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Clinical Trial
. 2022 Dec 28;227(1):23-34.
doi: 10.1093/infdis/jiac320.

Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19

Selin Somersan-Karakaya  1 , Eleftherios Mylonakis  2 , Vidya P Menon  3 , Jason C Wells  4 , Shazia Ali  1 , Sumathi Sivapalasingam  1 , Yiping Sun  1 , Rafia Bhore  1 , Jingning Mei  1 , Jutta Miller  1 , Lisa Cupelli  1 , Eduardo Forleo-Neto  1 , Andrea T Hooper  1 , Jennifer D Hamilton  1 , Cynthia Pan  1 , Viet Pham  1 , Yuming Zhao  1 , Romana Hosain  1 , Adnan Mahmood  1 , John D Davis  1 , Kenneth C Turner  1 , Yunji Kim  1 , Amanda Cook  1 , Bari Kowal  1 , Yuhwen Soo  1 , A Thomas DiCioccio  1 , Gregory P Geba  1 , Neil Stahl  1 , Leah Lipsich  1 , Ned Braunstein  1 , Gary A Herman  1 , George D Yancopoulos  1 , David M Weinreich  1 ; COVID-19 Phase 2/3 Hospitalized Trial Team
Affiliations
Clinical Trial

Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19

Selin Somersan-Karakaya et al. J Infect Dis. .

Abstract

Background: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD).

Methods: In this phase 1/2/3, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.0 g CAS + IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus.

Results: In total, 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met in seronegative patients, the least-squares mean difference (CAS + IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log10 copies/mL (95% confidence interval [CI], -.51 to -.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS + IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2%-74.0%). No safety concerns were noted.

Conclusions: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS + IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients.

Clinical trials registration: NCT04426695.

Keywords: COVID-19; SARS-CoV-2; coronavirus; hospitalized; monoclonal antibody.

Plain language summary

Lay Summary . Monoclonal antibody therapies that block the virus that causes COVID-19 (SARS-CoV-2) can prevent patients from being hospitalized. We hypothesized that these antibodies may also benefit patients who are already hospitalized with COVID-19. Therefore, we performed a study to determine if the monoclonal antibody combination of casirivimab and imdevimab (CAS + IMD) can decrease the amount of virus in the nose of hospitalized patients and prevent the disease from becoming more severe. The study, conducted from June 2020 to April 2021, found that CAS + IMD treatment reduced the amount of virus in these patients, and may reduce their chance of dying or needing a ventilator (a machine that helps patients breathe). Patients were examined in 2 groups: those whose immune systems, at the start of the study, had not produced their own antibodies to fight SARS-CoV-2 (seronegative patients); or those that had already produced their own antibodies (seropositive patients) at the start of the study. Seronegative patients benefited the most from CAS + IMD. No safety concerns related to CAS + IMD were observed. These results demonstrate that monoclonal antibody therapy can help hospitalized patients with COVID-19 and may decrease their chances of needing assistance to breathe or dying.

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Conflict of interest statement

Potential conflicts of interest. S. S.-K., S. A., Y. Sun, R. B., J. Mei, J. Miller, E. F.-N., C. P., V. P., Y. Z., A. M., J. D. D., Y. K., A. C., B. K., Y. Soo, A. T. D., G. P. G., L. L., N. B., and D. M. W. are employees/stockholders of Regeneron Pharmaceuticals, Inc, and report grants from Biomedical Advanced Research and Development Authority (BARDA). E. M. reports payments to his institution received from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases, NIH/National Institute of General Medical Sciences, SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc/NCI. V. P. M. and J. C. W. report grants from BARDA. S. S. is an Excision BioTherapeutics employee/stockholder and former Regeneron Pharmaceuticals, Inc, employee and current stockholder, and reports grants from BARDA. L. C. is a Regeneron Pharmaceuticals, Inc employee and reports grants from BARDA. A. T. H. is a Regeneron Pharmaceuticals, Inc employee/stockholder, a former Pfizer employee and current stockholder, has a patent pending with Regeneron Pharmaceuticals, Inc and reports grants from BARDA. J. D. H., K. C. T., and G. A. H. are employees/stockholders of Regeneron Pharmaceuticals, Inc and have a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, Inc. R. H. is a former employee and current stockholder of Regeneron Pharmaceuticals, Inc, and reports grants from BARDA. N. S. and G. D. Y. are employees/stockholders of Regeneron Pharmaceuticals, Inc, and have issued patents (US Patent Nos. 10 787 501, 10 954 289, and 10 975 139) and pending patents, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals, Inc, and reports grants from BARDA. Funding to pay the Open Access publication charges for this article was provided by Regeneron Pharmaceuticals, Inc.

