Iptacopan in IgA Nephropathy

Iptacopan in IgA Nephropathy — Final 24-Month Data Published March 28, 2026 N Engl J Med 2026;395:465-477 DOI: 10.1056/NEJMoa2600743 Abstract Background Overactivation of the alternative complement pathway contributes to IgA nephropathy and glomerular inflammation. In the 9-month interim analysis of this phase 3 trial, iptacopan, a complement factor B inhibitor, led to a significant reduction of 38.3% in the 24-hour urinary protein-to-creatinine ratio as compared with placebo and had an acceptable safety profile. Methods In this phase 3 trial, we enrolled adults who had IgA nephropathy, an estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m2 of body-surface area, and a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite supportive care. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily. The primary end point for the final analysis was the annualized total eGFR slope as estimated over a 24-month period. Secondary end points included a composite kidney-failure end point (i.e., a sustained decline in eGFR of ≥30%, a sustained eGFR of <15 ml per minute per 1.73 m2, the initiation of maintenance dialysis, receipt of kidney transplant, or death from kidney failure), assessed in a time-to-event analysis. Safety was also assessed. Results Among 477 patients included in the final analysis, 238 had been randomly assigned to iptacopan and 239 to placebo. The annualized total eGFR slope was −3.10 ml per minute per 1.73 m2 per year with iptacopan, as compared with −6.12 ml per minute per 1.73 m2 per year with placebo (difference, 3.02 ml per minute per 1.73 m2 per year; 95% confidence interval [CI], 2.02 to 4.01; adjusted P<0.001). A composite kidney-failure end-point event occurred in 21.4% of the patients in the iptacopan group, as compared with 33.5% of those in the placebo group (hazard ratio, 0.57; 95% CI, 0.40 to 0.81; adjusted P=0.003). The incidence of adverse events was 87.0% in the iptacopan group and 89.1% in the placebo group. Serious adverse events occurred in 12.2% of the patients who received iptacopan and in 11.7% of those who received placebo, and serious infections in 6.7% and 2.1%, respectively. No deaths occurred. Conclusions Iptacopan therapy led to a significantly slower decline in kidney function than placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.) Are you a member of an institution such as a university or hospital?Learn more about Institutional Access Notes This article was published on March 29, 2026, at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. Supported by Novartis. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the patients who participated in this trial and their families, the members of the data monitoring committee (see the Supplementary Appendix), and Yumiko Abeynayake, M.D., of Amiculum, for medical writing assistance, funded by Novartis Pharma in accordance with Good Publication Practice guidelines. Supplementary Material Information & Authors Information Published In Copyright Copyright © 2026 Massachusetts Medical Society. All rights reserved. For personal use only. Any commercial reuse of NEJM Group content requires permission. History Published online: March 28, 2026 Published in issue: July 30, 2026 Topics Authors Metrics & Citations Metrics Altmetrics Citations Export citation Select the format you want to export the citation of this publication. Cited by - Evidence-Based Medicine versus Personalized Medicine when attempting to block complement in IgA nephropathy, Nephrology Dialysis Transplantation, (2026).https://doi.org/10.1093/ndt/gfag159 - Complement Inhibition in the Clinic: Are We Doing Enough to Protect Patients From Infection?, European Journal of Immunology, 56, 7, (2026).https://doi.org/10.1002/eji.70233 - Complement Genetics in IgA Nephropathy, Clinical Journal of the American Society of Nephrology, 21, 7, (1123-1125), (2026).https://doi.org/10.2215/CJN.0000001125 - Complement inhibitors and B cell–modifying agents for IgA nephropathy—a Kidney Disease: Improving Global Outcomes (KDIGO) commentary, Kidney International, (2026).https://doi.org/10.1016/j.kint.2026.03.003 Loading...