AstraZeneca Announces FDA Breakthrough Therapy Designation for Farxiga (Dapagliflozin) in Chronic Kidney Disease

On October 2, AstraZeneca announced that the FDA had granted Breakthrough Therapy designation to Farxiga (dapagliflozin) for the treatment of patients with chronic kidney disease (regardless of whether they have type 2 diabetes).

Chronic kidney disease (CKD) is a serious condition characterized by progressive decline in kidney function (marked by reduced eGFR, kidney damage, or both, persisting for more than 3 months), affecting 700 million people worldwide, although the majority remain undiagnosed. There are approximately 37 million cases of chronic kidney disease in the United States.

The most common causes of chronic kidney disease (CKD) include diabetes, hypertension, and glomerulonephritis. CKD is typically associated with an increased risk of cardiovascular disease or stroke, and patients often present with numerous complications, including anemia, hyperkalemia, metabolic acidosis, hyperparathyroidism, and hyperphosphatemia, among others; consequently, these patients face a higher risk of mortality. Without early intervention and management, CKD can progressively worsen into chronic renal insufficiency, end-stage renal disease (ESRD), and kidney failure. Generally, patients who progress to ESRD require dialysis or kidney transplantation; however, the majority of patients die from cardiovascular disease before their condition deteriorates to end-stage renal disease.

The FDA’s designation of dapagliflozin as a breakthrough therapy for the treatment of chronic kidney disease (CKD) was primarily based on evidence from the DAPA-CKD study. The DAPA-CKD study was an international, multicenter, randomized, double-blind trial that enrolled 4,304 patients with stage 2–4 CKD and elevated urinary albumin excretion rate (with or without type 2 diabetes mellitus) to evaluate the efficacy difference between adding once-daily dapagliflozin 10 mg versus placebo to standard of care. The primary composite endpoint was worsening of renal function or death (defined as a ≥50% decline in eGFR from baseline, progression to end-stage renal disease, or renal or cardiovascular death). Secondary endpoints included worsening of renal function or renal death (a ≥50% decline in eGFR from baseline, progression to end-stage renal disease, or renal death), cardiovascular death or hospitalization for heart failure, and all-cause mortality.

The detailed results of the DAPA-CKD study were presented on August 31 at the ESC 2020 Congress. The results showed that, at a median follow-up of 2.4 years, dapagliflozin reduced the risk of the primary composite endpoint by 39% compared with placebo (HR=0.61, 95% CI: 0.51–0.72). For secondary endpoints, the risk of worsening renal function or death from kidney disease was reduced by 44%, the risk of cardiovascular death or hospitalization for heart failure was reduced by 29% (HR=0.71, 95% CI: 0.55–0.92), and the risk of all-cause mortality was reduced by 31% (HR=0.69, 95% CI: 0.53–0.88).

In the DAPA-CKD study, 67% of enrolled patients had diabetes at baseline. Subgroup analysis showed that the benefit on the primary endpoint was consistent in patients with diabetes (HR=0.64, 95% CI: 0.52–0.79) and those without diabetes (HR=0.50, 95% CI: 0.35–0.72).

Previously, renin-angiotensin-aldosterone system inhibitors (RAASi) were the preferred standard-of-care agents for patients with chronic kidney disease (CKD); however, due to a lack of effective therapeutic options, these patients still faced a substantial risk of disease progression. In the DAPA-CKD trial, dapagliflozin was evaluated in CKD patients regardless of type 2 diabetes status. It was the first drug demonstrated in a renal outcomes study to significantly prolong survival in CKD patients, without increasing the risk of serious adverse events such as renal-related adverse events, volume depletion, amputation, or fracture. These findings demonstrate its favorable renal protective effects and suggest that it is poised to be incorporated into the standard of care for CKD patients.

Dapagliflozin is the first SGLT2 inhibitor to be marketed globally. It has currently been approved in the United States as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus, and to reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes mellitus who have established cardiovascular disease or are at high cardiovascular risk. In May this year, the FDA also approved dapagliflozin to reduce the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), regardless of whether they have type 2 diabetes mellitus.