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Tablets and chemical structure of sparsentan

Mechanism of Protective Actions of Sparsentan in
the Kidney: Lessons From Studies in Models of
Chronic Kidney Disease

Journal article
Published on May 29, 2024

Topics: Nephrology FSGS IgAN Lit review MoA

Contributors:
Kohan DE, Bedard PW, Jenkinson C et al.
Name of Journal:
Clinical Science


View Publication
DOI:
10.1042/CS20240249
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Home » Publications » Mechanism of Protective Actions of Sparsentan

Summary

Endothelin-1 (ET-1) and angiotensin II (Ang II)

ET-1 and Ang II are important disease mediators in chronic progressive kidney disease such as IgA nephropathy and focal segmental glomerulosclerosis (FSGS)1

ET-1 and Ang II are present throughout the kidney and are strongly implicated in renal pathophysiology1-3
They have similar functions within the kidney and contribute to actions such as vasoconstriction, inflammation, and cellular proliferation1,2,4
Together, ET-1 and Ang II upregulate each other and exert an additive effect, driving ongoing kidney damage1,5,6

ET-1 and Ang II are present throughout the kidney

Class and structure of sparsentan

Sparsentan is a Dual Endothelin Angiotensin Receptor Antagonist (DEARA), with nephroprotective effects1

The sparsentan molecule consists of1:

A moiety that inhibits the endothelin type A receptor (ETAR)
A moiety that inhibits the angiotensin II subtype 1 receptor (AT1R)
ET1R AT1R targeting

The molecular structure of sparsentan targets ETAR and AT1R

Protective effects of sparsentan

Sparsentan targets glomerular injury and slows kidney function decline through several protective effects1,7

Preclinical data support the direct cellular, and resulting structural, actions of sparsentan1*

In IgA nephropathyIn FSGS
Anti-inflammatory8-11*Podocyte-protective13,14*
Anti-proliferative8,9,11*Glycocalyx-protective14*
Anti-fibrotic10,11*Glomerular vasodilation13,14*
Anti-proteinuric12Anti-fibrotic13*
Anti-inflammatory15*
Anti-proteinuric16,17

*These effects are based on pre-clinical animal modeling data.

Conclusions

Collectively, the protective effects of sparsentan contribute to nephroprotection in kidney disease1

  • By blocking important disease mediators, ET-1 and Ang II, sparsentan, a DEARA, can reduce glomerular injury and help preserve kidney function1

Downloadable Resource
Nephrology
PDP infographic

Explore the sparsentan mode of action in IgA nephropathy

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Footnotes

As of October 2024, sparsentan is not FDA approved for the treatment of FSGS.

Ang II, angiotensin II; AT1R, angiotensin II subtype 1 receptor; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; ET-1, endothelin-1; ETAR, endothelin type A receptor; FSGS, focal segmental glomerulosclerosis; IgA, immunoglobulin A.

  1. Kohan DE et al. Clin Sci. 2024;138(11):645-662.
  2. Rüster C and Wolf G. J Am Soc Nephrol. 2011;22:1189-1199.
  3. Kohan DE and Barton M. Kidney Int. 2014;86:896-904.
  4. Komers R and Plotkin H. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-R884.
  5. Kohno M et al. Kidney Int. 1992;42:860-866.
  6. Chen L et al. Hypertension. 1995;26:83-88.
  7. FILSPARI® (sparsentan) Prescribing Information. San Diego, CA: Travere Therapeutics, Inc. 9/2024.
  8. Jenkinson C et al. Poster presented at: ISN World Congress of Nephrology; April 12-15, 2019; Melbourne, Australia. SAT-010.
  9. Reily C et al. Am J Physiol Renal Physiol. 2024;326:F862-F875.
  10. Nagasawa H et al. Nephrol Dial Transplant. 2024;39:1494-1503.
  11. Jenkinson C et al. Presentation at: International Symposium on IgA Nephropathy; September 27-29, 2018; Buenos Aires, Argentina.
  12. Rovin BH et al. Lancet. 2023;402(10417):2077-2090.
  13. Gyarmati G et al. Presented at: 51st European Renal Association Congress 2021; June 5-8, 2021; Virtual and Berlin. 

  14. Gyarmati C et al. Presented at: American Society of Nephrology Kidney Week 2022; November 3-6, 2022; Orlando, Florida. FR OR56.
  15. Bedard PW et al. Presented at: 59st European Renal Association Congress 2022; May 19-21, 2022; Virtual and Paris.
  16. Trachtman H et al. J Am Soc Nephrol. 2018;29(11):2745-2754.
  17. Hogan J et al. Presented at: American Society of Nephrology Kidney Week 2022; October 23-28, 2018; San Diego. FR OR087.

MA-SP-24-0108 | October 2024