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. 2020 Nov:28:100590.
doi: 10.1016/j.eclinm.2020.100590. Epub 2020 Nov 5.

Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study

Djillali Annane  1 , Nicholas Heming  2 , Lamiae Grimaldi-Bensouda  3 , Véronique Frémeaux-Bacchi  4 , Marie Vigan  5 , Anne-Laure Roux  6 , Armance Marchal  7 , Hugues Michelon  8 , Martin Rottman  6 , Pierre Moine  2 ; Garches COVID 19 Collaborative Group
Affiliations

Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study

Djillali Annane et al. EClinicalMedicine. 2020 Nov.

Abstract

Background: Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19.

Methods: All patients (N = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed.

Findings: At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test, P = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%).

Interpretation: Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed.

Funding: Programme d'Investissements d'Avenir: ANR-18-RHUS60004.

Keywords: Acute respiratory distress syndrome; C5 inhibitor; Complement pathway; Coronavirus; Cytokines; Pneumonia; Sepsis.

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Conflict of interest statement

Djillali Annane: reports non-financial support from Alexion Pharmaceuticals Inc. and grants from Programme d'Investissements d'Avenir during the conduct of the study; other (investigator) from Alexion outside the submitted work. Nicholas Heming: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study; other (investigator) from Alexion outside the submitted work. Lamiae Grimaldi-Bensouda: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study. Véronique Frémeaux-Bacchi: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study; grants and personal fees from Alexion, personal fees from Roche, personal fees from Apellis, and personal fees from Biocryps outside the submitted work. Marie Vigan: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study. Anne-Laure Roux: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study. Armance Marchal: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study. Hugues Michelon: reports non-financial support from Alexion Pharmaceuticals Inc, during the conduct of the study. Martin Rottman: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study. Pierre Moine: reports non-financial support from Alexion Pharmaceuticals Inc. during the conduct of the study; non-financial support and other (investigator) from Alexion outside the submitted work.

Figures

Fig. 1
Fig. 1
Kaplan–Meier estimated probability of survival. Survival rates in patients treated with versus without eculizumab were estimated from the all-cause mortality data using the Kaplan–Meier method. The resulting Kaplan–Meier survival curves were compared using a log-rank test. Differences between survival curves were significant (P = 0.04).
Fig. 2
Fig. 2
Change from baseline to day 1 and day 7 in (a) CH50 activity in patients treated with and without eculizumab and (b) free residual eculizumab in patients treated with eculizumab. The 50% hemolytic complement (CH50) assay is a validated method used to measure hemolytic complement activity. The CH50 assay can be used to measure changes in levels of C5 activity. Eculizumab is a humanized monoclonal antibody that binds C5 and blocks complement activation at C5. Each diamond represents 1 patient sample.
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