C3-mediated pathways are broadly involved in a wide spectrum of pathogenic processes that exacerbate COVID-19 pathology ( 1, 6, 7). SARS-CoV-2 can trigger all three pathways of complement activation, which converge at the proteolytic cleavage of the central complement protein C3 ( 5). Innate immune pathways are excessively activated during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including neutrophil activation and the key defensive systems of complement and coagulation ( 1– 4). Severe coronavirus disease 2019 (COVID-19) is a systemic, multiorgan, hyperinflammatory disorder that is characterized by high in-hospital mortality. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug’s inhibitory activity. Complete and sustained C3 inhibition was observed in all responders. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101–treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Patients received AMY-101 ( n = 16) or placebo ( n = 15) in addition to standard of care. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Lambris +32 authors +30 authors +25 authors fewer Authors Info & AffiliationsĬomplement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. Risitano, Despina Yancopoulou, Konstantinos Ritis, and John D. Sander Connolly, Simona Iacobelli, Vasileios Papadopoulos, Rodrigo T. Dalekos, Loek Willems, Barbro Persson, Vivek Anand Manivel, Bo Nilsson, E. Gatselis, Charalampos Papagoras, Simeon Metallidis, Haralampos Milionis, George N. Mastellos, Christina Antoniadou, , Efstratios Gavriilidis, Georgios Kalopitas, Anna Samakidou, Angelos Liontos, Akrivi Chrysanthopoulou, , Maria Ntinopoulou, Dionysios Kogias, Ioanna Karanika, Andreas Smyrlis, Dainora Cepaityte, Iliana Fotiadou, Nikoleta Zioga, Ioannis Mitroulis, Nikolaos K. Panagiotis Skendros, Georgios Germanidis, , Dimitrios C.
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