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.

What is the incidence of putative resistant variants with bamlanivimab and etesevimab together treatment?

In the BLAZE-1 phase 3 trial, treatment-emergent variants were 9.0% with BAM 2800 mg/ETE 2800 mg treatment, 5.3% with BAM 700 mg/ETE 1400 mg treatment, and 4.0% with placebo. Genotypic and phenotypic testing are ongoing in clinical trials.

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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    

SARS-CoV-2 Viral Description and Mutation Potential

SARS-CoV-2 is a large β-coronavirus with a complex, non-segmented, positive-sense, ssRNA genome including structural and replicase genes as well as interspersed transcriptional regulatory sequences.3,4

All viruses have the potential to mutate during the course of replication. Mutations can arise from any of the following potential mechanisms:

  • replication errors
  • nucleic acid damage
  • editing of the genetic material by host-encoded proteins or by specialized molecular systems such as diversity-generating retro-elements
  • expression of host error-prone polymerases
  • recombination.5

RNA viruses, including SARS-CoV-2, tend to mutate more rapidly than DNA viruses at a rate within the 10−6 to 10−4 range of substitutions per nucleotide per cell infection compared to DNA viruses at a rate within the 10−8 to 10−6 range of substitutions per nucleotide per cell infection.5

The relatively rapid mutations of RNA viruses can complicate the management of viral illnesses.6-8 Because of their high mutation rates, RNA viruses and their viral variants are moving targets for successful treatments and can develop resistance to vaccines as well as medications.6,9

Viral Variants and Viral Strains

A viral variant is described in the literature as having a different genomic sequence as the reference virus, but without a different viral phenotype.10,11

A viral strain is defined as a biological variant of a reference virus that is recognizable due to unique phenotypic characteristics that remain stable under natural conditions.10,11

Recognizable viral strain phenotypic characteristics may include

  • biological properties (i.e. disease symptom or host),
  • chemical or antigenic properties, or
  • a genome sequence correlated with the phenotypic uniqueness of the strain.10,11

Bamlanivimab and Etesevimab Fact Sheet for Healthcare Providers

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.

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.

Nonclinical Results

Resistant variants were identified using directed evolution of the spike protein and serial passage in cell culture of SARS-CoV-2 in the presence of bamlanivimab or etesevimab individually. Resistant variants were not identified when bamlanivimab and etesevimab were tested together using the same methodology.1

  • Viral variants identified in these studies that had reduced susceptibility to bamlanivimab included spike protein amino acid substitutions E484D/K/Q, F490S, Q493R, and S494P.
  • Viral variants that had reduced susceptibility to etesevimab included substitutions K417N, D420N, and N460K/S/T/Y.

Neutralization assays using SARS-CoV-2 and vesicular stomatitis virus (VSV) virus-like particles (VLP) pseudotyped with variant SARS-CoV-2 spike protein confirmed reductions in susceptibility to the selecting antibody.1

Retention of susceptibility to the other antibody alone was observed, with the exception of the E484D and Q493R substitution.1

All variants maintained susceptibility to bamlanivimab and etesevimab together, with the exception of those with E484D, E484K, E484Q, and Q493R substitutions, which had reduced susceptibility of 145-fold, 24-fold, 17-fold, and 1054-fold, respectively in a pseudotyped VLP assay.1

Clinical Trial Results

Genotypic and phenotypic testing are ongoing to monitor for potential bamlanivimab- and etesevimab-resistance associated spike variations in clinical trials.1

Analysis of baseline samples show that 8.4% (188/2246) of clinical trial patients were infected with viral variants containing single amino acid substitutions at positions associated with reduced susceptibility to either bamlanivimab or etesevimab as predicted by pseudotyped virus-like particle (VLP) or authentic SARS-CoV-2 neutralization assays. No patients were infected with a variant that was predicted to have reduced susceptibility to both bamlanivimab and etesevimab by these assessments.1

Patient samples were also analyzed for treatment-emergent viral variants, defined as variants with single amino acid substitutions at positions that had reduced susceptibility to either bamlanivimab or etesevimab present at an allele fraction of ≥15%.1

