Этесевимаб инструкция по применению цена

1.1 TREATMENT

Bamlanivimab and etesevimab administered together are authorized for use under an EUA for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients, including neonates, 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.

Limitations of Authorized Use

• Bamlanivimab and etesevimab are 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 these drugs and regional variant frequency.
  • 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.1
• Bamlanivimab and etesevimab are not authorized for use in patients 2 years and older who are hospitalized due to COVID-19.2
• Bamlanivimab and etesevimab are not authorized for use in patients, regardless of age, who:
  • 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 bamlanivimab and etesevimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation [see Warnings and Precautions (5.3)].

1.2 POST-EXPOSURE PROPHYLAXIS

Bamlanivimab and etesevimab administered together are authorized for use under an EUA for post-exposure prophylaxis of COVID-19 in adults and pediatric individuals, including neonates, who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:

• not fully vaccinated3 or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications4) and
  • have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)5 or
  • who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons).

Limitations of Authorized Use

• Bamlanivimab and etesevimab are not authorized for post-exposure prophylaxis of COVID-19 in geographic regions where exposure is likely to have been to a non-susceptible SARS-CoV-2 variant based on available information including variant susceptibility to these drugs and regional variant frequency.
  • 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.1
• Post-exposure prophylaxis with bamlanivimab and etesevimab is not a substitute for vaccination against COVID-19.
• Bamlanivimab and etesevimab are not authorized for pre-exposure prophylaxis for prevention of COVID-19.

2.1 Patient Selection

The following medical conditions or other factors may place adults and pediatric patients, including neonates, at higher risk for progression to severe COVID-19:

• Older age (for example age ≥65 years of age)
• <1 year old
• Obesity or being overweight
• Pregnancy
• Chronic kidney disease
• Diabetes
• Immunosuppressive disease or immunosuppressive treatment
• Cardiovascular disease (including congenital heart disease) or hypertension
• Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension)
• Sickle cell disease
• Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)
• Having a medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19))

Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and authorization of bamlanivimab and etesevimab under the EUA is not limited to the medical conditions or factors listed above. For additional information on medical conditions and factors associated with increased risk for progression to severe COVID-19, see the 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.

2.2 Dosage

Treatment:

The dosage in adults (18 years and older) and pediatric patients (<18 years and weighing at least 40 kg) is bamlanivimab 700 mg and etesevimab 1,400 mg. The dosage for pediatric patients weighing less than 40 kg will vary depending on body weight:

• >20 kg to <40 kg: 350 mg bamlanivimab and 700 mg etesevimab
• >12 kg to 20 kg: 175 mg bamlanivimab and 350 mg etesevimab
• 1 kg to 12 kg: 12 mg/kg bamlanivimab and 24 mg/kg etesevimab

The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Use in Specific Populations (11.3) and Clinical Trials and Supporting Data for EUA (18.1)].

For treatment of COVID-19, bamlanivimab and etesevimab should be administered together as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset.

Post-Exposure Prophylaxis:

The dosage in adults (18 years and older) and pediatric individuals (<18 years and weighing at least 40 kg) is 700 mg bamlanivimab and 1,400 mg etesevimab administered together as a single intravenous infusion. The dosage for pediatric individuals weighing less than 40 kg will vary depending on body weight:

• >20 kg to <40 kg: 350 mg bamlanivimab and 700 mg etesevimab
• >12 kg to 20 kg: 175 mg bamlanivimab and 350 mg etesevimab
• 1 kg to 12 kg: 12 mg/kg bamlanivimab and 24 mg/kg etesevimab

The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Use in Specific Populations (11.3) and Clinical Trials and Supporting Data for EUA (18.1)]. Children were not enrolled in the post-exposure prophylaxis trial, BLAZE-2 [see Clinical Trials and Supporting Data for EUA (18.2)].

For post-exposure prophylaxis, bamlanivimab and etesevimab should be given together as soon as possible following exposure to SARS-CoV-2.

Under this EUA, bamlanivimab and etesevimab must be administered together as a single intravenous infusion.

