BOSTON — Sparsentan, a first-in-class, oral dual endothelin-angiotensin receptor antagonist, shows significant benefit in reducing proteinuria in the difficult-to-manage focal segmental glomerulosclerosis (FSGS) compared with the angiotensin II receptor blocker (ARB) irbesartan, a new post-hoc analysis of the phase 3 DUPLEX trial shows.
“Dual endothelin angiotensin receptor blockade with sparsentan led to partial or complete remission of proteinuria earlier and more often in patients with FSGS than did angiotensin receptor blockade alone with irbesartan,” said first author James Tumlin, MD, of NephroNet Clinical Trials Consortium and Emory University School of Medicine, Atlanta, Georgia, in presenting the findings at the National Kidney Foundation’s 2025 Spring Clinical Meeting.
“Taken together, these findings from the DUPLEX trial support the antiproteinuric and nephroprotective benefits of sparsentan in patients with FSGS.”
FSGS is known for its aggressive nature — up to half of patients with the condition with nephrotic-range proteinuria who do not reach remission or partial remission typically require a kidney transplant or dialysis within 5-10 years of diagnosis.
Even then, approximately a third of patients who do undergo kidney transplantation will have a recurrence in the transplanted kidney.
While current therapeutic strategies for the condition include angiotensin-converting enzyme inhibitors, ARB inhibitors, calcineurin inhibitors, and steroids, as many as 47% of children and 38% of adults do not respond to the treatment options, Tumlin reported.
“There remains an unmet need for safe and effective treatments that lower proteinuria and reduce the risk of kidney failure,” Tumlin said.
Reductions in proteinuria have been shown to be importantly linked to kidney survival in people with FSGS, and in pre-clinical studies, sparsentan, a non-immunosuppressive, dual endothelin angiotensin receptor antagonist, has been shown in achieve that. The drug is currently approved for the management of immunoglobin A nephropathy (IgAN).
Sparsentan’s benefits in FSGS were further observed in the phase 2 DUET trial in which sparsentan resulted in a reduction in proteinuria after 8 weeks that was significantly greater than the changes observed with irbesartan.
In the randomized, phase 3 DUPLEX trial— the largest interventional trial to date in FSGS, sparsentan showed no significant between-group difference in comparison with irbesartan in the primary endpoint of estimated glomerular filtration rate (eGFR) slope at 108 weeks.
Nevertheless, based on the previous favorable data on proteinuria, sparsentan has been subsequently granted orphan drug designation for the treatment of FSGS by the US Food and Drug Administration and the European Medicines Agency.
To expand on the DUPLEX trial findings and take a closer look at the clinical outcomes associated with the proteinuria reductions, Tumlin and colleagues conducted a post-hoc analysis of the study, evaluating further data on sparsentan and irbesartan.
In the original trial, patients with FSGS were randomized to treatment either with sparsentan 800 mg/day (n = 184) or irbesartan 300 mg/d (n = 187).
The study included children as well as adults. The children were aged 8-18, making up 8.7% in the sparsentan group and 10.2% in the irbesartan group. Among adults, the mean age was 41 in both treatment groups.
About 55% of patients were male and overall; the mean eGFR was 63.7 mL/min/1.73 m2.
Among all ages, 90% of patients in the sparsentan group received the maximum labeled dose, and 90.4% received the maximum irbesartan dose, underscoring good adherence and tolerability of both drugs.
The results showed that, for the outcome of partial remission of proteinuria — defined as urine protein-to-creatinine ratio (UPCR) ≤ 1.5 g/g and > 40% reduction from baseline through week 108 — sparsentan had a significantly higher rate of 64.7% vs 43.9% with irbesartan (relative risk [RR], 1.48; P < .0001).
The rate of complete remission of proteinuria, defined as UPCR < 0.3 g/g, was likewise significantly higher with sparsentan (18.5% vs 7.5%; RR, 2.47; P = .0008).
“At the end of the 108 weeks, 2.5-fold higher patients in the sparsentan group versus the irbesartan achieved complete remission.”
The probability of having kidney failure through week 108 was just 3% even among those who achieved a partial remission vs 15.9% of those with no partial remission (RR, 0.33). And the corresponding rates of kidney failure among those with complete remission were 2.1% vs 9.9% in those who did not achieve complete remission (RR, 0.23).
Sparsentan was well-tolerated, with a safety profile comparable with that of irbesartan, with the most common treatment-emergent adverse events being COVID-19, hyperkalemia, peripheral edema, and hypotension.
“Patients who reached partial remission or complete remission showed markedly reduced risk of progression to kidney failure versus those who did not, supporting the nephroprotective benefit of sparsentan in focal segmental glomerulosclerosis,” the authors report.
Commenting on the study, Sankar D Navaneethan, MD, associate chief of nephrology at Baylor College of Medicine, in Houston, Texas, noted that a “secondary analysis of the DUET trial showed potential benefits of sparsentan in reducing proteinuria.”
“The [current] results of the DUPLEX trial data reinforce the antiproteinuric benefits of the dual endothelin receptor blockade and the importance of reaching either complete or partial remission,” he told Medscape Medical News.
“Safety data – especially fluid retention, presented up to 108 weeks is reassuring,” he noted.
“Sparsentan is approved for IgAN management; we will await further studies and regulatory approval for considering the use of sparsentan for management of FSGS,” he said.
The study was supported by Travere Therapeutics, Inc. Tumlin reports relationships with Akebia Therapeutics, Alexion Pharmaceuticals, argenx, AstraZeneca, Aurinia Pharmaceuticals Inc., Blogen Inc. Dimerix Limited, Humacyte Global Inc., La Jolla Pharmaceutical Company, Mallinckrodt Pharmaceuticals, Medtronic Inc., Otsuka Pharmaceuticals, Palatin Technologies, Pfizer, Travere Therapeutics, Inc., Vera Therapeutics, and Vertex Pharmaceuticals. Navaneethan had no disclosures to report.
