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Clinical Trial
. 2022 Aug 1;5(8):e2225411.
doi: 10.1001/jamanetworkopen.2022.25411.

Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial

Cynthia Portal-Celhay  1 , Eduardo Forleo-Neto  1 , Will Eagan  1 , Bret J Musser  1 , John D Davis  1 , Kenneth C Turner  1 , Thomas Norton  1 , Andrea T Hooper  1 , Jennifer D Hamilton  1 , Cynthia Pan  1 , Adnan Mahmood  1 , Alina Baum  1 , Christos A Kyratsous  1 , Yunji Kim  1 , Janie Parrino  1 , Wendy Kampman  1 , Lilia Roque-Guerrero  2 , Roxana Stoici  3 , Adil Fatakia  4 , Yuhwen Soo  1 , Gregory P Geba  1 , Bari Kowal  1 , A Thomas DiCioccio  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 Dose-Ranging Study Team
Collaborators, Affiliations
Clinical Trial

Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial

Cynthia Portal-Celhay et al. JAMA Netw Open. .

Abstract

Importance: The monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients.

Objective: To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo.

Design, setting, and participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021.

Interventions: Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo.

Main outcomes and measures: The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline.

Results: Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1 (10.0) years (102 [45.3%] men; 75 [34.7%] Hispanic or Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusion-related or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported.

Conclusions and relevance: In this randomized clinical trial including outpatients with asymptomatic and low-risk symptomatic SARS-CoV-2, all IV and SC doses of casirivimab and imdevimab comparably reduced viral load.

Trial registration: ClinicalTrials.gov Identifier: NCT04666441.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Forleo-Neto, Eagan, Musser, Davis, Turner, Norton, Hooper, Hamilton, Baum, Kyratsous, Kim, Kampman, Soo, Geba, Kowal, DiCioccio, Braunstein, Herman, and Weinreich and Ms Pan reported being employed by and owning stock in Regeneron Pharmaceuticals outside the submitted work. Drs Portal-Celhay and Parrino reported being formerly employed by and owning stock in Regeneron Pharmaceuticals outside the submitted work. Dr Musser reported having been employed by and owning stock in Merck outside the submitted work. Drs Turner, Hooper, Hamilton, and Herman reported having a patent pending for Methods for Treating or Preventing SARS-CoV-2 Infections and COVID-19 With Anti-SARS-CoV-2-Spike Glycoprotein Antibodies (licensee: Roche; assigned to: Regeneron Pharmaceuticals, Inc). Dr Hooper reported being formerly employed by and holding stock in Pfizer outside the submitted work. Ms Pan reported holding stock in Zai Labs outside the submitted work. Dr Baum reported patents 10975139, 10954289, and 10787501 issued. Dr Kyratsous reported patents US10975139B1 and US10954289B1 issued and being an officer of Regeneron Pharmaceuticals. Dr Stahl reported receiving grants from Biomedical Advanced Research and Development Authority during the conduct of the study and holding stock in Regeneron outside the submitted work. Dr Lipsich reported being formerly employed by and holding stock in Regeneron Pharmaceuticals outside the submitted work. Dr Yancopoulos reported being an officer and director for Regeneron during the conduct of the study and having multiple patents pending for REGEN-COV antibody, all assigned to Regeneron. Dr Weinreich reporting multiple patents issued for Regeneron Pharmaceuticals. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
Inclusion in the overall modified full analysis set (mFAS) population required a positive polymerase chain reaction test from a central laboratory at baseline; the placebo groups are pooled. The seronegative mFAS population is a proper subset of the overall mFAS, in which patients were also required to be seronegative at baseline. CAS indicates casirivimab; IMD, imdevimab. aThese numbers include the pooled (intravenous [IV] and subcutaneous [SC]) placebo group members (98 in the overall mFAS and 77 in the seronegative mFAS).
Figure 2.
Figure 2.. Pairwise Comparisons of the Primary End Point
A, Results for the seronegative modified full analysis set. B, Results for the seronegative per-protocol set. IV indicates intravenous; LS, least squares; and SC, subcutaneous.
Figure 3.
Figure 3.. Mean Total Casirivimab (CAS) and Imdevimab (IMD) Concentrations in Serum in Nominal Time After a Single Dose
The pharmacokinetic analysis set included all patients who received any study drug and who had 1 or more nonmissing drug concentration measurement following study drug administration. IV indicates intravenous; SC, subcutaneous.
See this image and copyright information in PMC

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