Complement biomarkers during iptacopan treatment - Authors' reply.

# Complement biomarkers during iptacopan treatment – Authors' reply *The Lancet 2026* Correspondence Since C3 glomerulopathy is 2 West EE, Woodruff T, Fremeaux-Bacchi V, confirming sustained systemic and diagnosed exclusively by kidney biopsy Kemper C. Complement in human disease: intra-renal complement inhibition.1 approved and up-and-coming therapeutics. with immunofluorescence showing Lancet 2024; 403: 392–405. Histological assessments further dominant C3 deposition,3 and given 3 Servais A, Noël L-H, Roumenina LT, et al. support these observations. Iptacopan Acquired and genetic complement that serum C3 can be normal,3 we significantly reduced mesangial and abnormalities play a critical role in dense argue that the kidney is the crucial deposit disease and other C3 capillary C3 deposition (adjusted site for complement-targeted glomerulopathies. Kidney Int 2012; mean difference –1·875, p=0·0053) 82: 454–64. therapy. The minimal reduction in and improved disease activity scores, 4 Fakhouri F, Bomback AS, Ariceta G, et al. Trial glomerular C3 deposits might reflect of pegcetacoplan in C3 glomerulopathy and with notable effects on endocapillary immune-complex MPGN. N Engl J Med 2025; underdosing or limited intrarenal proliferation and leukocyte infiltration, 393: 2210–20. activity of iptacopan, especially since 5 Renner B, Poppelaars F, Laskowski J, et al. indicating reduced complement- other complement inhibitors have Noninvasive detection of iC3b/C3d deposits in driven inflammation.1 Comparable the kidney using a novel bioluminescent achieved more profound reductions disease activity scores were reported imaging probe. J Am Soc Nephrol 2023; in similar timeframes.4 This finding 34: 1151–54. with pegcetacoplan in the VALIANT raises the possibility that more study.1,4 complete clearance of glomerular C3 Authors’ reply The APPEAR-C3G trial used a deposits could yield greater clinical We appreciate the thoughtful rigorous 12-point histological scoring benefit. We therefore advocate for commentary on our Article by Felix system with masked central review. greater integration of tissue-based Poppelaars and colleagues, and their Differences in scoring system, staining complement biomarkers, whether emphasis on complement biomarker techniques, epitope recognition, histological or imaging-based,5 to interpretation in C3 glomerulopathy. and review methodologies between improve disease monitoring, guide Here, we would like to clarify several the APPEAR-C3G and VALIANT dosing, and enhance the efficacy of points and provide context from the trials might explain the observed anti-complement therapies. APPEAR-C3G trial.1 variability. Notwithstanding, In APPEAR-C3G, iptacopan led iptacopan significantly decreased FP received a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to rapid and sustained changes in the concentration of pathological (1K99DK138301-01A1); consulting fees from complement biomarkers: serum-C3 C3 fragments and improved Alnylam Pharmaceuticals and Invizius; support for nearly doubled, plasma and urinary inflammatory indices, supporting its attending meetings from Novartis; has patents planned focused on molecular imaging of tissue- soluble C5b-9 (sC5b-9; creatinine- mechanistic role.1 based complement markers in vivo; is a Board normalised) were markedly reduced, In the APPEAR-C3G trial, the Member of the European Complement Network; accompanied by clinically meaningful observed steady-state iptacopan and currently owns, or has previously owned, stock in Annexon Biosciences, Apellis Pharmaceuticals, reductions in proteinuria.1 Baseline trough concentrations achieved ChemoCentryx, InflaRx NV, Iveric Bio, Omeros C3-deposit score and serum-C3 levels with 200 mg twice daily (bid) were Corporation, and Rallybio Corporation. did not predict proteinuria response. consistent with the results from early VMH and JMT received consulting fees from Q32 However, changes in urine protein– phase studies and pharmacokinetic– Bio; hold stocks in Q32 Bio; hold a patent on the use creatinine ratio closely tracked early pharmacodynamic modelling, which of the monoclonal antibody to C3d (mAb 3d29) for imaging and associated methods for detecting increases in serum-C3 by day 14 and showed that iptacopan 200 mg infectious and inflammatory cells in vivo mirrored urinary sC5b-9 reductions, bid regimen resulted in more than (US20170290930A1); and have patents planned supporting a dynamic relationship 90% inhibition of alternative focused on molecular imaging of tissue-based complement markers in vivo. between complement control and pathway biomarkers across multiple proteinuria response. populations including patients with During the preparation of this work, the authors used ChatGPT for correcting spelling and grammar. While the kidney is a key site of C3 glomerulopathy.5 The consistency After using ChatGPT, the authors reviewed and complement-mediated injury