Iptacopan improves mesenchymal and capillary glomerular C3 deposition in patients with C3 glomerulopathy

Following 6 months of treatment in the APPEAR-C3G trial, iptacopan versus placebo decreased complement C3 deposition in the glomeruli, a known factor associated with prognosis in patients with C3 glomerulopathy.

APPEAR-C3G was a phase 3, randomised, double-blind trial in patients with C3 glomerulopathy with C3 levels <77 mg/dL, proteinuria ≥1.0 g/g, and eGFR ≥30 ml/min/1.73 m² [1]. Treatment consisted of 6 months of iptacopan 200 mg twice daily or placebo for 6 months, with a 6-month extended, open-label treatment period with iptacopan in all patients [2]. C3 glomerulopathy progression was assessed by renal histopathology of samples collected 45 days prior to baseline and at day 180. The C3 deposition score was defined as a composite of immunofluorescence intensity for deposition in the mesangium and capillary, with scores ranging between 0–12.

Assessment of glomerular C3 deposits was performed on a total of 67 trial participants at day 180. Baseline C3 immunofluorescence intensity scores were 9.2 and 9.6 in the iptacopan and placebo groups, respectively, showing elevated values. C3 deposit scores were lowered with iptacopan treatment compared with placebo after 6 months, corresponding to an adjusted mean difference of -1.88 (95% CI -3.30 to -0.45; P=0.0052) in C3 immunofluorescence intensity.

The authors concluded that “iptacopan reduced C3 deposition in the glomeruli after 6 months treatment in the APPEAR-C3G trial, compared with placebo. Iptacopan showed a reduction of both mesangial and capillary staining. Further follow-up is necessary to investigate whether these findings are associated with improved clinical outcomes.”

1. Weinmann-Menke J, et al. Evaluation of C3 deposition in patients with C3G: insights from the APPEAR-C3G Phase 3 study in patients treated with iptacopan. 62nd ERA Congress, 4–7 June 2025, Vienna, Austria.
2. Bomback AS, et al. Kidney Int Rep. 2022;7(10):2150-2159.

Medical writing support was provided by Mihai Surducan, PhD.

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Posted on 11 June 202522 August 2025