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A combination treatment of neutralizing monoclonal antibodies bamlanivimab and etesevimab was associated with a statistically significant reduction in SARS-CoV-2 at day 11 compared with placebo among nonhospitalized patients who had mild-to-moderate COVID-19, new data indicate.
However, bamlanivimab alone in three different single-infusion doses showed no significant reduction in viral load compared with placebo, according to the phase 2/3 study by Robert L. Gottlieb, MD, PhD, of the Baylor University Medical Center and the Baylor Scott & White Research Institute in Dallas, Texas, and colleagues.
Findings from the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) study were published online today in JAMA. The results represent findings through October 6, 2020.
BLAZE-1 was funded by Eli Lilly and Company, which makes both of the antispike neutralizing antibodies. The trial was conducted at 49 US centers and included 613 outpatients who tested positive for SARS-CoV-2 and had one or more mild-to-moderate symptoms.
Patients were randomized to one of five groups (four treatment groups and a placebo control), and researchers analyzed between-group differences.
All four treatment arms suggest a trend toward reduction in viral load, which was the primary endpoint of the trial, but only the combination showed a statistically significant reduction.
Table. Change in Log Viral Load at Day 11 Per Treatment Arms
Change in log viral load vs placebo at day 11
700 mg bamlanivimab
–0.35 to 0.52
2800 mg bamlanivimab
–0.71 to 0.16
7000 mg bamlanivimab
–0.13 to 0.76
Combination 2800 mg bamlanivimab and 2800 mg etesevimab
–1.00 to –0.14
The average age of patients was 44.7 years; 54.6% were female; 42.5% were Hispanic; 67.1% had at least one risk factor for severe COVID-19 (aged ≥ 55 years, body mass index of at least 30, or relevant comorbidity such as hypertension).
Among secondary outcomes, there were no consistent differences between the monotherapy groups or the combination group vs placebo for the other measures of viral load or clinical symptom scores.
The proportion of patients who had COVID-related hospitalizations or emergency department visits was 5.8% (nine events) for placebo; 1.0% (one event) for the 700 mg group; 1.9% (two events) for 2800 mg; 2.0% (two events) for 7000 mg; and 0.9% (one event) for combination treatment.
“Combining these two neutralizing monoclonal antibodies in clinical use may enhance viral load reduction and decrease treatment-emergent resistant variants,” the authors conclude.
Safety Profile Comparison
As for adverse events, immediate hypersensitivity reactions were reported in nine patients (six bamlanivimab, two combination treatment, and one placebo). No deaths occurred during the study.
Serious adverse events unrelated to SARS-CoV-2 infection or considered related to the study drug occurred in 0% (0/309) of patients in the bamlanivimab monotherapy groups; in 0.9% (1/112) of patients in the combination group; and in 0.6% (1/156) of patients in the placebo group.
The serious adverse event in the combination group was a urinary tract infection deemed unrelated to the study drug, the authors write.
The two most frequently reported side effects were nausea (3.0% for the 700 mg group; 3.7% for the 2800 mg group; 5.0% for the 7000 mg group; 3.6% for the combination group; and 3.8% for the placebo group) and diarrhea (1.0%, 1.9%, 5.9%, 0.9%, and 4.5%, respectively).
The authors include in the study’s limitations that the primary endpoint at day 11 may have been too late to best detect treatment effects.
“All patients, including those who received placebo, demonstrated substantial viral reduction by day 11,” they note. “An earlier time point like day 3 or day 7 could possibly have been more appropriate to measure viral load.”
Currently, only remdesivir has been approved by the US Food and Drug Administration for treating COVID-19, but convalescent plasma and neutralizing monoclonal antibodies have been granted Emergency Use Authorization.
In an accompanying editor’s note, Preeti N. Malani, MD, with the Division of Infectious Diseases at University of Michigan in Ann Arbor and associate editor of JAMA, and Robert M. Golub, MD, deputy editor of JAMA, point out that these results differ from an earlier interim analysis of BLAZE-1 data.
A previous publication by Peter Chen, MD, with the Department of Medicine at Cedars–Sinai Medical Center, Los Angeles, California, compared the three monotherapy groups (no combination group) with placebo, and in that study the 2800 mg dose of bamlanivimab vs placebo achieved statistical significance for reduction in viral load from baseline at day 11, whereas the other two doses did not.
The editors explain that in the study by Chen, “Follow-up for the placebo group was incomplete at the time of the database lock on September 5, 2020. In the final analysis reported in the current article, the database was locked on October 6, 2020, and the longer follow-up for the placebo group, which is now complete, resulted in changes in the primary outcome among that group.”
They conclude, “The comparison of the monotherapy groups against the final results for the placebo group led to changes in the effect sizes,” and the statistical significance of the 2800 mg group was erased.
The editors point out that monoclonal antibodies are likely to benefit certain patients but definitive answers regarding which patients will benefit and under what circumstances will likely take more time than clinicians have to make decisions on treatment.
Meanwhile, as Medscape Medical News reported, the US has spent $375 million on bamlanivimab and $450 million on Regeneron’s monoclonal antibody cocktail of casirivimab plus imdevimab, with the promise to spend billions more.
However, 80% of the 660,000 doses delivered by the two companies are still sitting on shelves, federal officials said in a press briefing last week, because of doubts about efficacy, lack of resources for infusion centers, and questions on reimbursement.
“While the world waits for widespread administration of effective vaccines and additional data on treatments, local efforts should work to improve testing access and turnaround time and reduce logistical barriers to ensure that monoclonal therapies can be provided to patients who are most likely to benefit,” Malani and Golub write.
This trial was sponsored and funded by Eli Lilly and Company. Gottlieb disclosed personal fees and nonfinancial support (medication for another trial) from Gilead Sciences; and serving on an advisory board for Sentinel. Several coauthors have financial ties to Eli Lilly; full disclosures are listed in the paper. Malani reported serving on the National Institute of Allergy and Infectious Diseases COVID-19 Preventive Monoclonal Antibody data and safety monitoring board but was not compensated. Golub has disclosed no relevant financial relationships.
Marcia Frellick is a freelance journalist based in Chicago. She has previously written for the Chicago Tribune, Science News, and Nurse.com and was an editor at the Chicago Sun-Times, the Cincinnati Enquirer, and the St. Cloud (Minnesota) Times. Follow her on Twitter at @mfrellick.
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