2.3 Dosage Adjustment in Specific Populations

Pregnancy or Lactation

No dosage adjustment is recommended in pregnant or lactating women [see Use in Specific Populations (11.1, 11.2)].

Pediatric Use

No dosage adjustment is recommended in pediatric patients <18 years who weigh at least 40 kg. For pediatric patients weighing less than 40 kg, dosage adjustment on the basis of body weight is required [see Dosage and Administration (2.4)]. The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Use in Specific Populations (11.3) and Clinical Trials and Supporting Data for EUA (18.1)]. Children were not enrolled in the post-exposure prophylaxis trial, BLAZE-2 [see Clinical Trials and Supporting Data for EUA (18.2)].

Geriatric Use

No dosage adjustment is recommended in geriatric patients [see Use in Specific Populations (11.4)].

Renal Impairment

No dosage adjustment is recommended in patients with renal impairment [see Use in Specific Populations (11.5)].

Hepatic Impairment

No dosage adjustment is recommended in patients with mild hepatic impairment. Bamlanivimab and etesevimab has not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (11.6)].

2.4 Dose Preparation and Administration

5.1 Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of bamlanivimab and etesevimab. 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, occurring during the infusion and up to 24 hours after the infusion, have been observed with administration of bamlanivimab and etesevimab together. These reactions may be severe or life threatening.

Signs and symptoms of infusion related reactions may include [see Overall Safety Summary (6.1)]:

• 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.

Consider slowing or stopping the infusion and administer appropriate medications and/or supportive care if an infusion-related reaction occurs.

Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of bamlanivimab and etesevimab under Emergency Use Authorization.

5.2 Clinical Worsening After Bamlanivimab and Etesevimab Administration

Clinical worsening of COVID-19 after administration of bamlanivimab and etesevimab together 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 bamlanivimab and etesevimab use or were due to progression of COVID-19.

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

Treatment with bamlanivimab and etesevimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore,

• Bamlanivimab and etesevimab are not authorized for use in patients 2 years and older who are hospitalized due to COVID-192,
• Bamlanivimab and etesevimab are not authorized for use in patients, regardless of age, who:
  • 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 [see Limitations of Authorized Use (1.1)].

6.1 Clinical Trials Experience

11.1 Pregnancy

11.2 Lactation

11.3 Pediatric Use

Bamlanivimab and etesevimab administered together are authorized for the treatment of mild to moderate COVID-19 and post-exposure prophylaxis for prevention of COVID-19 in pediatric patients, including neonates [see Authorized Use (1)]. Given the similar course of COVID-19, the authorization of bamlanivimab and etesevimab for treatment and post-exposure prophylaxis in younger pediatric patients, including neonates, is supported by safety and efficacy data in adolescents and adults, together with additional pharmacokinetic and safety data from the clinical trial in pediatric patients studying bamlanivimab and etesevimab for the treatment of mild to moderate COVID-19.

Use of bamlanivimab and etesevimab in pediatric patients is based on analyses of data from BLAZE-1 in subjects aged 10 months to 18 years of age [see Clinical Pharmacology (14.3) and Clinical Trials and Supporting Data for EUA (18.1)]. No dosage adjustment is recommended in pediatric patients 12-18 years of age who weigh at least 40 kg. Pediatric patients weighing less than 40 kg should be dosed on the basis of body weight [see Dosage and Administration (2.2, 2.4)]. The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Clinical Trials and Supporting Data for EUA (18.1)]. Safety in pediatric patients was similar to what was observed in adults [see Clinical Trial Experience (6.1)]. Children were not enrolled in the post-exposure prophylaxis trial, BLAZE-2 [see Clinical Trials and Supporting Data for EUA (18.2)].

11.4 Geriatric Use

Of the 1141 patients receiving bamlanivimab and etesevimab in BLAZE-1, 30% were 65 years of age and older and 10% were 75 years of age and older. Based on population PK analyses, there is no difference in PK of bamlanivimab or etesevimab in geriatric patients compared to younger patients [see Clinical Trial Results and Supporting Data for EUA (18.1)].

