#VisualAbstract: Sparsentan superior to irbesartan for reduction of proteinuria in patients with IgA nephropathy

1. Patients in sparsentan group reported a 50% reduction in proteinuria compared to 15% in the irbesartan group at week 36.
2. Complete remission of proteinuria was significantly higher in the sparsentan group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: IgA nephropathy is the most common cause of primary glomerulonephritis worldwide. Although renin-angiotensin blockers (ARBs), such as irbesartan, have been primarily used for treatment, some patients continue to have persistent proteinuria. Sparsentan, a novel single-molecule, angiotensin II receptor antagonist, may have improved efficacy in patients with refractory proteinuria although existing trials suggest mixed results. This randomized controlled trial aimed to assess the safety and efficacy of sparsentan in adults with IgA nephropathy. The primary efficacy outcome was the mean change in protein excretion from baseline to 26 weeks while a secondary outcome included remission of proteinuria. According to study results, once-daily sparsentan significantly reduced proteinuria compared to irbesartan. This study was strengthened by a randomized design with individuals from multiple clinical sites across various countries, thus increasing its generalizability.

Click to read the study in The Lancet

Relevant Reading: Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants

In-depth [randomized-controlled trial]: Between Dec 20, 2018, and May 26, 2021, 671 patients were screened for eligibility across 134 clinical sites in 18 countries. Included were patients ≥ 18 years with biopsy-confirmed IgA nephropathy and using angiotensin-converting enzyme (ACE) inhibitor or ARB therapy. Altogether, 404 patients (202 in sparsentan and 202 in irbesartan) were included in the final analysis. The primary outcome of reduction in urine protein excretion at 36 weeks was significantly greater in the sparsentan group (-49.8%) than the irbesartan group (-15.1%; geometric least squares mean ratio 0.59 [95 % CI 0.51-0.69], p<0.0001). Similarly, complete remission of proteinuria occurred in 21% of sparsentan patients compared to 8% of irbesartan patients (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.6-5.8, p=0.0005). Treatment-related adverse events and change in body weight were comparable between both groups; there were no fatalities. Overall, findings from this study suggest that sparsentan may be safe and effective for treatment of proteinuria in patients with biopsy-proven IgA nephropathy.

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