Antiproteinuric Effect of Sparsentan in Patients with Genetic-Associated FSGS Enrolled in the DUPLEX Trial

KEY POINTS: Sparsentan lowered proteinuria, with more frequent complete remission of proteinuria versus irbesartan in patients with genetic forms of FSGS. Fewer patients with genetic forms of FSGS progressed to the composite kidney endpoint with sparsentan versus irbesartan. Consistent with the overall DUPLEX population, the results support sparsentan's antiproteinuric benefit in patients with genetic forms of FSGS. BACKGROUND: FSGS is a podocytopathy that is diagnosed based on characteristic histopathologic lesions. Certain forms of FSGS with underlying genetic variants associated with the disease, including variants in podocyte proteins, as well as apolipoprotein L1 ( APOL1 ) risk alleles, and variants in collagen type 4 α 3, α 4, and α 5 ( COL4A3-5 ) proteins, are typically resistant to current treatments. METHODS: The DUPLEX clinical trial assessed the efficacy and safety of sparsentan, a dual endothelin angiotensin receptor antagonist, in patients with biopsy-proven or genetic FSGS (gFSGS) and demonstrated a greater antiproteinuric effect over 108 weeks compared with the active control irbesartan. This post hoc , exploratory analysis assessed the efficacy of sparsentan in the subset of patients enrolled in DUPLEX who had pathogenic variants in genes coding for podocyte proteins, COL4A3-5 variants, and APOL1 high-risk genotypes, all together referred to as gFSGS. RESULTS: Next-generation sequencing identified 31 patients with podocyte gene variants, 25 with COL4A3-5 gene variants, and 14 with APOL1 high-risk genotypes. Baseline characteristics varied between genetic subgroups, with slightly younger patients, on average, in the podocyte gene variant group, and more African American patients in the APOL1 high-risk genotype group. In this exploratory analysis, sparsentan treatment resulted in substantial and sustained proteinuria reductions and numerically more frequent complete remission of proteinuria compared with irbesartan, consistent with observations in the full DUPLEX study population. Moreover, a lower proportion of sparsentan-treated versus irbesartan-treated patients reached composite kidney endpoints. CONCLUSIONS: These findings support sparsentan's antiproteinuric benefit in patients with gFSGS, a subgroup that is often resistant to other therapeutic interventions. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Clinicaltrials.gov, NCT03493685 .