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
Authors: 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 ,   the Amsterdam UMC COVID-19 Biobank Investigators, van Agtmael Michiel , Algera Anne Geke , Appelman Brent , van Baarle Floor , Beudel Martijn , Bogaard Harm Jan , Bomers Marije , Bonta Peter , Bos Lieuwe D. J. , 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 , Piña-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 
Published: December 2022

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.