Effect of Sparsentan Versus Irbesartan With Genetic FSGS

The DUPLEX trial examined the efficacy and safety of two potential treatments for focal segmental glomerulosclerosis (FSGS): sparsentan and irbesartan. Sparsentan demonstrated a greater reduction in proteinuria, but it is unclear whether its efficacy depends on the underlying pathogenesis of FSGS.

Genetic FSGS (gFSGS) is caused by mutations in podocyte genes and tends to be hard to treat. In a post hoc analysis of DUPLEX data, Jennifer Lai Yee, MD, PhD, and colleagues evaluated the efficacy of sparsentan in a subset of patients with gFSGS. Their results were shared in a poster at ASN Kidney Week 2024 titled Outcomes of the DUPLEX Trial in Patients With Genetic Focal Segmental Glomerulosclerosis (gFSGS).

Three hundred and fifty-five DUPLEX patients were genotyped by the FSGS panel of PreventionGenetics. Those who had pathogenic or likely pathogenic variants in podocyte genes were classified as having gFSGS with Mendelian inheritance. In total, 8.7% (n=31) of patients were identified as having gFSGS. These patients were younger and had higher eGFR compared to the overall DUPLEX population at baseline, and most of them had proteinuria within nephrotic range.

The post hoc analysis studied changes in proteinuria, namely percentage reduction or achievement of complete remission (urine protein-to-creatinine ratio <0.3 g/g at any time) and percentage of patients reaching end-stage kidney disease (eGFR <15 mL/min/1.73 m², dialysis, or transplant) with sparsentan compared to irbesartan.

Sparsentan demonstrated a faster and more pronounced reduction in proteinuria than irbesartan. The effect was sustained and was also observed in a subset of patients with NPHS2 mutations.

The only patients with gFSGS to achieve complete remission were those treated with sparsentan (n=1 [8%] vs n=0). Patients with gFSGS taking irbesartan more often reached end-stage kidney disease (n=3 [17%] vs n=1 [8%]). A pronounced early antiproteinuric response that was sustained over the treatment period was more common with sparsentan than with irbesartan.

The researchers concluded that, “The findings support a recommendation for [sparsentan] administration to reduce proteinuria and achieve long-term kidney health benefits in this high-risk group of patients with gFSGS.”

Source: Lai Yee J, Gong W, Inrig JK, Rheault MN, Komers R, Trachtman H. Outcomes of the DUPLEX trial in patients with genetic focal segmental glomerulosclerosis (gFSGS). TH-PO1199. Abstract of a poster presented at the American Society of Nephrology Kidney Week 2024; October 24, 2024; San Diego, California. Commercial support for the study was provided by Travere Therapeutics, Inc.