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Randomized Controlled Trial
. 2022 Dec 20;13(6):e0169922.
doi: 10.1128/mbio.01699-22. Epub 2022 Oct 18.

Casirivimab and Imdevimab Treatment Reduces Viral Load and Improves Clinical Outcomes in Seropositive Hospitalized COVID-19 Patients with Nonneutralizing or Borderline Neutralizing Antibodies

Andrea T Hooper #  1 , Selin Somersan-Karakaya #  1 , Shane E McCarthy  1 , Eleftherios Mylonakis  2 , Shazia Ali  1 , Jingning Mei  1 , Rafia Bhore  1 , Adnan Mahmood  1 , Gregory P Geba  1 , Paula Dakin  1 , David M Weinreich  1 , George D Yancopoulos  1 , Gary A Herman  1 , Jennifer D Hamilton  1 ; COVID-19 Phase 2/3 Hospitalized Trial Team
Affiliations
Randomized Controlled Trial

Casirivimab and Imdevimab Treatment Reduces Viral Load and Improves Clinical Outcomes in Seropositive Hospitalized COVID-19 Patients with Nonneutralizing or Borderline Neutralizing Antibodies

Andrea T Hooper et al. mBio. .

Abstract

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 (CAS+IMD) 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 CAS+IMD, 8.0 g CAS+IMD, 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. CAS+IMD 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 CAS+IMD 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 CAS+IMD 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 CAS+IMD 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, CAS+IMD 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 CAS+IMD 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 CAS+IMD 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.

Trial registration: ClinicalTrials.gov NCT04426695.

Keywords: COVID-19; anti-SARS-CoV-2 serostatus; casirivimab and imdevimab; hospitalized; monoclonal antibodies; neutralizing antibodies.

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Conflict of interest statement

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.

Figures

FIG 1
FIG 1
Viral load by baseline neutralizing antibody titer. Serostatus was determined using composite serostatus based on Euroimmun anti-spike S1 IgA and IgG assays and the Abbott anti-nucleocapsid IgG assay. Seropositive is defined as positive in any test; seronegative is defined as negative in all available tests. Neutralizing titer was determined by IMMUNO-COV neutralization assay in seropositive patients only; the seronegative group was not tested in the neutralizing assay. Dots represent individual patient data; boxes represent median and interquartile range. The LLOQ for the viral load determination RT-qPCR assay was 2.85-log10 copies/mL. mFAS presented. Ig, immunoglobulin; LLOQ, lower limit of quantification; mFAS, modified full analysis set; RT-qPCR, quantitative reverse transcription-PCR; VNT, viral neutralizing titer; U, M, and I, unknown, missing, and indeterminant, respectively.
FIG 2
FIG 2
Change from baseline in viral load in seropositive patients by baseline neutralizing antibody status. (A) LS mean viral load following administration of CAS+IMD (2.4 g, 8.0 g, or combined analysis of 2.4 g and 8.0 g) or placebo for seropositive patients who were negative or borderline for neutralizing antibodies. (B) Same as panel A but for seropositive patients who were positive for neutralizing antibodies. Seropositive mFAS presented. CAS+IMD, casirivimab and imdevimab; IV, intravenous; mFAS, modified full analysis set; LS, least squares.
FIG 3
FIG 3
Cumulative incidence of death or mechanical ventilation in seropositive patients by baseline neutralizing antibody status. Kaplan-Meier curves for the proportion of patients who died or required mechanical ventilation through study day 29 after administration of CAS+IMD (2.4 g, 8.0 g, or combined analysis of 2.4 g and 8.0 g) or placebo in patients who were negative or borderline for neutralizing antibodies (A) or patients who were positive for neutralizing antibodies (B). Symbols indicate censoring. Seropositive mFAS presented. CAS+IMD, casirivimab and imdevimab; IV, intravenous; mFAS, modified full analysis set.
FIG 4
FIG 4
Cumulative incidence of death in seropositive patients by baseline neutralizing antibody status. Kaplan-Meier curves for the proportion of patients who died through study day 29 after administration of CAS+IMD (2.4 g, 8.0 g, or combined analysis of 2.4 g and 8.0 g) or placebo in patients who were negative or borderline for neutralizing antibodies (A) or patients who were positive for neutralizing antibodies (B). Symbols indicate censoring. Seropositive mFAS presented. CAS+IMD, casirivimab and imdevimab; IV, intravenous; mFAS, modified full analysis set.
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