Complement biomarkers during iptacopan treatment.

# Complement biomarkers during iptacopan treatment *The Lancet 2026* Correspondence 7 Reddel HK, O’Byrne PM, FitzGerald JM, et al. aged 12–15 years compared with those 2 Beasley R, Holliday M, Reddel HK, et al, and the Efficacy and safety of as-needed budesonide- aged 5–11 years, should be interpreted Novel START Study Team. Controlled trial of formoterol in adolescents with mild asthma. budesonide–formoterol as needed for mild J Allergy Clin Immunol Pract 2021; 9: 3069–77. with appropriate caution as repeated asthma. N Engl J Med 2019; 380: 2020–30. statistical testing could inflate type 3 O’Byrne PM, FitzGerald JM, Bateman ED, et al. Authors’ reply I error. Furthermore, this significant Inhaled combined budesonide–formoterol as needed in mild asthma. N Engl J Med 2018; We thank Stéphanie Lejeune and interaction does not imply an absence 378: 1865–76. colleagues for their insightful of benefit in the younger group; rather, 4 Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue comments on the Article1 reporting that the treatment effect between treatment for children with mild persistent the CARE study, and welcome the them differs by more than would be asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet 2011; opportunity to clarify the points raised. expected by chance alone. 377: 650–57. Maintenance low-dose inhaled The Symbicort Rapihaler 5 Pavord ID, Beasley R, Agusti A, et al. After corticosteroid plus as-needed (AstraZeneca, Cambridge, UK; asthma: redefining airways diseases. Lancet 2018; 391: 350–400. salbutamol is proposed as a more budesonide 50 μg–formoterol 3 μg) appropriate control than as-needed is no longer commercially available. salbutamol, given the not-so-mild This inaccessibility does not reduce the Complement status of the trial population. Although strength of the evidence of the efficacy we acknowledge that many of the and safety of budesonide–formoterol biomarkers during CARE study participants would have reliever therapy in childhood asthma, iptacopan treatment qualified for inhaled corticosteroid although it does mean that alternative treatment according to current pressurised metred-dose inhalers or dry asthma guidelines, this did not powder inhalers would need to be used We read with interest the Article1 happen in clinical practice; none of in current clinical practice. by David Kavanagh and colleagues the participants had used medication Several randomised controlled trials showing that the complement containing inhaled corticosteroid for of budesonide–formoterol reliever- factor B inhibitor iptacopan at least 6 months before enrolment. based regimens in children are significantly reduces proteinuria in Treatment was not de-escalated for the underway and will provide additional patients with C3 glomerulopathy.1 purposes of the study and participants evidence for anti-inflammatory With its approval, the reach of in the control group continued their reliever therapy across the spectrum of complement inhibitors continues to See Online for appendix pre-study salbutamol monotherapy. asthma severity (appendix). expand, underscoring their emerging The results of our trial are therefore role in diseases previously considered RB has received personal fees from AstraZeneca, generalisable to clinical practice Avillion, and Teva, and institutional research not complement-mediated or and to this at-risk population. They funding from AstraZeneca (including the ongoing untreatable.2 While the authors START CARE study), Teva, Health Research Council also reflect the wider issues of non- commendably included complement of New Zealand, CureKidz NZ, and the Barbara prescribing of (or poor adherence to) Basham Medical Charitable Trust (managed by biomarkers and repeat biopsies, they inhaled corticosteroid medication and Perpetual Guardian). All other authors declare no failed to comprehensively examine competing interests. of defining asthma as mild based on their value for monitoring and guiding current medication use. We also note *Lee Hatter, Karen Oldfield, therapy. that our eligibility criteria were broadly Mark Weatherall, Andrew Bush, In patients treated with iptacopan, consistent with those of similar clinical Richard Beasley plasma soluble C5b-9 levels fell by trials in both children and adults.2–4 lee.hatter@mrinz.ac.nz two-thirds and serum C3 nearly Preventing severe asthma attacks is a Medical Research Institute of New Zealand, doubled, yet glomerular C3 deposition priority in managing asthma; however, Newtown, Wellington 6242, New Zealand decreased only slightly (–0·78 on a (LH, KO, RB); School of Biological Sciences, Victoria we also echo the sentiments of the 12-point scale).1 Whether greater University Wellington, Wellington, New Zealand Lancet Commission on asthma in that (LH, RB); Department of Medicine, Otago University biomarker changes correlated with there should be zero tolerance for any Wellington, Wellington, New Zealand (MW); Royal greater reductions in proteinuria Brompton & Harefield NHS Foundation Trust, asthma attacks.5 To this end, our primary was not reported, leaving their London, UK (AB); National Heart and Lung Institute, outcome included moderate and severe Imperial College London, London, UK (AB); clinical utility unclear. Moreover, attacks to reflect the substantial burden Te Whatu Ora Capital, Coast and Hutt Valley, the discordant responses between Wellington, New Zealand (RB); Faculty of Medicine, on patient symptoms, health-care circulating and tissue complement University of Southampton, Southampton, UK (RB) use, and missed school or work days biomarkers raise a fundamental 1 Hatter L, Holliday M, Oldfield K, et al, and the associated with these events. CARE study team. Budesonide–formoterol question: in C3 glomerulopathy, is The interaction analysis for the versus salbutamol as reliever therapy in children effective complement inhibition with mild asthma (CARE): a 52-week, open- primary outcome, which showed a required primarily in the circulation or label, multicentre, superiority, randomised greater treatment effect in children controlled trial. Lancet 2025; 406: 1473–83. (also) within the kidney? 1234 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 --- [PDF原文](https://sci-net.xyz/storage/7932541/63a330a740da79cc7e68183a23ce8a86754afe89e0a9aca301ee118748999656/Complement-biomarkers-during-iptacopan-treatment.pdf) DOI: 10.1016/S0140-6736(26)00040-1