bebtelovimab

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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.

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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

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:

  • 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), and Omicron BA.2 variant lineages (see Bebtelovimab Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Spike Protein Variants ). The Mu (B.1.621, Colombia origin) variant showed a reduction in susceptibility to bebtelovimab of 5.3-fold.1

Bebtelovimab Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Spike Protein Variants 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
(B.1.617.2 sublineages)

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

G339D + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G496S + Q498R + N501Y + Y505H

No changeb

BA.1.1

South Africa

Omicron [+R346K]

G339D + R346K + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G496S + Q498R + N501Y + Y505H

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

 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) 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

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).

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), and Omicron [+R346K] (BA.1.1) 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 Authentic SARS-CoV-2 Neutralizing Data for Bebtelovimab).1

Authentica SARS-CoV-2 Neutralizing Data for Bebtelovimab1

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

No changecd

P.1

Brazil

Gamma

K417T, E484K, N501Y

No changec

B.1.617.2/AY.3

India

Delta

L452R, T478K

No changecd

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

No changecd

BA.1.1

South Africa

Omicron [+R346K]

G339D + R346K + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G496S + 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, and B.1.1.529/BA.1 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, and BA.1.1 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 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 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 were available for 611 of the patients in the BLAZE-4 (Arms 9-14) study. Of these, 551 (90.2%) 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 (49.8%) 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 (2.9%), or the lineage was not able to be determined based on the baseline sequence data (6.9%).1

Baseline Variants With Reduced Susceptibility to Bebtelovimab

Detection of viral variants with a ≥5-fold reduction in susceptibility to bebtelovimab at baseline have 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

Preliminary 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 K444N, V445G, G446V, and P499H/R. These substitutions resulted in a 5-fold or greater reduction in susceptibility to bebtelovimab in pseudotyped VLP assays: K444N (>1,901-fold), V445G (>730-fold), G446V (8-fold), P499H (>1,606-fold), and P499R (>1,870-fold). Additional treatment-emergent substitutions with no phenotypic data detected at an epitope contact position included K444E (n=1), seen in BEB-only arms, or detected at ≥15% or >50% allele fractions outside the epitope in at least 2 subjects included Q321H (n=2), 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, 5.0% (10/199) 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

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 February 11, 2022. Accessed February 11, 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: March 25, 2022


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