Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial

• Published in: The Lancet infectious diseases Vol. 22; no. 10; pp. 1444 - 1454
• Main Authors: Herman, Gary A, O'Brien, Meagan P, Forleo-Neto, Eduardo, Sarkar, Neena, Isa, Flonza, Hou, Peijie, Chan, Kuo-Chen, Bar, Katharine J, Barnabas, Ruanne V, Barouch, Dan H, Cohen, Myron S, Hurt, Christopher B, Burwen, Dale R, Marovich, Mary A, Musser, Bret J, Davis, John D, Turner, Kenneth C, Mahmood, Adnan, Hooper, Andrea T, Hamilton, Jennifer D, Parrino, Janie, Subramaniam, Danise, Baum, Alina, Kyratsous, Christos A, DiCioccio, A Thomas, Stahl, Neil, Braunstein, Ned, Yancopoulos, George D, Weinreich, David M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.10.2022; Elsevier Ltd
• Subjects: Adverse events; Antibodies, Monoclonal, Humanized - therapeutic use; Asymptomatic; Coronaviruses; COVID-19 - prevention & control; COVID-19 vaccines; COVID-19 Vaccines - adverse effects; Disease prevention; Disease transmission; Double-Blind Method; Double-blind studies; Drug dosages; Effectiveness; Exposure; Households; Humans; Immune response; Immunosuppressive agents; Infections; Infectious diseases; Interactive systems; Monoclonal antibodies; Pharmaceutical Preparations; Pharmacists; Placebos; Polymerase chain reaction; Prevention; Prophylaxis; Public health; Randomization; Risk management; SARS-CoV-2; Seroconversion; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signs and symptoms; Vaccines; United States > US
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(22)00416-9

There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings. This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318. From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal p<0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal p<0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal p<0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs. CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown. Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.