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Clinical Study Outcomes in IgA Nephropathy: A Systematic Literature Review and Narrative Synthesis

Journal article
Published on June 10, 2025

Topics: Nephrology IgAN Sparsentan PROTECT Review Publication Summary

Contributors:
Jeyabalan A, Jhaveri KD, Bunke M et al.
Name of Journal:
PLoS One


View Publication
DOI:
10.1371/journal.pone.0323530
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Home » Publications » IgAN Clinical Study Outcomes Review

Summary

Comprehensive IgA nephropathy review highlights key evidence from clinical trials1*


Background

IgA nephropathy is the most common primary glomerulonephritis worldwide and a leading cause of kidney failure if left untreated.1,2

Traditional therapies are non-targeted and often fail to provide long-term control of proteinuria and kidney preservation, highlighting a critical unmet need.3-6 Recently, targeted-release formulation budesonide (TRF-B) and sparsentan have been approved in the US and Europe, offering new therapeutic options.1


Aim

This systematic literature review (SLR) evaluated the efficacy of therapies for IgA nephropathy by collating and assessing data from clinical trials.1 The review focused on proteinuria and estimated glomerular filtration rate (eGFR) outcomes in IgA nephropathy trials, key markers of disease progression.1


Approach

In accordance with PRISMA and Cochrane guidelines, researchers systematically searched literature databases for relevant IgA nephropathy clinical trial data in October 2021 and again in December 20231:

Peer-reviewed articles, conference presentations, and conference abstracts published in English were included.1

The clinical studies included in the SLR1:

  • Were between Phases 1 and 4
  • Had >30 participants
  • Evaluated pharmacological interventions
  • Reported proteinuria and/or eGFR outcomes

Findings

Overall evidence base

Many studies were small, non-randomized, or single-arm, leading to a high risk of bias that required further filtering to prioritize larger, randomized controlled trials (RCT).1 This resulted in the inclusion of 76 studies across four main treatment classes1:

  • Supportive therapy (18 studies)
  • Immunosuppressive/immunomodulatory therapies (42 studies)
  • Combination therapies (8 studies)
  • Non-immunosuppressive therapies (7 studies)

Supportive therapies with angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB)

Renin-angiotensin system inhibitor (RASi) use reduced proteinuria and slowed eGFR decline.1 These therapies also demonstrated a relatively good safety profile, with few reported deaths and adverse events (AE).1 While supportive therapies may be effective in slowing kidney function decline, they do not target the underlying disease.1

Notably, losartan and valsartan were significantly more effective in slowing eGFR decline versus enalapril and placebo, respectively.1

  • In a RCT, losartan 200 mg/day (n=63) significantly slowed the rate of eGFR decline versus losartan 100 mg/day (n=43) or enalapril 10 (n=40) or 20 mg/day (n=61) (P<0.0005)1,7
  • In the Phase 3 HKVIN Study, valsartan 80 mg/day (n=54) significantly slowed the rate of eGFR decline versus placebo (n=55) (P =0.025)1,8

Immunosuppressive and immunomodulatory therapies

When treated with immunosuppressive and immunomodulatory therapies, patients have experienced reduced proteinuria and eGFR decline.1

Notably:

  • In the Phase 3 NefIgArd Study, TRF-B (n=182) significantly outperformed placebo (n=182) in proteinuria reduction (24-month follow-up: -30.7% vs. -1%, P <0.0001) and eGFR decline (-6.11 vs. -12.00 mL/min per 1.73 m², P <0.0001)1,9
  • In the Phase 2 TESTING Study, methylprednisolone (n=136) was more effective than placebo (n=126); at 42-month follow-up, patients in the methylprednisolone group had lower levels of proteinuria (1.70 vs. 2.39, P <0.001) and a smaller change in eGFR (-2.50 vs. -4.97 mL/min per 1.73 m², P =0.002)1,10
  • In the Phase 3 MAIN Study, at 36-month follow-up, mycophenolate mofetil (n=85) led to a significantly greater reduction in proteinuria vs. supportive care (n=85) (-57.1% vs. -28.2%, P <0.001) and a significantly slower eGFR decline (-1.2 vs. -3.8 mL/min per 1.73 m², P <0.001)1,11

Collectively, these findings highlight the efficacy and benefit of various immunosuppressive and immunomodulatory therapies in mitigating proteinuria and eGFR decline.1 

Combination therapies

Combination therapies typically included at least one supportive therapy or immunosuppressive therapy.1 Of the handful of studies included in this SLR, combination therapies tended to reduce proteinuria and maintain eGFR.1

Non-immunosuppressive therapies

Studies on sparsentan, allopurinol, pioglitazone, dapagliflozin, and sodium cromoglycate were evaluated.1 In the Phase 3 PROTECT study, sparsentan compared to maximum labeled dose irbesartan led to greater reductions in proteinuria (27.5-month follow-up: -42.8 vs -4.4%) and preservation of kidney function (eGFR: -5.8 vs. -9.5 mL/min per 1.73 m²).1,12†

Watch a video on the two-year findings from the Phase 3 PROTECT Study.‡

Key takeaway

This IgA nephropathy review highlights significant progress with newer targeted therapies demonstrating meaningful improvements in proteinuria and eGFR outcomes, such as the TRF-B and sparsentan in the NefIgArd and PROTECT trials, respectively.1

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Footnotes

This work was funded by Travere Therapeutics. Please see the publication for the full list of disclosures.

*As of December 2023.

†Findings represent all patients who were randomized and received treatment.12

‡Findings represent all patients who were randomized to a treatment arm regardless if they were on treatment.13,14

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; PER, protein excretion rate; RCT, randomized controlled trial; SLR, systematic literature review; TRF-B, targeted-release formulation budesonide.

  1. Jeyabalan A et al. PLoS One. 2025;20(6):e0323530.
  2. Nasri H, Mubarak M. J Nephropathol. 2015;4(1):1-5.
  3. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. Kidney Int. 2021;100(4S):S1-S276.
  4. Woo KT et al. Kidney Int. 2000;58(6):2485-2491.
  5. Komers R, Plotkin H. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-R888.
  6. Huang X, Xu G. Front Pharmacol. 2021;12:715253.
  7. Woo KT et al. Clin Nephrol. 2009;71(6):617-624.
  8. Li PK-T et al. Am J Kidney Dis. 2006;47(5):751-760.
  9. Lafayette R et al. Lancet. 2023;402(10405):859-870.
  10. Lv J et al. JAMA. 2022;327(19):1888-1898.
  11. Hou FF et al. JAMA Netw Open. 2023;6(2):e2254054.
  12. Rovin BH et al. Lancet. 2023;402(10417):2077-2090.
  13. Data on file, REF-SP-24-0530. Travere Therapeutics, Inc.
  14. Gupta SK. Perspect Clin Res. 2011;2(3):109-112.

MA-SP-25-0144 | November 2025