Distinct Pharmacodynamic Complement Biomarker Signatures Define Iptacopan and Pegcetacoplan Treatment in C3 Glomerulopathy.
- 1Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
- 2Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Abstract
Introduction
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.Methods
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 posttreatment 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.Results
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 3 iptacopan-treated patients, all nephritic factor-positive, and 2 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 posttransplant sample during subsequent iptacopan treatment.Conclusion
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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BibTeX
@article{zhang2026distinct,
title = {{Distinct Pharmacodynamic Complement Biomarker Signatures Define Iptacopan and Pegcetacoplan Treatment in C3 Glomerulopathy.}},
author = {Yuzhou Zhang and Héctor Martín Merinero and Anna R Carmen and Kameron Kruger and Renee X Goodfellow and Dingwu Shao and Sarah M Roberts and Angela F M Nelson and Nicole C Meyer Horning and Sydney S Jellison and Didier Mandelbrot and Neetika Garg and Carla M Nester and Richard J H Smith},
journal = {Kidney international reports},
year = {2026},
month = sep,
doi = {10.1016/j.ekir.2026.107087},
url = {https://europepmc.org/article/MED/42898424},
note = {CC BY},
}
RIS
TY - JOUR
TI - Distinct Pharmacodynamic Complement Biomarker Signatures Define Iptacopan and Pegcetacoplan Treatment in C3 Glomerulopathy.
AU - Yuzhou Zhang
AU - Héctor Martín Merinero
AU - Anna R Carmen
AU - Kameron Kruger
AU - Renee X Goodfellow
AU - Dingwu Shao
AU - Sarah M Roberts
AU - Angela F M Nelson
AU - Nicole C Meyer Horning
AU - Sydney S Jellison
AU - Didier Mandelbrot
AU - Neetika Garg
AU - Carla M Nester
AU - Richard J H Smith
PY - 2026
DA - 2026/09/18
JO - Kidney international reports
DO - 10.1016/j.ekir.2026.107087
UR - https://europepmc.org/article/MED/42898424
AB - Introduction 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.Methods 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 posttreatment 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.Results 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 3 iptacopan-treated patients, all nephritic factor-positive, and 2 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 posttransplant sample during subsequent iptacopan treatment.Conclusion 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.
SN - 2468-0249
ER -