Interpreting Sparsentan’s Proteinuria Benefits Despite Missed eGFR Outcomes

The US Food and Drug Administration's April 2026 approval of sparsentan (Filspari) for focal segmental glomerulosclerosis (FSGS) marked a historic milestone in nephrology, making the dual endothelin and angiotensin receptor antagonist the first therapy approved specifically for the rare glomerular disease.

The decision was supported by findings from the phase 3 DUPLEX trial, which demonstrated significantly higher rates of partial remission of proteinuria with sparsentan than irbesartan at 36 weeks, although the study did not meet its primary endpoint for estimated glomerular filtration rate (eGFR) slope over 108 weeks.

The approval has generated considerable discussion among nephrologists regarding how to interpret proteinuria reduction in FSGS, where validated surrogate endpoints remain less established than in diseases such as IgA nephropathy (IgAN). Questions also remain about which patients are most likely to benefit from therapy and how sparsentan should be incorporated into an increasingly complex treatment landscape.

To better understand these issues, HCPLive spoke with Miriam Chung, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai. In this Q&A, Chung discusses the clinical data supporting sparsentan, the role of proteinuria as a surrogate endpoint in FSGS and IgAN, and how she identifies appropriate candidates for treatment in clinical practice.

HCPLive: Where does sparsentan fit into the current treatment landscape for proteinuric kidney diseases such as IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS)?

Chung: First of all, sparsentan is a non-immunosuppressive dual endothelin and angiotensin receptor blocker. It has more than a hemodynamic effect—it can have kidney-protective effects on podocytes, inflammation, and fibrosis, and can play a supportive role in chronic kidney disease management by helping delay nephron loss.

Specifically in IgA nephropathy, sparsentan is included in the KDIGO 2025 IgAN guideline, which states that it can be considered as an alternative to renin-angiotensin system (RAS) blockade, such as ACE inhibitors or angiotensin receptor blockers. In FSGS, sparsentan was recently the first drug approved by the FDA for use in patients aged 8 years and older without nephrotic syndrome.

The data supporting sparsentan in IgAN come from the PROTECT trial, which compared sparsentan with irbesartan. The sparsentan group showed a 43% reduction in proteinuria compared with approximately a 4.5% reduction in the irbesartan group. The chronic eGFR slope also showed benefit, with lower eGFR loss between weeks 6 and 110. Based on these findings, the KDIGO 2025 guideline recommends considering sparsentan as an alternative to RAS blockade for people with IgAN who are at risk for progression.

For FSGS, the DUPLEX study compared sparsentan with irbesartan in patients with primary or genetic FSGS. The study demonstrated early and sustained reductions in proteinuria. Investigators evaluated partial remission, defined as a urine protein-creatinine ratio of ≤1.5 g/g and a >40% reduction from baseline. At 36 weeks, 42% of patients receiving sparsentan achieved partial remission compared with 26% of those receiving irbesartan. Based on these findings, the FDA approved sparsentan for proteinuria reduction in patients with FSGS without nephrotic syndrome.

However, we do need to use caution when interpreting the FSGS data. Although it is exciting to have a drug that lowers proteinuria in a disease with significant unmet need, the study did not show a significant eGFR benefit between groups. The primary endpoint was eGFR, and the trial did not meet that endpoint because there was no statistically significant difference between sparsentan and irbesartan. The study was conducted over 2 years, and questions remain about whether a longer duration or a larger sample size may have been needed to detect a benefit. What we do know is that the proteinuria reduction was significant as early as 6 weeks and was sustained throughout the 2-year study period.

HCPLive: Do you view proteinuria reduction as a reliable surrogate for long-term kidney outcomes at this stage?

Chung: At this point, proteinuria reduction is a promising surrogate for long-term outcomes, and it is a reliable surrogate for IgA nephropathy. The KDIGO 2025 guideline states that urine protein excretion is the only validated early biomarker to help guide clinical decision-making in IgAN.

