Regulatory Decision Summary for Forxiga

Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) is an international, multicenter, randomized, double-blind, placebo-controlled trial in chronic kidney disease (CKD) patients with baseline estimated glomerular filtration rate (eGFR) between 25 and 75 milliliters (mL)/minute (min)/1.73 meters squared (m²) and albuminuria (urine albumin creatinine ratio between 22.6 and 565 milligram (mg)/millimole (mmol)). A total of 4,304 patients were randomised to Forxiga 10 mg [number of subjects (N) = 2,152] or placebo (N = 2,152) once daily, on top of standard of care, and followed for a median of 28.5 months. Treatment could be continued if eGFR fell to levels below 25 mL/min/1.73m² during the study and if dialysis was needed. The primary composite endpoint included ≥50% sustained decline in eGFR, deterioration to end-stage kidney disease (ESKD), and cardiovascular (CV) or renal death.

Forxiga treatment reduced the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, deterioration to ESKD, CV or renal death by 39% compared to placebo [hazard ratio (HR) 0.61 [95% confidence interval (CI) 0.51, 0.72]; p-value (p) <0.0001]. For the secondary endpoints, Forxiga reduced the incidence of the composite endpoint of ≥50% sustained decline in eGFR, ESKD or renal death [HR 0.56 (95% CI 0.45, 0.68), p <0.0001], the composite endpoint of CV death or hospitalization for heart failure [HR 0.71 (95% CI 0.55, 0.92), p = 0.0089], and all-cause mortality [HR 0.69 (95% CI 0.53, 0.88), p = 0.0035]. The treatment benefits of Forxiga demonstrated on the primary composite, the individual components of the primary composite, and all 3 secondary endpoints were consistent in CKD patients with type 2 diabetes mellitus (T2DM) and without diabetes. The effects of Forxiga over placebo on the primary and secondary endpoints were consistent across other key subgroups, including baseline eGFR and urine albumin-to- creatinine ratio (UACR) level, age, sex, and region.

The safety results of DAPA-CKD were consistent with the known safety profile of Forxiga. In total, 2,149 CKD patients were exposed to Forxiga 10 mg with a median exposure of 27.3 months. There were slightly fewer patients who had serious AEs in the Forxiga group (29.5%) than that in the placebo group (33.9%). Numbers of patients who prematurely discontinued the treatment due to adverse event were similar in Forxiga (5.5%) and placebo (5.7%) groups. More AEs of symptoms of volume depletion were reported in the Forxiga group (5.6%) than the placebo (3.9%). More serious AEs of genital infections and urinary tract infections were reported in patients treated with Forxiga (0.1% and 1.3%) than the placebo (0 and 0.8%), respectively. CKD patients with T2DM generally reported more AEs in all categories compared with patients without diabetes, irrespective of treatment. No case of diabetic ketoacidosis was observed in patients treated with Forxiga, and hypoglycemic episode did not occur in CKD participants without diabetes.

Data for initiating Forxiga treatment in patients with baseline eGFR below 25 mL/min/1.73m² remains unknown.

A Risk Management Plan (RMP) for Forxiga was reviewed by the Marketed Health Products Directorate (MHPD) and was considered acceptable.

Overall, the benefit-harm-uncertainty assessment of Forxiga is considered favorable for the treatment of CKD in adults to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular and renal death.