Association Between Complete Proteinuria Remission and Kidney Function in Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy
Clinical Journal of the American Society of Nephrology – 2025
Sparsentan: The First and Only Non-Immunosuppressive Therapy for the Reduction of Proteinuria in IgA Nephropathy
Journal article
Published on February 26, 2024
Contributors:
Trachtman H, Komers R, Inrig J.
Trachtman H, Komers R, Inrig J.
DOI:
10.1080/1744666X.2024.2319132
10.1080/1744666X.2024.2319132
Summary
Sparsentan, a treatment for IgA nephropathy, has demonstrated safety, tolerability, and therapeutic efficacy; long-term efficacy and safety continues to be an area of research1
Aim
This expert review summarizes the scientific rationale of the use of sparsentan in IgA nephropathy.1
IgA Nephropathy and Sparsentan
IgA nephropathy is the most common primary glomerular disorder worldwide.1,2 Prevalence may significantly vary across the world and within specific racial and ethnic groups.1,3
Although historically considered a benign disease, the the UK National Registry of Rare Kidney Diseases (RaDaR) study demonstrated that most patients, including those with urine protein-creatinine ratio (UPCR) 0.5-1, developed end-stage kidney disease (ESKD) within 5 to 10 years.1,5 These findings indicated a need for treatments for IgA nephropathy.1
Sparsentan is a non-immunosuppressive, single-molecule, Dual Endothelin Angiotensin Receptor Antagonist (DEARA).1
Models of kidney disease have demonstrated multiple beneficial effects of dual inhibition of the endothelin type A receptor (ETAR) and angiotensin II (Ang II) subtype 1 receptor (AT1R) as compared to single inhibition of the renin-angiotensin-aldosterone axis.1,6-9
Findings
Efficacy and safety data from PROTECT
Proteinuria
- From baseline to Week 36, sparsentan significantly reduced UPCR by 49.8% versus 15.1% for irbesartan (P <0.0001)1,10
- UPCR reduction was maintained over 110 weeks with a 42.8% reduction with sparsentan versus a 4.4% reduction with irbesartan1,11
Estimated glomerular filtration rate (eGFR)
- eGFR declined over 110 weeks and was consistently lower with sparsentan than with irbesartan1,11
- The absolute change in eGFR was -5.8 with sparsentan compared to -9.5 with irbesartan (Difference [95% confidence interval (CI)]: 3.7 [1.5 to 6.0])1,11
Safety
Sparsentan had a comparable safety profile to irbesartan.1,10,11 The most common adverse events (AEs) were peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia.1
Authors anticipate that sparsentan, a treatment for IgA nephropathy, will replace the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) as first-line therapy prior to the implementation of immunosuppressive therapy1
Overall, sparsentan has demonstrated safety, tolerability, and therapeutic efficacy in PROTECT.1 Findings reinforced the relationship between proteinuria and beneficial outcomes.1
The dual inhibitory nature of sparsentan leverages the relationship between endothelin 1 (ET-1) and (Ang II), resulting in prevention of glomerular injury.1
Key takeaway
The authors believe that sparsentan, a treatment for IgA nephropathy, is a valuable addition to the current treatment options.1 It may either act as a standalone treatment for patients with low-grade proteinuria, or in combination with immunosuppressive agents for those with declining kidney function or moderate-to-severe proteinuria.1
The long-term efficacy and safety of sparsentan continues to be areas of ongoing research across various glomerular diseases.1
Related Content
Association Between Complete Proteinuria Remission and Kidney Function in Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy
Clinical Journal of the American Society of Nephrology – 2025
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
Footnotes
H. Trachtman is a consultant to Travere Therapeutics, Inc. and Jula Inrig and Radko Komers are employees of Travere Therapeutics, Inc. and own shares of the company. Please see the publication for the full list of disclosures.
ACEi, angiotensin-converting enzyme inhibitor; AE, adverse event; Ang II, angiotensin II; ARB, angiotensin receptor blocker; AT1R, angiotensin II subtype 1 receptor; CI, confidence interval; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ET-1, endothelin 1; ETaR, endothelin type A receptor; RaDaR, National Registry of Rare Kidney Diseases; UPCR, urine protein-to-creatinine ratio.
- Trachtman H et al. Expert Rev Clin. Immunol. 2024;20(6):571-576.
- Gesualdo L et al. Semin Immunopathol. 2021;43(5):657-668.
- Schena FP, Nistor I. Semin Nephrol. 2018;38(5):435-442.
- Trimarchi H et al. Kidney Int. 2017;91(5):1014-1021.
- Pitcher D et al. Clin J Am Soc Nephrol. 2023;18(6):727-738.
- Cosgrove D et al. J Pathol. 2023;260(3):353-364.
- Gyarmati G et al. Presented at: American Society of Nephrology Kidney Week 2022; November 3-6, 2024; Orlando, United States. FR-OR56.
- Nagasawa H et al. Poster presented at: American Society of Nephrology Kidney Week 2020; November 3-6, 2020; Virtual. PO1808.
- Reily C. Poster presented at: American Society of Nephrology Kidney Week 2020; October 19-25, 2020; Virtual. PO1808.
- Heerspink HJL et al. Lancet. 2023;401(10388):1584-1594.
- Rovin BH et al. Lancet. 2023;402(10417):2077-2090.
MA-SP-24-0083 | February 2026