TY - JOUR
T1 - Casirivimab and Imdevimab Treatment Reduces Viral Load and Improves Clinical Outcomes in Seropositive Hospitalized COVID-19 Patients with Nonneutralizing or Borderline Neutralizing Antibodies
AU - for the COVID-19 Phase 2/3 Hospitalized Trial Team
AU - Hooper, Andrea T.
AU - Somersan-Karakaya, Selin
AU - McCarthy, Shane E.
AU - Mylonakis, Eleftherios
AU - Ali, Shazia
AU - Mei, Jingning
AU - Bhore, Rafia
AU - Mahmood, Adnan
AU - Geba, Gregory P.
AU - Dakin, Paula
AU - Weinreich, David M.
AU - Yancopoulos, George D.
AU - Herman, Gary A.
AU - Hamilton, Jennifer D.
N1 - Funding Information:
Editor Matthew S. Miller, McMaster University Copyright © 2022 Hooper et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to Andrea T. Hooper, andrea.hooper@regeneron.com. The authors declare a conflict of interest. A.T.H. is a Regeneron Pharmaceuticals, Inc. employee/stockholder; a former Pfizer employee and current stockholder; has a pending patent application with Regeneron Pharmaceuticals, Inc.; and reports grants from BARDA. S.S.-K., S.E.M., S.A., J.M., R.B., A.M., P.D., and D.M.W. are Regeneron Pharmaceuticals, Inc. employees/stockholders; and report grants from BARDA. E.M. reports payments to his institution received from NIH/NIAID, NIH/ NIGMS, SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Pfizer, Chemic Labs/ KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc./NCI; and reports grants from BARDA. G.D.Y. is a Regeneron Pharmaceuticals, Inc. employee/stockholder; has issued (U.S. Patent Nos. 10,787,501, 10,954,289, and 10,975,139) and pending patent applications with Regeneron Pharmaceuticals, Inc.; and reports grants from BARDA. G.A.H. and J.D.H. are Regeneron Pharmaceuticals, Inc. employees/stockholders; and have a pending patent application, with Regeneron Pharmaceuticals, Inc.; and report grants from BARDA. Received 16 June 2022 Accepted 20 September 2022 Published 18 October 2022
Funding Information:
A.T.H. is a Regeneron Pharmaceuticals, Inc. employee/stockholder, a former Pfizer employee and current stockholder, has a pending patent application with Regeneron Pharmaceuticals, Inc., and reports grants from Biomedical Advanced Research and Development Authority (BARDA). S.S.-K., S.E.M., S.A., J.M., R.B., A.M., P.D., and D.M.W. are Regeneron Pharmaceuticals, Inc. employees/stockholders and report grants from BARDA. E.M. reports payments to his institution received from NIH/NIAID, NIH/NIGMS, SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc./NCI; and reports grants from BARDA. G.D.Y. is a Regeneron Pharmaceuticals, Inc. employee/stockholder; has issued U.S. patent nos. 10,787,501, 10,954,289, and 10,975,139 (granted 09/29/2020, 03/23/2021, and 03/24/2021, respectively; authors include Robert Babb, Alina Baum, Gang Chen, Cindy Gerson, Johanna Hansen, Tammy T. Huang, Christos Kyratsous, Wen-Yi Lee, Marine Malbec, Andrew J. Murphy, William Olson, Neil Stahl, George D. Yancopoulos; Title: Anti-SARS-CoV-2-Spike Glycoprotein Antibodies and Antigen-Binding Fragments) and pending patent applications, with Regeneron Pharmaceuticals, Inc.; and reports grants from BARDA. G.A.H. and J.D.H. are Regeneron Pharmaceuticals, Inc. employees/stockholders and have a pending patent application with Regeneron Pharmaceuticals, Inc., and report grants from BARDA.
Funding Information:
This work was supported by Regeneron Pharmaceuticals, Inc. Certain aspects of this project were supported by federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, and Biomedical Advanced Research and Development Authority, under OT number HHSO100201700020C.
Publisher Copyright:
Copyright © 2022 Hooper et al.
