• Vlado Perkovic, Jonathan Barratt, Brad Rovin, Naoki Kashihara, Bart Maes, Hong Zhang, Hernán Trimarchi, Dmitrij Kollins, Olympia Papachristofi, Severina Jacinto-Sanders, Tobias Merkel, Nicolas Guerard, Ronny Renfurm, Thomas Hach, and Dana V Rizk.
• From the University of New South Wales, Sydney (V.P.); the Mayer IgA Nephropathy Laboratories, University of Leicester, Leicester, United Kingdom (J.B.); Ohio State University Wexner Medical Center, Columbus (B.R.); Kawasaki Medical School, Okayama, Japan (N.K.); AZ Delta, Roeselare, Belgium (B.M.); Peking University First Hospital, Beijing (H.Z.); Hospital Britanico, Buenos Aires (H.T.); Novartis Pharma, Basel, Switzerland (D.K., O.P., S.J.-S., T.M., N.G., R.R., T.H.); and the University of Alabama at Birmingham, Birmingham (D.V.R.).
• N. Engl. J. Med. 2024 Oct 25.

BackgroundThe alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria (defined as a 24-hour urinary protein-to-creatinine ratio of ≥1 [with protein and creatinine both measured in grams]) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period.ResultsThe main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed.ConclusionsAmong patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).Copyright © 2024 Massachusetts Medical Society.

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