in in exposure–response relationship edited the content as needed and take full C3 glomerulopathy, fluid-phase between early-phase studies and the responsibility for the content of the publication. complement activation also APPEAR-C3G trial underscores the *Felix Poppelaars, V Michael Holers, contributes to disease pathogenesis.2 efficacy of this regimen in effectively Joshua M Thurman Because sC5b-9 (>1000 KDa) is unlikely inhibiting the alternative pathway. felix.poppelaars@cuanschutz.edu to traverse the glomerular filtration Together, iptacopan’s ability to School of Medicine, Anschutz Medical Campus, barrier, its urinary presence reflects improve systemic complement Aurora, CO 80045, USA (FP, VMH, JMT) intra-renal terminal complement marker levels and reduce intra-renal 1 Kavanagh D, Bomback AS, Vivarelli M, et al. activity.3 Importantly, urinary sC5b-9 complement activation translated into Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, decreased by more than 80% by sustained proteinuria reduction and parallel group, multicentre, placebo- day 180 and remained suppressed for stabilisation of estimated glomerular controlled, phase 3 study. Lancet 2025; 406: 1587–98. 12 months of iptacopan treatment, filtration rate. The clinical utility of Correspondence biomarker changes remains an area 2 Smith RJH, Appel GB, Blom AM, et al. C3 of active investigation, and these glomerulopathy – understanding a rare complement-driven renal disease. markers could eventually help monitor Nat Rev Nephrol 2019; 15: 129–43. and guide therapy for all complement- 3 Ogrodowski JL, Hebert LA, Sedmak D, targeted treatments. Cosio FG, Tamerius J, Kolb W. Measurement of SC5b-9 in urine in patients with the nephrotic DK is scientific founder of and holds stock in syndrome. Kidney Int 1991; 40: 1141–47. Gyroscope Therapeutics; received consultancy fees 4 Bomback AS, Daina E, Remuzzi G, et al. Efficacy from Achillion, Alexion, AstraZeneca, Catalyst, and safety of pegcetacoplan in kidney Chemocentryx, Novartis, Roche, and Silence transplant recipients with recurrent Therapeutics; received grants or contracts from complement 3 glomerulopathy or primary immune complex membranoproliferative Gyroscope Therapeutics, Kidney Research UK, glomerulonephritis. Kidney Int Rep 2024; Macular Society, Medical Research Council, and the 10: 87–98. Wellcome Trust; and his spouse works for GSK. ASB 5 Wong E, Nester C, Cavero T, et al. Efficacy and received consulting fees from Achillion, Alexion, safety of iptacopan in patients with C3 Amgen, Apellis, Catalyst, GSK, Novartis, Otsuka, and glomerulopathy. Kidney Int Rep 2023; Silence Therapeutics. MV received honoraria for 8: 2754–64. advisory boards and consulting fees from Alexion, Apellis, Bayer, Chinook Therapeutics, Novartis, PureSpring, Roche, Retrophin/Travere, Santhera, and SOBI; received honoraria for lectures, speaker bureaus, or educational events from Alexion, Cambridge Medical, Novartis, Roche, SOBI, and WebMD; participated in the European Union C4C (conect4children); participated in managed access programmes for Alexion, Novartis, and SOBI; and participated as Principal Investigator in clinical studies sponsored by Alexion, Apellis, Bayer, Boehringer Ingelheim, Chemocentryx, Chinook Therapeutics, Novartis, Roche, and Retrophin/Travere. CMN reports clinical trial research support from Achillion, Apellis, Biocryst Pharmaceuticals, Novartis, and Travere; consulting fees from Alexion, Apellis, Novartis, Silence Therapeutics, and Vertex; royalties from UpToDate; and participation on a data safety monitoring board for Kira. RJHS reports research funding from the National Institute for Health and Care Research; is on an advisory board for Novartis; and is the Director of Molecular Otolaryngology and Renal Research Laboratories. The APPEAR-C3G trial (NCT04817618) was funded by Novartis. Medical writing support was provided by Carol Crawford at Novartis (funded by Novartis), under the direction of the authors and in accordance with good publication practice guidelines. *David Kavanagh, Andrew S Bomback, Marina Vivarelli, Carla M Nester, Richard J H Smith david.kavanagh@newcastle.ac.uk Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK (DK); National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK (DK); David Koch Jr Glomerular Kidney Center, Columbia University Irving Medical Center, New York, NY, USA (ASB); Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy (MV); Stead Family Children’s Hospital–University of Iowa, Iowa City, IA, USA (CMN); Carver College of Medicine, University of Iowa, Iowa City, IA, USA (RJHS) 1 Kavanagh D, Bomback AS, Vivarelli M, et al. Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo- controlled, phase 3 study. Lancet 2025; 406: 1587–98. 1236 --- [PDF原文](https://sci-net.xyz/storage/7932541/204dda4d5a1ecbbcf895da107902b0f7661435ca1a30637890933a891f19eeea/Complement-biomarkers-during-iptacopan-treatment-Authors-reply.pdf) DOI: 10.1016/S0140-6736(26)00370-3