• N. Engl. J. Med. · Dec 2023

    Randomized Controlled Trial

    Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis.

    • Michelle N Rheault, Charles E Alpers, Jonathan Barratt, Stewart Bieler, Pietro Canetta, Dong-Wan Chae, Gaia Coppock, Ulysses Diva, Loreto Gesualdo, Hiddo J L Heerspink, Jula K Inrig, Gianna M Kirsztajn, Donald Kohan, Radko Komers, Laura A Kooienga, Kenneth Lieberman, Alex Mercer, Irene L Noronha, Vlado Perkovic, Jai Radhakrishnan, William Rote, Brad Rovin, Vladimir Tesar, Hernán Trimarchi, James Tumlin, Muh Geot Wong, Howard Trachtman, and DUPRO Steering Committee and DUPLEX Investigators.
    • From the Division of Pediatric Nephrology, University of Minnesota Medical School, Minneapolis (M.N.R.); the Department of Laboratory Medicine and Pathology, University of Washington, Seattle (C.E.A.); the Department of Cardiovascular Sciences, University of Leicester General Hospital, Leicester, United Kingdom (J.B.); Travere Therapeutics, San Diego, CA (S.B., U.D., J.K.I., R.K., W.R.); the Division of Nephrology, Columbia University Irving Medical Center, New York (P.C., J.R.); the Division of Nephrology, Department of Internal Medicine, Seoul Red Cross Hospital, Seoul, South Korea (D.-W.C.); Penn Renal Electrolyte and Hypertension Perelman, University of Pennsylvania, Philadelphia (G.C.); the Nephrology, Dialysis, and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy (L.G.); the Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands (H.J.L.H.); the George Institute for Global Health (H.J.L.H., V.P.) and the Faculty of Medicine and Health (V.P.), University of New South Wales, Sydney, and the Department of Renal Medicine, Concord Repatriation General Hospital, and Concord Clinical School, University of Sydney, Concord, NSW (M.G.W.) - all in Australia; the Department of Medicine (Nephrology), Federal University of São Paulo (G.M.K.), and the Division of Nephrology, University of São Paulo (I.L.N.) - both in São Paulo; the Department of Internal Medicine, Division of Nephrology, School of Medicine, University of Utah, Salt Lake City (D.K.); Colorado Kidney Care, Denver (L.A.K.); Hackensack University Medical Center, Hackensack, NJ (K.L.); JAMCO Pharma Consulting, Stockholm (A.M.); the Division of Nephrology, Ohio State University Wexner Medical Center, Columbus (B.R.); Všeobecná fakultní nemocnice v Praze, Prague, Czech Republic (V.T.); the Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires (H. Trimarchi); the Renal Division, Emory University, Atlanta, and the NephroNet Clinical Trials Consortium, Lawrenceville - both in Georgia (J.T.); and the Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor (H. Trachtman).
    • N. Engl. J. Med. 2023 Dec 28; 389 (26): 243624452436-2445.

    BackgroundAn unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown.MethodsIn this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated.ResultsA total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m2 with sparsentan and -12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups.ConclusionsAmong patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.).Copyright © 2023 Massachusetts Medical Society.

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