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Sparsentan Versus Irbesartan in Focal Segmental Glomerulosclerosis

Journal article
Published on November 3, 2023

Topics: Nephrology FSGS Sparsentan Phase 3 DUPLEX

Contributors:
Rheault MN, Alpers CE, Barratt J et al.
Name of Journal:
New England Journal of Medicine


View Publication
DOI:
10.1056/NEJMoa2308550
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Home » Publications » DUPLEX Study Results

Summary

The DUPLEX study found a greater reduction in proteinuria but no significant difference in estimated glomerular filtration rate (eGFR) with sparsentan versus irbesartan in focal segmental glomerulosclerosis (FSGS)1

Background

Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney failure worldwide with no approved treatment options available.2,3 Animal models demonstrate angiotensin II (Ang II) and endothelin-1(ET-1) as key mediators of glomerular injury leading to proteinuria.4 Clinical studies have also demonstrated that renin-angiotensin system inhibitors (RASis) and endothelin-1 receptor antagonists (ETAR), alone or in combination, can reduce proteinuria in human kidney diseases.5,6

Sparsentan is a first-in-class dual endothelin-angiotensin receptor antagonist.7 The Phase 2 DUET study assessed sparsentan versus irbesartan in FSGS and demonstrated a greater proteinuria reduction at 8 weeks compared with irbesartan.7


Aim

The DUPLEX study aimed to evaluate the long-term efficacy and safety of sparsentan compared to irbesartan in patients with FSGS.1


Approach

DUPLEX was a Phase 3, multicenter, double-blind, randomized trial that assessed sparsentan versus irbesartan in FSGS without known secondary causes.1 Eligibility criteria included1:

  • Biopsy-confirmed FSGS
  • Urine protein-creatinine ratio (UPCR) of ≥1.5
  • Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2

Patients were randomized to sparsentan (n=184; target dose 800 mg/day) or irbesartan (n=187; target dose 300 mg/day) for up to 108 weeks.1

The primary efficacy endpoint was eGFR slope (rate of change per year) at time of final analysis.1 The secondary endpoint was change in eGFR from baseline to 4 weeks after end of treatment (Week 112).1 Safety was also evaluated.1


Findings

Baseline characteristics were similar between treatment groups1

  • Mean age (years): Sparsentan: 41.7; Irbesartan: 41.5
  • eGFR (mL/min per 1.73m2): Sparsentan: 63.3; Irbesartan: 64.1
  • Median UPCR: Sparsentan: 3.1; Irbesartan: 3.0
  • Previous use of RASi: Sparsentan: 82.6%; Irbesartan: 76.5%

There was no significant between-group difference in the eGFR slope after 108 weeks1

A greater decrease in eGFR over the first 6 weeks was seen with sparsentan versus irbesartan (-4.1 vs -0.8 mL/min per 1.73 m2).1

The between-group difference in the slope from Week 6 to Week 108 (i.e. chronic slope) was 0.9 mL/min/1.73 m2 per year.1

After 108 weeks, the difference in eGFR total slope was 0.3 mL/min/1.73 m2 per year (P=0.75)1:

  • Sparsentan: -5.4 mL/min/1.73 m2 per year
  • Irbesartan: -5.7 mL/min/1.73 m2 per year

Partial remission of proteinuria was higher in the sparsentan group1

In a prespecified interim analysis, the proportion of patients with partial remission of proteinuria at 36 weeks was 42.0% and 26.0% in the sparsentan and irbesartan groups, respectively (P=0.009).1

Reduction of UPCR was greater in the sparsentan group1

A greater reduction of UPCR with sparsentan versus irbesartan was seen at 6 weeks and sustained over 108 weeks.1

Mean change in UPCR at 108 weeks.1

  • Sparsentan: 50%
  • Irbesartan: 32%

Sparsentan and irbesartan had similar safety profiles1

Similar rates of adverse events (AEs) were seen in both groups.1 The most common AE was corona virus disease 2019 (COVID-19), followed by peripheral edema.1


Key takeaway

The DUPLEX study assessed the efficacy and safety of sparsentan versus irbesartan in FSGS.1 Despite a greater reduction in proteinuria with sparsentan, no significant difference in eGFR slope was observed.1




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Focal Segmental Glomerulosclerosis Patient Baseline Characteristics in the Sparsentan Phase 3 DUPLEX Study

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Footnotes

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

AE, adverse event; Ang II, angiotensin II; COVID-19, corona virus disease 2019; eGFR, estimated glomerular filtration rate; ET-1, endothelin-1; ETAR, endothelin type A receptor; FDA, Food and Drug Administration; FSGS, focal segmental glomerulosclerosis; RASi, renin-angiotensin system inhibitor; UPCR, urine protein-creatinine ratio.

  1. Rheault MN et al. N Engl J Med. 2023;389(26):2436-2445.
  2. Rosenberg AZ, Kopp JB. Clin J Am Soc Nephrol. 2017;12(3):502-517.
  3. Gipson DS et al. JAMA Netw Open. 2022;5(8):e2228701.
  4. Komers R, Plotkin H. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-R884.
  5. Du YH et al. Ann Palliat Med. 2022;11(3):1093-1101.
  6. Campbell KN et al. Kidney Med. 2022;4(5):100457.
  7. Trachtman H et al. J Am Soc Nephrol. 2018;29(11):2745-2754.

MA-DS-24-0035 | September 2024