Disease-Targeted Therapies and eGFR Slope over 2 Years in IgA Nephropathy: A Systematic Review and Network Meta-Analysis

Background: Several disease-targeted therapies for IgA nephropathy have reported effects on eGFR slope over 2 years or longer in phase 3 trials, but they have not been compared directly. We compared their effects on the annualized total eGFR slope. Methods: We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from January 2018 and reviewed nephrology congress abstracts. Randomized trials reporting the annualized eGFR slope over at least 96 weeks were eligible. Placebo-controlled trials were combined in a frequentist network meta-analysis. The primary outcome was the between-group difference in total eGFR slope; secondary outcomes included the relative reduction in eGFR slope, chronic slope, proteinuria, and safety. Results: Of 1523 records screened, six placebo-controlled trials (2437 participants) were included in the main analysis. Compared with placebo, the difference in total eGFR slope was 5.1 (95% confidence interval [CI], 3.5 to 6.7) ml/min per 1.73 m2 per year for telitacicept, 5.0 (3.6 to 6.5) for atacicept, 4.7 (3.8 to 5.6) for sibeprenlimab, 3.0 (2.0 to 4.0) for iptacopan, 1.8 (0.5 to 3.1) for targeted-release budesonide, and 1.4 (0.5 to 2.3) for atrasentan. The pooled effect of the three agents targeting a proliferation-inducing ligand (APRIL) or B-cell activating factor (BAFF) and APRIL was 4.8 (4.2 to 5.5), and their pooled reduction relative to the control-arm decline was 98% (82% to 113%) versus 34% to 49% for the other agents. Serious adverse events were less frequent with telitacicept and atacicept than with placebo, serious infections were more frequent with iptacopan, and discontinuations were more frequent with targeted-release budesonide. Conclusions: In indirect comparisons, agents targeting APRIL or BAFF/APRIL may provide greater improvements in total eGFR slope over approximately 2 years than the other disease- targeted therapies. One of the three B-cell-directed trials was available only as a conference presentation, and direct comparisons are lacking.