Is the new sparsentan/sparsentan kidney disease drug effective for iga nephropathy?

In a previously reported interim analysis of the phase 3 PROTECT trial, the angiotensin II receptor blocker irbesartan (Irbesartan) In comparison, Sparsentan, a novel non-immunosuppressive, single-molecule, dual endothelin-angiotensin receptor antagonist, significantly reduced proteinuria in patients with immunoglobulin A (IgA) nephropathy at 36 weeks (the primary endpoint). Here, we report renal function and outcomes over 110 weeks from a double-blind final analysis.

PROTECT is a double-blind, randomized, active-controlled, Phase 3 study conducted at 134 clinical practice sites in 18 countries in the Americas, Asia and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 10 g/day despite maximal suppression of the renin-angiotensin system for at least 12 weeks were randomly assigned (1:1) according to a permuted block randomization method to receive either spaxentan (target dose 400 mg orally once daily) or irbesartan (target dose 300 mg orally once daily). The primary endpoint was change in proteinuria between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) in estimated glomerular filtration rate (eGFR), change in proteinuria, a composite of renal failure (confirmed 40% decrease in eGFR, end-stage renal disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomization. Secondary efficacy outcomes were assessed in the full analysis data set and safety in the safety data set, both defined as all patients who were randomized and received at least one dose of the randomly assigned study drug.

The results of the study showed that: The patients in the sparsentan group had a slower decline in eGFR than the irbesartan group. eGFR chronic 2-year slope (6-110 weeks) was -2.7 mL/min per 1.73 m2 per year versus -3.8 mL/min per 1.72 m2 per year (difference 1.1 mL/min per 0.73 m2 per year, 95% CI 0.1 to 2.1; p=0.037) ; The 2-year total slope (110 days in week 1) was -2.9 mL/min per 1.73 m² per year versus -3.9 mL/min per 1.72 m² per year (difference 1.0 mL/min per 0.73 m² per year, 95CI: -0.03 to 1.94; p=0.058). There was a significant reduction in proteinuria at 36 weeks on sparsentan throughout the study; at 110 weeks, proteinuria was 40% lower in the sparsentan group than in the irbesartan group (-42. 8%, 95% CI -49.8 to -35.0, sparsentan versus irbesartan -4.4%, -15.8 to 8.7; geometric least squares mean ratio 0.60, 95% CI 0.50 to 0.72). Eighteen of 202 (9%) patients in the sparsentan group achieved the composite renal failure endpoint compared with 26 of 202 (13%) in the irbesartan group (relative risk 0.7, 95% CI 0.4-1.2). Adverse events arising from treatment with sparsentan and irbesartan were well balanced and there were no new safety signals.

Thus over 110 weeks, in patients with IgA nephropathy, proteinuria was significantly reduced and renal function was preserved with sparsentan compared with maximal titration of irbesartan.