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Tablets and chemical structure of sparsentan

Sparsentan: The First and Only Non-Immunosuppressive Therapy for the Reduction of Proteinuria in IgA Nephropathy

Journal article
Published on February 26, 2024

Topics: Nephrology IgAN Sparsentan Expert perspective Lit review PROTECT

Contributors:
Trachtman H, Komers R, Inrig J.
Name of Journal:
Expert Review of Clinical Immunology


View Publication
DOI:
10.1080/1744666X.2024.2319132
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Home » Publications » Expert Review on Sparsentan in IgAN

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.2 Prevalence may significantly vary across the world and within specific racial and ethnic groups.3

IgA nephropathy is thought to occur due to a multiple-hit hypothesis.2 Resulting histological injury can be evaluated using the MEST-C scoring system.4

Although historically considered a benign disease, the 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.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 versus that of single inhibition.6-9


Findings

Efficacy and safety data from PROTECT study

Listen to more about PROTECT.

Proteinuria

  • From baseline to Week 36, sparsentan significantly reduced UPCR by 49.8% versus 15.1% for irbesartan (P <0.0001)10
  • UPCR reduction was maintained over 110 weeks with a 42.8% reduction with sparsentan versus a 4.4% reduction with irbesartan11

Estimated glomerular filtration rate (eGFR)

  • eGFR declined over 110 weeks and was consistently lower with sparsentan than with irbesartan11
  • 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])11

Safety

Sparsentan had a comparable safety profile to irbesartan.10,11

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. 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 angiotensin II (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 for IgA nephropathy.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





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Sparsentan Is Superior to Losartan in the gddY Mouse Model 1 of IgA Nephropathy

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Footnotes

ACEi, angiotensin-converting enzyme inhibitor; Ang II, angiotensin II; ARB, angiotensin receptor blocker; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ET-1, endothelin 1; UPCR, urine protein-creatinine ratio.

  1. Trachtman H et al. Expert Rev Clin. Immunol. 2024;20(6):571-576.
  2. Gesualdo L et al. Semin Immunopathol. 2021;43(5):657-668.
  3. Schena FP, Nistor I. Semin Nephrol. 2018;38(5):435-442.
  4. Trimarchi H et al. Kidney Int. 2017;91(5):1014-1021.
  5. Pitcher D et al. Clin J Am Soc Nephrol. 2023;18(6):727-738.
  6. Cosgrove D et al. J Pathol. 2023;260(3):353-364.
  7. Gyarmati G et al. Presented at: American Society of Nephrology Kidney Week 2022; November 3-6, 2024; Orlando, United States. FR-OR56.
  8. Nagasawa H et al. Poster presented at: American Society of Nephrology Kidney Week 2020; November 3-6, 2020; Virtual. PO1808.
  9. Reily C. Poster presented at: American Society of Nephrology Kidney Week 2020; October 19-25, 2020; Virtual. PO1808.
  10. Heerspink HJL et al. Lancet. 2023;401(10388):1584-1594.
  11. Rovin BH et al. Lancet. 2023;402(10417):2077-2090.

MA-SP-24-0083 | September 2024