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Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile

Journal article
Published on March 14, 2024

Topics:

Nephrology IgAN
Contributors:
Rovin B, Hendry B, Cheung CK.
Name of Journal:
European Medical Journal


View Publication
DOI:
10.33590/emj/11000020
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Summary

Sparsentan clinical trials demonstrate sustained proteinuria reduction and kidney function preservation in IgA nephropathy1


Background

IgA nephropathy is the leading cause of primary glomerulonephritis, particularly in males.2,3

IgA nephropathy is thought to occur as a result of several processes4:

  1. Increase in circulating galactose-deficient IgA1 (Gd-IgA1)4
  2. Autoantigens develop to Gd-IgA12,5
  3. Immune complexes form2,5
  4. Immune complexes are deposited in the glomerular mesangium, leading to several downstream effects including endothelin 1 (ET-1) and angiotensin II (Ang II) overexpression2,5

The RaDaR study demonstrated poor long-term outcomes in patients with IgA nephropathy.6 Higher proteinuria was significantly associated with worse kidney survival, and thus treatments should target lower proteinuria.6,7 Treating IgA nephropathy is key to slowing disease progression.7

Sparsentan is a non-immunosuppressive, single-molecule, Dual Endothelin Angiotensin Receptor Antagonist (DEARA).8


Aim

This article summarizes key findings from sparsentan clinical trials, presented at the American Society of Nephrology Kidney Week 2023.1


Findings

In the PROTECT study, sparsentan demonstrated significantly reduced proteinuria, preservation of kidney function, and a comparable safety profile to irbesartan9-11

Proteinuria

  • From baseline to Week 36, sparsentan significantly reduced urinary protein-to-creatinine ratio (UPCR) by 49.8% versus 15.1% for irbesartan (P<0.0001)9
  • UPCR reduction was maintained over 110 weeks with a 42.8% reduction with sparsentan versus a 4.4% reduction with irbesartan10,11

Estimated glomerular filtration rate (eGFR)

  • Overall eGFR decline over 110 weeks was consistently lower with sparsentan than with irbesartan10,11
  • The absolute change in eGFR was -5.8 ml/min/1.73 m2 per year with sparsentan compared to -9.5 ml/min/1.73 m2 per year 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

Preliminary data from the SPARTAN study demonstrated rapid and sustained proteinuria reductions and relatively stable eGFR levels over 36 weeks12

Proteinuria

  • As observed in the PROTECT study, sparsentan led to rapid UPCR reduction by Week 4 and was maintained through 36 weeks12
  • Sixty-seven percent of patients experienced complete remission of proteinuria at any timepoint during the first 36 weeks1

eGFR

  • Over 36 weeks, patients had relatively stable eGFR levels (Baseline mean: 70.2 ml/min/1.73 m2 [±25.0])12

Safety

  • At 6 weeks, one participant discontinued treatment due to hypotension12
  • Overall, there were three non-treatment-related serious adverse events (AEs)12

Pharmacokinetic (PK) modeling supports that the maintenance of normal fluid balance by sparsentan may be related to DEARA properties13

  • Utilizing PK data from PROTECT, substantial receptor occupancy was shown throughout the dosing interval, with 99% protein binding13
  • Sparsentan was found to occupy angiotensin II subtype 1 receptor (AT1R) at levels exceeding endothelin type A receptor (ETAR) occupancy13
  • This may contribute to the minimal risk of fluid retention with sparsentan13
  • Typically drugs that only target ETAR can lead to fluid retention, while drugs that only target AT1R can lead to fluid excretion,14,15 suggesting that the dual mechanism nature of sparsentan balances fluid levels1

Key takeaway

The sparsentan clinical trials, PROTECT and SPARTAN, demonstrate sparsentan as an effective and well-tolerated treatment for IgA nephropathy due to its dual antagonism of endothelin and angiotensin receptors.1




Related Content

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

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

Read more
Long-Term Outcomes in IgA Nephropathy
Publication NephrologyIgAN

Long-Term Outcomes in IgA Nephropathy

Clinical Journal of the American Society of Nephrology – 2023

Read more
See more
Footnotes

AE, adverse event; Ang II, angiotensin II; AT1R, angiotensin II subtype 1 receptor; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; eGFR, estimated glomerular filtration rate; ET-1, endothelin 1; ETAR, endothelin type A receptor; FDA, Food and Drug Administration; Gd-IgA1, galactose-deficient IgA; IgA, immunoglobulin A; PK, pharmacokinetic; UPCR, urinary protein-to-creatinine ratio.

  1. Rovin BH et al. EMJ. 2024;9(1):13-21.
  2. Lai KN et al. Nat Rev Dis Primers. 2016;2:16001.
  3. O’Shaughnessy MM et al. Nephrol Dial Transplant. 2018;33:661-669.
  4. Knoppova B et al. J Clin Med. 2021;10(19):4501.
  5. Suzuki H, Novak J. SeminImmunopathol. 2021;43(5):669-678.
  6. Pitcher D et al. Clin J Am Soc Nephrol. 2023;18(6):727-738.
  7. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100:S1-S276.
  8. Komers R et al. Am J Physiol Regul Integr Comp Physiol. 2016; 15;310(10):R877-R884.
  9. Heerspink HJL et al. Lancet. 2023;401(10388):1584-1594.
  10. Rovin BH et al. Lancet. 2023;402(10417):2077-2090.
  11. Rovin B et al. Poster presented at: American Society of Nephrology Kidney Week 2023; November 2-5, 2023; Philadelphia, United States. FR-OR109.
  12. Cheung CK et al. Poster presented at: American Society of Nephrology Kidney Week 2023; November 2-5, 2023; Philadelphia, United States. SA-PO901.
  13. Hendry B et al. Poster presented at: American Society of Nephrology Kidney Week 2023; November 2-5, 2023; Philadelphia, United States. SA-PO276.
  14. Mann JFE et al. J Am Soc Nephrol. 2010;21(3):527-535.
  15. Navar LG et al. J Am Soc Nephrol. 1999:10 Suppl 12:S266-S272.

MA-SP-24-0082 | August 2024