Sparsentan and Progression to Kidney Failure in FSGS, with James Tumlin, MD

Findings from a posthoc analysis of the phase 3 DUPLEX study of sparsentan (Filspari) are providing new insight into the dual endothelin angiotensin receptor antagonist’s nephroprotective benefit in patients with focal segmental glomerulosclerosis (FSGS).1

The data were presented during a late-breaking session at the National Kidney Foundation (NKF) Spring Clinical Meetings 2025 in Boston, Massachusetts, and showed patients with FSGS treated with sparsentan achieved partial and complete remission more rapidly and with higher incidence than those treated with irbesartan. Additionally, patients who reached partial or complete remission showed a markedly reduced risk of progression to kidney failure versus those who did not.1

“A substantial number of people have very few options. Prednisone is really not used by most anyone today, certainly not by me,” James Tumlin, MD, president of NephroNet, director of research at Georgia Nephrology, and a professor of medicine in nephrology at Emory University School of Medicine, explained to HCPLive. “CNIs, tacrolimus, and cyclophosphamide are still used, but you still have the same problem with long-term toxicity… We've been desirous of having a new type of therapeutic pathway for quite some time.”

Sparsentan may be poised to address this unmet need in FSGS – in March 2025, Travere Therapeutics submitted a supplemental New Drug Application to the US Food and Drug Administration seeking priority review for traditional approval of sparsentan for the treatment of FSGS, supported by results from the phase 3 DUPLEX study and the phase 2 DUET study.2

A multicenter, double-blind, active-controlled trial, DUPLEX enrolled 371 patients 8-75 years of age with biopsy-confirmed FSGS or a documented pathogenic variant in a podocyte protein associated with FSGS, a urinary protein-to-creatinine ratio ≥ 1.5, and an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 of body-surface area at screening.1,3

Following randomization in a 1:1 ratio, 184 participants were randomly assigned to sparsentan and 187 were randomly assigned to irbesartan. Results showed there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan.1,3

In the posthoc analysis presented at NKF, investigators investigated the impact of sparsentan versus irbesartan on partial or complete remission of proteinuria and the effect of achieving these thresholds on progression to kidney failure.1

Results showed both partial remission and complete remission were achieved more frequently with sparsentan than with irbesartan:

• Partial remission: 64.7% vs 43.9% (relative risk [RR], 1.48; 95% CI, 1.23-1.78)
• Complete remission: 18.5% vs 7.5% (RR, 2.47; 95% CI, 1.37-4.45)

Additionally, investigators noted partial and complete remission were achieved earlier with sparsentan than with irbesartan.1

Of note, irrespective of treatment group, lowering proteinuria to reach partial and complete remission resulted in a marked reduction in progression to kidney failure. For partial remission the odds of progressing to kidney failure were 3% compared with 15.9% without partial remission. For complete remission, the odds of progressing to kidney failure were 2.1% compared with 9.9% without complete remission.1

“Those numbers seem similar, but there's a really important point behind that, which is that even a partial reduction in proteinuria has resulted in a profound reduction in the risk of progression of renal disease,” Tumlin explained. “From my standpoint, I think this will be a significant weapon in the argument to change the accepted clinical endpoints for drug development. I suspect that drug development FSGS will explode if that ruling goes through by the FDA.”

Editors’ note: Tumlin has relevant disclosures with Aurinia Pharmaceuticals, Biogen, Mallinckrodt, Novartis, Vertex Pharmaceuticals, and others.

References

1. Tumlin J, Tesar V, Trimarchi H, et al. Patients (Pts) in DUPLEX Achieved Partial or Complete Remission of Proteinuria Earlier and More Often With Sparsentan (SPAR) vs Irbesartan (IRB): Implications for Slowing Progression to Kidney Failure (KF) in Focal Segmental Glomerulosclerosis (FSGS). Abstract presented at: National Kidney Foundation Spring Clinical Meetings 2025. Boston, MA. April 9 - 13, 2025.

2. Brooks A. Travere Therapeutics Submits sNDA for Sparsentan (Filspari) in FSGS. HCPLive. March 17, 2025. Accessed April 14, 2025. https://www.hcplive.com/view/travere-therapeutics-submits-snda-sparsentan-filspari-fsgs

3. Campbell P. Sparsentan Use Could Lower Risk of Kidney Failure, Death in FSGS. HCPLive. November 3, 2023. Accessed April 14, 2025. https://www.hcplive.com/view/sparsentan-use-could-lower-risk-of-kidney-failure-death-in-fsgs