11.5 Renal Impairment

Bamlanivimab and etesevimab are not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of bamlanivimab or etesevimab.

11.6 Hepatic Impairment

Based on population PK analysis, there is no difference in PK of bamlanivimab or etesevimab in patients with mild hepatic impairment compared to patients with normal hepatic function. Bamlanivimab and etesevimab have not been studied in patients with moderate or severe hepatic impairment.

11.7 Other Specific Populations

Based on population PK analysis, the PK of bamlanivimab and etesevimab was not affected by sex, race, or disease severity. Body weight had no clinically relevant effect on the PK of bamlanivimab and etesevimab in adults with COVID-19 over the body weight range of 41 kg to 173 kg.

Bamlanivimab

Bamlanivimab is a human immunoglobulin G-1 (IgG1 variant) monoclonal antibody consisting of 2 identical light chain polypeptides composed of 214 amino acids each and 2 identical heavy chain polypeptides composed of 455 amino acids produced by a Chinese Hamster Ovary (CHO) cell line and molecular weight of 146 kDa.

Bamlanivimab injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution in a vial for intravenous infusion.

Each mL contains 35 mg of bamlanivimab, and L-histidine (0.4 mg), L-histidine hydrochloride monohydrate (0.6 mg), sodium chloride (2.9 mg), sucrose (60 mg), polysorbate 80 (0.5 mg), and Water for Injection. The bamlanivimab solution has a pH range of 5.5-6.5.

Etesevimab

Etesevimab is a human IgG1 variant monoclonal antibody (mAb) consisting of 2 identical light chain polypeptides composed of 216 amino acids each and 2 identical heavy chain polypeptides composed of 449 amino acids produced by a Chinese Hamster Ovary (CHO) cell line and molecular weight of 145 kDa.

Etesevimab injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution in a vial for intravenous infusion.

Each mL contains 35 mg of etesevimab, L-histidine (1.55 mg), L-histidine hydrochloride monohydrate (2.10 mg), sucrose (80.4 mg), polysorbate 80 (0.5 mg), and Water for injection. The etesevimab solution has a pH range of 5.5.-6.5.

14.1 Mechanism of Action

Bamlanivimab is a recombinant neutralizing human IgG1ϰ monoclonal antibody (mAb) to the spike protein of SARS-CoV-2 and is unmodified in the Fc region. Bamlanivimab binds the spike protein with a dissociation constant KD = 0.071 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.17 nM (0.025 μg/mL).

Etesevimab is a recombinant neutralizing human IgG1ϰ mAb to the spike protein of SARS-CoV-2, with amino acid substitutions in the Fc region (L234A, L235A) to reduce effector function. Etesevimab binds the spike protein with a dissociation constant KD = 6.45 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.32 nM (0.046 μg/mL).

Bamlanivimab and etesevimab bind to different but overlapping epitopes in the receptor binding domain (RBD) of the S-protein. Using both antibodies together is expected to reduce the risk of viral resistance.

14.2 Pharmacodynamics

A flat exposure-response relationship for efficacy was identified for bamlanivimab and etesevimab administered together within the dose range of 700 mg bamlanivimab and 1,400 mg etesevimab to 2,800 mg bamlanivimab and 2,800 mg etesevimab (4 and 2 times the authorized dose, respectively), based on clinical data and pharmacokinetic/pharmacodynamic modeling.

For post-exposure prophylaxis of COVID-19, a dose of 700 mg bamlanivimab and 1,400 mg etesevimab was supported based on clinical data and pharmacokinetic/pharmacodynamic modeling.

14.3 Pharmacokinetics

A summary of PK parameters of bamlanivimab and etesevimab following administration of a single dose of 700 mg bamlanivimab and 1,400 mg etesevimab is provided in Table 3. There is no change in PK of bamlanivimab or etesevimab administered alone or together suggesting there is no interaction between the two antibodies. There were no differences in PK of etesevimab between mild/moderate ambulatory participants and healthy participants.

Bamlanivimab and etesevimab are expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies.