  • In the phase 3 portion of BLAZE-1, treatment-emergent variants were observed in
    • 9.0% (42/467) of patients treated with bamlanivimab 2800 mg and etesevimab 2800 mg together
    • 5.3% (21/394) of patients treated with bamlanivimab 700 mg and etesevimab 1,400 mg together, and
    • 4.0% (27/674) of patients treated with placebo.1
    • The majority of these were only detected at one time point in the sequential series with 0.9% (4/467), 1.0% (4/394), and 0.3% (2/674) of patients having multiple instances of detection in the bamlanivimab 2800 mg and etesevimab 2800 mg together, bamlanivimab 700 mg and etesevimab 1400 mg together, and placebo groups, respectively.1
  • In patients treated with bamlanivimab and etesevimab together, substitutions detected in one or more patients included
    • ones with reduced susceptibility (≥5-fold) to bamlanivimab only: L452R/W, E484K, G485V, F490L, and S494P, and
    • ones with reduced susceptibility to etesevimab only: D405G/Y, K417N, D420N/Y, N460H/I/T, A475S/V, Y489H, and N501I/Y.1
    • While these variants had reduced susceptibility to either bamlanivimab or etesevimab compared to wild-type in a pseudotyped vesicular stomatitis virus (VSV) virus-like particle (VLP) or authentic virus assay they still retained susceptibility to the other antibody in the combination.1 
  • There were also observations of variants with reduced susceptibility (≥5-fold) to both bamlanivimab and etesevimab and to bamlanivimab plus etesevimab tested together:
    • E484D (n=1; 145-fold reduction to bamlanivimab plus etesevimab tested together at a molar ratio of 1:2), and
    • Q493K/R (n=9; 584-fold and 1054-fold reduction to bamlanivimab plus etesevimab tested together at a molar ratio of 1:2 for Q493K and Q493R, respectively) out of a total of 861 patients treated with bamlanivimab and etesevimab together.1 
  • In a subgroup of participants infected with virus harboring L452R substitution found in the B.1.427/B.1.429 (Epsilon) lineage, a S459P treatment-emergent substitution was identified in one subject. Concurrent L452R+S459P substitutions conferred a 1656-fold reduction in susceptibility to bamlanivimab plus etesevimab together (1:2 molar ratio).1
  • Additional treatment-emergent substitutions in patients treated with bamlanivimab and etesevimab together, with no phenotypic data, include
    • D405del
    • D420G
    • C480R
    • G485D
    • S494L, and
    • P499L.1 
    • The impact of these substitutions on susceptibility is not currently known.1 

It is possible that bamlanivimab and etesevimab resistance-associated variants could have cross-resistance to other monoclonal antibodies targeting the receptor binding domain of SARS-CoV-2. The clinical impact is not known.1

Bamlanivimab and Etesevimab Available Clinical Data

The information presented in the sections below contain data on unauthorized doses of bamlanivimab and etesevimab administered together. The only authorized dose of bamlanivimab and etesevimab administered together for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) is bamlanivimab 700 mg and etesevimab 1400 mg.

The EUA for bamlanivimab alone has been revoked by the US FDA as of April 16, 2021. Therefore, any information on bamlanivimab alone in the sections below is being provided for scientific and/or educational purposes, and is regarding an unauthorized and unapproved medication and dose. 

BLAZE-1 Clinical Overview

BLAZE-1 is a phase 2/3 randomized, double-blind, placebo-controlled trial evaluating bamlanivimab alone and together with etesevimab, in non-hospitalized patients with mild to moderate COVID-19.12,13

An estimated 3160 patients will be randomized to the following treatment arms in the BLAZE-1 study:

  • bamlanivimab (700 mg, 2800 mg, and 7000 mg) IV infusion
  • bamlanivimab (2800 mg) and etesevimab (2800 mg) together IV infusion
  • bamlanivimab (700 mg) and etesevimab (1400 mg) together IV Infusion, or
  • placebo IV infusion.12,13

BLAZE-1 Phase 2 Results: Putative Resistant Variants

A prior interim analysis was triggered on September 5th, 2020 and investigated the combined bamlanivimab treatment arms vs placebo. A subsequent analysis was triggered on October 6th, 2020 to include patients treated with bamlanivimab and etesevimab together.12

At time of database lock (October 6th, 2020), a total of 577 patients had been enrolled in the BLAZE-1 phase 2 study including

  • 101 patients assigned to bamlanivimab 700 mg alone
  • 107 patients assigned to bamlanivimab 2800 mg alone
  • 101 patients assigned to bamlanivimab 7000 mg alone
  • 112 patients assigned to bamlanivimab 2800 mg and etesevimab 2800 mg together, and
  • 156 patients assigned to placebo.12

All patients had completed at least day 29 of the trial.12

Putative Resistant Variant Results

Incidence of Putative Resistant Variants

Putative treatment-emergent bamlanivimab-resistant variants were observed in 1% of patients who received bamlanivimab and etesevimab together and in 4.8% of patients who received placebo (see BLAZE-1 Exploratory Analysis of Bamlanivimab and Etesevimab Treatment-Emergent Resistance-Associated Putative Variations at Positions E484K, E484Q, F490S, and S494P).12

BLAZE-1 Exploratory Analysis of Bamlanivimab and Etesevimab Treatment-Emergent Resistance-Associated Putative Variations at Positions E484K, E484Q, F490S, and S494P12

Treatment Group

Any Occurrence, n (%)

Multiple Occurrences, %

BAM 700 mg (N=98)

