Mildly to moderately ill COVID-19 adult outpatients given a combination of the monoclonal antibodies bamlanivimab and etesevimab early in the disease had significantly lower viral loads at day 11 than those who received a placebo, but a similar effect was not seen in those given bamlanivimab alone, a study published today in JAMA finds.
Bamlanivimab manufacturer Eli Lilly sponsored the double-blind phase 2/3 BLAZE-1 clinical trial, which involved 533 COVID-19 patients at 49 US medical centers. The goal was to assess the antispike neutralizing antibodies' effects on viral loads of SARS-CoV-2, the virus that causes COVID-19, at 11 days and clinical outcomes at 29 days.
Patients who received either bamlanivimab alone or a placebo were enrolled from Jun 17 to Aug 21, 2020, while those given the bamlanivimab and etesevimab combination or placebo were enrolled from Aug 22 to Sep 3, 2020.
Participants were randomly assigned to receive single infusions of 700, 2,800, or 7,000 milligrams (mg) of bamlanivimab, a combination of 2,800 mg each of bamlanivimab and etesevimab, or placebo.
Fewer hospitalizations, ED admissions
The change in SARS-CoV-2 log viral load from baseline to day 11 was -.372 for patients who received 700 mg of bamlanivimab, -4.08 for those who received 2,800 mg of the agent, and -3.49 for those who received 7,000 mg. Log viral load dropped 4.37 for participants given combination treatment and 3.80 for placebo recipients.
Compared with placebo, differences in log viral load at day 11 were not significant for any of the bamlanivimab groups (0.09 for patients on 700 mg, -0.27 for those on 2,800 mg, and 0.31 for the 7,000-mg group). In the combination treatment group, the difference in log SARS-CoV-2 viral load was -0.57.
Differences between each study arm versus the placebo group were statistically significant for 10 of 84 end points, including proportion of COVID-19 patients hospitalized or seen in the emergency department (1% in the 700-mg bamlanivimab group, 1.9% in the 2,800-mg group, and 2.0% in the 7,000-mg group, compared with 0.9% with combination treatment and 5.8% with placebo).
Nine patients had immediate mild hypersensitivity reactions that could have been related to the infusions (6 with bamlanivimab, 2 with combination treatment, and 1 with placebo). No patients in the bamlanivimab group had serious adverse events, but one each in the combination and the placebo group had adverse events deemed unrelated to the infusions. No patients died during the treatment period.
Mean patient age was 44.7 years, 42.5% of patients were Hispanic, and 67.1% had one or more risk factors for severe COVID-19 outcomes (age 55 years or older, body mass index of 30 kg/m2 or higher, or an underlying condition such as high blood pressure).
Key questions on clinical outcomes remain
The combination of bamlanivimab and etesevimab was proposed to further lower SARS-CoV-2 viral load and reduce the likelihood of treatment-emergent resistant viral variants. The US Food and Drug Administration issued an emergency use authorization for bamlanivimab on Nov 9, 2020, for use in outpatients with mild to moderate COVID-19 at high risk for severe outcomes.
"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," the authors said.
The researchers said the ongoing parts of the clinical trial taking place with high-risk patients will further understanding the clinical benefit of monoclonal antibodies for the treatment of COVID-19. "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," they said.
In an editor's note on the study, Preeti Malani, MD, MSJ, and Robert Golub, MD, observed that the outcomes of the analysis differ from those of an interim analysis published online in the New England Journal of Medicine on Oct 28, 2020 and today in print.
The reason, they said, was that the placebo-group follow-up was about a month longer than that of the treatment groups, resulting in changes in that group's primary outcome, and the comparison of the bamlanivimab-only group with the placebo group changed the effect size, leading to the loss of previously reported statistical significance in the 2,800-mg bamlanivimab group.
Malani and Golub said that while monoclonal antibodies probably improve clinical outcomes in some patients, questions about which patients may derive clinical benefit and under what circumstances remain.
"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," they wrote.