bamlanivimab and etesevimab together

This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.

Will bamlanivimab and etesevimab together be effective in the treatment of COVID-19 infections caused by circulating SARS-CoV-2 variants?

Lilly continually monitors the COVID-19 environment, assessing the neutralization of bamlanivimab and etesevimab together against a wide array of emerging mutations and variants.

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Bamlanivimab and Etesevimab Emergency Use Authorization

Bamlanivimab and etesevimab have not been approved, but have only been authorized for emergency use by Food and Drug Administration (FDA) for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of the bamlanivimab and etesevimab under Section 564(b)(1)(C) of the Act, 21 U.S.C. § 360bbb-3, unless the authorization is terminated or revoked sooner.1,2   

Bamlanivimab and etesevimab are authorized to be administered together in adults and pediatric patients (12 years of age and older weighing at least 40 kg) who are at high risk for progression to severe coronavirus disease 2019 (COVID-19), including hospitalization or death for

  • the treatment of mild to moderate COVID-19, or
  • post-exposure prophylaxis of COVID-19.1,2    

For information on the authorized use of bamlanivimab and etesevimab together and mandatory requirements under the emergency use authorization (EUA), please review the FDA Letter of Authorization, Fact Sheet for Healthcare Providers, and Fact Sheet for Patients/Caregivers at www.LillyAntibody.com. 1,2    

Bamlanivimab and etesevimab are not authorized for use in states, territories, and US jurisdictions in which the combined frequency of variants resistant to bamlanivimab and etesevimab exceeds 5%, as determined by FDA. A list of states, territories, and US jurisdictions in which bamlanivimab and etesevimab are and are not currently authorized is available on the following FDA website: https://www.fda.gov/media/151719/download. 1,2    

Emerging SARS-CoV-2 Variants and Prevalence

Multiple variants of SARS-CoV-2 have been identified and are circulating globally. Information on emerging SARS-CoV-2 variants in the US is available on the CDC COVID-19 website.3

Prevalence of these variants or mutations can differ by country or even by state.4,5

Global and local variant information can be found at

Lilly continually monitors the COVID-19 environment, assessing the neutralization of our antibody therapies against a wide array of emerging mutations and variants.8

The prevalence and distribution of variants will change over time, and data on variants is not routinely collected from patients being treated.8

Bamlanivimab and Etesevimab Fact Sheet for Healthcare Providers

Bamlanivimab and etesevimab are not authorized for use in states, territories, and US jurisdictions in which the combined frequency of variants resistant to bamlanivimab and etesevimab exceeds 5%. A list of states, territories, and US jurisdictions in which bamlanivimab and etesevimab are and are not currently authorized is available on the following FDA website: https://www.fda.gov/media/151719/download .1

FDA will make this determination considering

FDA will update the list of states, territories, and US jurisdictions in which bamlanivimab and etesevimab are and are not currently authorized as new data and information becomes available. Healthcare providers should refer to the FDA website regularly for updates.1 

Antiviral Resistance

There is a potential risk of treatment failure due to the development of viral variants that are resistant to bamlanivimab and/or etesevimab. There are other authorized monoclonal antibody treatments available and healthcare providers should choose an authorized therapeutic option with activity against circulating variants in their state, territory, or US jurisdiction.1 Variant frequency data for states, territories, and US jurisdictions can be accessed on the following CDC website: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html.

Review travel and contact history within 2 weeks prior to infection or exposure to SARS-CoV-2. Persons who have traveled to, resided in, or had close contact with an infected individual from an area where the frequency of resistant variants to bamlanivimab and etesevimab exceeds 5% should not receive bamlanivimab and etesevimab. Other monoclonal antibody therapy options should be considered.1

Global Variants Surveillance

Evaluation of susceptibility of variants identified through global surveillance in subjects treated with bamlanivimab and etesevimab is ongoing.1

Susceptibility Against Amino Acid Substitutions

Pseudotyped virus-like particles evaluation of amino acid substitutions identified in global surveillance showed that the

  • V483A substitution reduced susceptibility to bamlanivimab 48-fold, but activity was maintained with etesevimab, and with bamlanivimab and etesevimab together, and
  • N501Y and N501T substitutions reduced susceptibility to etesevimab approximately 5-fold and 20-fold, respectively. Activity against variants with N501Y or N501T substitutions was maintained with bamlanivimab alone, and with bamlanivimab and etesevimab together.1

Variant Data

It is unclear how small reductions in susceptibility to bamlanivimab and etesevimab seen in authentic or recombinant SARS-CoV-2 or pseudotyped VLP assays correlate with clinical outcomes.1

Alpha (B.1.1.7; UK Origin)

Bamlanivimab and etesevimab together retained activity against a SARS-CoV-2 B.1.1.7 lineage (Alpha; UK origin) virus and related pseudotyped VLPs expressing the spike protein found in the B.1.1.7 variant (see Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio) and Authentic SARS-CoV-2 Neutralization Data for Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

