Efficacy and Safety of Sparsentan Versus Irbesartan in Patients with IgA Nephropathy (PROTECT): 2-Year Results From a Randomised Active-Controlled Phase 3 Trial
The Lancet – 2023
Association Between Complete Proteinuria Remission and Kidney Function in Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy
Published on December 22, 2025
Contributors:
Heerspink HJL, Rovin B, Komers R et al.
Heerspink HJL, Rovin B, Komers R et al.
DOI:
10.2215/CJN.0000000961
10.2215/CJN.0000000961
Summary
Background
- IgA nephropathy is a rare kidney disease that can lead to progressive kidney function decline and kidney failure within 10-20 years of diagnosis.1,2 Patients with elevated proteinuria — even at levels traditionally considered low risk — face a greater likelihood of progression to kidney failure1,2
- The Kidney Disease: Improving Global Outcomes (KDIGO) 2025 Guideline recommends proteinuria to be sustained at levels <0.5 g/day, ideally <0.3 g/day (complete remission of proteinuria) in IgA nephropathy1,3
- In the 2-year results of the Phase 3 PROTECT trial, sparsentan demonstrated significantly greater reductions in proteinuria than maximum-labeled dose irbesartan, with a comparable safety profile1,4,5
- In the PROTECT trial, patients treated with sparsentan achieved complete remission of proteinuria (<0.3 g/day) earlier and more often than those treated with irbesartan1,5
- Sparsentan is a Dual Endothelin Angiotensin Receptor Antagonist (DEARA) indicated to slow kidney function decline in adults with primary IgA nephropathy who are at risk for disease progression1,6,7
Aim
The aim of this post hoc analysis of the Phase 3 PROTECT trial was to evaluate the impact of achieving complete remission of proteinuria (<0.3 g/day) [CR], through Week 36 or at any time up to Week 110, on kidney function decline in patients treated with sparsentan or maximum-labeled dose irbesartan regardless of original treatment arm randomization1
Figure. PROTECT is a randomized, active-controlled, Phase 3 study that evaluates the long-term safety and efficacy of sparsentan vs. maximum-labeled dose irbesartan in IgA nephropathy
About the figure
Key eligibility criteria for this analysis included1:
- Age ≥18 years
- Biopsy-proven primary IgA nephropathy
- 24-hour proteinuria ≥1.0 g/d
- eGFR ≥30 ml/min per 1.73 m2
- Systolic BP at or below 150 mm Hg
- Diastolic BP at or below 100 mm Hg
- Stable ACEi/ARB ≥12 weeks at max tolerated dose, which was at least half of the max labeled dose
The post hoc analysis assessed1:
- Achieving complete remission of proteinuria (<0.3 g/day) [CR] through Week 36 or at any time up to Week 110
- Change from baseline in proteinuria (UPE, UPCR, and UACR)
- Absolute change in eGFR from baseline
- Proportion of patients who reached the composite kidney endpoint
- Safety outcomes1: TEAEs
Key Findings
Patients who achieved CR through Week 36 or at any time up to Week 110 demonstrated a substantially greater and more rapid reduction in urine protein excretion (UPE) compared to those who did not.1 This reduction was sustained through study follow-up1
After an initial decline, patients who achieved CR through Week 36 or at any time up to Week 110 experienced stable estimated glomerular filtration rate (eGFR), whereas patients who did not achieve CR experienced a gradual decline1
Few patients who achieved CR at any time up to Week 110 reached the composite kidney endpoint,* consistent with sustained eGFR preservation over time, irrespective of treatment arm.1† No patient who achieved CR through Week 36 reached the composite kidney endpoint during the study period1
The most frequently reported treatment-emergent adverse events (TEAEs) among patients who achieved CR were COVID-19‡ and headache, whereas hypertension, proteinuria, and chronic kidney disease (CKD) were more frequent among patients who did not achieve CR.1 Patients who achieved CR at any time up to Week 110 were also more likely to experience TEAEs associated with hypotension1§
The safety profile was similar between patients who achieved CR at any time up to Week 110 and those who did not; however, a higher proportion of patients who did not achieve CR discontinued treatment due to an adverse event (AE)1
Conclusions
In this post hoc analysis of the Phase 3 PROTECT trial, patients who achieved CR through Week 36 or at any time up to Week 110 demonstrated greater eGFR preservation and fewer kidney failure events than those who did not1
Patients who achieved CR through Week 36 or at any time up to Week 110 showed similar safety profiles to those who did not achieve CR1
These findings underscore the relationship between complete remission of proteinuria and kidney function preservation, supporting the KDIGO 2025 guideline recommendation to maintain proteinuria at ideally less than 0.3 g/day1,3
CR was achieved more frequently in the sparsentan group compared with the irbesartan group, consistent with the previous 2-year results1,5
Related Content
Efficacy and Safety of Sparsentan Versus Irbesartan in Patients with IgA Nephropathy (PROTECT): 2-Year Results From a Randomised Active-Controlled Phase 3 Trial
The Lancet – 2023
Sparsentan in Patients With IgA Nephropathy: A Prespecified Interim Analysis From a Randomised, Double-Blind, Active-Controlled Clinical Trial
The Lancet – 2023
Implementing the Kidney Health Initiative Surrogate Efficacy Endpoint in Patients With IgA Nephropathy (the PROTECT Trial)
Kidney International Reports – 2019
Footnotes
This study was supported by Travere Therapeutics, Inc. Please see the publication for the full list of disclosures.
ACEi, angiotensin-converting enzyme inhibitor; AE, adverse event; ARB, angiotensin receptor blocker; BP, blood pressure; CKD, chronic kidney disease; COVID-19, coronavirus disease 2019; CR, complete remission; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; TEAE, treatment-emergent adverse event; UACR, urine albumin-to-creatinine ratio; UPCR, urine protein-to-creatinine ratio; UPE, urine protein excretion.
*Defined as a confirmed 40% eGFR decline, kidney failure or initiation of kidney replacement therapy, or mortality due to any cause.
†Patients who achieved CR by Week 36 or at any time up to Week 110 experienced similar outcomes across study outcomes, regardless of treatment arm.
‡Participants were enrolled between December 2018 and May 2021 during the COVID-19 pandemic.
§Defined as hypotension, orthostatic hypotension, or BP systolic decreased.
- Heerspink HJL et al. Clin J Am Soc Nephrol. 2025; doi: 10.2215/CJN.0000000961.
- Pitcher D et al. Clin J Am Soc Nephrol. 2023;18(6):727-738.
- Kidney Disease: Improving Global Outcomes (KDIGO) IgAN and IgAV Work Group. Kidney Int. 2025;108(Suppl 4S):S1-S71.
- Heerspink HJL et al. Lancet. 2023;401:1584-1594.
- Rovin BH et al. Lancet. 2023;402(10417):2077-2090.
- Kohan DE et al. Clin Sci (Lond). 2024;138(11):645-662.
- FILSPARI® (sparsentan) Prescribing Information. San Diego, CA: Travere Therapeutics, Inc.
MA-SP-26-0010 | April 2026