Journal article
Distinct Pharmacodynamic Complement Biomarker Signatures Define Iptacopan and Pegcetacoplan Treatment in C3 Glomerulopathy
Kidney international reports, Vol.11(12), 107087
09/18/2026
DOI: 10.1016/j.ekir.2026.107087
Abstract
C3 glomerulopathy (C3G) is driven by alternative pathway (AP) dysregulation. Iptacopan inhibits factor B, whereas pegcetacoplan inhibits C3/C3b, suggesting distinct pharmacodynamic (PD) biomarker profiles.
We conducted an exploratory, nonrandomized observational cohort study of patients with biopsy-confirmed C3G treated with iptacopan (n = 9) or pegcetacoplan (n = 9), using paired pretreatment and approximately 3-month post-treatment samples. Complement activity, protein levels, activation products, autoantibodies, and genetic findings were assessed. Profiles were classified as PD-concordant (PDC), largely PD-concordant (LPDC), or PD-discordant (PDD) using treatment-specific signatures.
Both treatments suppressed AP activity and terminal pathway activation but produced distinct profiles. The expected PDC signature for iptacopan included increases in C3, factor B, C5, properdin, and CH50 and reductions in complement activation products (C3a, C3c, C3d, Bb, and sC5b-9). The expected pegcetacoplan signature included supranormal increases in C3, C3c, and properdin, reductions in C3a, C3d, Bb, and sC5b-9, and generally preserved or increased CH50. PDC profiles occurred in 6 of 9 patients in each cohort. LPDC profiles occurred in three iptacopan-treated patients, all nephritic factor-positive, and two pegcetacoplan-treated patients with nephritic factors or a likely pathogenic C3 variant. One patient with severe factor H deficiency showed a PDD profile during pegcetacoplan treatment and again in a descriptive post-transplant sample during subsequent iptacopan treatment.
Iptacopan and pegcetacoplan produce distinct, mechanism-specific PD signatures in C3G. Pathway-based biomarker assessment may distinguish expected treatment effects from incomplete or discordant biochemical control. These categories describe PD patterns rather than clinical efficacy and require validation against clinical outcomes.
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Details
- Title: Subtitle
- Distinct Pharmacodynamic Complement Biomarker Signatures Define Iptacopan and Pegcetacoplan Treatment in C3 Glomerulopathy
- Creators
- Yuzhou Zhang - University of IowaHéctor Martín Merinero - University of IowaAnna R. Carmen - University of IowaKameron Kruger - University of IowaRenee X. Good - University of IowaDingwu Shao - University of IowaSarah M. Roberts - University of IowaAngela F.M. Nelson - University of IowaNicole C. Meyer Horning - University of IowaSydney S. Jellison - University of IowaDidier Mandelbrot - University of Wisconsin–MadisonNeetika Garg - University of Wisconsin–MadisonCarla M. Nester - University of IowaRichard J.H. Smith - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Kidney international reports, Vol.11(12), 107087
- DOI
- 10.1016/j.ekir.2026.107087
- ISSN
- 2468-0249
- eISSN
- 2468-0249
- Publisher
- Elsevier Inc
- Language
- English
- Electronic publication date
- 09/18/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9985236435302771
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