Antiproteinuric Effect of Sparsentan in Patients with Genetic-Associated FSGS Enrolled in the DUPLEX Trial

Summary

A post hoc exploratory analysis of the Phase 3 DUPLEX sparsentan trial assesses sparsentan vs. irbesartan in a subgroup with genetic-associated focal segmental glomerulosclerosis (gFSGS)¹

Background

Focal segmental glomerulosclerosis (FSGS) is a rare, progressive kidney condition classified as primary FSGS, genetic-associated FSGS (gFSGS), secondary FSGS, or FSGS of unknown cause.^1,2 gFSGS is often caused by variants in genes required for normal podocyte structure or function and is often resistant to standard treatments.^1,3 Patients with gFSGS are at high risk of progression to kidney failure.^1,4

Sparsentan is a Dual Endothelin Angiotensin Receptor Antagonist (DEARA) that blocks endothelin-1 (ET-1) and angiotensin II (Ang II), both of which are involved in podocyte damage and kidney injury in FSGS.^1,3 In the Phase 3 DUPLEX trial, sparsentan demonstrated significantly greater and sustained proteinuria reduction vs. maximum labeled dose irbesartan, with a comparable safety profile.^1,5

Aim

This post hoc analysis of the DUPLEX trial evaluated the efficacy of sparsentan vs. maximum labeled dose irbesartan in reducing proteinuria among a subgroup of patients with gFSGS.¹

Approach

DUPLEX was a Phase 3, multicenter, double-blind, randomized trial that investigated the safety and efficacy of sparsentan vs. maximum labeled dose irbesartan in FSGS. The study design and overall results have been previously described.^1,5,6

Genetic classification was completed for the majority (355/371) of enrolled patients using next-generation sequencing.¹

Patients with pathogenic or likely pathogenic gene variants coding for podocyte genes, type 4 collagen proteins (COL4A3-5 variants), and APOL1 high-risk genotypes were analyzed separately to ensure that the analysis was not confounded by heterogeneous forms of kidney disease.¹

Study outcomes included¹:

Findings

Data were reported from 70 patients in whom genetic variants could contribute to the development or progression of FSGS¹

Baseline characteristics varied between genetic subgroups¹

On average, patients were slightly younger in the podocyte gene variant group compared to patients with COL4A3-5 variants or APOL1 high-risk genotypes.¹ Across all groups, most patients were White except in the APOL1 high-risk group, which included 64% (9/14) African American patients.¹

Patients with COL4A3-5 variants or APOL1 high-risk genotypes had lower baseline eGFR compared to those with podocyte gene variants.¹ Although nephrotic-range proteinuria was common across groups, the podocyte gene variant group had higher baseline UPCR levels than the other two groups.¹

Findings support an antiproteinuric effect of sparsentan in gFSGS¹

By Week 6, patients treated with sparsentan saw greater reductions in UPCR than those treated with irbesartan.¹ The treatment effect was sustained over the study period, except during the second year among patients with APOL1 high-risk genotypes, where the reduction was not maintained.¹

Time-weighted analyses of UPCR change from baseline further demonstrated a greater antiproteinuric effect of sparsentan compared with irbesartan in patients with podocyte and COL4A3-5 variants.¹

Time-weighted UPCR change from baseline over 108 weeks by genetic and treatment groups¹:

A numerically greater percentage of patients treated with sparsentan achieved complete remission of proteinuria (UPCR <0.3 g/g) than those treated with irbesartan across all gFSGS subgroups¹:

The composite kidney outcome* occurred numerically less frequently in patients receiving sparsentan vs. irbesartan across all gFSGS subgroups¹

The safety of sparsentan and irbesartan was evaluated in the Phase 3 DUPLEX Study⁵

Key takeaway

In this post hoc analysis of the DUPLEX trial, sparsentan was associated with substantial and sustained reductions in proteinuria and numerically higher rates of complete remission of proteinuria compared to irbesartan among patients with gFSGS.¹

Footnotes

This work was supported by Travere Therapeutics, Inc. Please see the publication for the full list of disclosures.

*Defined as a 40% reduction in eGFR, progression to end-stage kidney disease (ESKD), or death.

Ang II, angiotensin II; CI, confidence interval; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ET-1, endothelin-1; FSGS, focal segmental glomerulosclerosis; gFSGS, genetic-associated FSGS; UPCR, urine protein-to-creatinine ratio.

MA-SP-26-0009 | April 2026