Antiviral Activity

The cell culture neutralization activity of bamlanivimab and of etesevimab against SARS-CoV-2 was measured in a dose-response model quantifying plaque reduction using cultured Vero E6 cells. Bamlanivimab, etesevimab and a 1:1 (weight/weight) ratio of bamlanivimab and etesevimab together neutralized the USA/WA/1/2020 isolate of SARS-CoV-2 with estimated EC50 values = 0.14 nM (0.02 μg/mL), 0.97 nM (0.14 μg/mL) and 0.14 nM (0.02 μg/mL), respectively.

Bamlanivimab demonstrated antibody-dependent cell-mediated cytotoxicity on reporter Jurkat cells expressing FcγRIIIa following engagement with target cells expressing spike protein. Bamlanivimab did not elicit complement-dependent cytotoxicity activity in cell-based assays.

Etesevimab did not demonstrate detectable antibody-dependent cell-mediated cytotoxicity on Jurkat reporter cells expressing FcγRIIIa. Etesevimab did not elicit complement-dependent cytotoxicity activity in cell-based assays.

Antibody Dependent Enhancement (ADE) of Infection

The risk that bamlanivimab and etesevimab could mediate viral uptake and replication by immune cells was studied in THP-1 and Raji cell lines and primary human macrophages. In general, experiments with bamlanivimab, with etesevimab, and with bamlanivimab and etesevimab together did not demonstrate productive viral infection in immune cells exposed to SARS-CoV-2 at concentrations of mAb(s) down to at least 100-fold below the respective EC50 value(s).

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 (Table 5). 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 US jurisdictions can be accessed on the following CDC website: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html.

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. 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, and 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. Retention of susceptibility to the other antibody alone was observed, with the exception of the E484D and Q493R substitution. 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 1,054-fold, respectively in a pseudotyped VLP assay.

Evaluation of susceptibility of variants identified through global surveillance in subjects treated with bamlanivimab and etesevimab is ongoing. Pseudotyped VLP evaluation of amino acid substitutions identified in global surveillance showed that the V483A substitution reduced susceptibility to bamlanivimab 48-fold, but activity was maintained with etesevimab, and with bamlanivimab and etesevimab together. N501Y and N501T substitutions reduced susceptibility to etesevimab approximately 5-fold and 20-fold, respectively. Activity against variants with N501Y or N501T substitutions was maintained with bamlanivimab alone, and with bamlanivimab and etesevimab together.

Bamlanivimab and etesevimab together retained activity against a SARS-CoV-2 B.1.1.7 lineage (Alpha; UK origin) virus and related pseudotyped VLPs expressing the spike protein found in the B.1.1.7 variant (Tables 5 and 6). SARS-CoV-2 B.1.351 lineage (Beta; South Africa origin) virus and related pseudotyped VLPs expressing spike proteins from B.1.351 lineage or substitutions K417N + E484K + N501Y found in this lineage had reduced susceptibility to bamlanivimab and etesevimab together of >324, 431-fold or >45-fold, respectively. Pseudotyped VLPs expressing spike protein from the P.1 lineage (Gamma; Brazil origin) or K417T + E484K + N501Y found in the P.1 lineage had reduced susceptibility to bamlanivimab and etesevimab together of 252-fold or >3,351-fold, respectively.

