Dapagliflozin Gets Nod as a Breakthrough Therapy Designation for CKD

Dapagliflozin (Farxiga®) has been granted US Food and Drug Administration Breakthrough Therapy Designation for patients with chronic kidney disease (CKD) whether or not they have type 2 diabetes.

This decision was based on the DAPA-CKD Phase III clinical trial results. AstraZeneca’s Farxiga®, along with the standard of care, demonstrated a 39% decline in the risk of worsening renal function or cardiovascular (CV) or renal death in patients with CKD, compared to placebo. The results also showed that dapagliflozin significantly reduced death from any cause by 31% vs. placebo. 

The United States FDA grants the Breakthrough Therapy Designation (BTD) for medications to treat a new or severe condition and address a truly significant unmet medical need. The potential new medicine needs to demonstrate definite improvement in the clinical endpoint. In addition, it has to show promising early clinical trial results before it can be granted the BTD classification. 

According to the Centers for Disease Control and Prevention (CDC), it is estimated that 37 million individuals in the United States have chronic kidney disease (CKD), which is a severe, progressive, and debilitating condition. CKD is defined by significantly decreased renal function and is often associated with an increased risk of heart disease and stroke and an increased need for dialysis. 

In the United States, Farxiga® is indicated as a treatment to improve glycemic control in patients with type 2 diabetes mellitus (T2DM), on top of regular diet and exercise. It is also used to reduce the risk of heart failure (HF) hospitalization in patients with T2DM and those with established CV disease or multiple risk factors. Moreover, the FDA has approved Farxiga® to reduce the risk of CV death and hospitalization for heart failure in adult patients (NYHA class II-IV) with reduced ejection fraction (HFrEF), with or without T2DM. 

Furthermore, dapagliflozin (Farxiga®) is a first-in-class, oral, once-daily SGLT2 (sodium-glucose co-transporter 2) inhibitor, which acts by blocking the transporter mechanism in the kidneys, causing blood glucose to get eliminated through the urine. It can be given as monotherapy or as part of combination therapy to improve glycemic control, with the added benefits of weight loss and subsequent blood pressure lowering. Per the DECLARE CV outcomes trial, dapagliflozin reduced the risk of the composite endpoint of heart failure or CV death compared to placebo when given with standard of care treatment. In ongoing clinical trials, dapagliflozin is being studied in patients with HFpEF (heart failure with preserved ejection fraction) through the DELIVER trial and HFpEF HFrEF patients through the DETERMINE trial. In terms of future studies, dapagliflozin will be tested in patients without T2DM following an acute coronary syndrome (ACS) such as myocardial infarction (MI) in the DAPA-MI trial. This will be the first of its kind randomized controlled trial, seeking a new indication for Farxiga®. 

DAPA-CKD is a multi-center, randomized, double-blinded placebo-controlled trial in different countries wherein 4,304 patients were designated to have either dapagliflozin 10 mg or placebo, to evaluate its efficacy in patients with chronic kidney disease stages 2-4 and elevated urinary albuminuria, with or without type 2 diabetes mellitus. Dapagliflozin is given once daily, in addition to the standard of care. The primary composite endpoint exacerbates patients’ renal function or the risk of death, as defined by an eGFR decline of greater than 50%, onset of ESRD, and death from any CV or renal cause. 

According to Mene Pangalos, Executive Vice President of BioPharmaceuticals R&D: “There is a serious, unmet need for better and earlier treatment options for patients with chronic kidney disease. Following the groundbreaking DAPA-CKD results, the Breakthrough Therapy Designation is further testament to Farxiga®’s potential to slow the progression of chronic kidney disease.” Indeed, dapagliflozin (Farxiga®) is now indicated to reduce the risk of worsening renal function or death in patients with CKD. 

Practice Pearls: 

• Dapagliflozin (Farxiga®) gets a breakthrough therapy designation for patients with chronic kidney disease (CKD), with or without diabetes. 
• CKD is defined by significantly decreased renal function and is often associated with increased heart disease and stroke risk. 
• Dapagliflozin (Farxiga®) significantly reduced the risk of worsening renal function or CV or renal death in patients with CKD by 39%, compared to placebo. 

References for “Dapagliflozin Gets Nod as a Breakthrough Therapy Designation for CKD”:
Heerspink, Hiddo J L et al. “Dapagliflozin in patients with chronic kidney disease.” The New England journal of medicine, 10.1056/NEJMoa2024816. 24 Sep. 2020, doi:10.1056/NEJMoa2024816 

Sternlicht, Hillel K, and George L Bakris. “Reductions in albuminuria with SGLT2 inhibitors: a marker for improved renal outcomes in patients without diabetes?.” The lancet. Diabetes & endocrinology vol. 8,7 (2020): 553-555. doi:10.1016/S2213-8587(20)30185-6 

Arjay Mendoza, PharmD Candidate, University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences 

See more about dapagliflozin and other SGLT-2 inhibitors in our Therapy center.