Pharmacodynamic, Prognostic, and Predictive Biomarkers in Severe and Critical COVID-19 Patients Treated with Sirukumab

Overview

Journal Sci Rep

Specialty Science

Date 2024 Oct 3

PMID 39362933

Authors

Kim Thys

Matthew J Loza

Linghua Lynn

Katleen Callewaert

Lisa Varma

Marjolein Crabbe

Liesbeth Van Wesenbeeck

Erika Van Landuyt

Sandra De Meyer

Jeroen Aerssens

Inge Verbrugge

Affiliations

Soon will be listed here.

Abstract

We examined candidate biomarkers for efficacy outcomes in hospitalized COVID-19 patients who were treated with sirukumab, an IL-6 neutralizing antibody, in a randomized, double-blind, placebo-controlled, phase 2 trial. Between May 2020 and March 2021, 209 patients were randomized (sirukumab, n = 139; placebo, n = 70); 112 had critical COVID-19. Serum biomarkers were evaluated for the pharmacodynamic effect of sirukumab and for their potential prognostic and predictive effect on time to sustained clinical improvement up to Day 28, clinical improvement at Day 28, and mortality at Day 28. The absence of detectable IL-4 increase and smaller increases in CCL13 post-baseline were most significantly associated with better response to sirukumab (versus placebo) treatment for all clinical efficacy outcomes tested, especially in patients with critical COVID-19. These data suggest that patients with critical COVID-19 without detectable sirukumab-induced IL-4 levels are more likely to benefit from sirukumab treatment. ClinicalTrials.gov Identifier: NCT04380961.

References

Murray L, Argentieri R, Farrell F, Bracht M, Sheng H, Whitaker B . Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2. Int J Biochem Cell Biol. 2008; 40(10):2174-82. DOI: 10.1016/j.biocel.2008.02.016. View

Ponthieux F, Dauby N, Maillart E, Fils J, Smet J, Claus M . Tocilizumab-Induced Unexpected Increase of Several Inflammatory Cytokines in Critically Ill COVID-19 Patients: The Anti-Inflammatory Side of IL-6. Viral Immunol. 2022; 35(1):60-70. DOI: 10.1089/vim.2021.0111. View

Varga J, Abraham D . Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007; 117(3):557-67. PMC: 1804347. DOI: 10.1172/JCI31139. View

Carpenter K, Hogaboam C . Immunosuppressive effects of CCL17 on pulmonary antifungal responses during pulmonary invasive aspergillosis. Infect Immun. 2005; 73(11):7198-207. PMC: 1273903. DOI: 10.1128/IAI.73.11.7198-7207.2005. View

Schrijver B, Assmann J, van Gammeren A, Vermeulen R, Portengen L, Heukels P . Extensive longitudinal immune profiling reveals sustained innate immune activation in COVID-19 patients with unfavorable outcome. Eur Cytokine Netw. 2021; 31(4):154-167. PMC: 7937051. DOI: 10.1684/ecn.2020.0456. View

Gottlieb R, Clement M, Cook P, Deveikis A, Foong K, Robinson P . The IL-6 hypothesis in COVID-19: A phase 2, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of free IL-6 sequestration by the monoclonal antibody sirukumab in severe and critical COVID-19. J Infect. 2024; 89(4):106241. DOI: 10.1016/j.jinf.2024.106241. View

Ling L, Chen Z, Lui G, Wong C, Wong W, Ng R . Longitudinal Cytokine Profile in Patients With Mild to Critical COVID-19. Front Immunol. 2021; 12:763292. PMC: 8685399. DOI: 10.3389/fimmu.2021.763292. View

Leisman D, Ronner L, Pinotti R, Taylor M, Sinha P, Calfee C . Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med. 2020; 8(12):1233-1244. PMC: 7567529. DOI: 10.1016/S2213-2600(20)30404-5. View

Coperchini F, Chiovato L, Ricci G, Croce L, Magri F, Rotondi M . The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved. Cytokine Growth Factor Rev. 2021; 58:82-91. PMC: 7837329. DOI: 10.1016/j.cytogfr.2020.12.005. View

10.

Del Valle D, Kim-Schulze S, Huang H, Beckmann N, Nirenberg S, Wang B . An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020; 26(10):1636-1643. PMC: 7869028. DOI: 10.1038/s41591-020-1051-9. View

11.

Gharaee-Kermani M, McCullumsmith R, Charo I, Kunkel S, Phan S . CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis. Cytokine. 2003; 24(6):266-76. DOI: 10.1016/j.cyto.2003.08.003. View

12.

Belperio J, Dy M, Murray L, Burdick M, Xue Y, Strieter R . The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis. J Immunol. 2004; 173(7):4692-8. DOI: 10.4049/jimmunol.173.7.4692. View

13.

Inoue T, Fujishima S, Ikeda E, Yoshie O, Tsukamoto N, Aiso S . CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis. Eur Respir J. 2004; 24(1):49-56. DOI: 10.1183/09031936.04.00110203. View

14.

Malik P, Patel U, Mehta D, Patel N, Kelkar R, Akrmah M . Biomarkers and outcomes of COVID-19 hospitalisations: systematic review and meta-analysis. BMJ Evid Based Med. 2020; 26(3):107-108. PMC: 7493072. DOI: 10.1136/bmjebm-2020-111536. View

15.

Aletaha D, Bingham 3rd C, Tanaka Y, Agarwal P, Kurrasch R, Tak P . Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet. 2017; 389(10075):1206-1217. DOI: 10.1016/S0140-6736(17)30401-4. View

16.

Au-Yeung B, Fowell D . A key role for Itk in both IFN gamma and IL-4 production by NKT cells. J Immunol. 2007; 179(1):111-9. DOI: 10.4049/jimmunol.179.1.111. View

17.

Tom J, Bao M, Tsai L, Qamra A, Summers D, Carrasco-Triguero M . Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial. Crit Care Med. 2021; 50(3):398-409. PMC: 8855771. DOI: 10.1097/CCM.0000000000005229. View

18.

Giamarellos-Bourboulis E, Netea M, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N . Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020; 27(6):992-1000.e3. PMC: 7172841. DOI: 10.1016/j.chom.2020.04.009. View

19.

Shankar-Hari M, Vale C, Godolphin P, Fisher D, Higgins J, Spiga F . Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA. 2021; 326(6):499-518. PMC: 8261689. DOI: 10.1001/jama.2021.11330. View

20.

Zhao Y, Qin L, Zhang P, Li K, Liang L, Sun J . Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. JCI Insight. 2020; 5(13). PMC: 7406242. DOI: 10.1172/jci.insight.139834. View