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bebtelovimab
bebtelovimab
175mgThis 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 bebtelovimab be effective against circulating SARS-CoV-2 variants?
Lilly continually monitors the COVID-19 environment, assessing the neutralization of bebtelovimab against a wide array of emerging mutations and variants.
Bebtelovimab Emergency Use Authorization
Bebtelovimab has not been approved, but has 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 bebtelovimab 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
Bebtelovimab is authorized for the treatment of mild-to-moderate coronavirus disease 2019 (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 progression to severe COVID-19, including hospitalization or death, and
- for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate.1,2
For information on the authorized use of bebtelovimab 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/bebtelovimab. 1,2
Emerging SARS-CoV-2 Variants and Prevalence
Multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been identified and are circulating globally. Information on emerging SARS-CoV-2 variants in the United States (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
- GISAID COVID-19 variant tracker: https://www.gisaid.org
- Centers for Disease Control and Prevention (CDC) website: https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant-cases.html .4,5
Lilly continually monitors the COVID-19 environment, assessing the neutralization of our antibody therapies against a wide array of emerging mutations and variants.6
The prevalence and distribution of variants will change over time, and data on variants is not routinely collected from patients being treated.6
Bebtelovimab 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 bebtelovimab.1
Characterization of Resistant Mutations
Nonclinical selection studies using a directed evolution of a yeast displayed Spike receptor-binding domain (RBD) identified that substitutions at residues K444, V445, G446, and P499 interfered with bebtelovimab’s ability to block the Spike RBD: angiotensin-converting enzyme 2 (ACE-2) interaction.1
Pseudotyped virus-like particle (VLP) neutralization assays confirmed a ≥5-fold reduction in susceptibility to bebtelovimab of viral variants with the following substitutions:
- K444E (>862)
- K444N (>1901-fold)
- K444Q (208-fold)
- K444T (>1814-fold)
- V445A (111-fold)
- V445F (369-fold)
- V445G (>730-fold)
- G446D (69-fold)
- G446R (7-fold)
- G446V (8-fold)
- P499H (>1606-fold)
- P499R (>1870-fold), and
- P499S (25-fold).1
In the context of Delta spike protein, G446V substitution had reduced susceptibility of 16.4-fold.1
Neutralization Activity Against Variant Lineages in Global Circulation
Pseudotyped VLP assessment using the full-length spike genes from different variant lineages indicate that bebtelovimab retains activity (<5-fold reduction) against the Alpha (B.1.1.7, UK origin), Beta (B.1.351, South Africa origin), Gamma (P.1, Brazil origin), Delta (B.1.617.2, India origin), Delta [+K417N] (AY.1/AY.2, India origin), Epsilon (B.1.427/B.1.429, California origin), Iota (B.1.526, New York origin), Kappa (B.1.617.1, India origin), Lambda (C.37, Peru origin), Omicron (B.1.1.529/BA.1, South Africa origin), Omicron [+R346K] (BA.1.1), Omicron BA.2, Omicron BA.2 [+L452Q] (BA.2.12.1), Omicron BA.2 [+D339H, G446S, N460K, R493Q (reversion)] (BA.2.75), Omicron BA.2 [BA.2.75+R346T+F486S] (BA.2.75.2), Omicron BA.4/BA.5, and Omicron BA.4 [+R346T] (BA.4.6/BF.7) variant lineages (see ). The Mu (B.1.621, Colombia origin) variant showed a reduction in susceptibility to bebtelovimab of 5.3-fold. The Omicron BA.5 [+N444T, N460K] (BQ.1) and Omicron BA.5 [+R346T, N444T, N460K] (BQ.1.1) variants showed a large reduction in susceptibility to bebtelovimab of >672-fold.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 |
No changeb |
P.1 |
Brazil |
Gamma |
K417T + E484K + N501Y |
No changeb |
B.1.617.2/AY.3 |
India |
Delta |
L452R + T478K |
No changeb |
AY.1/AY.2 |
India |
Delta [+K417N] |
L452R + T478K + K417N |
No changeb |
B.1.427/B.1.429 |
USA (California) |
Epsilon |
L452R |
No changeb |
B.1.526c |
USA (New York) |
Iota |
E484K |
No changeb |
B.1.617.1 |
India |
Kappa |
L452R + E484Q |
No changeb |
C.37 |
Peru |
Lambda |
L452Q + F490S |
No changeb |
B.1.621 |
Columbia |
Mu |
R346K + E484K + N501Y |
5.3 |
B.1.1.529/BA.1 |
South Africa |
Omicron [BA.1] |
G339D + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G496S + Q498R + N501Y + Y505H |
No changeb |
BA.1.1 |
South Africa |
