsening of Heart Failure

DAPA-HF is the first outcomes trial with an SGLT2 inhibitor in patients with heart failure with reduced ejection fraction, with and without type 2 diabetes

September 3, 2019 – AstraZeneca announced detailed results from the landmark Phase III DAPA-HF trial that showed FARXIGA (dapagliflozin) on top of standard of care reduced both the incidence of cardiovascular (CV) death and the worsening of heart failure.

DAPA-HF is the first outcomes trial with an SGLT2 inhibitor investigating the treatment of heart failure in patients with reduced ejection fraction (HFrEF), with and without type 2 diabetes (T2D). FARXIGA is currently approved to improve glycemic control in patients with T2D.

Top-line results announced in August 2019 showed DAPA-HF met the primary endpoint. The detailed results of the trial presented today at the ESC Congress 2019 in Paris, France, showed FARXIGA reduced the composite of CV death or worsening of heart failure by 26% (p<0.0001) and showed a reduction in each of the individual components of the composite endpoint. FARXIGA is not indicated to reduce the risk of heart failure or CV death.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “FARXIGA is well established in the treatment of type 2 diabetes, and these exciting new findings offer clinically meaningful insights into the potential of the medicine to reduce the burden of heart failure in patients with and without type 2 diabetes. We are proud to be contributing to the scientific body of evidence during the ESC Congress 2019.”

John McMurray, MD, University of Glasgow, Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, said: “We are very pleased that FARXIGA was so effective in our trial – it did all the things we would like any drug to do in heart failure, which are to improve symptoms, reduce hospital admissions and increase survival. Even better, FARXIGA was as effective in heart failure patients without diabetes as in those with diabetes.”

In analyzing each of the components of the primary composite endpoint, there was a 30% decrease (p<0.0001) in the risk of experiencing a first episode of worsening heart failure and an 18% decrease (p=0.0294) in the risk of dying from CV causes. The effect of FARXIGA on the primary composite endpoint was generally consistent across the key subgroups examined.

The trial results also showed a significant improvement in patient reported outcomes measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score and a nominally significant reduction in all-cause mortality by 17% (7.9 vs 9.5 patients with an event per 100 patient-years) in favor of FARXIGA.

The safety profile of FARXIGA in the DAPA-HF trial was consistent with the well-established safety profile of the medicine. The proportion of patients with volume depletion (7.5% vs 6.8%) and renal adverse events (6.5% vs 7.2%), which are commonly of concern when treating heart failure, were comparable to placebo. Major hypoglycemic events (0.2% vs 0.2%) were rare in both treatment groups.

FARXIGA is also being studied in patients with heart failure with preserved ejection fraction (HFpEF) in the DELIVER and DETERMINE (HFrEF and HFpEF) trials.

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.

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 and Impairment in Renal Function: FARXIGA causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.

FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. 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

·        Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. Monitor LDL-C and treat per standard of care

·        Bladder cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to FARXIGA, and insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. FARXIGA should not be used in patients with active bladder cancer. Use with caution in patients with a history of bladder cancer

·        Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA

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.

About DAPA-HF
DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) is an international, multi-center, parallel group, randomized, double-blinded 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.

About heart failure
Heart failure (HF) is a life-threatening disease in which the heart cannot pump enough blood around the body. It affects approximately 6.5 million people in the US (half of which have a reduced ejection fraction) and is a chronic and degenerative disease where half of patients will die within five years of diagnosis. HF remains as ‘malignant’ as some of the most common cancers in both men (prostate and bladder cancers) and women (breast cancers). It is the leading cause of hospitalization for those over the age of 65 and represents a significant clinical and economic burden.

About the DapaCare Clinical Program
AstraZeneca is taking a holistic, patient-centric approach to disease management by addressing the underlying morbidity, mortality and organ damage associated with CV, metabolic and renal diseases. Due to the interconnectivity of these diseases, AstraZeneca has developed the DapaCare clinical program to explore the CV and renal profile of FARXIGA in people with and without T2D. The clinical program will enroll nearly 30,000 patients in randomized clinical trials and is supported by a multinational real-world evidence study. DapaCare will generate data across a spectrum of patients with established CV disease, CV risk factors and varying stages of renal disease, both with and without T2D, providing healthcare providers with evidence needed to improve patient outcomes.

FARXIGA is also being developed for patients with heart failure in the DELIVER (HFpEF) and DETERMINE (HFrEF and HFpEF) trials, in addition to chronic kidney disease in the DAPA-CKD trial. DapaCare underscores our commitment to following the science by pursuing a holistic patient approach to address the multiple risk factors associated with CV, renal and metabolic diseases. FARXIGA is not indicated to reduce the risk of heart failure, CV death or kidney disease.

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.