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Clinical Trial
. 2024 Aug;30(8):2328-2336.
doi: 10.1038/s41591-024-03043-1. Epub 2024 May 25.

IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial

Glenn M Chertow  1 , Anna Marie Chang  2 , G Michael Felker  3 , Mark Heise  2 , Elena Velkoska  4 , Bengt Fellström  5 , David M Charytan  6 , Regina Clementi  2 , C Michael Gibson  7 , Shaun G Goodman  8 , Meg Jardine  9 , Adeera Levin  10 , Yuliya Lokhnygina  3 , Jenny Mears  2 , Roxana Mehran  11 , Peter Stenvinkel  12 , Angela Yee-Moon Wang  13 , David C Wheeler  14 , Carmine Zoccali  15 , Paul M Ridker  7 , Kenneth W Mahaffey  16 , Pierluigi Tricoci  2 , Myles Wolf  3
Affiliations
Clinical Trial

IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial

Glenn M Chertow et al. Nat Med. 2024 Aug.

Erratum in

Abstract

Inflammation mediated by interleukin-6 (IL-6) is strongly associated with cardiovascular risk. Here we evaluated clazakizumab, a monoclonal antibody targeting the IL-6 ligand, in a phase 2b dose-finding study. Adults with cardiovascular disease and/or diabetes receiving maintenance dialysis with high-sensitivity C-reactive protein (hs-CRP) ≥ 2 mg l-1 at baseline were randomized to receive clazakizumab (2.5 mg, 5 mg or 10 mg, n = 32 per dose group) or placebo (n = 31) every 4 weeks. The primary endpoint was the change from baseline in hs-CRP to week 12, expressed as the geometric mean ratio. Clazakizumab treatment signficantly reduced serum hs-CRP concentrations at week 12 by 86%, 90% and 92% relative to placebo in patients randomized to 2.5 mg, 5 mg or 10 mg clazakizumab, respectively (all P < 0.0001), meeting the primary outcome. With regard to secondary endpoints, clazakizumab treatment reduced serum fibrinogen, amyloid A, secretory phospholipase A2, and lipoprotein(a) concentrations, as well as increased mean serum albumin concentrations at 12 weeks, relative to placebo. The proportion of patients who achieved hs-CRP < 2.0 mg l-1 was 79%, 82% and 79% in the 2.5 mg, 5 mg and 10 mg clazakizumab groups, respectively, compared with 0% of placebo-treated patients. With regard to safety, no cases of sustained grade 3 or 4 thrombocytopenia or neutropenia were observed. Serious infections were seen with similar frequency in the placebo, clazakizumab 2.5 mg and clazakizumab 5 mg groups, but were numerically more frequent in the clazakizumab 10 mg group. The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events. ClinicalTrials.gov registration: NCT05485961 .

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Conflict of interest statement

