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Complement C3 inhibition in severe COVID-19 using compstatin AMY-101
Panagiotis Skendros1, Georgios Germanidis2, Dimitrios C Mastellos3
1First Department of Internal Medicine and Laboratory of Molecular Hematology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
Insights
AMY-101, a complement C3 inhibitor, shows promise in treating severe COVID-19 by reducing inflammation and improving oxygenation. Further trials are warranted to explore its therapeutic potential.
Area of Science:
- Immunology
- Virology
- Pharmacology
Background:
- Complement C3 activation is implicated in severe COVID-19 pathogenesis.
- Targeting C3 presents a potential therapeutic avenue for COVID-19.
Purpose of the Study:
- To evaluate the safety and efficacy of AMY-101, a C3 inhibitor, in patients with severe COVID-19.
- To assess the impact of C3 inhibition on clinical outcomes and biomarkers.
Main Methods:
- Interim analysis of the ITHACA randomized trial.
- Comparison of AMY-101 (n=16) versus placebo (n=15) in severe COVID-19 patients.
- Assessment of oxygen independence, inflammatory markers (CRP, ferritin), and complement activation.
Main Results:
- AMY-101 was safe and well-tolerated.
- A higher proportion of AMY-101 patients achieved oxygen independence by day 14 (81.3% vs 53.3%).
- AMY-101 significantly reduced CRP and ferritin, and inhibited thrombin and NET generation; responders showed complete C3 inhibition.
Conclusions:
- C3 inhibition with AMY-101 demonstrates potential in severe COVID-19.
- Non-responders suggested alternative C3 activation pathways, necessitating further investigation.
- Larger trials are recommended to confirm efficacy and explore C3 inhibition in other complement-mediated diseases.
Abstract:
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 (n = 16) or placebo (n = 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.
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