In the PROTECT phase 3 trial, the novel, nonimmunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist sparsentan significantly reduced proteinuria and preserved kidney function in patients with primary IgA nephropathy compared with maximally titrated irbesartan.
At 134 clinical practice sites in 18 countries on 4 continents, 404 adult participants (70% male, 67% White) had biopsy-proven primary IgA nephropathy and proteinuria of at least 1.0 g per day despite maximized renin–angiotensin system inhibition for at least 12 weeks. They were block-randomized to sparsentan with a target oral dose of 400 mg once daily or irbesartan with a target oral dose of 300 mg once daily. The primary endpoint was proteinuria change between treatment groups at 36 weeks.
“Patients in the sparsentan group had a slower rate of [estimated glomerular filtration rate (eGFR)] decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2.7 mL/min per 1.73 m2 per year versus −3.8 mL/min per 1.73 m2 per year (difference 1.1 mL/min per 1.73 m2per year, 95% CI 0.1 to 2.1; P = 0.037); total 2-year slope (day 1–week 110) was −2.9 mL/min per 1.73 m2 per year versus −3.9 mL/min per 1.73 m2 per year (difference 1.0 mL/min per 1.73 m2 per year, 95% CI −0.03 to 1.94; P = 0.058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42.8%, 95% CI −49.8 to −35.0, with sparsentan versus −4.4%, −15.8 to 8.7, with irbesartan; geometric least-squares mean ratio 0.60, 95% CI 0.50 to 0.72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0.7, 95% CI 0.4 to 1.2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.”