Importance Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.
Objective 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.
Interventions 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).
Results 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.
In this phase 2/3 clinical trial that evaluated the efficacy and adverse effects of bamlanivimab monotherapy and bamlanivimab and etesevimab combination therapy in outpatients with recently diagnosed mild to moderate COVID-19, the primary end point, mean change from baseline in log viral load at day 11, was not significantly different for the bamlanivimab monotherapy groups compared with the placebo group, but was significantly different for the bamlanivimab and etesevimab combination therapy group compared with the placebo group.
Among the secondary outcomes, there were no consistent differences between the monotherapy groups or the combination therapy group vs placebo for the other measures of viral load or clinical symptom scores. The proportion of patients with COVID-19–related hospitalizations or emergency department visits was numerically lower for the monotherapy groups and the combination therapy group compared with the placebo group, but the difference was only significant for the combination group. Additional study is needed to understand whether the greater reduction of viral load shown by combination therapy would eventually translate to clinical benefit compared with monotherapy.
Consistent with the literature,the post hoc analyses indicated that hospitalization rates were higher in placebo-treated patients with the comorbidities of advanced age (≥65 years) or morbid obesity (BMI ≥35) (13.5%), although no hospitalizations were observed in this high-risk subgroup in the combination therapy group. These preliminary data are hypothesis generating and suggest the need for further study to determine whether patients with these risk factors should be prioritized for this particular treatment.
In the exploratory analysis of ongoing viral sequencing, putative bamlanivimab-resistant variants were observed in all treatment groups, including placebo. Even though the combination group had the largest reductions in viral load, the monotherapy groups all performed comparably with the combination group on several clinical end points (eg, mean total symptom score and hospitalization rate). Therefore, the clinical significance of the resistant variants remains unclear.
Currently, only remdesivir is approved by the US Food and Drug Administration for the treatment of patients with COVID-19 who are seriously ill, although corticosteroids are generally considered the treatment of choice in this population and baricitinib recently received Emergency Use Authorization. COVID-19 convalescent plasma is available for use in hospitalized patients through Emergency Use Authorization; although, efficacy has not been established definitively and it is still considered investigational.Recently, the 700 mg dose of bamlanivimab has been authorized for emergency use in the US and Canada for the treatment of outpatients with mild to moderate COVID-19. Additional studies, including the ongoing subsequent portions of this trial in high-risk patients, are needed to fully elucidate the clinical benefit of therapeutic monoclonal antibodies for COVID-19.
Limitations
This study had several limitations. First, the trial was originally designed as a safety and biomarker study.
Second, the patient population was small, which made detecting clinically meaningful differences between treatment groups more difficult.
Third, only 1 combination dose was chosen for this study. Because the antiviral activity of etesevimab monotherapy or different combination doses was not investigated, it is difficult to determine whether the greater reduction in viral load observed in the combination group was due to additive or synergistic effects vs differential efficacy of etesevimab.
Fourth, the primary end point at day 11 may have been too late in the immune response to optimally detect treatment effects. All patients, including those who received placebo, demonstrated substantial viral reduction by day 11. An earlier time point like day 3 or day 7 could possibly have been more appropriate to measure viral load.
Fifth, the full genotypic and phenotypic analysis of the trial is still ongoing, and the resistance data presented here are limited to the sample sequences that were available at the time of this analysis.
Conclusions
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.
Reference & source information: https://jamanetwork.com/
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