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What is the effect of early treatment with antispike neutralizing antibodies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in outpatients with mild to moderate coronavirus disease 2019 (COVID-19)?
In the phase 2 portion of a randomized phase 2/3 clinical trial with 577 patients, there was no significant difference in change in viral load with 3 different doses of bamlanivimab monotherapy compared with placebo; treatment with a combination of bamlanivimab and etesevimab significantly decreased SARS-CoV-2 log viral load at day 11 compared with placebo (between-group difference, –0.57 [95% CI, –1.00 to –0.14], P = .01).
Treatment with bamlanivimab and etesevimab combination therapy, but not bamlanivimab monotherapy, resulted in a reduction in SARS-CoV-2 log viral load at day 11 in patients with mild to moderate COVID-19.
Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.
To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.
Design, Setting, and Participants
The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020.
Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).
Main Outcomes and Measures
The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19–related hospitalization, an emergency department [ED] visit, or death at day 29).
Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was –3.72 for 700 mg, –4.08 for 2800 mg, –3.49 for 7000 mg, –4.37 for combination treatment, and –3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, –0.35 to 0.52; P = .69) for 700 mg, –0.27 (95% CI, –0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, –0.13 to 0.76; P = .16) for 7000 mg, and –0.57 (95% CI, –1.00 to –0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19–related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment.
Conclusions and Relevance
Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.
ClinicalTrials.gov Identifier: NCT04427501
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Corresponding Author: Daniel M. Skovronsky, MD, PhD, Eli Lilly and Company, 893 Delaware St, Indianapolis, IN 46225 (firstname.lastname@example.org).
Accepted for Publication: January 8, 2021.
Published Online: January 21, 2021. doi:10.1001/jama.2021.0202
Author Contributions: Drs Gottlieb and Nirula had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Gottlieb and Nirula made equal contributions and are co–first authors.
Concept and design: Nirula, Huhn, Adams, Van Naarden, Custer, Durante, Sabo, Klekotka, Shen, Skovronsky.
Acquisition, analysis, or interpretation of data: Gottlieb, Nirula, Chen, Boscia, Heller, Morris, Huhn, Cardona, Mocherla, Stosor, Shawa, Kumar, Adams, Van Naarden, Custer, Durante, Oakley, Schade, Holzer, Ebert, Higgs, Kallewaard, Patel, Klekotka, Shen, Skovronsky.
Drafting of the manuscript: Gottlieb, Nirula, Adams, Oakley, Holzer, Sabo, Patel, Klekotka, Shen, Skovronsky.
Critical revision of the manuscript for important intellectual content: Gottlieb, Nirula, Chen, Boscia, Heller, Morris, Huhn, Cardona, Mocherla, Stosor, Shawa, Kumar, Adams, Van Naarden, Custer, Durante, Oakley, Schade, Holzer, Ebert, Higgs, Kallewaard, Sabo, Patel, Klekotka, Shen, Skovronsky.
Statistical analysis: Cardona, Adams, Durante, Higgs, Shen.
Obtained funding: Sabo.
Administrative, technical, or material support: Gottlieb, Morris, Huhn, Mocherla, Kumar, Adams, Oakley, Schade, Ebert, Kallewaard, Sabo, Patel, Klekotka.
Supervision: Gottlieb, Nirula, Huhn, Adams, Van Naarden, Custer, Sabo, Klekotka, Shen, Skovronsky.
Conflict of Interest Disclosures: Dr Gottlieb reported receiving personal fees and nonfinancial support (medication for another trial) from Gilead Sciences; and serving on an advisory board for Sentinel. Drs Nirula and Adams, Mr Van Naarden, Dr Custer, Mr Durante, and Drs Oakley, Schade, Holzer, Ebert, Higgs, Kallewaard, Sabo, Patel, Klekotka, Shen, and Skovronsky are all employees and shareholders of Eli Lilly and Company. Dr Chen reported receiving consulting fees from Eli Lilly and Company. Dr Boscia reported receiving honoraria for serving on the GlaxoSmithKline speakers bureau. Dr Huhn reported receiving grants and personal fees from Gilead, Viiv, and Janssen; receiving grants from Proteus and Bristol-Myers Squibb; and receiving personal fees from TheraTechnologies. Dr Kumar reported receiving grants and consulting fees from GlaxoSmithKline, Amgen, TheraTechnologies, Merck, and Gilead Sciences; and owning stock in GlaxoSmithKline, Johnson & Johnson, Merck, Gilead Sciences, and Pfizer. No other disclosures were reported.
Funding/Support: This trial was sponsored and funded by Eli Lilly and Company.
Role of the Funder/Sponsor: Eli Lilly and Company was responsible for the design of the clinical trial; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript. Eli Lilly and Company did not have the right to veto publication or to control the decision regarding to which journal the paper was submitted. All final content decisions were made by the authors.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank David McIlwain, PhD, medical writer and employee of Eli Lilly and Company, for writing and editorial support. The names of those who assisted in this program, including investigators and support staff, are listed in Supplement 1. In addition, we thank the patients and the network of mobile home health research nurses, whose contribution was vital to this project.
Additional Information: Bamlanivimab emerged from the collaboration between Eli Lilly and Company and AbCellera Biologics to create antibody therapies for the prevention and treatment of COVID-19. Eli Lilly and Company developed the antibody after it was discovered by AbCellera Biologics and scientists at the National Institute of Allergy and Infectious Diseases Vaccine Research Center. Etesevimab emerged from the collaboration among Eli Lilly and Company, Junshi Biosciences, and the Institute of Microbiology of the Chinese Academy of Sciences.
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