First Real-World Evidence of Sparsentan Efficacy in Patients with IgA Nephropathy Treated with SGLT2 Inhibitors

Background: Following the publication of the PROTECT trial, sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy and is currently under review for approval in Europe. However, real-world evidence, particularly on the additive antiproteinuric effect under SGLT2 inhibitors, which were an exclusion criterion in the double-blind period of the PROTECT trial, is lacking. Methods: We started treating n=7 patients with sparsentan with IgA nephropathy from December 2023 through the Managed Access Program prior to official launch. Patients were stable under maximum tolerated RAAS and SGLT2 inhibitor therapy with an eGFR >30 ml/min/1.73 m2 and a urine protein-creatinine ratio (UPCR) >0.75 g/gCreatinine. All patients provided their informed written consent. Statistical analysis was conducted using the Wilcoxon matched-pairs signed rank test. Results: Of the seven patients, the median (IQR) baseline eGFR (CKD-EPI) was 35 mL/min/1.73 m2 (29-69) and the median (IQR) baseline UPCR was 1.79 g/g (0.94-3.84). The median blood pressure before initiating sparsentan was 130/80 mmHg. After initiating sparsentan, the UPCR significantly decreased (p=0.016) to a median of 0.86 g/g (IQR: 0.63-2.12) in the 2-week follow-up and further significantly declined (p=0.031) to a median of 0.67 g/g (0.43-1.07) after 6 weeks, corresponding to a relative reduction of proteinuria greater than 60%. A similar significant reduction was observed for the urine albumin-creatinine ratio (UACR). No serious adverse events were reported. Conclusion: In a real-world setting, sparsentan demonstrates a significant effect on proteinuria and albuminuria as early as 2 weeks after initiation, resulting in a relative reduction of UPCR greater than 60% after 6 weeks, even in patients already being treated with SGLT2 inhibitors and steroids.