Omicron [+R346K] |
BA.1 + R346K |
No changeb |
BA.2 |
South Africa |
Omicron [BA.2] |
G339D + S371F + S373P + S375F + T376A + D405N + R408S + K417N + N440K + S477N + T478K + E484A + Q493R + Q498R + N501Y + Y505H |
No changeb |
BA.2.12.1 |
USA |
Omicron [BA.2+L452Q] |
BA.2 + L452Q |
No changeb |
BA.2.75 |
India |
Omicron [BA.2+D339H, G446S, N460K, R493Q (reversion)] |
BA.2 + D339H + G446S + N460K + R493Q (reversion) |
No changeb |
BA.2.75.2 |
India |
Omicron [BA.2.75+R346T+F486S] |
BA.2.75 + R346T + F486S |
No changeb |
BA.4/BA.5 |
South Africa |
Omicron [BA.4/BA.5] |
G339D + S371F + S373P + S375F + T376A + D405N + R408S + K417N + N440K + L452R + S477N + T478K + E484A + F486V + Q498R + N501Y + Y505H |
No changeb |
BA.4.6/BF.7 |
USA/Belgium |
Omicron [BA.4+R346T] |
BA.4 + R346T |
No changeb |
BQ.1 |
Nigeria |
Omicron [BA.5+K444T+N460K] |
BA.5 + K444T + N460K |
>672d |
BQ.1.1 |
Multiple |
Omicron [BA.5+R346T+K444T+N460K] |
BA.5 + R346T + K444T + N460K |
>672d |
Abbreviations: UK = United Kingdom; USA = United States of America; WHO = World Health Organization.
aKey substitutions occurring in the receptor binding domain of spike protein are listed. Pseudotyped VLP contained the full-length spike protein reflective of the consensus sequence for each of the variant lineages with the exception of BA.2.75.2 which is a full-length spike of BA.2.75+R346T+F486S substitutions.
bNo change: <5-fold reduction in susceptibility
cIsolates 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).
dBebtelovimab is unlikely to be active against this variant.
In authentic SARS-CoV-2 assays, bebtelovimab retained activity (<5-fold reduction) against variant virus isolates from the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2/AY.3), Omicron (B.1.1.529/BA.1), Omicron [+R346K] (BA.1.1), Omicron BA.2, Omicron BA.2 [+L452Q] (BA.2.12.1), Omicron BA.2 [+D339H, G446S, N460K, R493Q (reversion)] (BA.2.75), Omicron BA.4, Omicron BA.4 [+R346T] (BA.4.6), and Omicron BA.5 lineages, as well as SARS-CoV-2 (USA/WA/1/2020 isolate) engineered to express the L452R substitution present in the Epsilon (B.1.427/B.1.429) lineage or the E484K substitution present in the Iota (B.1.526) lineage (see ).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 |
|
P.1 |
Brazil |
Gamma |
K417T, E484K, N501Y |
No changec |
B.1.617.2/AY.3 |
India |
Delta |
L452R, T478K |
|
B.1.427/B.1.429 |
USA (California) |
Epsilon |
L452R |
No changec |
B.1.526e |
USA (New York) |
Iota |
E484K |
No changec |
B.1.1.529/BA.1 |
South Africa |
Omicron |
G339D + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G496S + Q498R + N501Y + Y505H |
|
BA.1.1 |
South Africa |
Omicron [+R346K] |
BA.1 + R346K |
No changec |
BA.2 |
South Africa |
Omicron [BA.2] |
G339D + S371F + S373P + S375F + T376A + D405N + R408Q + K417N + N440K + S477N + T478K + E484A + Q493R + Q498R + N501Y + Y505H |
|
BA.2.12.1 |
USA |
Omicron [BA.2+L452Q] |
BA.2 + L452Q |
No changec |
BA.2.75 |
India |
Omicron [BA.2+D339H, G446S, N460K, R493Q (reversion)] |
BA.2 + D339H + G446S + N460K + R493Q (reversion) |
|
BA.4 |
South Africa |
Omicron [BA.4] |
G339D + S371F + S373P + S375F + T376A + D405N + R408S + K417N + N440K + L452R + S477N + T478K + E484A + F486V + Q498R + N501Y + Y505H |
No changec |
BA.4.6 |
USA |
Omicron [BA.4+R346T] |
BA.4 + R346T |
No changec |
BA.5 |
South Africa |
Omicron [BA.4/BA.5] |
G339D + S371F + S373P + S375F + T376A + D405N + R408S + K417N + N440K + L452R + S477N + T478K + E484A + F486V + Q498R + N501Y + Y505H |
No changec |
Abbreviations: UK = United Kingdom; USA = United States of America; WHO = World Health Organization.
aThe B.1.1.7, B.1.351, B.1.617.2, B.1.1.529/BA.1, and BA.2 variants were assessed using cell culture-expanded virus isolates and tested using a plaque reduction assay; the B.1.351, P.1, B.1.617.2, B.1.1.529/BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, BA.4, BA.4.6, and BA.5 variants were assessed using cell culture-expanded isolates and tested using a microneutralization assay with a CPE-based endpoint titer to determine the IC>99; the B.1.526/E484K, B.1.427/B.1.429/L452R and BA.2.75 spike substitutions were assessed using recombinant SARS-CoV-2 (USA/WA/1/2020 isolate with E484K, L452R, or full spike of BA.2.75) 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 when compared to ancestral control isolate using the same methodology.
dThese viral variants have been tested with two different neutralization methodologies, both yielding <5-fold reductions in susceptibility.
eIsolates 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).
