FARXIGA Granted Fast Track Designation in the US for Heart Failure Following Acute Myocardial Infarction Leveraging an Innovative Registry-Based Trial Design

AstraZeneca has been granted Fast Track Designation in the US for the development of FARXIGA® (dapagliflozin)to reduce the risk of hospitalization for heart failure (hHF) or cardiovascular (CV) death in adults following an acute myocardial infarction (MI) or heart attack.

The designation is based on the Phase III DAPA-MI trial that will explore the efficacy and safety of FARXIGA in this patient population. Acute MI is a serious condition and a known cause of heart failure (HF). Approximately seven million heart attacks occur globally each year.1

The Food and Drug Administration’s (FDA) Fast Track program is designed to accelerate the development and review of new medicines for the treatment of serious conditions where there is an unmet treatment need. In addition to Fast Track Designation, the FDA recently granted Special Protocol Assessment (SPA) agreement to the DAPA-MI trial. The SPA is a rarely granted, advanced declaration by the FDA that a Phase III trial's design is acceptable for a future marketing application.

The DAPA-MI trial integrates routine care and registries with the requirements of a rigorous placebo-controlled, randomized clinical trial, thus aiming for an approvable label indication. Registries are used by physicians to store patient health data collected over time, often during regular recurrent visits. In DAPA-MI, patients and their treating physicians participating in registries can join the trial and integrate it within their routine clinical practice. Unlike conventional studies where patients often need to travel to a trial center that may be far from home, this pragmatic, innovative approach delivers rigorous safety and efficacy data, while reducing patient burden and streamlining trial delivery.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The Phase III DAPA-MI trial is the first indication-seeking registry-based randomized controlled trial which will provide quicker access to data and reduce recruitment time and cost, while minimizing patient and investigator burden. Today's FDA Fast Track Designation acknowledged the importance of this trial, which will provide valuable insights into FARXIGA’s potential in patients who had a heart attack and went on to develop heart failure and also into how we can improve clinical trial design in the future.”

The DAPA-MI trial is conducted in collaboration with Uppsala Clinical Research Center (UCR) and Minap in the UK. It will explore the benefit of FARXIGA in patients without type-2 diabetes (T2D) following an acute MI. It is expected to begin recruiting in the fourth quarter of 2020.

In May 2020, FARXIGA was approved in the US to reduce the risk of CV death and hHF in adults with HF (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without T2D. FARXIGA is also indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D.Additionally, FARXIGAis being evaluated for patients with chronic kidney disease (CKD) in the Phase III DAPA-CKD trial, which was stopped early after a Data Monitoring Committee determination of overwhelming efficacy.

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.

Acute Myocardial Infarction

Acute MI, also known as a heart attack, is a common, serious condition and cause of HF.1,2 The strongest predictor of in-hospital mortality following an acute coronary event is HF.3 Many patients who experience acute MI will develop HF, and these patients have a higher mortality risk than patients already presenting with HF at admission.4 The standard of care for patients with acute MI has improved considerably over the years, but the prognosis has not shown a dramatic change indicating that novel approaches are needed to reduce CV risk.5

DAPA-MI

DAPA-MI (DAPAgliflozin effects in patients without diabetes with Myocardial Infarction) is an international, multi-center, double-blinded registry-based randomized controlled trial designed to assess the efficacy and safety of FARXIGA 10mg, compared to placebo, given once daily to reduce the risk of hHF and CV disease in adults without T2D following an acute MI. DAPA-MI integrates traditional, pragmatic, and innovative study design elements with the goal of minimizing patient and investigator burden while producing real world evidence of efficacy that adds to the existing body of evidence generated by FARXIGA randomized controlled trials. The trial will recruit around 6,400 patients from approximately 50 sites in Sweden and 50 sites in the UK. Prospective data collection is done through two national CV disease quality registries.

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.

References

1. Roth GA et al. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 2017; 70(1):1–25.
2. Gerber Y et al. Mortality Associated With Heart Failure After Myocardial Infarction: A Contemporary Community Perspective. Circ Heart Fail 2016; 9(1):e002460.
3. Granger CB et al. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 2003; 163(19):2345–53.
4. Torabi, Azam et al. “Development and course of heart failure after a myocardial infarction in younger and older people.” Journal of geriatric cardiology : JGC vol. 11,1 (2014): 1-12. doi:10.3969/j.issn.1671-5411.2014.01.002
5. Professor Tomas Jernberg. ESC Congress News 2018: No changes in survival after acute myocardial infarction in the last decade – new data from SWEDEHEART. Available from: URL: https://www.escardio.org/Congresses-&-Events/ESC-Congress/Congress-resources/Congress-news/no-changes-in-survival-after-acute-myocardial-infarction-in-the-last-decade-new-data-from-swedeheart.

US-42243 Last Updated 7/20

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