학술논문
Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial
Document Type
Report
Author
Lim, Endry H. T.; Vlaar, Alexander P. J.; Bos, Lieuwe D. J.; van Vught, Lonneke A.; Boer, Anita M. Tuip-de; Dujardin, Romein W. G.; Habel, Maria; Xu, Zhongli; Brouwer, Matthijs C.; van de Beek, Diederik; de Bruin, Sanne; van Agtmael, Michiel; Algera, Anne Geke; Appelman, Brent; van Baarle, Floor; Beudel, Martijn; Bogaard, Harm Jan; Bomers, Marije; Bonta, Peter; Botta, Michela; de Brabander, Justin; Bree, Godelieve; Bugiani, Marianna; Bulle, Esther; Chouchane, Osoul; Cloherty, Alex; Buis, David T. P.; de Rotte, Maurits C. F. J.; Dijkstra, Mirjam; Dongelmans, Dave A.; Elbers, Paul; Fleuren, Lucas; Geerlings, Suzanne; Geijtenbeek, Theo; Girbes, Armand; Goorhuis, Bram; Grobusch, Martin P.; Hagens, Laura; Hamann, Jorg; Harris, Vanessa; Hemke, Robert; Hermans, Sabine M.; Heunks, Leo; Hollmann, Markus; Horn, Janneke; Hovius, Joppe W.; de Jong, Menno D.; Koning, Rutger; van Mourik, Niels; Nellen, Jeannine; Nossent, Esther J.; Paulus, Frederique; Peters, Edgar; Piéa-Fuentes, Dan A. I.; van der Poll, Tom; Preckel, Bennedikt; Prins, Jan M.; Raasveld, Jorinde; Reijnders, Tom; Schinkel, Michiel; Schrauwen, Femke A. P.; Schultz, Marcus J.; Schuurman, Alex; Schuurmans, Jaap; Sigaloff, Kim; Slim, Marleen A.; Smeele, Patrick; Smit, Marry; Stijnis, Cornelis S.; Stilma, Willemke; Teunissen, Charlotte; Thoral, Patrick; Tsonas, Anissa M.; Tuinman, Pieter R.; van der Valk, Marc; Veelo, Denise; Volleman, Carolien; de Vries, Heder; van Vugt, Michèle; Wouters, Dorien; Zwinderman, Aeilko H.; Wiersinga, W. Joost
Source
Respiratory Research. December 24, 2022, Vol. 23 Issue 1
Subject
Language
English
ISSN
1465-9921
Abstract
Author(s): Endry H. T. Lim[sup.1,2,3,4,7] , Alexander P. J. Vlaar[sup.1,2] , Lieuwe D. J. Bos[sup.1,2] , Lonneke A. van Vught[sup.1,5] , Anita M. Tuip-de Boer[sup.1,2] , Romein W. G. Dujardin[sup.1,2] [...]
We recently reported in the phase 3 PANAMO trial that selectively blocking complement 5a (C5a) with vilobelimab led to improved survival in critically ill COVID-19 patients. C5a is an important contributor to the innate immune system and can also activate the coagulation system. High C5a levels have been reported in severely ill COVID-19 patients and correlate with disease severity and mortality. Previously, we assessed the potential benefit and safety of vilobelimab in severe COVID-19 patients. In the current substudy of the phase 2 PANAMO trial, we aim to explore the effects of vilobelimab on various biomarkers of inflammation and coagulation. Between March 31 and April 24, 2020, 17 patients with severe COVID-19 pneumonia were enrolled in an exploratory, open-label, randomised phase 2 trial. Blood markers of complement, endothelial activation, epithelial barrier disruption, inflammation, neutrophil activation, neutrophil extracellular trap (NET) formation and coagulopathy were measured using enzyme-linked immunosorbent assay (ELISA) or utilizing the Luminex platform. During the first 15 days after inclusion, change in biomarker concentrations between the two groups were modelled with linear mixed-effects models with spatial splines and compared. Eight patients were randomized to vilobelimab treatment plus best supportive care (BSC) and nine patients were randomized to BSC only. A significant decrease over time was seen in the vilobelimab plus BSC group for C5a compared to the BSC only group (p < 0.001). ADAMTS13 levels decreased over time in the BSC only group compared to the vilobelimab plus BSC group (p < 0.01) and interleukin-8 (IL-8) levels were statistically more suppressed in the vilobelimab plus BSC group compared to the BSC group (p = 0.03). Our preliminary results show that C5a inhibition decreases the inflammatory response and hypercoagulability, which likely explains the beneficial effect of vilobelimab in severe COVID-19 patients. Validation of these results in a larger sample size is warranted. Keywords: SARS-CoV-2, COVID-19, Complement, Complement inhibition, Vilobelimab, C5a
We recently reported in the phase 3 PANAMO trial that selectively blocking complement 5a (C5a) with vilobelimab led to improved survival in critically ill COVID-19 patients. C5a is an important contributor to the innate immune system and can also activate the coagulation system. High C5a levels have been reported in severely ill COVID-19 patients and correlate with disease severity and mortality. Previously, we assessed the potential benefit and safety of vilobelimab in severe COVID-19 patients. In the current substudy of the phase 2 PANAMO trial, we aim to explore the effects of vilobelimab on various biomarkers of inflammation and coagulation. Between March 31 and April 24, 2020, 17 patients with severe COVID-19 pneumonia were enrolled in an exploratory, open-label, randomised phase 2 trial. Blood markers of complement, endothelial activation, epithelial barrier disruption, inflammation, neutrophil activation, neutrophil extracellular trap (NET) formation and coagulopathy were measured using enzyme-linked immunosorbent assay (ELISA) or utilizing the Luminex platform. During the first 15 days after inclusion, change in biomarker concentrations between the two groups were modelled with linear mixed-effects models with spatial splines and compared. Eight patients were randomized to vilobelimab treatment plus best supportive care (BSC) and nine patients were randomized to BSC only. A significant decrease over time was seen in the vilobelimab plus BSC group for C5a compared to the BSC only group (p < 0.001). ADAMTS13 levels decreased over time in the BSC only group compared to the vilobelimab plus BSC group (p < 0.01) and interleukin-8 (IL-8) levels were statistically more suppressed in the vilobelimab plus BSC group compared to the BSC group (p = 0.03). Our preliminary results show that C5a inhibition decreases the inflammatory response and hypercoagulability, which likely explains the beneficial effect of vilobelimab in severe COVID-19 patients. Validation of these results in a larger sample size is warranted. Keywords: SARS-CoV-2, COVID-19, Complement, Complement inhibition, Vilobelimab, C5a