Genotypic Analysis of Clinical Samples from Participants Treated with Bebtelovimab
Genotypic analysis and phenotypic testing are ongoing to monitor for potential bebtelovimab-resistance-associated spike variations in clinical trials.1
Baseline Sequencing Results
Baseline sequencing data are available for 611 of the patients in the BLAZE-4 (Arms 9-14) study. Of these, 552 (90.3%) were infected with a variant of interest or concern, as designated by the World Health Organization (WHO). No subject was infected with virus of the Omicron lineage or sub-lineages.1
The majority of patients in the trial were infected with Delta (49.9%) and Alpha (28.6%).1 These were distributed across the treatment groups with Delta and Alpha infection rates of
- 60.2% and 23.1% in placebo
- 31.3% and 41.8% in bebtelovimab alone arms, and
- 58.3% and 21.9% in the bebtelovimab, bamlanivimab and etesevimab arms.1
Gamma and Mu infections comprised 5.6% and 3.8% of the total infections respectively.1
Patients infected with other WHO-classified variants were the minority of the total infections with
- Beta comprising 0.5%
- Delta +K417N comprising 0.8%
- Iota comprising 0.7%, and
- Lambda comprising 0.5%.1
All other patients in the trial had SARS-CoV-2 infections from either non-WHO classified viruses (3.3%), or the lineage was not able to be determined based on the baseline sequence data (6.4%).1
Baseline Variants With Reduced Susceptibility to Bebtelovimab
Detection of viral variants with a ≥5-fold reduction in susceptibility to bebtelovimab at baseline has been rare, with only one G446V substitution (8-fold shift) observed transiently out of 611 patients in the BLAZE-4 (Arms 9-14) study that had baseline sequencing available (0.2%, 1/611).1
Treatment-emergent Variants
Analysis of treatment-emergent variants focused on changes at amino acid positions with known phenotypically confirmed bebtelovimab-associated variations (ie, K444, V445, G446, and P499) in serial viral samples obtained in the BLAZE-4 (Arms 9-14) bebtelovimab Phase 2 Study.1
Treatment-emergent substitutions detected at ≥15% or ≥50% allele fractions at these positions included K444E/N, V445G, G446V, and P499H/R. These substitutions resulted in a 5-fold or greater reduction in susceptibility to bebtelovimab in pseudotyped VLP assays: K444E (>862), K444N (>1,901-fold), V445G (>730-fold), G446V (8-fold), P499H (>1,606-fold), and P499R (>1,870-fold). Additional treatment-emergent substitutions detected at ≥15% or >50% allele fractions outside the epitope in at least 2 subjects included C379F (n=2) and G404C (n=2), seen in bebtelovimab in combination with bamlanivimab and etesevimab arms.1
Considering all substitutions detected at ≥15% allele fraction at positions K444, V445, G446, and P499, 5.5% (11/199) of patients treated with bebtelovimab alone harbored a variant that was treatment-emergent. This was more frequent than observed in placebo arm (0%, 0/112) or when bebtelovimab was administered together with bamlanivimab and etesevimab (0.3%, 1/312).1
The appearance of these treatment-emergent bebtelovimab resistance-associated substitutions was associated with higher viral loads in the subjects in whom they were detected, but none of these patients were hospitalized.1 The majority of the variants were first detected on Day 5 (n=3) and Day 7 (n=6) following treatment initiation.1
Cross-Resistance with Other Monoclonal Antibodies
It is possible that bebtelovimab 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.1
Enclosed Fact Sheet Information
References
1Fact sheet for healthcare providers. Emergency Use Authorization (EUA) of bebtelovimab. US Food and Drug Administration (FDA). 2022.
2United States Food and Drug Administration. Bebtelovimab FDA Emergency Use Authorization letter. Issued August 5, 2022. Accessed August 8, 2022. http://pi.lilly.com/eua/bebtelovimab-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 February 5. 2022. https://www.gisaid.org/hcov19-variants/
5Centers for Disease Control and Prevention. What you need to know about variants. Updated February 2, 2022. Accessed February 5, 2022. https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant.html
6Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Date of Last Review: November 04, 2022