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Iptacopan in IgA Nephropathy - Final 24-Month Data. 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.).