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Practical Considerations for the Use of Sparsentan in the Treatment of Patients with IgAN in Clinical Practice

Journal article
Published on December 22, 2023

Topics: Nephrology IgAN Sparsentan PROTECT Review Publication

Contributors:
Campbell KN, Griffin S, Trachtman H et al.
Name of Journal:
International Journal of Nephrology and Renovascular Disease


View Publication
DOI:
10.2147/IJNRD.S430377
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Home » Publications » Sparsentan Use in IgAN: Practical Considerations

Summary

Practical considerations for sparsentan use in adults with IgA nephropathy1


Background

IgA nephropathy is the most common primary glomerulonephritis worldwide and a leading cause of kidney failure, with over half of patients progressing to kidney failure within 20 years.1-5

Sparsentan is the first novel, non-immunosuppressive, single-molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA) to be FDA-approved in adults with IgA nephropathy at high risk of disease progression.1


Aim

This review aims to outline practical guidance for sparsentan treatment for IgA nephropathy in adults.1


Approach

This guidance reflects the authors’ experience with treating patients with sparsentan as clinical investigators in the Phase 3 PROTECT and DUPLEX trials, and the Phase 2 DUET trial and open-label extension.1


Findings

IgA nephropathy pathophysiology

  • In IgA nephropathy, mesangial deposition of immune complexes triggers glomerular injury and promotes upregulation of endothelin 1 (ET-1) and angiotensin II (Ang II), which further amplifies damage.1,6-10
  • Binding of ET-1 and Ang II to the ET-1 type A (ETAR) and Ang II type 1 (AT1R) receptors, respectively, works in tandem to promote proteinuria and progressive damage to kidney structure and function, ultimately leading to kidney failure.1,9-13

Sparsentan mechanism of action

  • Sparsentan selectively inhibits both ETAR and AT1R, blocking the tandem actions of ET-1 and Ang II that contribute to progressive glomerular injury.1,7,11,14,15

PROTECT

In the Phase 3 PROTECT study, sparsentan maintained a greater reduction in proteinuria and better kidney function preservation versus irbesartan.1,16

Sparsentan was found to be generally safe and well tolerated.1,16

Deep dive into the two-year findings from the PROTECT study.

Authors’ clinical recommendations for initiating sparsentan treatment in IgA nephropathy

Patient selection and treatment initiation

  • In adults with IgA nephropathy, sparsentan can replace use of renin-angiotensin system inhibitors (RASi) and should be added to standard-of-care lifestyle interventions.1
  • In the United States, pretreatment baseline labs per the Risk Evaluation and Mitigation Strategy (REMS) program guidance should be obtained.1
  • Per the US Prescribing Information, initiate sparsentan at 200 mg once daily; increase to 400 mg once daily after 14 days, if tolerated by the patient.1

Monitoring safety and efficacy

  • In line with the REMS program guidance, monitor liver function to mitigate the potential risk of hepatotoxicity and perform pregnancy testing to due to embryo-fetal toxicity with sparsentan.1
  • Monitor blood pressure, fluid retention or edema, kidney function, and serum potassium during sparsentan treatment.1
  • Assess proteinuria before starting sparsentan and again at 3 to 6 months, using the sample and analytic method employed at the individual practice. 1

Considerations for special populations

  • Pregnancy must be excluded before the start of sparsentan, monthly during treatment, and 1 month after discontinuation; advise patients not to breastfeed during sparsentan treatment.1
  • Avoid sparsentan use in patients with any hepatic impairment.1
  • Sparsentan use should be guided by the physician’s clinical judgement in elderly patients and those with advanced chronic kidney disease (CKD), accounting for the patient’s clinical status.1
  • Sparsentan was not evaluated in patients in the medical intensive care unit or those with chronic heart failure.1
  • Efficacy and safety of sparsentan for IgA nephropathy in pediatric patients is not yet known.1
Key takeaway

The authors believe the clinical benefits of sparsentan, including its greater antiproteinuric effect compared to irbesartan and manageable safety profile, will be clear to both patients and physicians and support its use in clinical practice as an IgA nephropathy treatment option.1,16,17

Related Content

Publication Nephrology IgAN

Efficacy and Safety of Sparsentan Versus Irbesartan in Patients with IgA Nephropathy (PROTECT): 2-Year Results From a Randomised Active-Controlled Phase 3 Trial

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Publication Nephrology IgAN

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

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Publication Nephrology FSGS

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

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Footnotes

Ang II, angiotensin II; AT1R, Ang II type 1 receptor; CKD, chronic kidney disease; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; ET-1, endothelin 1; ETAR, ET-1 type A receptor; FDA, Food and Drug Administration; IgA, immunoglobulin A; RASi, renin-angiotensin system inhibitor; REMS, Risk Evaluation and Mitigation Strategy.

  1. Campbell KN et al. Int J Nephrol Renovasc Dis. 2023;16:281-291.
  2. Mcgrogan A et al. Nephrol Dial Transplant. 2010;26(2):414-430.
  3. Schena FP et al. Semin Nephrol. 2018;38(5):435-442.
  4. Kwon CS et al. J Health Econ Outcomes Res. 2021;8(2):36-45.
  5. Pitcher D et al. Clin J Am Soc Nephrol. 2023;18(6):727-738.
  6. Magistroni R et al. Kidney Int. 2015;88(5):974-989.
  7. Trachtman H et al. Drug Future. 2020;45:79.
  8. Rodrigues JC et al. Clin J Am Soc Nephrol. 2017;12(4):677-686.
  9. Kohan DE et al. Clin Sci (Lond). 2024;138(11):645-662.
  10. Lehrke I et al. J Am Soc Nephrol. 2001;12(11):2321-2329.
  11. Komers R et al. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-R884.
  12. Barton M et al. Clin Kidney J. 2012;5:17-27.
  13. Siragy HM et al. Am J Nephrol. 2010;31(6):541-550.
  14. Benigni A et al. Pediatr Nephrol. 2021;36(4):763-775.
  15. Coppo R et al. Am J Kidney Dis. 1993;21(6):593-602.
  16. Rovin BH et al. Lancet. 2023;402(10417):2077-2090.
  17. Rheault MN et al. N Engl J Med. 2023;389(26):2436-2445.

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