PY - 2022/12
Y1 - 2022/12
N2 - We conducted a post hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline from a phase 1, 2, and 3 trial of casirivimab and imdevimab (CAS1IMD) treatment in hospitalized coronavirus disease 2019 (COVID-19) patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS1IMD, 8.0 g CAS1IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline neutralizing antibody status. At baseline, 20.6% (178/864) of seropositive patients were negative or borderline for neutralizing antibodies, indicating negative or very low functionally neutralizing anti-SARS-CoV-2 antibodies. CAS1IMD reduced viral load in patients who were negative or borderline for neutralizing antibodies versus placebo, but not in patients who were positive for neutralizing antibodies. In patients who were negative or borderline for neutralizing antibodies, we observed a trend in reduction of the proportion of patients who died or required mechanical ventilation, as well as in all-cause mortality, by day 29 with CAS1IMD versus placebo. The proportions of patients who died or required mechanical ventilation from days 1 to 29 were 19.1% in the placebo group and 10.9% in the CAS1IMD combined-dose group, and the proportions of patients who died (all-cause mortality) from days 1 to 29 were 16.2% in the placebo group and 9.1% in the CAS1IMD combined-dose group. In patients who were positive for neutralizing antibodies, no measurable harm or benefit was observed in either the proportion of patients who died or required mechanical ventilation or the proportion of patients who died (all-cause mortality). In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS1IMD reduced viral load, the risk of death or mechanical ventilation, and all-cause mortality in seropositive patients who were negative or borderline for neutralizing antibodies. IMPORTANCE The clinical benefit of CAS1IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2-seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19 with antibodies against SARS-CoV-2 who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post hoc analysis demonstrates that there is a subset of hospitalized seropositive patients with inadequate SARS-CoV-2-neutralizing antibodies (i.e., those who were negative or borderline for neutralizing antibodies) who may still benefit from CAS1IMD treatment if infected with a susceptible SARS-CoV-2 variant. Therefore, utilizing serostatus alone to guide treatment decisions for patients with COVID-19 may fail to identify those seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies known to be effective against circulating strains, dependent upon how effectively their endogenous antibodies neutralize SARS-CoV-2.
AB - We conducted a post hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline from a phase 1, 2, and 3 trial of casirivimab and imdevimab (CAS1IMD) treatment in hospitalized coronavirus disease 2019 (COVID-19) patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS1IMD, 8.0 g CAS1IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline neutralizing antibody status. At baseline, 20.6% (178/864) of seropositive patients were negative or borderline for neutralizing antibodies, indicating negative or very low functionally neutralizing anti-SARS-CoV-2 antibodies. CAS1IMD reduced viral load in patients who were negative or borderline for neutralizing antibodies versus placebo, but not in patients who were positive for neutralizing antibodies. In patients who were negative or borderline for neutralizing antibodies, we observed a trend in reduction of the proportion of patients who died or required mechanical ventilation, as well as in all-cause mortality, by day 29 with CAS1IMD versus placebo. The proportions of patients who died or required mechanical ventilation from days 1 to 29 were 19.1% in the placebo group and 10.9% in the CAS1IMD combined-dose group, and the proportions of patients who died (all-cause mortality) from days 1 to 29 were 16.2% in the placebo group and 9.1% in the CAS1IMD combined-dose group. In patients who were positive for neutralizing antibodies, no measurable harm or benefit was observed in either the proportion of patients who died or required mechanical ventilation or the proportion of patients who died (all-cause mortality). In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS1IMD reduced viral load, the risk of death or mechanical ventilation, and all-cause mortality in seropositive patients who were negative or borderline for neutralizing antibodies. IMPORTANCE The clinical benefit of CAS1IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2-seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19 with antibodies against SARS-CoV-2 who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post hoc analysis demonstrates that there is a subset of hospitalized seropositive patients with inadequate SARS-CoV-2-neutralizing antibodies (i.e., those who were negative or borderline for neutralizing antibodies) who may still benefit from CAS1IMD treatment if infected with a susceptible SARS-CoV-2 variant. Therefore, utilizing serostatus alone to guide treatment decisions for patients with COVID-19 may fail to identify those seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies known to be effective against circulating strains, dependent upon how effectively their endogenous antibodies neutralize SARS-CoV-2.
KW - COVID-19
KW - anti-SARS-CoV-2 serostatus
KW - casirivimab and imdevimab
KW - hospitalized
KW - monoclonal antibodies
KW - neutralizing antibodies
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U2 - 10.1128/mbio.01699-22
DO - 10.1128/mbio.01699-22
M3 - Article
C2 - 36255239
AN - SCOPUS:85144433134
VL - 13
JO - mBio
JF - mBio
SN - 2161-2129
IS - 6
ER -