The Medical Letter on Drugs and Therapeutics
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ARTICLE
An EUA for Bamlanivimab and Etesevimab for COVID-19
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The FDA has issued an Emergency Use Authorization (EUA) for Lilly's investigational monoclonal antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) to be administered together by IV infusion for treatment of mild to moderate COVID-19 in adults and pediatric patients (aged ≥12 years and weighing ≥40 kg) who are at high risk of progressing to severe disease and/or hospitalization (see Table 1).1 Bamlanivimab received an EUA for use as monotherapy in such patients in November 2020.2 Regeneron's investigational monoclonal antibodies casirivimab (REGN10933) and imdevimab (REGN10987) are also authorized for use together for this indication.3

Monoclonal antibodies have been associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 who require high-flow oxygen or mechanical ventilation. Bamlanivimab and etesevimab are not authorized for use in patients who are hospitalized for COVID-19 or require oxygen therapy because of COVID-19.

MECHANISM OF ACTION — Bamlanivimab and etesevimab bind to different but overlapping sites on the receptor binding domain of the spike protein of SARS-CoV-2, blocking its attachment to the human ACE2 receptor.

CLINICAL STUDIES — Issuance of the EUA for bamlanivimab and etesevimab was based on the results of two randomized, double-blind trials in outpatient adults with mild to moderate COVID-19.

The first trial (BLAZE-1) had a phase 2 and a phase 3 component. In the phase 2 component, 612 patients (42% high risk) received bamlanivimab 2800 mg plus etesevimab 2800 mg, one of three doses of bamlanivimab alone (700 mg, 2800 mg, or 7000 mg), or placebo. The primary endpoint, mean decrease from baseline in log SARS-CoV-2 viral load from baseline at day 11, was significantly greater with bamlanivimab plus etesevimab than with placebo (-4.37 vs -3.80). None of the doses of bamlanivimab alone significantly reduced viral load at day 11 compared to placebo.4

In the phase 3 component of BLAZE-1 (unpublished; summarized in the FDA Fact Sheet), 1035 patients (all high-risk) received either bamlanivimab 2800 mg plus etesevimab 2800 mg or placebo. The primary endpoint, hospitalization due to COVID-19 or death from any cause by day 29, occurred significantly less often with the antibodies than with placebo (2% vs 7%; HR 0.31; NNT 20.7). No deaths occurred in the antibody group, compared to 10 in the placebo group (p <0.001).5

In the second trial (BLAZE-4; unpublished and summarized in the FDA fact sheet), 259 patients <65 years old with a BMI <35 kg/m2 received either bamlanivimab 2800 mg plus etesevimab 2800 mg or bamlanivimab 700 mg plus etesevimab 1400 mg. The mean change in SARS-CoV-2 viral load was similar with the two doses of the combination. These data showing similar antiviral activity led the FDA to select 700 mg/1400 mg as the authorized dose for use of bamlanivimab and etesevimab together.5

No studies directly comparing bamlanivimab and etesevimab with casirivimab and imdevimab are available.

ADVERSE EFFECTS — In BLAZE-1, adverse effects occurred less commonly with bamlanivimab plus etesevimab than with placebo. Hypersensitivity reactions including anaphylaxis have been reported with use of bamlanivimab with and without etesevimab.

VARIANTS — In BLAZE-1, treatment-emergent SARS-CoV-2 variants developed less frequently in patients who received bamlanivimab plus etesevimab than in those who received bamlanivimab alone. The combination has been found to retain activity against the B.1.1.7 (UK) variant of SARS-CoV-2, but it is likely to have reduced activity against the B.1.351 (S. African) variant. Studies evaluating the antiviral activity of bamlanivimab and etesevimab against the P.1 (Brazilian) variant of SARS-CoV-2 are ongoing.

DOSAGE AND ADMINISTRATION — Bamlanivimab and etesevimab are supplied separately in 700 mg/20 mL vials, but when used together, they must be administered as a single IV infusion; the authorized dose is 700 mg (one vial) of bamlanivimab and 1400 mg (two vials) of etesevimab. The antibodies should be diluted in 50, 100, 150, or 250 mL of normal saline and infused at a maximum rate of 310 mL/hr (266 mL/hr when mixed with 250 mL normal saline for patients weighing <50 kg) immediately after preparation. If immediate use is not possible, the solution can be refrigerated for up to 24 hours or left at room temperature for up to 7 hours, including infusion time. If refrigerated, the solution should be allowed to sit at room temperature for 20 minutes before use.

Bamlanivimab and etesevimab should be administered as soon as possible after a positive SARS-CoV-2 test result and within 10 days of COVID-19 symptom onset. Patients should be treated in a facility staffed and equipped to manage anaphylaxis and they should be monitored for hypersensitivity reactions during administration of the drug and for at least 1 hour after completion of the infusion.

AVAILABILITY — Bamlanivimab and etesevimab will be allocated to state health departments by the US Department of Health and Human Services (HHS) based on case counts and severity of outbreaks. State health departments will then be responsible for allocating the antibodies to local health facilities. The manufacturer plans to produce 1 million doses of etesevimab for use with bamlanivimab by mid-2021.6

CONCLUSION — The FDA has issued an Emergency Use Authorization (EUA) for the monoclonal antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) to be administered together by IV infusion for treatment of COVID-19. Administration of the antibodies to high-risk outpatients recently diagnosed with mild to moderate COVID-19 reduced viral load and decreased the risk of hospitalization and death. Compared to bamlanivimab alone, use of the combination appears to be more effective in reducing viral load and less likely to result in development of treatment-emergent variants. How bamlanivimab and etesevimab compare with casirivimab (REGN10933) and imdevimab (REGN10987), two other monoclonal antibodies available for use together through an EUA, remains to be determined.

REFERENCES

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