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

Abstract

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.

A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19

“…However, a Bayesian analysis indicated that participants treated with C5 inhibition had an > 89% chance of an improved oxygenation compared to untreated patients, and an > 91% chance of better survival 34 . In addition, complement inhibition lowered serum IL-8 levels 34 , a granulocyte-attracting chemokine, which was also noted in an independent cohort treated with a C5a blocking antibody 54 . Despite these observations, the scope of biological responses affected by complement blockade in COVID-19 remains unexplored.…”

“…Activation of the alternative pathway can amplify inflammation and tissue injury through multiple mechanisms. C3a and C5a promote key features of COVID-19, including myeloid cell recruitment and activation 42 , cytokine production 7 , T cell cytotoxicity 25, 26 , neutrophil extracellular trap formation and coagulopathy 13, 54 . Moreover, complement-driven myeloid migration into the alveolar space might induce a feed forward loop via myeloid derived IL-8, a chemokine which decreases upon inhibition of both C5 34 and C5a 54 .…”

“…C3a and C5a promote key features of COVID-19, including myeloid cell recruitment and activation 42 , cytokine production 7 , T cell cytotoxicity 25, 26 , neutrophil extracellular trap formation and coagulopathy 13, 54 . Moreover, complement-driven myeloid migration into the alveolar space might induce a feed forward loop via myeloid derived IL-8, a chemokine which decreases upon inhibition of both C5 34 and C5a 54 . Surprisingly, C5a might signal to ciliated cells and hepatocytes as well, which express C5AR1.…”

A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

“…However, a Bayesian analysis indicated that participants treated with C5 inhibition had an >89% chance of an improved oxygenation compared with untreated patients and an >91% chance of better survival ( 35 ). In addition, complement inhibition lowered serum IL-8 ( 35 ), a granulocyte-attracting chemokine, which was also noted in an independent cohort treated with a C5a blocking antibody ( 60 ). Despite these observations, the scope of biological responses affected by complement blockade in COVID-19 remains unexplored.…”

Missense Variants of von Willebrand Factor in the Background of COVID-19 Associated Coagulopathy

“…CAC is derived from an inflammation-related imbalance of elevated plasma vWF levels and decreased ADAMTS13 activities, presumably mediated by inflammatory cytokines and complement factors. Importantly, clarification of the pathogenesis incited clinical trials with targeted therapeutic modalities, including administration of caplacizumab, an anti-vWF monoclonal antibody [ 44 ], activated complement C5a inhibitors [ 45 ], recombinant ADAMTS13 [ 46 ], and IL1 és IL6 antibodies [ 47 ].…”