7 (7.1)a

4.1

BAM 2800 mg (N=102)

10 (9.8)b

5.9

BAM 7000 mg (N=97)

11 (11.3)c

7.2

BAM 2800 mg and ETE 2800 mg (N=102)

1 (1.0)d

0

Placebo (N=145)

7 (4.8)

0

Note: Treatment-emergent variants were determined by comparing the sequencing results from the study participant’s baseline sample to those obtained from that participant post‐treatment. Analysis was then focused on variants that were phenotypically confirmed to be resistant to bamlanivimab (E484K, E484Q, F490S, and S494P) and that occurred with ≥15% variant allele frequency.

ap=.26 vs placebo.

bp=.07 vs placebo.

cp=.20 vs placebo.

dp<.001 vs placebo.

The S494P variant reported in the single patient receiving bamlanivimab and etesevimab together treatment was detected on day 11 at an allele fraction of 0.198 and a viral load of 3.64 (N1 cycle threshold of approximately 32).  It was transient in nature and was not detected in subsequent samples through study day 25.12

Neutralization of Variants

Etesevimab has been shown to neutralize bamlanivimab-resistant variants (see Pseudovirus Neutralization of Spike Variants in Presence of Bamlanivimab and Etesevimab).12

Pseudovirus Neutralization of Spike Variants in Presence of Bamlanivimab and Etesevimab12

Spike Variant

Bamlanivimab

Etesevimab

 

IC50, μg/mL (95% CI)

Fold-shift in IC50

IC50, μg/mL (95% CI)

Fold-shift in Neutralization

Wuhana

0.01 (0.01, 0.02)

1

0.13 (0.07, 0.41)

1

E484K

>1

>100

0.57 (0.36, 1.11)

4.4

E484Q

>1

>100

0.17 (0.10, 0.36)

1.4

F490S

>1

>100

0.1 (0.04, >2)b

0.8

S494P

>1

>100

0.07 (0.03, >2)b

0.5

Abbreviations: CI = confidence interval; E = glutamate; F = phenylalanine; IC50 = 50% of maximal inhibitory concentration; K = lysine; P = proline; Q = glutamine; S = serine; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Note: IC50 and IC90 values were calculated as absolute IC values. 

aSARS-CoV-2 S Genbank MN908947.3.

bCI cannot be calculated.

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

3Yang Y, Peng F, Wang R, et al. The deadly coronaviruses: the 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun. 2020;109:102434. http://dx.doi.org/10.1016/j.jaut.2020.102434

4Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1-23. http://dx.doi.org/10.1007/978-1-4939-2438-7_1

5Sanjuan R and Domingo-Calap P. Mechanisms of viral mutation. Cellular and Molecular Life Sciences. 2016:73;4433–4448. https://doi.org/10.1007/s00018-016-2299-6

6Lauring AS, Andino R. Quasispecies Theory and the Behavior of RNA Viruses. PLoS Pathog. 2010:6(7);e1001005. https://doi.org/10.1371/journal.ppat.1001005

7Domingo E, Baranowski E, Ruiz-Jarabo CM, et al. Quasispecies structure and persistence of RNA viruses. Emerg Infect Dis. 1998:4;521–527. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640251/

8Domingo E, Martin V, Perales C, et al. (2006). Viruses as quasispecies: biological implications. In: Domingo E. (eds) Quasispecies: Concept and Implications for Virology. Current Topics in Microbiology and Immunology, vol 299. Springer, Berlin, Heidelberg.

9Gerrish PJ, Garcia-Lerma JG. Mutation rate and the efficacy of antimicrobial drug treatment. Lancet Infect Dis. 2003:3;28–32. https://doi.org/10.1016/S1473-3099(03)00485-7

10Van Regenmortel MHV. Virus species and virus identification: past and current controversies. Infection, Genetics and Evolution. 2007; 133–144. http://dx.doi.org/10.1016/j.meegid.2006.04.002

11Kuhn JH, Bao Y, Bavari S, et al. Virus nomenclature below the species level: a standardized nomenclature for natural variants of viruses assigned to the family Filoviridae. Arch Virol. 2013; 158(1): 301–311. https://doi.org/10.1007/s00705-012-1454-0

12Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021;325(7):632-644. http://dx.doi.org/10.1001/jama.2021.0202

13A study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in participants with mild to moderate COVID-19 illness (BLAZE-1). ClinicalTrials.gov identifier: NCT04427501. Updated September 8, 2021. Accessed September 14, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04427501

Glossary

COVID-19 = coronavirus disease 2019

DNA = deoxyribonucleic acid

EUA = emergency use authorization

FDA = Food and Drug Administration

IV = intravenous

mAb = monoclonal antibody

RNA = ribonucleic acid

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

US = United States

VLP = virus-like particles

VSV = vesicular stomatitis virus

Date of Last Review: September 15, 2021


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