G.M.C. has served on the Board of Directors of Satellite Healthcare, a nonprofit dialysis provider. His institution (Stanford University) has received a grant from the trial sponsor, CSL Behring. G.M.C. has served as Chair or Cochair of Trial Steering Committees with Akebia, AstraZeneca, CSL Behring, Sanifit and Vertex. He has served as an Advisor to Alexion, Applaud, Ardelyx, CalciMedica, Calico, CloudCath, Durect, Eliaz Therapeutics, Miromatrix, Outset, Renibus and Unicycive. He has served as Chair or Member of Data Safety Monitoring Boards for clinical trials sponsored by Bayer, Mineralys and ReCor. A.M.C., M.H., R.C., J.M. and P.T. are employees of and hold stock in CSL Behring. E.V. is an employee of CSL Limited. G.M.F. received research grants from NIH, Bayer, BMS, Novartis, Daxor, Merck, Cytokinetics and CSL Behring. He has acted as a consultant to Novartis, BMS, Cytokinetics, Innolife, Boehringer Ingelheim, Abbott, Sanofi, Regeneron, Myovant, Sequana, Windtree Therapeutics and Whiteswell, and has served on clinical endpoint committees/data safety monitoring boards for Merck, Medtronic, EBR Systems, Rocket Pharma, V-Wave and LivaNova. B.F. has served in from CSL Behring. D.M.C. reports consultancy with Eli Lilly/Boehringer Ingelheim, AstraZeneca, Allena Pharmaceuticals (DSMB), Gilead, Novo Nordisk, GSK, Medtronic, Merck, CSL Behring, Zogenix, Renalytix and LG Chemical. He has received research funding from Medtronic, Gilead; Novo Nordisk; Amgen, Boehringer Ingelheim/Eli Lilly; and has held patents or royalties with UpToDate.com for authorship/editorials on reviews. C.M.G. receives research and consulting support from CSL Behring. S.G.G. received research grant support (for example, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (for example, advisory boards) from CSL Behring, Alnylam, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CYTE Ltd., Daiichi Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Roche, Sanofi, Servier, Tolmar Pharmaceuticals and Valeo Pharma and salary support/honoraria from the Canadian Heart Failure Society, Canadian Heart Research Center and MD Primer, Canadian VIGOUR Center, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, Jewish General Hospital\CIUSSS Center-Ouest-de-l’Ile-de-Montreal, New York University Clinical Coordinating Center, PERFUSE Research Institute, Peter Munk Cardiac Center Clinical Trials and Translation Unit, Ted Rogers Heart Center and TIMI Study Group (Brigham Health). M.J. has received support from CSL Behring. A.L. has received support from CSL Behring. R.M. has received institutional research payments from Abbott, Abiomed, Affluent Medical, Alleviant Medical, Amgen, AM Pharma, Arena, AstraZeneca, AtriCure, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, CERC, Chiesi, Cleerly Health, Concept Medical, Cytosorbents, Daiichi Sankyo, Duke, Element Science, Essential Medical, Faraday, Idorsia Pharmaceuticals, Janssen, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi Cardia, PLx Pharma, Population Health Research Institute, Protembis, RecCor Medical, RenalPro, RM Global, Sanofi, Shockwave and Vivasure, Zoll. She received personal fees from Affluent Medical, Boehringer Ingelheim, Cardiovascular Research Foundation (CRF), Cordis, Daiichi Sankyo Brasil, E.R. Squibb Sons, Esperion Science/Innovative Biopharma, Europa Group/Boston Scientific, Gaffney Events, Educational Trust, Henry Ford Health Cardiology, Ionis Pharmaceuticals, Lilly and Company, MedCon International, Novartis, Novo Nordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Vectura, VoxMedia, WebMD, IQVIA, Radcliffe and TARSUS Cardiology. She received honoraria from the American Medical Association for her role as Associate Editor of JAMA Cardiology, ACC (BOT Member, SC Member CTR Program), and holds less than 1% equity in Elixir Medical, Stel. P.S. has received research support from AstraZeneca and Bayer. He has been a member of SAB for Baxter, FMC, Boehinger Mannheim, CSL, Alexion, GSK, lnvizius. D.C.W. has received honoraria/consultancy fees and/or speakers fees from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Eledon, Galderma, GSK, Gilead, Merck, Pharmacosmos, ProKidney, Tricida and Vifor. P.M.R. received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, Novo Nordisk and the NHLBI; during the past 5 years he has served as a consultant to Novartis, Flame, Agepha, Ardelyx, Arrowhead, AstraZeneca, CSL Behring, Janssen, Civi Biopharm, GSK, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer Ingelheim and RTI; Zomagen, Cytokinetics, Horizon Therapeutics and Cardio Therapeutics. He has minority shareholder equity positions in Uppton, Bitterroot Bio and Angiowave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR and the Baim Institute (Boston, MA). K.W.M. has received institutional and consulting funding from CSLB. M.W. has received research support from CSL through his institution, the Duke Clinical Research Institute, for the current study.

Figures

Fig. 1
Fig. 1. CONSORT diagram.
mITT analysis included 127 participants who all received at least one dose of the study drug or placebo. Discontinued treatment refers to treatment discontinuation before the common treatment end date. CONSORT, Consolidated Standards of Reporting Trials.
Fig. 2
Fig. 2. hs-CRP concentrations in the placebo and clazakizumab groups.
a, Median (25–75%) serum hs-CRP concentrations in the placebo and three clazakizumab dose groups from baseline to week 24. The number of patients at weeks 0, 12 and 24, respectively, are placebo: 30, 26 and 10; clazakizumab 2.5 mg: 31, 24 and 13; clazakizumab 5 mg: 31, 26 and 10; clazakizumab 10 mg: 31, 25 and 10. b, GMRs to baseline (95% CI) of serum hs-CRP concentrations in the placebo and three clazakizumab dose groups and at week 12 after randomization are shown (P < 0.001 for each of the clazakizumab dose groups versus placebo). Two-sided P values shown are from the MMRM analysis, using a t test, and are not adjusted for multiplicity. Number of patients are placebo (n = 26); 2.5 mg (n = 24); 5 mg (n = 26); 10 mg (n = 25). CI, confidence interval.
Fig. 3
Fig. 3. Waterfall plots of change in hs-CRP.
Waterfall plots of hs-CRP percentage changes from baseline to 12 weeks of individual participants in placebo (a) and the three clazakizumab dose groups (mITT analysis) 2.5 mg (b), 5 (c), 10 mg (d).
Fig. 4
Fig. 4. Changes in biomarkers of IL-6 activity.
Changes from baseline to 12 weeks of treatment for biomarkers of IL-6 activity (mITT analysis). GMR to baseline serum amyloid A (a), lipoprotein(a) (b), fibrinogen (c), secretory phospholipase A2 (d) and albumin (e) (95% CI). Number of patients ranged from n = 25–26 for placebo, n = 24 for 2.5 mg, n = 27–28 for 5 mg and 26–29 for 10 mg.
Extended Data Fig. 1
Extended Data Fig. 1
hs-CRP concentrations in the placebo and clazakizumab, mITT analysis.
Extended Data Fig. 2
Extended Data Fig. 2
Study design schema.
See this image and copyright information in PMC

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