Figures

Figure 1.
Figure 1.
Flow diagram for the phase 2/3 population receiving low-flow or no supplemental oxygen (cohorts 1 and 1A). The flow diagram depicts patients randomized, treated, and discontinued for patients receiving either 2.4 or 8.0 g of CAS + IMD, or placebo. aThe FAS included all randomized patients who received at least 1 dose (full or partial) of the study drug. Analysis of the FAS population was done according to the treatment allocated (as randomized). The FAS was the same as the SAF for this study. bThe mFAS included all FAS patients with a positive SARS-CoV-2 RT-qPCR conducted in the central laboratory in nasopharyngeal swab samples at randomization, and analysis was based on the treatment allocated (as randomized). cThe seronegative mFAS was defined as all patients in mFAS with documented seronegative status at baseline. Abbreviations: EOS, end of study; FAS, full analysis set; IV, intravenous; mFAS, modified full analysis set; RT-qPCR, quantitative reverse transcription polymerase chain reaction; SAF, safety analysis set; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Viral load by serostatus. A, Graph shows LS mean viral load following administration of CAS + IMD (2.4 g, 8.0 g, or combined analysis of 2.4 and 8.0 g) or placebo for patients who tested negative for all SARS-CoV-2 antibodies at baseline (seronegative). B, The same but for patients who tested positive for any SARS-CoV-2 antibody at baseline (seropositive). A and B, Lower limit of quantification was 2.85 log10 copies/mL. Corresponding tables list values for time-weighted average change from baseline and difference for CAS+IMD versus placebo. Abbreviations: CAS + IMD, casirivimab and imdevimab; CI, confidence interval; IV, intravenous; mFAS, modified full analysis set; LS, least-squares; PBO, placebo; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE, standard error; TWA, time-weighted average.
Figure 3.
Figure 3.
Mortality outcomes by serostatus for combined dose CAS + IMD from day 1 though day 29. The Kaplan-Meier curve shows the proportion of patients who died through study day 29, after administration of CAS + IMD (combined analysis of 2.4 g or 8.0 g) or placebo. Results were analyzed separately for patients who were seronegative or seropositive at baseline; + indicates censoring. Abbreviations: CAS + IMD, casirivimab and imdevimab.
Figure 4.
Figure 4.
Efficacy outcomes by serostatus for combined dose CAS + IMD from day 1 though day 29. Forest plot shows relative risk and relative risk reduction with 95% CIs for CAS + IMD combined dose analysis (2.4 g and 8.0 g) versus placebo. Parameters examined included death within 28 days, discharge alive from hospital from days 1 to 29, and death or mechanical ventilation from days 1 to 29. For all populations, the mFAS comprised patients who tested positive for SARS-CoV-2 at baseline. Populations analyzed included patients who tested negative for all SARS-CoV-2 antibodies at baseline (seronegative mFAS), patients who tested positive for any SARS-CoV-2 antibody at baseline (seropositive mFAS), those with borderline, inconclusive, or missing baseline serology (other), and the overall population regardless of serostatus (overall mFAS). For the proportion of death within 28 days and the proportion of death or mechanical ventilation with 28 days, the lower bounds of the CI of the relative risk reduction were –342.0% and –241.0%, respectively (NA in the figure). Abbreviations: CAS + IMD, casirivimab and imdevimab; CI, confidence interval; mFAS, modified full analysis set; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
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