Bamlanivimab and etesevimab together and etesevimab alone retained activity against SARS-CoV-2 B.1.617.2 lineage (Delta; India origin) virus and related pseudotyped VLPs, but bamlanivimab alone had reduced activity (>1,136 and >1,868-fold, respectively). Bamlanivimab and etesevimab are expected to retain activity against B.1.617.2 sublineage AY.3 (India origin). B.1.617.2 sublineages AY.1/AY.2 (India origin) have an additional K417N substitution; pseudotyped VLPs expressing AY.1/AY.2 related spike sequence had a reduced susceptibility to bamlanivimab and etesevimab together of 1,235-fold. SARS-CoV-2 recombinant virus containing the L452R substitution present in B.1.427/B.1.429 lineages (Epsilon; USA [California] origin) and pseudotyped VLPs expressing the full-length spike protein or the L452R substitution found in this lineage showed reduced susceptibility to bamlanivimab and etesevimab together of 11-fold, 9-fold or 5-fold, respectively. Pseudotyped VLPs expressing spike protein from the B.1.617.1 lineage (Kappa; India origin) showed reduced susceptibility to bamlanivimab and etesevimab together of 6-fold; for this variant, susceptibility to etesevimab alone was maintained, but not to bamlanivimab alone (>1,030-fold reduction). Bamlanivimab and etesevimab together and etesevimab alone retained activity against pseudotyped VLPs expressing the full-length spike protein from the C.37 lineage (Lambda; Peru origin), but bamlanivimab alone had reduced activity (>2,112-fold reduction). Pseudotyped VLPs expressing spike protein from the B.1.621 lineage (Mu; Colombia origin) show reduced susceptibility to bamlanivimab and etesevimab together of 116-fold, due to susceptibility reductions to bamlanivimab (>1,863-fold) and etesevimab (17-fold) alone. Pseudotyped VLPs expressing the spike protein from the B.1.1.529/BA.1 lineage (Omicron; South Africa origin) show reduced susceptibility to bamlanivimab alone (>1,465-fold), etesevimab alone (>616-fold), and bamlanivimab and etesevimab together (>2,938-fold).

Due to the large reduction of pseudotyped VLP neutralization activity of both bamlanivimab and etesevimab against the substitutions in B.1.351 (Beta; South Africa origin), P.1 (Gamma; Brazil origin), AY.1/AY.2 (Delta [+K417N]; India origin), B.1.621 (Mu; Colombia origin), and B.1.1.529/BA.1 (Omicron; South Africa origin), it is unlikely that bamlanivimab and etesevimab together will be active against these variants.

It is unclear how small reductions in susceptibility to bamlanivimab and etesevimab seen in authentic or recombinant SARS-CoV-2 or pseudotyped VLP assays correlate with clinical outcomes.

In authentic SARS-CoV-2 assays, bamlanivimab and etesevimab together retained activity against variants of B.1.1.7 (Alpha) and B.1.617.2/AY.3 (Delta) lineages (Table 6), although bamlanivimab alone had reduced activity to B.1.617.2/AY.3 (Delta) in this assay (>1,136-fold). SARS-CoV-2 (USA/WA/1/2020 isolate) engineered to express the E484K substitution present in the B.1.526 lineage (Iota; USA [New York] origin) or the L452R substitution present in the B.1.427/B.1.429 lineage (Epsilon; USA [California] origin) showed reduced susceptibility to bamlanivimab and etesevimab together of 11-fold. Susceptibility to etesevimab alone was maintained for both isolates, but not to bamlanivimab alone (>833-fold and >1,460-fold reduction for E484K and L452R viruses, respectively). Available nonclinical and clinical PK data indicate that etesevimab at the authorized dose may retain activity against the B.1.526 variant clinically, although only very limited data are currently available from patients infected with this variant in clinical trials. Preliminary clinical evidence indicates that the administration of bamlanivimab and etesevimab together result in similar viral load reductions in participants infected with the L452R variant (Epsilon; USA [California] origin) as observed in those who were infected with bamlanivimab-sensitive strains. Of the 134 participants infected with the L452R variant at baseline in the Phase 3 portion of BLAZE-1, 3 of the 50 individuals treated with placebo (6%) and 1 of the 84 participants treated with bamlanivimab 700 mg and etesevimab 1,400 mg (1%) were hospitalized (p=0.15).

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

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%.

