bamlanivimab and etesevimab together

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

At positions K417, D420, N460, E484, F490 and S494, 3.9% and 0% bamlanivimab and etesevimab-treated patients harbored a variant post-baseline at ≥15% and ≥50% allele fractions, respectively. 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 FDA to be 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) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization.1,2

Bamlanivimab and etesevimab are authorized to be 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) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization only 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) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.1,2

For information on the authorized use of bamlanivimab and etesevimab together and mandatory requirements under the EUA, please review the FDA Letter of Authorization, Fact Sheet for Healthcare Providers, and Fact Sheet for Patients/Caregivers at BAMandETE.com.

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, and 
  • 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 both bamlanivimab and etesevimab. Prescribing healthcare providers should consider the prevalence of SARS-CoV-2 variants in their area, where data are available, when considering treatment options.2

Clinical Trial Results

Genotypic and phenotypic testing are ongoing to monitor for potential bamlanivimab- and etesevimab-resistance associated spike variations in clinical trials.2

SARS-CoV-2 Spike Protein Putative Resistant Variants

Detection of phenotypically confirmed bamlanivimab- or etesevimab-resistant variants in baseline samples were observed at a frequency of

  • 0% (0/14) in the Phase 1 clinical study PYAA, and
  • 0.4% (2/523) in clinical study BLAZE-1.2

In BLAZE-1, treatment-emergent variants were detected at spike protein amino acid positions K417, D420, N460, E484, F490 and S494, and included K417N, D420N, N460T, E484A/D/G/K/Q/V, F490L/S/V and S494L/P substitutions. Only K417N, D420N, N460T, E484D/K/Q, F490S and S494P have been assessed phenotypically to date.2

At positions K417, D420, N460, E484, F490 and S494, 9.2% (9/98) and 6.1% (6/98) of participants in the 700 mg bamlanivimab arm harbored such a variant post-baseline at ≥15% and ≥50% allele fractions, respectively.2

  • For subjects treated with bamlanivimab and etesevimab, the variant frequencies were 3.9% (4/102) and 0% (0/102) at ≥15% and ≥50% allele fractions, respectively.
  • The majority of the variants were first observed on Day 7 following treatment initiation.
    • Some of the variants were detected in individuals at more than one time point in the 700 mg bamlanivimab arm: 4/9 and 4/6 at ≥15% and ≥50% allele fractions, respectively; however, in the bamlanivimab and etesevimab arm there were no such observations (0/4 at ≥15% allele fraction). 
  • When the genotypic analysis was restricted to high-risk participants, the 700 mg bamlanivimab arm showed a 14.0% (6/43) and 9.3% (4/43) variant frequency for the ≥15% and ≥50% allele fractions, respectively, and no variants were detected in the bamlanivimab and etesevimab arm.2

The clinical relevance of these findings is not known.2

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

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 3300 patients will be randomized to the following 3 treatment arms in the BLAZE-1 study:

  • bamlanivimab (700 mg, 2800 mg, and 7000 mg) IV infusion,
  • bamlanivimab (2800 mg) plus etesevimab (2800 mg) IV infusion, or
  • placebo IV infusion.2,12,13

The primary efficacy endpoints are

  • change from baseline to day 11 in SARS-CoV-2 viral load
  • percentage of participants who experience COVID-related hospitalization or death from baseline through day 29, and
  • percentage of participants with SARS-CoV-2 viral load greater than a prespecified threshold at day 7.12,13

BLAZE-1 Interim Results: Putative Resistant Variants

Bamlanivimab and Etesevimab Interim Results

A prior interim analysis was triggered on September 5th, 2020 and investigated the combined bamlanivimab treatment arms vs placebo.14 A subsequent analysis was triggered on October 6th, 2020 to include patients treated with bamlanivimab and etesevimab together.13

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.2,13

All patients had completed at least day 29 of the trial.2

Putative Resistant Variant Results

Preliminary analysis has focused on the presence of variations at sites of phenotypically confirmed bamlanivimab- or etesevimab-resistance-associated variations (bamlanivimab: E484,F490, Q493, S494; etesevimab: K417, D420 and N460).15

Treatment-emergent variants were detected at S-protein amino acid positions K417, D420, N460, E484, F490, and S494, and included K417N, D420N, N460T, E484A/D/G/K/Q/V, F490L/S/V, and S494L/P substitutions. Only K417N, D420N, E484K/Q, F490S, and S494P have been assessed phenotypically to date.15

Treatment-emergent frequencies are summarized BLAZE-1 Exploratory Analysis of Bamlanivimab and Etesevimab Treatment-Emergent Resistance-Associated Putative Variations at Positions K417, D420, N460, E484, F490, and S494.

BLAZE-1 Exploratory Analysis of Bamlanivimab and Etesevimab Treatment-Emergent Resistance-Associated Putative Variations at Positions K417, D420, N460, E484, F490, and S49415

Data shown as % (n/N)

Placebo

Bamlanivimab Alone
700 mg

Bamlanivimab + Etesevimab Together

Exploratory Outcomes

All Participants ≥50% VAF

3.4% (5/145)

6.1% (6/98)

0% (0/102)

All Participants ≥15% VAF

6.2% (9/145)

9.2% (9/98)

3.9% (4/102)

Only Single Time Point Detection ≥50% VAF

5/5

2/6

0/0

Only Single Time Point Detection ≥15% VAF

9/9

5/9

3/3

High-Riska Participant ≥50% VAF

1.5% (1/65)

9.3% (4/43)

0% (0/33)

High-Riska Participant ≥15% VAF

3.1% (2/65)

14.0% (6/43)

0% (0/33)

Abbreviations: VAF = virus-activated factor.

aHigh-risk for this analysis was defined as age ≥55 or BMI ≥30 or medical history event of interest.

References

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

1United States Food and Drug Administration. Bamlanivimab and Etesevimab FDA Emergency Use Authorization Letter. Issued February 9, 2021. Accessed February 9, 2021. http://pi.lilly.com/eua/bam-and-ete-eua-fda-authorization-letter.pdf

2Fact sheet for healthcare providers. Emergency Use Authorization (EUA) of bamlanivimab and etesevimab. US Food and Drug Administration (FDA). 2021.

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

12A 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 January 27, 2021. Accessed January 27, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04427501

13Gottlieb 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. JAMA. Published online January 21, 2021. http://dx.doi.org/10.1001/jama.2021.0202

14Chen P, Nirula A, Heller B, et al; BLAZE-1 Investigators. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with covid-19. N Engl J Med. Published online October 28, 2020. https://doi.org/10.1056/nejmoa2029849

15Data on file, Eli Lilly and Company and/or one of its subsidiaries.

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

Date of Last Review: March 24, 2021


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