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Antiviral Resistance

  • Bebtelovimab has not been approved, but has been authorized for emergency use by the FDA under an EUA, 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) 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.
  • The emergency use of bebtelovimab is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the declaration is terminated or authorization is revoked sooner.

There is a potential risk of treatment failure due to the development of viral variants that are resistant to bebtelovimab. There are other authorized treatments available and healthcare providers should choose an authorized therapeutic option with activity against circulating variants in their state, territory, or US jurisdiction. Variant frequency data for states, territories, and U.S. jurisdictions can be accessed here.

Table 1: Bebtelovimab Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Spike Protein Variants

Lineage with Spike Protein Substitution Country First Identified WHO Nomenclature Key Substitutions Testeda Fold Reduction in Susceptibility
Lineage with Spike Protein Substitution: B.1.1.7 Country First Identified: UK WHO Nomenclature: Alpha Key Substitutions Testeda: N501Y Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: B.1.351 Country First Identified: South Africa WHO Nomenclature: Beta Key Substitutions Testeda: K417N + E484K + N501Y Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: P.1 Country First Identified: Brazil WHO Nomenclature: Gamma Key Substitutions Testeda: K417T + E484K + N501Y Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: B.1.617.2/AY.3 Country First Identified: India WHO Nomenclature: Delta Key Substitutions Testeda: L452R + T478K Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: AY.1/AY.2
(B.1.617.2 sublineages)
Country First Identified: India WHO Nomenclature: Delta
[+K417N]
Key Substitutions Testeda: L452R + T478K + K417N Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: B.1.427/B.1.429 Country First Identified: USA (California) WHO Nomenclature: Epsilon Key Substitutions Testeda: L452R Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: B.1.526c Country First Identified: USA (New York) WHO Nomenclature: Iota Key Substitutions Testeda: E484K Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: B.1.617.1 Country First Identified: India WHO Nomenclature: Kappa Key Substitutions Testeda: L452R + E484Q Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: C.37 Country First Identified: Peru WHO Nomenclature: Lambda Key Substitutions Testeda: L452Q + F490S Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: B.1.621 Country First Identified: Colombia WHO Nomenclature: Mu Key Substitutions Testeda: R346K + E484K + N501Y Fold Reduction in Susceptibility: 5.3
Lineage with Spike Protein Substitution: B.1.1.529/BA.1 Country First Identified: South Africa WHO Nomenclature: Omicron Key Substitutions Testeda: G339D + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G493S + Q498R + N501Y + Y505H Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: BA.1.1 Country First Identified: South Africa WHO Nomenclature: Omicron [+R346K] Key Substitutions Testeda: G339D + R346K + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G496S + Q498R + N501Y + Y505H Fold Reduction in Susceptibility: No changeb
Lineage with Spike Protein Substitution: BA.2 Country First Identified: South Africa WHO Nomenclature: Omicron [BA.2] Key Substitutions Testeda: G339D + S371F + S373P + S375F + T376A + D405N + R408S + K417N + N440K + S477N + T478K + E484A + Q493R + Q498R + N501Y + Y505H Fold Reduction in Susceptibility: No changeb

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).

Table 2: Authentica SARS-CoV-2 Neutralization Data for Bebtelovimab

Lineage with Spike Protein Substitution Country First Identified WHO Nomenclature Key Substitutions Testedb Fold Reduction in Susceptibility
Lineage with Spike Protein Substitution: B.1.1.7 Country First Identified: UK WHO Nomenclature: Alpha Key Substitutions Testedb: N501Y Fold Reduction in Susceptibility: No changec
Lineage with Spike Protein Substitution: B.1.351 Country First Identified: South Africa WHO Nomenclature: Beta Key Substitutions Testedb: K417N, E484K, N501Y Fold Reduction in Susceptibility: No changec
Lineage with Spike Protein Substitution: B.1.617.2/AY.3 Country First Identified: India WHO Nomenclature: Delta Key Substitutions Testedb: L452R, T478K Fold Reduction in Susceptibility: No changec
Lineage with Spike Protein Substitution: B.1.427/B.1.429 Country First Identified: USA (California) WHO Nomenclature: Epsilon Key Substitutions Testedb: L452R Fold Reduction in Susceptibility: No changec
Lineage with Spike Protein Substitution: B.1.526d Country First Identified: USA (New York) WHO Nomenclature: Iota Key Substitutions Testedb: E484K Fold Reduction in Susceptibility: No changec
Lineage with Spike Protein Substitution: B.1.1.529/BA.1 Country First Identified: South Africa WHO Nomenclature: Omicron Key Substitutions Testedb: G339D + S371L + S373P + S375F + K417N + N440K + G446S + S477N + T478K + E484A + Q493R + G496S + Q498R + N501Y + Y505H Fold Reduction in Susceptibility: No changec

aThe B.1.1.7, 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.1.1.529 variant was assessed using cell culture-expanded isolate 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.
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).

