Association between Complete Proteinuria Remission and Kidney Function in the Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy

Background: In the phase 3, randomized, double-blind PROTECT (NCT03762850) trial, sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist (DEARA), reduced proteinuria and preserved kidney function compared to maximum labeled dose irbesartan in adults with immunoglobulin A nephropathy. In this post hoc analysis of PROTECT, we assessed the association between complete remission of proteinuria (CR) and preservation of kidney function. Methods: This analysis compared kidney function in patients who achieved CR (urine protein excretion <0.3 g/day) by Week 36 (CR36) or at any time up to Week 110 (CR110) vs. those who did not (non-CR), regardless of original treatment allocation. Endpoints assessed by CR status were change in proteinuria, estimated glomerular filtration rate (eGFR), and blood pressure, rate of eGFR decline, a composite kidney endpoint, and safety. Results: Of 404 patients who were randomized and received study drug, 43 (11%) achieved CR36 and 85 (21%) achieved CR110. CR patients demonstrated greater and more rapid reductions in proteinuria compared with non-CR patients. CR110 patients had a smaller absolute change in eGFR vs. non-CR patients (-4.0 vs. -8.6 mL/min/1.73 m 2 ) and a slower rate of eGFR decline (Day 1-Week 110; -0.7 vs. -4.2 mL/min/1.73 m 2 /year). Fewer CR110 patients (1%) reached the composite kidney endpoint vs. non-CR patients (14%). CR110 patients were more likely to experience treatment-emergent adverse events (TEAEs) associated with hypotension (hypotension, orthostatic hypotension, or blood pressure systolic decreased) and less likely to experience TEAEs of hypertension than non-CR patients. More non-CR patients vs. CR110 patients discontinued treatment due to adverse events (11% vs. 4%, respectively) or patient decision (8% vs. 2%, respectively). Conclusions: Participants in PROTECT who achieved CR36 or CR110 showed greater eGFR preservation, fewer kidney failure events, and similar safety profiles compared to non-CR participants. These data reinforce recommendations to maintain proteinuria levels ideally <0.3 g/day and underscore its relationship with kidney function preservation.