• In the Phase 3 portion of BLAZE-1, treatment-emergent variants were observed in 9.0% (42/467) of patients treated with bamlanivimab 2,800 mg and etesevimab 2,800 mg together, in 5.3% (21/394) of patients treated with bamlanivimab 700 mg and etesevimab 1,400 mg together, and in 4.0% (27/674) of patients treated with placebo. 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 2,800 mg and etesevimab 2,800 mg together, bamlanivimab 700 mg and etesevimab 1,400 mg together, and placebo groups, respectively.
• 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. While these variants had reduced susceptibility to either bamlanivimab OR etesevimab compared to wild-type in a pseudotyped VSV VLP or authentic virus assay they still retained susceptibility to the other antibody in the combination.
• There were also observations of variants with reduced susceptibility (≥5-fold) to both bamlanivimab and etesevimab and to bamlanivimab + etesevimab tested together: E484D (n=1; 145-fold reduction to bamlanivimab + etesevimab tested together at a molar ratio of 1:2), Q493K/R (n=9; 584-fold and 1,054-fold reduction to bamlanivimab + 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.
• 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 1,656-fold reduction in susceptibility to bamlanivimab + etesevimab together (1:2 molar ratio).
• Additional treatment-emergent substitutions in patients treated with bamlanivimab and etesevimab together, with no phenotypic data, include D405del, D420G, C480R, G485D, S494L, and P499L. The impact of these substitutions on susceptibility is not currently known.
• In a subgroup of 53 pediatric subjects who were infected with a B.1.617.2 (Delta)-related variant, which has reduced susceptibility to bamlanivimab (>1,136-fold), the following treatment-emergent substitutions with reduced susceptibility to etesevimab were detected: D420A (n=2), N460T (n=1), N460Y (n=1). Three of these four subjects had high viral load (>5.27 log10) on Day 7.
• Additional treatment-emergent substitutions with no phenotypic data detected in other pediatric subjects who were infected with a B.1.617.2 (Delta)-related variant at an allele fraction of ≥50% included: F347C, V401L, G431S and I434V.

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.

Immune Response Attenuation

There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.

Antiviral Activity In Vivo

Prophylactic administration of bamlanivimab to female Rhesus macaques (n=3 or 4 per group) resulted in 1 to 4 log10 decreases in viral genomic RNA and viral replication (sub-genomic RNA) in bronchoalveolar lavage samples relative to control animals, but less of an impact on viral RNA in throat and nasal swabs following SARS-CoV-2 inoculation.

Prophylactic or therapeutic administration of etesevimab to male Rhesus macaques (n=3 per group) resulted in approximately 4 or 3 log10 average decreases, respectively, in viral genomic RNA in oropharyngeal swabs at Day 4 post infection relative to control animals.

The applicability of these findings to a prophylaxis or treatment setting is not known.

18.1 Treatment of Mild to Moderate COVID-19 (BLAZE-1)

18.2 Post-Exposure Prophylaxis of COVID-19 (BLAZE-2)

The data supporting this EUA for post-exposure prophylaxis of COVID-19 are based on the final analysis of Part 1 of the Phase 3 trial BLAZE-2 (NCT04497987). The database lock occurred after all enrolled subjects completed Day 57. BLAZE-2 Part 1 is a randomized, double-blind, placebo-controlled study evaluating bamlanivimab alone for prevention of COVID-19 in residents and staff of skilled nursing facilities following a confirmed reported case of SARS-CoV-2 infection at the facility. No pediatric participants were enrolled.

All participants in Part 1 were randomized and treated with a single infusion of bamlanivimab 4,200 mg or placebo. Results of baseline testing for SARS-CoV-2 were not known until after the therapy was administered. Those with a positive baseline SARS-CoV-2 RT-PCR test were included in the Treatment Population (N=132) and those with a negative test were included in the Prevention Population (N=966). Individuals in these populations were also required to have a baseline negative SARS-CoV-2 serology test; those who tested positive were only included in the overall safety population.

Data are presented for the Prevention Population only. No data were collected on the type or extent of exposure to the index case in the Prevention Population.

In the overall Prevention Population (N=484 for bamlanivimab 4,200 mg and N=482 for placebo) at baseline, the median age was 53 years (with 29% of subjects aged 65 or older); 75% of subjects were female, 89% were White, 5% were Hispanic or Latino, and 8% were Black. The baseline demographics and disease characteristics were well balanced across bamlanivimab and placebo treatment groups.

