Skendros Panagiotis, Germanidis Georgios, Mastellos Dimitrios C, Antoniadou Christina, Gavriilidis Efstratios, Kalopitas Georgios, Samakidou Anna, Liontos Angelos, Chrysanthopoulou Akrivi, Ntinopoulou Maria, Kogias Dionysios, Karanika Ioanna, Smyrlis Andreas, Cepaityte Dainora, Fotiadou Iliana, Zioga Nikoleta, Mitroulis Ioannis, Gatselis Nikolaos K, Papagoras Charalampos, Metallidis Simeon, Milionis Haralampos, Dalekos George N, Willems Loek, Persson Barbro, Manivel Vivek Anand, Nilsson Bo, Connolly E Sander, Iacobelli Simona, Papadopoulos Vasileios, Calado Rodrigo T, Huber-Lang Markus, Risitano Antonio M, Yancopoulou Despina, Ritis Konstantinos, Lambris John D
First Department of Internal Medicine and Laboratory of Molecular Hematology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
First Department of Internal Medicine, AHEPA University Hospital, and Basic and Translational Research Unit, Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Sci Adv. 2022 Aug 19;8(33):eabo2341. doi: 10.1126/sciadv.abo2341. Epub 2022 Aug 17.
Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 ( = 16) or placebo ( = 15) in addition to standard of care. AMY-101 was safe and well tolerated. 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. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.
补体C3激活促成了新型冠状病毒肺炎的病理过程，而靶向C3已成为一种有前景的治疗策略。我们提供了ITHACA试验的中期数据，这是首个评估C3抑制剂AMY-101用于治疗重症新型冠状病毒肺炎（动脉血氧分压/吸入氧分数值≤300 mmHg）的随机试验。除标准治疗外，患者接受了AMY-101治疗（n = 16）或安慰剂治疗（n = 15）。AMY-101安全且耐受性良好。与安慰剂组（15例中的8例，53.3%）相比，接受AMY-101治疗的患者中在第14天时无需吸氧的比例更高，尽管差异不显著（16例中的13例，81.3%）。3例无反应者和2例接受安慰剂治疗的患者死于疾病相关并发症。AMY-101显著降低了C反应蛋白和铁蛋白水平，并抑制了凝血酶和中性粒细胞胞外陷阱的生成。在所有有反应者中均观察到了完全且持续的C3抑制作用。3例无反应者体内残余的C3活性表明存在一种不依赖转化酶的C3激活途径，该途径优先于药物的抑制活性。这些发现支持开展更大规模试验，以探索基于C3抑制在新型冠状病毒肺炎或其他补体介导疾病中的潜力。