For FSGS, it is less clear. A Kidney Health Initiative analysis found that complete remission, defined as urine protein excretion of less than 0.3 g/day, is a validated surrogate endpoint in patients with nephrotic-range proteinuria. In the phase 2 DUET study comparing sparsentan and irbesartan, investigators later examined long-term follow-up over a median of approximately 4 years. Patients who achieved complete remission at any point during follow-up experienced lower rates of eGFR decline compared with those who never achieved complete remission.

Having said that, smaller reductions in proteinuria, such as those observed in the DUPLEX study over 2 years, have not yet been shown to translate into eGFR benefit and therefore have not been validated as surrogates for kidney function preservation.

I am eager to see what the long-term data show. FSGS is a very heterogeneous disease with multiple underlying causes. It can be primary, genetic, secondary to other conditions, or of unclear etiology. There was also an open-label extension analysis from the DUET study showing that patients who achieved partial remission within 9 months of sparsentan treatment experienced significantly lower eGFR decline than those who never achieved partial remission. Overall, I think proteinuria is a promising surrogate for long-term kidney outcomes, but its predictive value depends on the disease and the mechanism of the therapy.

HCPLive: In your practice, which patients are the most ideal candidates for sparsentan?

Chung: For IgA nephropathy, I would consider sparsentan as an alternative to ACE inhibitors or angiotensin receptor blockers as part of supportive chronic kidney disease management. In IgAN, we want to address both the immune-mediated component of disease and supportive CKD management simultaneously.

I would consider sparsentan in patients with an eGFR above 30 mL/min/1.73 m² and in patients with hypertension, since blood pressure lowering is one of its effects. I would also consider it for patients who are already maximized on RAS blockade but have not achieved their proteinuria goals, such as those with a urine protein-creatinine ratio greater than 0.5 g/g.

For FSGS, I would consider using sparsentan in patients with subnephrotic proteinuria, meaning less than 3.5 g/day, and in patients with primary or genetic FSGS. I am particularly excited about its availability for genetic FSGS because these patients are often resistant to immunosuppression and have limited treatment options. A recent post hoc analysis of the DUPLEX trial also showed greater reductions in proteinuria among patients with genetic FSGS.

There are also patients in whom I would not use sparsentan. It should not be used in patients who are pregnant or may become pregnant. I would also avoid it in patients with significant liver disease or elevated liver function tests, as the REMS program requires monitoring of liver function every 3 months.

Additionally, I would not use it in patients with FSGS and nephrotic syndrome, as it is not approved for that population and those patients often require immunosuppressive therapy. I would also be cautious in patients with low baseline blood pressure, very advanced CKD with an eGFR below 25 mL/min/1.73 m², or a tendency toward volume overload or heart failure.

Although the PROTECT and DUPLEX studies did not show heart failure as a first event, endothelin receptor antagonists are associated with fluid retention as a class effect. In those situations, I might consider adding an SGLT2 inhibitor if appropriate.

HCPLive: Is there anything else you would like to highlight about sparsentan and its role in FSGS?

Chung: For FSGS especially, the exciting part is that sparsentan is the first FDA-approved therapy for the disease. There is a significant unmet need in FSGS. We know there are approximately 200,000 children and adults in the United States living with FSGS, and as many as 40% to 50% develop kidney failure within 5 to 10 years.

It is exciting to finally have an approved treatment option, but we should also use it with caution. Although sparsentan lowers proteinuria, the initial study did not demonstrate an eGFR benefit, and the current approval is specifically for patients with non-nephrotic syndrome FSGS.

Editor’s Note: Chung reports relevant disclosures with Calliditas, Kyverna, Travere, and Vera.

References

1. Hillenbrand A. FDA Approves Sparsentan for Focal Segmental Glomerulosclerosis. HCPLive. Published April 13, 2026. Accessed June 1, 2026. https://www.hcplive.com/view/fda-approves-sparsentan-for-focal-segmental-glomerulosclerosis

2. Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. The New England Journal of Medicine. 2023;389(26). doi:https://doi.org/10.1056/nejmoa2308550