Genotypic analysis and phenotypic testing are ongoing to monitor for potential bebtelovimab-resistance-associated spike variations in clinical trials. Baseline sequencing data were available for 611 of the subjects 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 WHO. No subject was infected with virus of the Omicron lineage or sub-lineages. The majority of subjects in the trial were infected with Delta (49.8%) and Alpha (28.6%). 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 with bamlanivimab and etesevimab arms, respectively. Gamma and Mu infections comprised 5.6% and 3.8% of the total infections respectively. Subjects infected with Beta, Delta [ +K417N ], Iota, and Lambda variants were the minority with 0.5%, 0.8%, 0.7%, and 0.5% total infections, respectively. All other subjects 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%). Detection of viral variants with a 5-fold or greater reduction in susceptibility to bebtelovimab at baseline have been rare, with only one G446V substitution (8-fold shift) observed transiently out of 611 subjects in the BLAZE-4 (Arms 9-14) study that had baseline sequencing available (0.2%, 1/611).

Authorized Use

Bebtelovimab is authorized to be administered 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 risk1 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.

Limitations of Authorized Use

  • Bebtelovimab is not authorized for treatment of mild-to-moderate COVID-19 in geographic regions where infection is likely to have been caused by a non-susceptible SARS-CoV-2 variant based on available information including variant susceptibility to this drug and regional variant frequency.
    • FDA will monitor conditions to determine whether use in a geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility, and CDC regional variant frequency data available at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions.
    • FDA's determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs.
  • Bebtelovimab is not authorized for use in patients, who:
    • are hospitalized due to COVID-19, OR
    • require oxygen therapy and/or respiratory support due to COVID-19, OR
    • require an increase in baseline oxygen flow rate and/or respiratory support due to COVID-19 and are on chronic oxygen therapy and/or respiratory support due to underlying non-COVID-19 related comorbidity.
  • Treatment with bebtelovimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bebtelovimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation.
  • Bebtelovimab is not FDA-approved for any use, including for use as treatment of COVID-19.
  • Bebtelovimab is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of bebtelovimab under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb 3(b)(1), unless the authorization is terminated or revoked sooner.

IMPORTANT SAFETY INFORMATION

There are limited clinical data available for bebtelovimab. Serious and unexpected adverse events may occur that have not been previously reported with bebtelovimab use.

WARNINGS
Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of other SARS-CoV-2 monoclonal antibodies and could occur with administration of bebtelovimab. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration, and initiate appropriate medications and/or supportive care.

Infusion-related reactions, which may occur up to 24 hours after the injection, have been observed in clinical trials of bebtelovimab when administered with other monoclonal antibodies and may occur with use of bebtelovimab alone. These reactions may be severe or life-threatening. Signs and symptoms of infusion-related reactions may include:

  • fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g. atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions (e.g. pre-syncope, syncope), dizziness, and diaphoresis.

Administer appropriate medications and/or supportive care if an infusion-related reaction occurs.

Hypersensitivity reactions occurring more than 24 hours after the injection have also been reported with the use of SARS-CoV-2 monoclonal antibodies under Emergency Use Authorization.

Clinical Worsening After Monoclonal Antibody Administration

Clinical worsening of COVID-19 after administration of SARS-CoV-2 monoclonal antibody treatment has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to SARS-CoV-2 monoclonal antibody use or were due to progression of COVID-19.

Limitations of Benefit and Potential Risk in Patients with Severe COVID-19

Treatment with bebtelovimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bebtelovimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation. See Limitations of Authorized Use.

Adverse Reactions

Adverse reactions observed in those who have received bebtelovimab, alone or in combination with bamlanivimab and etesevimab, at the authorized dose or higher, are infusion-related reactions (n=2, 0.3%), pruritus (n=2, 0.3%) and rash (n=5, 0.8%). The most common treatment-emergent adverse events observed in subjects treated with bebtelovimab, alone or in combination with bamlanivimab and etesevimab, at the authorized dose or higher, included nausea (0.8%) and vomiting (0.7%).

USE IN SPECIFIC POPULATIONS
Pregnancy

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Bebtelovimab should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.

Breastfeeding

There are no available data on the presence of bebtelovimab in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

Healthcare providers should review the Fact Sheet for Healthcare Providers for information on the authorized use of bebtelovimab and mandatory requirements of the EUA. Please also see the FDA Letter of Authorization and the Fact Sheet for Patients, Parents and Caregivers on the authorized use of bebtelovimab.

BB HCP EUA ISI 11FEB2022

1For information on medical conditions and factors associated with increased risk for progression to severe COVID-19, see the Centers for Disease Control and Prevention (CDC) website: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient.

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