February 2025

Below is in response to the inquiry: A 43 yo Asian female with IgA nephropathy and an eGFR of 67 ml/min/1.73 m² came into my clinic today with questions regarding a newly approved drug, Vilspari (sparsentan). Are there benefits in using Vilspari (sparsentan) over irbesartan in patients with IgA nephrology? If so, what are they?

Sparsentan is a dual endothelin and angiotensin II receptor antagonist. Due to its additional mechanism of action compared to irbesartan, which is only an angiotensin II receptor antagonist, sparsentan potentially offers a more comprehensive approach to kidney protection. This is because both the RAS and endothelial system contribute to the disease progression of IgA nephropathy. 

According to PROTECT, an international, randomized, double-blind, active-controlled study that compares sparsentan to irbesartan with a primary endpoint of change from baseline of urine protein-creatinine ratio based on a 24-h urine sample at week 36, sparsentan showed superiority both clinically (-49.8% vs -15.1%) and statistically (p<0.0001 vs p=0.0005) in the reduction of protein-creatinine ratio [1]. However, the study showed a slightly greater proportion of treatment emergent adverse events (TEAEs) in patients receiving sparsentan compared to irbesartan (88% vs 78%). However, there was no significant difference in the number of serious adverse events. Other endpoints of the study included measured change in urine albumin-creatinine ratio, proportion of patients reaching 40% reduction in eGFR from baseline, kidney failure, all-cause mortality, and blood pressure reduction. These endpoints either showed non-inferiority or superiority in patients taking sparsentan compared to irbesartan. 

In conclusion, the clinical trial PROTECT indicates sparsentan offers an advantage over irbesartan for your specific patient case in nephro-protection and reducing progression of IgA nephropathy. However, “existing data do not yet support the use of sparsentan as initial supportive therapy for IgAN (ie, as a replacement for maximally tolerated angiotensin inhibition with or without SGLT2 inhibition)  [2]. However, sparsentan should be considered as an alternative option to patients with proteinuria of “ >1g/day in spite of optimal treatment with ACE inhibitor or ARB and an SGLT2 inhibitor for at least three to six months.” 

References:

[1] Heerspink, H. J. L., Radhakrishnan, J., Alpers, C. E., Barratt, J., Bieler, S., Diva, U., Inrig, J., Komers, R., Mercer, A., Noronha, I. L., Rheault, M. N., Rote, W., Rovin, B., Trachtman, H., Trimarchi, H., Wong, M. G., & Perkovic, V. (2023). Sparsentan in patients with IgA nephropathy: A prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. The Lancet, 401(10388), 1584–1594. 

[2] UpToDate. (2024, March 21). IgA nephropathy: Treatment and prognosis (D. Cattran, G. Appel, R. Coppo, R. Glassock, F. Fervenza, & A. Lam, Eds.) [Review of IgA nephropathy: Treatment and prognosis]. UpToDate; UpToDate. https://www-uptodate-com.proxy.cc.uic.edu/contents/iga-nephropathy-treatment-and-prognosis? search=treatment%20of%20iga%20nephropathy&source=search_result&selectedTitle=1~100& usage_type=default&display_rank=1#