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Introduction: IgA nephropathy is one of the most common forms of glomerular disease. Patients with persistent proteinuria are at increased risk of progression to kidney failure. There is a significant need for safe and effective therapies to lower proteinuria in these patients. Sparsentan is a non-immunosuppressive agent that acts as a dual angiotensin and endothelin receptor antagonist. It lowers proteinuria in experimental models of glomerular disease and in affected patients., Areas Covered: This review covers the immunological and non-immunological actions of sparsentan in glomerular disease. It reviews the clinical trials that evaluated the impact of the drug in pediatric and adult patients with IgA nephropathy. It places the use of sparsentan in an overall treatment paradigm for the full spectrum of patients with IgA nephropathy including nonspecific renoprotective agents such as inhibitors of the renin-angiotensin-aldosterone axis and SGLT2 transporter and immunosuppressive drugs. The review represents a search of the current literature about the effect of the drug on normal physiology and the pathogenesis of IgA nephropathy., Expert Opinion: The safety, tolerability, and therapeutic efficacy of sparsentan have been demonstrated in long-term studies of patients with primary glomerular diseases extending over 5 years. The evidence in support of a beneficial treatment effect of sparsentan is stronger in IgAN than in FSGS. It is anticipated that sparsentan will supplant the use of ACEI or ARB as the first-line therapy to reduce proteinuria prior to the implementation of immunosuppressive agents in patients with IgA nephropathy. It may be combined with other renoprotective drugs like SGLT2 inhibitors. Practice guidelines are needed to promote safe and effective use of this new drug by nephrologists caring for patients with IgAN in all clinical settings.

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety., Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m 2 and ≥60 mL/min per 1·73 m 2 ) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850., Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups., Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan., Funding: Travere Therapeutics., Competing Interests: Declaration of interests HJLH reports consulting fees from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Merck, Novartis, Novo Nordisk, and Travere Therapeutics; research support for clinical trials from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk; honoraria from AstraZeneca and Novo Nordisk; travel expenses from Eli Lilly; and reports that The George Institute for Global Health and George Clinical hold research contracts for trials in kidney disease. CEA reports consulting fees from AstraZeneca and Mantra Bio; and grant support from Sana. JB reports research grants from Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos, GlaxoSmithKline, Novartis, and Travere Therapeutics; and is medical and/or scientific advisor to Alnylam Pharmaceuticals, Argenx, Astellas Pharma, BioCryst Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, Dimerix, Galapagos, Novartis, Omeros, Travere Therapeutics, UCB, Vera Therapeutics, and Visterra. SB, UD, JI, RK, and WR are employees and stockholders of Travere Therapeutics. AM reports consulting fees from Travere Therapeutics through a contract with JAMCO Pharma Consulting and consulting fees from Vera Therapeutics. ILN reports receiving honoraria for scientific presentations from AstraZeneca, Bayer, Novartis, and Roche; travel expenses from AstraZeneca; and reports that The George Institute for Global Health holds research contracts for trials in kidney disease. JR reports consulting fees from Calliditas, Chinook, and Travere Therapeutics; and grant support from Travere Therapeutics. MNR reports acting as clinical trial site principal investigator for Chinook, Kaneka, Reata, River 3 Renal Corp, Sanofi, and Travere Therapeutics; consulting fees from Visterra; is a member of the Data and Safety Monitoring Board for Advicenne; and is in a leadership or fiduciary role for Pediatric Nephrology Research Consortium, Women in Nephrology, and #NephJC. BR reports consulting fees from Calliditas, Novartis, Omeros, Travere Therapeutics, and Vera; and clinical trial funding to his institution from Travere Therapeutics. HTra reports consulting fees and membership on data monitoring committees for Akebia, ChemoCentryx, Goldfinch Bio, Natera, Otsuka, Travere Therapeutics, and Walden; and serves on a data safety monitoring board or advisory board for DUPRO. HTri reports receiving honoraria for scientific work from AstraZeneca, Bayer, Calliditas, Chinook, Dimerix, GSK, Novartis, Omeros, Roche, Travere Therapeutics, and Visterra Otsuka; and reports that The George Institute for Global Health holds research contracts for trials in kidney disease. MGW reports receiving honoraria for scientific presentations from Alpine, Amgen, AstraZeneca, Baxter, Chinook, CSL Behring, Dimerix, Eledon, George Clinical, Horizon, Otuska, and Travere Therapeutics. VP is an employee of UNSW Sydney and serves as a Board Director for St. Vincent's Health Australia, George Clinical, and several Medical Research Institutes; has received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Medimmune, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pfizer, Pharmalink, Reata, Relypsa, Roche, Sanofi, Servier, Travere Therapeutics, Tricida, and Vifor Pharma; honoraria from Janssen; serves on a data safety monitoring board or advisory board for Dimerix; has stock or stock options in George Clinical; and reports that The George Institute for Global Health and George Clinical hold research contracts for trials in kidney disease., (Copyright © 2023 Elsevier Ltd. All rights reserved.)