Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis
Kidney International Reports – 2020
Sparsentan Clinical Trials in Glomerular Diseases: Defining Endpoints and a Path Forward in Light of the PARASOL Initiative
Published on February 8, 2025
Contributors:
Trachtman H, Inrig JK, Komers R.
Trachtman H, Inrig JK, Komers R.
DOI:
10.1080/23995270.2025.2461966
10.1080/23995270.2025.2461966
Summary
Findings from the PARASOL initiative may guide reassessment of the DUPLEX trial and potentially support regulatory approval of sparsentan as a novel therapy for focal segmental glomerulosclerosis (FSGS)1
Background
Focal segmental glomerulosclerosis (FSGS) is a rare and progressive glomerular disorder characterized by podocyte injury and proteinuria, leading to kidney failure in a substantial proportion of patients.1,2 Existing treatments, including corticosteroids and immunosuppressive agents, are often associated with limited efficacy and adverse effects.1,3 There are no Food and Drug Administration (FDA)-approved therapies for FSGS,* creating a critical unmet need.1
Sparsentan is a novel, non-immunosuppressive, single-molecule, Dual Endothelin Angiotensin Receptor Antagonist (DEARA) being studied for the treatment of FSGS.4 In the Phase 2 DUET trial in patients with FSGS, sparsentan demonstrated significantly greater reductions in proteinuria compared with maximum-labeled dose irbesartan and was well-tolerated, prompting further investigation in the pivotal Phase 3 DUPLEX study.1,5
Aim
The commentary reflects on the results of the DUPLEX trial and explores the role of the PARASOL initiative in supporting the use of proteinuria-based endpoints to enable accelerated and traditional approval of novel therapies for FSGS.1
Findings
In the Phase 3 DUPLEX study, sparsentan was well-tolerated and led to a greater reduction in proteinuria versus maximum-labeled dose irbesartan1,6
The DUPLEX trial was a Phase 3, multicenter, double-blind, randomized trial enrolling 371 patients with biopsy-confirmed or genetically diagnosed FSGS.6
Sparsentan, compared to irbesartan1,6:
- Led to greater achievement of the FSGS partial remission endpoint (FPRE, defined as ≥40% reduction in proteinuria to a level <1.5 g/g) achievement at Week 36 (42% vs. 26%, respectively)
- Demonstrated a greater reduction in proteinuria at Week 108 (50% vs. 32%, respectively)
- Resulted in complete remission of proteinuria (defined as urine protein-creatinine ratio [UPCR] <0.3 g/g) more frequently (18.5% vs. 7.5%, respectively)
Read more about the DUPLEX study findings.
The lack of association in the DUPLEX trial between interim changes in proteinuria and eGFR slope at 2 years has prompted debate around FSGS clinical trial endpoints.1 This includes the relevance of proteinuria as a reasonably likely surrogate endpoint for accelerated approval and eGFR slope as a primary outcome for traditional approval in FSGS trials.1
Despite these questions, proteinuria warrants reconsideration as a clinical trial endpoint in FSGS because1:
- FSGS is a clear-cut podocytopathy1,7
- Proteinuria plays a key role in the integrity of the glomerular filtration barrier1,7
- Proteinuria is a primary manifestation of FSGS1,7
- There is strong biological plausibility that increased urinary protein excretion contributes to ongoing glomerular and tubular injury1,7
PARASOL is an ongoing international effort sponsored by the FDA, NephCure, International Society of Glomerular Disease, Kidney Health Initiative, and the National Kidney Foundation aiming to validate proteinuria as a surrogate endpoint in clinical studies1,8
Using existing data from patients with FSGS who participated in observational cohort studies, regional or national registries, or real-world data sets, the goal is to create a working model to relate changes in proteinuria with hard clinical outcomes.1,8
There is hope that findings of PARASOL will identify valid endpoints to support documentation of clinical benefit for future FSGS treatments.1
Key takeaway
The DUPLEX trial showed that sparsentan was well-tolerated and associated with antiproteinuric effects.1 The data also highlighted the uncertainty regarding the use of proteinuria and eGFR as clinical trial endpoints in FSGS.1
Given the role of proteinuria in FSGS, authors believe that sparsentan may have a role in the future disease management.1 Initiatives, such as PARASOL, may help identify valid endpoints to assess the clinical benefit of sparsentan and other future FSGS therapies.1
Related Content
Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis
Kidney International Reports – 2020
Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis
New England Journal of Medicine – 2023
Implications of Complete Proteinuria Remission at Any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial
Kidney International Reports – 2023
Footnotes
*As of March 2026.
Radko Komers MD, PhD and Jula K. Inrig MD are employees of Travere Therapeutics Inc. Please see the publication for the full list of disclosures.
DEARA, Dual Endothelin Angiotensin Receptor Antagonist; FDA, Food and Drug Administration; FPRE, FSGS partial remission endpoint; FSGS, focal segmental glomerulosclerosis; UPCR, urine protein-creatinine ratio.
- Trachtman H et al. Future Rare Diseases. 2025;5(1).
- Gipson DS et al. JAMA Netw Open. 2022;5(8):e2228701.
- Caster DJ et al. Kidney Med. 2022;4(8):100501.
- Komers R et al. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-R884.
- Trachtman H et al. J Am Soc Nephrol. 2018;29(11):2745-2754.
- Rheault MN et al. N Engl J Med. 2023;389(26):2436-2445.
- Faivre A et al. J Am Soc Nephrol. 2024;35(7):854-869.
- PARASOL Proteinuria and Other Biomarkers as Endpoints for Clinical Trials in Kidney Disease. Accessed 26 January 2026. https://www.is-gd.org/parasol
MA-SP-25-0089 | March 2026