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

To improve COVID-19 therapy, it is essential to understand the mechanisms driving critical illness. The complement system is an essential part of innate host defense that can also contribute to injury. All complement pathways have been implicated in COVID-19 pathogenesis, however the upstream drivers and downstream consequences on tissue injury remain ill-defined. Here, we demonstrate that complement activation is mediated by the alternative pathway and we provide a comprehensive atlas of the alterations in complement around the time of respiratory deterioration. Proteome and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal and myeloid cells in the production of complement, in addition to liver-derived factors. Upstream, IL-6 drives complement responses, linking complement dysregulation to approved COVID-19 therapies. In an exploratory proteomic study, C5 inhibition improves epithelial damage and markers of disease severity. Collectively, these results identify complement dysregulation as a key druggable feature of COVID-19.

Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with Covid-19: an open-label randomized controlled trial (preprint)

Background: The efficacy and safety of complement inhibition in Covid-19 patients is unclear.Methods: A multicenter randomized controlled, open-label trial. Hospitalized Covid-19 patients with signs of hyperinflammation and hypoxemia (PaO2/FiO2 below 350 mHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15.Results: 81 patients were randomly assigned to zilucoplan (n=55) or the control group (n=26). 78 patients were included in the safety and primary analysis. Most  were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56·4 mmHg in the zilucoplan group and 20·6 mmHg in the control group (mean difference +35.8; 95% confidence interval (CI) -9.4 to 80.9; p=0.12), an effect also observed  at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0·4; 95% CI 0·1 to 1·5) At long-term follow up, the distance walked in a 6 min test was 539·7 m in zilucoplan and 490·6 m in the control group (p=0·18). Zilucoplan lowered serum C5b-9 (p<0·001) and interleukin-8 (p=0·03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified.Conclusion: Administration of zilucoplan to Covid-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function and clinical outcome suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.(Funded by UCB and Ghent University Special Research Fund for COVID-19 Research; ClinicalTrials.gov, NCT04382755 – May 11, 2020; EudraCT, 2020-002130-33 – May 6, 2020)

Early treatment with inhaled GM-CSF improves oxygenation and anti-viral immunity in COVID-19 induced lung injury – a randomized clinical trial (preprint)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) instructs monocytes to differentiate into alveolar macrophages (AM) that preserve lung homeostasis. By comparing AM development in mouse and human, we discovered that COVID-19 patients showed marked defects in GM-CSF-dependent AM instruction. The multi-center, open-label, randomized, controlled SARPAC-trial evaluated the efficacy and safety of 5 days of inhalation of rhu-GM-CSF (sargramostim, Leukine®) in 81 non-ventilated patients with COVID-19 and hypoxemic respiratory failure identified by PaO2/FiO2 ratio < 350mmHg. At day 6, more patients in the sargramostim group experienced at least 25% improvement in oxygenation compared with the standard of care group. Higher numbers of circulating class-switched B cells and effector virus-specific CD8 lymphocytes were found in the sargramostim group. Treatment adverse events, including signs of cytokine storm, were not different between active and control group. This proof-of-concept study demonstrates the feasibility and safety of inhaled GM-CSF in restoring alveolar gas exchange, while simultaneously boosting anti-COVID-19 immunity. ClinicalTrials.gov (NCT04326920).