A Randomized, Placebo-Controlled Clinical Trial of Bamlanivimab and Etesevimab Together in High-Risk Ambulatory Patients With COVID-19 and Validation of the Prognostic Value of Persistently High Viral Load

Michael Dougan, Masoud Azizad, Bharat Mocherla, Robert L Gottlieb, Peter Chen, Corey Hebert, Russell Perry, Joseph Boscia, Barry Heller, Jason Morris, Chad Crystal, Awawu Igbinadolor, Gregory Huhn, Jose Cardona, Imad Shawa, Princy Kumar, Andra Blomkalns, Andrew C Adams, Jacob Van Naarden, Kenneth L Custer, Jack Knorr, Gerard Oakley, Andrew E Schade, Timothy R Holzer, Philip J Ebert, Richard E Higgs, Janelle Sabo, Dipak R Patel, Matan C Dabora, Mark Williams, Paul Klekotka, Lei Shen, Daniel M Skovronsky, Ajay Nirula, Michael Dougan, Masoud Azizad, Bharat Mocherla, Robert L Gottlieb, Peter Chen, Corey Hebert, Russell Perry, Joseph Boscia, Barry Heller, Jason Morris, Chad Crystal, Awawu Igbinadolor, Gregory Huhn, Jose Cardona, Imad Shawa, Princy Kumar, Andra Blomkalns, Andrew C Adams, Jacob Van Naarden, Kenneth L Custer, Jack Knorr, Gerard Oakley, Andrew E Schade, Timothy R Holzer, Philip J Ebert, Richard E Higgs, Janelle Sabo, Dipak R Patel, Matan C Dabora, Mark Williams, Paul Klekotka, Lei Shen, Daniel M Skovronsky, Ajay Nirula

Abstract

Background: Based on interim analyses and modeling data, lower doses of bamlanivimab and etesevimab together (700/1400 mg) were investigated to determine optimal dose and expand availability of treatment.

Methods: This Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate coronavirus disease 2019 (COVID-19), and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700/1400 mg) or placebo were infused intravenously within 3 days of patients' first positive COVID-19 test.

Results: In total, 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% confidence interval {CI}] = -5.0 [-8.0, -2.1], P < .001). No deaths occurred in the bamlanivimab and etesevimab group compared with 4 deaths (all COVID-19-related) in the placebo group. Patients receiving antibody treatment had a greater mean reduction in viral load from baseline to Day 7 (Δ[95% CI] = -0.99 [-1.33, -.66], P < .0001) compared with those receiving placebo. Persistently high viral load at Day 7 correlated with COVID-19-related hospitalization or any-cause death by Day 29 in all BLAZE-1 cohorts investigated.

Conclusions: These data support the use of bamlanivimab and etesevimab (700/1400 mg) for ambulatory patients at high risk for severe COVID-19. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants will require continued monitoring to determine the applicability of this treatment.

Clinical trials registration: NCT04427501.

Keywords: COVID-19; bamlanivimab; etesevimab; persistently high viral load.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Patient enrolment and treatment assignment.
Figure 2.
Figure 2.
Kaplan-Meier analysis of time to COVID-19-related hospitalization or any-cause death (A) and time to COVID-19-related hospitalization (B) among high-risk patients that received bamlanivimab and etesevimab (700 mg and 1400 mg) or placebo. Number of patients at risk are presented below each graph with the number of events occurring after each timepoint, up to and including the next timepoint, in brackets. Time to event analyses were calculated using the Kaplan-Meier product limit method. Patients were infused on Study Day 1. Abbreviation: COVID-19, coronavirus disease 2019.
Figure 3.
Figure 3.
Least squares (LS) mean change in viral load from baseline. LS mean change in viral load from baseline following treatment with (A) 700 mg and 1400 mg of bamlanivimab and etesevimab together as compared with placebo and (B) 2800 mg and 2800 mg of bamlanivimab and etesevimab together, as compared with placebo (data from Dougan et al [18]). Change in viral load from baseline for patients treated with a combination of bamlanivimab and etesevimab is significantly lower than placebo at all time points investigated for both panels A and B. Data analyzed as a mixed model repeat measure (MMRM) model. Error bars represent standard error of the mean.
Figure 4.
Figure 4.
SARS-COV-2 viral load in phase 2 and phase 3 BLAZE-1 cohorts on Day 7. A–D, The cumulative probability that patients would have the PCR cycle threshold at or above the specified cycle threshold value on Day 7. Phase 2 patients receiving bamlanivimab (700, 2800, and 7000 mg pooled) or placebo (data from Chen et al [7]) (A), and bamlanivimab and etesevimab (2800/2800 mg) or placebo (B). Phase 3 patients receiving bamlanivimab and etesevimab (2800/2800 mg) or placebo (C), and bamlanivimab and etesevimab (700/1400 mg) or placebo (D). Cycle threshold value of 27.5 (corresponding to PHVL) is indicated by the vertical dotted line. PHVL threshold was calculated using a cut-point analysis and PHVL and viral load were analyzed using a logistic regression. Abbreviations: PCR, polymerase chain reaction; PHVL, persistently high viral load; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

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