Sparsentan Lowers Inflammatory, Complement Biomarkers in IgAN

Sparsentan (Filspari), a dual endothelin and angiotensin receptor antagonist, reduced urinary biomarkers of macrophage activation, B-cell activation, complement activation, and inflammation through 110 weeks versus irbesartan in adults with IgA nephropathy, according to a biomarker analysis of the phase 3 PROTECT trial.1

Travere Therapeutics announced the data, delivered as an oral presentation at ASN Kidney Week 2026 in Denver, Colorado.1

“These findings extend the exploratory signal observed in SPARTAN and show in a larger, randomized study that dual endothelin and angiotensin receptor antagonism may modulate several biological pathways associated with IgAN pathophysiology,” Chee Kay Cheung, MBChB, PhD, consultant nephrologist at University Hospitals of Leicester NHS Trust, said in a statement.1

In PROTECT, sparsentan reduced proteinuria by 49.8% versus 15.1% with irbesartan at week 36 and improved chronic 2-year eGFR slope by approximately 1.1 mL/min/1.73 m² per year.2 The new analysis builds on an exploratory signal from the smaller SPARTAN study, in which urinary biomarkers of inflammation, fibrosis, and complement activation fell 16% to 76% in 11 adults with newly diagnosed IgA nephropathy.3

Which IgA Nephropathy Biomarkers Did Sparsentan Reduce in PROTECT?

PROTECT randomly assigned 404 adults with biopsy-confirmed IgA nephropathy, urine protein excretion of ≥ 1.0 g/day, and an eGFR of ≥ 30 mL/min/1.73 m² despite optimized renin-angiotensin system inhibition. Participants received sparsentan 400 mg/day or irbesartan 300 mg/day for up to 110 weeks. The primary endpoint was change in proteinuria at week 36, with rate of eGFR change through week 110 as the key secondary end point.1

The biomarker analysis included 295 participants, with 4 urinary biomarkers measured at multiple timepoints through week 110 and normalized to urine creatinine.1

At week 110, urinary soluble CD163, a marker of macrophage activation, decreased by 60.1% with sparsentan compared with 26.0% with irbesartan (relative between-group difference, 46.1%; P < .001). B-cell activating factor (BAFF) fell 64.4% versus 45.2%, respectively (difference, 34.9%; P = .02).1

Soluble C5b-9, a marker of terminal complement activation, decreased by 50.2% with sparsentan compared with 7.3% with irbesartan (difference, 46.3%; P = .032). Interleukin-6 decreased by 45.4% with sparsentan and increased by 8.7% with irbesartan (difference, 49.7%; P < .001). According to Travere, reductions with sparsentan were rapid and sustained across all 4 biomarkers.1

What Do the PROTECT Biomarker Findings Mean for Sparsentan in IgAN?

“These biomarker data provide new insight into how [sparsentan]’s dual mechanism of action may modify the underlying biology of IgA nephropathy,” said Jula Inrig, MD, chief medical officer of Travere Therapeutics.1 “When considered alongside the PROTECT results which demonstrated superior proteinuria reduction and a slower rate of kidney function decline compared with maximum labeled dose irbesartan, as well as published real-world evidence showing consistent outcomes in clinical practice, the totality of evidence supports the use of [sparsentan] as a non-immunosuppressive, kidney-targeted, foundational first-line treatment for IgA nephropathy.”

Sparsentan is FDA approved to slow kidney function decline in adults with primary IgA nephropathy at risk for disease progression. It is also approved to reduce proteinuria in adults and pediatric patients aged 8 years and older with focal segmental glomerulosclerosis without nephrotic syndrome. Sparsentan carries a boxed warning for hepatotoxicity and embryo-fetal toxicity and is available only through a Risk Evaluation and Mitigation Strategy program.1

In August 2025, the FDA approved a REMS update reducing liver function monitoring from monthly to every 3 months and removing the embryo-fetal toxicity monitoring requirement.4

References

1. Travere Therapeutics. Travere presents new biomarker data at ASN Kidney Week suggesting FILSPARI (sparsentan) may modify underlying disease pathophysiology in IgA nephropathy. Business Wire. Published October 23, 2026. Accessed October 24, 2026. https://www.businesswire.com/news/home/20261023530930/en/

2. Campbell P. PROTECT: sparsentan outperforms irbesartan in IgA nephropathy. HCPLive. Published November 3, 2023. Accessed October 24, 2026. https://www.hcplive.com/view/protect-sparsentan-outperforms-irbesartan-in-iga-nephropathy

3. Sparsentan’s effect on urinary biomarkers in IgAN, with Chee Kay Cheung, MBChB, PhD. HCPLive. Published November 7, 2025. Accessed October 24, 2026. https://www.hcplive.com/view/sparsentan-effect-urinary-biomarkers-igan-with-chee-kay-cheung-mbchb-phd

4. Brooks A. FDA approves REMS label update for sparsentan (Filspari) in IgA nephropathy. HCPLive. Published August 27, 2025. Accessed October 24, 2026. https://www.hcplive.com/view/fda-approves-rems-label-update-for-sparsentan-filspari-in-iga-nephropathy