Proteinuria reduction is greater with sparsentan than with irbesartan in patients with immunoglobulin A (IgA) nephropathy, according to the latest findings from the ongoing randomized, double-blind phase 3 PROTECT trial.

From baseline to 36 weeks, the urine protein to creatinine ratio declined significantly more among patients randomly assigned to sparsentan than irbesartan: – 49.8% vs –15.1%, resulting in a relative 41% proteinuria reduction between the groups, Hiddo J.L. Heerspink, PhD, PharmD, of the University of Groningen in the Netherlands, and colleagues reported in The Lancet and at the National Kidney Foundation’s 2023 Spring Clinical meetings. The sparsentan group also had higher rates of complete (21% vs 8%) and partial (70% vs 44%) remission of proteinuria, defined as less than 0.3 and 0.1 g/day, respectively.

In the PROTECT trial (, NCT03762850), investigators randomly assigned 404 patients with IgA nephropathy to receive sparsentan, a dual endothelin and angiotensin receptor antagonist, or irbesartan, an antihypertensive drug, titrated to 400 mg and 300 mg once daily, respectively. At baseline, patients had an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73m2 and proteinuria of 1 g/day or higher, despite optimal blockade of the renin-angiotensin system. During treatment, the investigators observed minimal differences in blood pressure changes between the sparsentan and irbesartan groups.

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Patients with persistent proteinuria above 1 g/day are at high risk of kidney failure.

“The substantial and sustained reduction in proteinuria observed with sparsentan in this context is clinically important and supports a favourable effect on long-term kidney function,” Dr Heerspink’s team wrote. As the trial continues to 110 weeks, the investigators will assess whether sparsentan slows eGFR decline.

Treatment-emergent adverse events occurred in 88% of the sparsentan group and 78% of the irbesartan group. Non-severe edema (14% vs 9%), hypotension (14% vs 6%), and dizziness (13% vs 5%) occurred in a higher proportion of the sparsentan than irbesartan groups, respectively. Dose reduction was required by 13% and 9% of these groups, respectively. None of the patients discontinued treatment for severe edema, heart failure, or hepatotoxicity.

In an accompanying editorial, Sigrid Lundberg, MD, PhD, and Karin Bergen, MD, MS, of Karolinska Institutet in Stockholm, Sweden, commented that the interim results from the PROTECT trial “offer hope that sparsentan will be a valuable treatment option for patients with IgA nephropathy and high risk of progressive kidney disease.” They noted that the reduction in proteinuria and acceptable safety profile has already led to accelerated FDA approval.

Disclosure: This research was supported by Travere Therapeutics. Please see the original reference for a full list of disclosures.


Heerspink HJL, Radhakrishnan J, Alpers CE, et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. Published online March 31, 2023. doi:10.1016/S0140-6736(23)00569-X

Lundberg S, Bergen K. We can go further in non-immunosuppressive treatment of IgA nephropathy. Lancet. Published online April 1, 2023. doi:10.1016/S0140-6736(23)00630-X

Interim Analysis of the Phase 3 PROTECT Study of FILSPARI™ (Sparsentan) in IgA Nephropathy. Presented at: NKF 2023, Austin, Texas, April 11-15.