In authentic SARS-CoV-2 assays, bamlanivimab and etesevimab together retained activity against variant of B.1.1.7 (Alpha) lineage (see Authentic SARS-CoV-2 Neutralization Data for Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)). 1

Beta (B.1.351; South Africa Origin)

SARS-CoV-2 B.1.351 lineage (Beta; South Africa origin) virus and related pseudotyped VLPs expressing spike proteins from B.1.351 lineage or substitutions K417N + E484K + N501Y found in this lineage had reduced susceptibility to bamlanivimab and etesevimab together of >324, 431-fold or >45-fold, respectively (see Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

Gamma (P.1; Brazil Origin)

Pseudotyped VLPs expressing spike protein from the P.1 lineage (Gamma; Brazil origin) or K417T + E484K + N501Y found in the P.1 lineage had reduced susceptibility to bamlanivimab and etesevimab together of 252-fold or >3351-fold, respectively (see Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

Delta (B.1.617.2 and sublineages; India Origin)

Bamlanivimab and etesevimab together and etesevimab alone retained activity against SARS-CoV-2 B.1.617.2 lineage (Delta; India origin) virus and related pseudotyped VLPs, but bamlanivimab alone had reduced activity (>1136 and >1868-fold, respectively) (see Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

Bamlanivimab and etesevimab are expected to retain activity against B.1.617.2 sublineage AY.3 (India origin). B.1.617.2 sublineages AY.1/AY.2 (commonly known as "Delta Plus"; India origin) have an additional K417N substitution; pseudotyped VLPs expressing AY.1/AY.2 related spike sequence had a reduced susceptibility to bamlanivimab and etesevimab together of 1235-fold.

In authentic SARS-CoV-2 assays, bamlanivimab and etesevimab together retained activity against variant of B.1.617.2/AY.3 (Delta) lineage (see Authentic SARS-CoV-2 Neutralization Data for Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

Epsilon (B.1.427/B.1.429; US California origin)

SARS-CoV-2 recombinant virus containing L452R substitution present in B.1.427/B.1.429 lineages (Epsilon; US California origin) and pseudotyped VLPs expressing the full-length spike protein or the L452R substitution found in this lineage showed reduced susceptibility to bamlanivimab and etesevimab together of 11-fold, 9-fold or 5-fold, respectively (see Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

SARS-CoV-2 (USA/WA/1/2020 isolate) engineered to express the L452R substitution present in the B.1.427/B.1.429 lineage (Epsilon; US California origin) showed reduced susceptibility to bamlanivimab and etesevimab together of 11-fold. Susceptibility to etesevimab alone was maintained, but not to bamlanivimab alone (>1,460-fold reduction for L452R virus) 1

Preliminary clinical evidence indicates that the administration of bamlanivimab and etesevimab together result in similar viral load reductions in participants infected with the L452R variant (Epsilon; US California origin) as observed in those who were infected with bamlanivimab-sensitive strains.1

Of the 134 participants infected with the L452R variant at baseline in the Phase 3 portion of BLAZE-1, 3 of the 50 individuals treated with placebo (6%) and 1 of the 84 participants treated with bamlanivimab 700 mg and etesevimab 1400 mg (1%) were hospitalized (p=.15).1

Iota (B.1.526; US New York origin)

SARS-CoV-2 (USA/WA/1/2020 isolate) engineered to express the E484K substitution present in the B.1.526 lineage (Iota; US New York origin) showed reduced susceptibility to bamlanivimab and etesevimab together of 11-fold; for this variant, susceptibility to etesevimab alone was maintained, but not to bamlanivimab alone (>833-fold reduction) (see Authentic SARS-CoV-2 Neutralization Data for Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

Available nonclinical and clinical PK data indicate that etesevimab at the authorized dose may retain activity against the B.1.526 variant clinically, although only very limited data are currently available from patients infected with this variant in clinical trials.1

Kappa (B.1.617.1; India Origin)

Pseudotyped VLPs expressing spike protein from the B.1.617.1 lineage (Kappa; India origin) showed reduced susceptibility to bamlanivimab and etesevimab together of 6-fold; for this variant, susceptibility to etesevimab alone was maintained, but not to bamlanivimab alone (>1030-fold reduction) (see Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

Lambda (C.37; Peru Origin)

Bamlanivimab and etesevimab together and etesevimab alone retained activity against pseudotyped VLPs expressing the full-length spike protein from the C.37 lineage (Lambda; Peru origin), but bamlanivimab alone had reduced activity (>2,112-fold reduction).1

Mu (B.1.621; Colombia Origin)

Pseudotyped VLPs expressing spike  protein from the B.1.621 lineage (Mu; Colombia origin) show reduced susceptibility to bamlanivimab and etesevimab together of 116-fold due to susceptibility reductions to bamlanivimab (>1863-fold) and etesevimab (17-fold) alone.1 

