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In the PROTECT trial of patients with biopsy-proven IgAN, sparsentan met the primary endpoint with a significantly greater geometric mean percent reduction in urine protein-to-creatinine ratio (UPCR) vs active comparator irbesartan at the interim 36-week analysis (−49.8% vs −15.1%, respectively; P<.0001) (Heerspink et al. Lancet. 2023). Based on these data, sparsentan was granted accelerated approval in the US for adults with primary IgAN at risk of rapid disease progression. Here we present key efficacy results from the final analysis of the PROTECT double-blind period (≈2 years) on proteinuria and kidney function, including subgroup analyses of kidney function by baseline proteinuria.
PROTECT is a phase 3, global, randomized, double-blind, parallel-group, active-controlled trial that evaluated the efficacy and safety of sparsentan vs irbesartan in adults with IgAN at high risk of progression to kidney failure despite maximized treatment with an angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker. Patients ≥18 years old with biopsy-proven IgAN, urine protein excretion of ≥1.0 g/day, and estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2 were randomized 1:1 to receive sparsentan 400 mg/day or irbesartan 300 mg/day for up to 110 weeks. We report absolute change from baseline in eGFR, annualized rate of eGFR change (slope), change in proteinuria (UPCR), and safety; eGFR results were analyzed in subgroups of baseline proteinuria level quartiles.
A total of 404 patients were randomized to and received sparsentan (n=202) or irbesartan (n=202). At final analysis, sparsentan showed sustained reductions in UPCR over 110 weeks, with a 40% relative reduction vs irbesartan at 110 weeks and long-term kidney function preservation vs irbesartan. Absolute change in eGFR from baseline to week 110 was lower with sparsentan vs irbesartan (Table); results consistently favored sparsentan across subgroups, with larger effects seen with higher baseline proteinuria. In the total study population, sparsentan treatment led to a statistically significant reduction in the rate of eGFR decline over weeks 6 to 110 (chronic slope) vs irbesartan (difference=1.1 mL/min/1.73 m2/year; P=.037). The difference in the rate of eGFR decline from day 1 to week 110 (total slope) with sparsentan vs irbesartan was 1.0 mL/min/1.73 m2/year (P=.058). Subgroup analyses of eGFR slope showed that treatment effects of sparsentan were consistent across different levels of baseline proteinuria, with greater effects seen in patients with higher baseline proteinuria. Sparsentan was generally well tolerated; the overall safety profile was consistent between sparsentan and irbesartan.
The final analysis of the phase 3 PROTECT trial showed that sparsentan had a clinically meaningful benefit on long-term kidney preservation, with absolute change in eGFR and rate of eGFR change favoring sparsentan vs irbesartan across baseline proteinuria subgroups over 2 years. These results may significantly impact the treatment landscape of patients with IgAN.