The effect of FILSPARI on proteinuria and kidney function (estimated glomerular filtration rate, eGFR) was assessed in a randomized, double-blind, active-controlled, multicenter, global study (PROTECT, NCT03762850) in adults with biopsy-proven primary IgAN, eGFR ≥30 mL/min/1.73 m2, and total urine protein ≥1.0 g/day on a stable dose of maximally-tolerated RAS inhibitor treatment. Patients with chronic kidney disease due to another condition in addition to IgAN or those who had been recently treated with systemic immunosuppressants were excluded.

Patients were randomized (1:1) to either FILSPARI (400 mg once daily following 200 mg once daily for 14 days) or irbesartan (300 mg once daily following 150 mg once daily for 14 days). Rescue immunosuppressive treatment could be initiated per investigator discretion during the trial. Concomitant use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, other RAS inhibitors, and aldosterone blockers were prohibited.

The primary efficacy endpoint for the interim analysis was the change from baseline in urine protein/creatinine ratio (UPCR) at Week 36 based on the first 281 randomized patients who had reached the Week 36 visit. The key secondary efficacy endpoint for the final analysis was the rate of change in eGFR over a 110-week period following initiation of randomized therapy.

The 404 patients who enrolled and received study medication had a mean age of 46 years (range 18 to 76 years); 70% were male, 67% White, 28% Asian, and 1% Black or African American. Approximately 78% had a history of hypertension, 11% had diabetes or impaired fasting glucose, and 56% had hematuria based on urine dipstick. At baseline, the mean eGFR was 57 mL/min/1.73 m2, the geometric mean UPCR was 1.2 g/g, and 49 (12%) patients had proteinuria >3.5 g/24 hours.

Urine Protein/Creatinine Ratio (UPCR)

  
The trial met the prespecified primary endpoint of relative change from baseline in UPCR at Week 36 based on an interim analysis of 281 randomized patients who had reached the Week 36 visit. The interim analysis showed a 45% decrease in UPCR at Week 36 relative to baseline for patients treated with FILSPARI compared to a 15% decrease for patients treated with irbesartan resulting in a 35% reduction in the ratio of mean UPCR (95% CI: 23% to 45% reduction; p<0.0001). In the final analysis of 404 randomized patients, the treatment effects in UPCR observed at Week 36 and Week 110 were consistent with the results obtained at the interim analysis. The mean percent change from baseline over the course of the double-blind period is displayed in Figure 1.

Estimated Glomerular Filtration Rate (eGFR)

In the final analysis of 404 randomized patients, FILSPARI reduced the rate of decline in kidney function from baseline to Week 110 compared to irbesartan. The mean eGFR slope from baseline to Week 110 was -3.0 mL/min/1.73 m2 per year for FILSPARI and -4.2 mL/min/1.73 m2 per year for irbesartan, corresponding to a treatment effect of 1.2 mL/min/1.73 m2 per year (95 %CI: 0.2 to 2.1; p=0.0168). The mean change from baseline in eGFR during the double-blind period is shown in Figure 2. The treatment effect on the rate of change in eGFR through Week 110 was generally consistent across key subgroups, including key demographic (such as age, sex, race, ethnicity, and region) and baseline disease (such as baseline BMI and baseline proteinuria) characteristics. The treatment benefit with FILSPARI on the rate of change in eGFR through Week 110 was not evident in patients with an eGFR ≥90 mL/min/1.73 m2; however, there was a small number of patients in this subgroup.