Tables of Variant Data

Due to the large reduction of pseudotyped VLP neutralization activity of both bamlanivimab and etesevimab against the substitutions in B.1.351 (Beta; South Africa origin), P.1 (Gamma; Brazil origin), AY.1/AY.2 ("Delta plus"; India origin), and B.1.621 (Mu; Colombia origin) it is unlikely that bamlanivimab and etesevimab together will be active against these variants (see Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio) and Authentic SARS-CoV-2 Neutralization Data for Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)).1

Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions With Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)1

Lineage With Spike Protein Substitution

Country First Identified

WHO Nomenclature

Key Substitutions Testeda

Fold Reduction in Susceptibility

B.1.1.7

UK

Alpha

N501Y

no changeb

B.1.351

South Africa

Beta

K417N + E484K + N501Y

431c

P.1

Brazil

Gamma

K417T + E484K + N501Y

252c

B.1.617.2/AY.3

India

Delta

L452R + T478K

no changeb

AY.1/AY.2 (B.1.617.2 sublineages)

India

Delta [+K417N]d

L452R + T478K + K417N

1235c

B.1.427/B.1.429

USA (California)

Epsilon

L452R

9e

B.1.526f

USA (New York)

Iota

E484K

30

B.1.617.1

India

Kappa

L452R + E484Q

6e

C.37

Peru

Lambda

L452Q + F490S

no changeb

B.1.621

Colombia

Mu

R346K + E484K + N501Y

116c

 Abbreviation: WHO = World Health Organization.

aKey substitutions occurring in the receptor binding domain of spike protein are listed. Pseudoviruses containing the full-length spike protein reflective of the consensus sequence for each of the variant lineages were tested.

bNo change: <5-fold reduction in susceptibility.

cBamlanivimab and etesevimab together are unlikely to be active against variants from this lineage.

dCommonly known as "Delta plus."

eEtesevimab retains activity against this variant.

fIsolates of the B.1.526 lineage harbor several spike protein amino acid substitutions, and not all isolates contain the E484K substitution (as of February 2021).

Authentica SARS-CoV-2 Neutralization Data for Bamlanivimab and Etesevimab Together (1:2 Molar Ratio)1

Lineage With Spike Protein Substitution

Country First Identified

WHO Nomenclature

Key Substitutions Testedb

Fold Reduction in Susceptibility

B.1.1.7

UK

Alpha

N501Y

no changec

B.1.351

South Africa

Beta

K417N, E484K, N501Y

>325

B.1.617.2/AY.3

India

Delta

L452R, T478K

no changec

B.1.427/B.1.429

USA (California)

Epsilon

L452R

11

B.1.526d

USA (New York)

Iota

E484K

11

 Abbreviation: WHO = World Health Organization.

aThe B.1.1.7 variant was assessed using cell culture-expanded virus isolates and tested using an immunofluorescence based microneutralization assay and by plaque reduction assay; B.1.351 and B.1.617.2 variants were assessed using cell culture-expanded virus isolates and tested using a plaque reduction assay; the B.1.526/E484K and B.1.427/B.1.429/L452R substitutions were assessed using recombinant SARS-CoV-2 (USA/WA/1/2020 isolate with E484K or L452R) and tested using a plaque reduction assay.

bKey substitutions occurring in receptor binding domain of spike protein which are associated with each lineage.

cNo change: <5-fold reduction in susceptibility.

dIsolates of the B.1.526 lineage harbor several spike protein amino acid substitutions, and not all isolates contain the E484K substitution (as of February 2021). This assay was conducted using recombinant SARS-CoV-2 with the E484K substitution only.

References

The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

1Fact sheet for healthcare providers. Emergency Use Authorization (EUA) of bamlanivimab and etesevimab. US Food and Drug Administration (FDA). 2021.

2United States Food and Drug Administration. Bamlanivimab and Etesevimab FDA Emergency Use Authorization Letter. Issued September 16, 2021. Accessed September 16, 2021. http://pi.lilly.com/eua/bam-and-ete-eua-fda-authorization-letter.pdf

3Science Brief: Emerging SARS-CoV-2 Variants. Centers for Disease Control and Prevention COVID-19 website. Last updated January 28, 2021. Accessed August 30, 2021. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/scientific-brief-emerging-variants.html

4GISAID. Tracking of hcov19 Variants. Accessed April 22, 2021. https://www.gisaid.org/hcov19-variants/

5Centers for Disease Control and Prevention. About variants of the virus that causes COVID-19. Updated April 2, 2021. Accessed April 22, 2021. https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant.html

6Centers for Disease Control and Prevention. New Variants of the Virus that Causes COVID-19. Updated February 12, 2021. Accessed March 13, 2021. https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant.html

7GISAID. Tracking of hcov19 Variants. Accessed March 12, 2021. https://www.gisaid.org/hcov19-variants/

8Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

CDC = Centers for Disease Control and Prevention

COVID-19 = coronavirus disease 2019

EUA = emergency use authorization

FDA = Food and Drug Administration

SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2

UK = United Kingdom

US = United States

VLP = virus-like particles

Date of Last Review: September 17, 2021


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