Sparsentan: A First-in-Class Dual Endothelin and Angiotensin II Receptor Antagonist

Objective: To provide an overview of the guidelines on the management of immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), review the evidence for sparsentan, and discuss its place in therapy. Data Sources: A literature search was conducted using MEDLINE, EMBASE, and clinicaltrials.gov using the search terms "sparsentan" and "RE-021" up to the end of Jun 2023. Study Selection and Data Extraction: English studies were included if they evaluated the pharmacology, pharmacokinetics, efficacy, and safety of sparsentan in human subjects. Information from the Food and Drug Administration (FDA) and manufacturer's monograph were also extracted. Data Synthesis: In comparison with irbesartan, sparsentan reduced urine protein-to-creatinine ratio (UPCR) in both IgAN (-49.8% vs -15.1% at interim 36 weeks) and FSGS (-44.8% vs -18.5% at 8 weeks). Hypotension and edema were the most common adverse events in the sparsentan groups. Hepatotoxicity appears to be comparable between sparsentan and irbesartan in short-term results. Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs: Sparsentan provides a new option for patients with IgAN who are otherwise at high risk of progressive kidney disease. Continued FDA approval is dependent on long-term study results on renal function decline and safety. Conclusion: Sparsentan reduces proteinuria in IgAN and FSGS, and has expedited approval by the FDA for IgAN in patients at risk of rapid disease progression, generally at urine protein-to-creatinine ratio (UPCR) =1.5 g/g. Interim results from PROTECT and results from DUET showed promise for improving proteinuria in IgAN and FSGS. Long-term renal function benefit and safety data are pending.