The primary endpoint (cases of symptomatic COVID-19 by Day 57) was assessed after all participants in the Prevention Population reached 8 weeks of follow-up, and analysis were adjusted for facility, sex, and role within facility (resident/staff). There were 114 cases of symptomatic COVID-19, with a lower frequency occurring in participants treated with bamlanivimab as compared to placebo (residents and staff; adjusted odds ratio 0.43; p<0.001) reducing the risk of being infected with COVID-19 by up to 57%. As a supplementary analysis, the time to symptomatic COVID-19 is shown for each arm in Figure 2. Four COVID-19-related deaths were reported in the overall Prevention Population; all occurred in the placebo arm (0.8%). No COVID-19-related deaths occurred in the bamlanivimab arm.

Figure 2: Time to symptomatic COVID-19 in the overall prevention population (residents and staff).

For the pre-specified subgroup of nursing home residents, there were 45 cases of symptomatic COVID-19, with a lower frequency in those treated with bamlanivimab versus placebo (adjusted odds ratio 0.20; p<0.001), reducing the risk of being infected with COVID-19 by up to 80%. The time to symptomatic COVID-19 in nursing home residents is shown by treatment arm in Figure 3. In this same cohort of residents within the Prevention Population, 6 deaths due to any cause occurred in residents treated with placebo (4.3%) and 5 deaths due to any cause occurred in residents treated with bamlanivimab (3.1%).

Figure 3: Time to symptomatic COVID-19 in residents only.

For the post-hoc subgroup of patients who met the high risk criteria (all residents and all high risk staff7), there were 75 cases of symptomatic COVID-19, with a lower frequency in those treated with bamlanivimab versus placebo (adjusted odds ratio 0.28; nominal p<0.001), reducing the risk of being infected with COVID-19 by up to 72%.

For the post-hoc subgroup of staff who did not meet high risk criteria, there were 39 cases of symptomatic COVID-19, with less evidence of a preventative effect for bamlanivimab versus placebo (adjusted odds ratio 0.64; nominal p=0.26).

7

All high risk participants in the Prevention Population were either residents in a skilled nursing or assisted living facility, or staff in a skilled nursing or assisted living facility who satisfied at least 1 of the following at the time of screening: were ≥65 years of age, had a BMI ≥35, had CKD, had diabetes, had immunosuppressive disease, were currently receiving immunosuppressive treatment, OR were ≥55 years of age AND had cardiovascular disease, OR hypertension, OR COPD or other chronic respiratory disease.

How Supplied

UNDER THIS EUA, BAMLANIVIMAB AND ETESEVIMAB MUST BE ADMINISTERED TOGETHER.

Bamlanivimab

Bamlanivimab injection is a sterile, preservative-free clear to opalescent and colorless to slightly yellow to slightly brown solution supplied in a vial.

Etesevimab

Etesevimab injection is a sterile, preservative-free clear to opalescent and colorless to slightly yellow to slightly brown solution supplied in a vial.

Bamlanivimab and etesevimab are supplied as:

Storage and Handling

Bamlanivimab is preservative-free. Discard unused portion.

Etesevimab is preservative-free. Discard unused portion.

Store unopened vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

FDA has authorized an extension to the shelf-life (i.e., expiration date) of both bamlanivimab and etesevimab following a thorough review of data submitted by Eli Lilly and Company. The extension applies to all unopened vials of bamlanivimab and etesevimab that have been held in accordance with storage conditions. Confirm the shelf-life of unopened vials of bamlanivimab and etesevimab by batch number at the FDA EUA website under the Drug and Biological Therapeutic Products bamlanivimab and etesevimab. This site includes a complete listing of extended expiration dates by batch number. If the batch number on the vial/carton is not included in this listing, the product is labeled with the correct expiration date.

DO NOT FREEZE, SHAKE, OR EXPOSE TO DIRECT LIGHT.

The prepared infusion solution is intended to be used immediately. If immediate administration is not possible, store infusion solution in the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours and at room temperature (20°C to 25°C [68°F to 77°F]) and for up to 7 hours, including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature prior to administration.

1.1 TREATMENT

Bamlanivimab and etesevimab administered together are authorized for use under an EUA for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients, including neonates, 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.

Limitations of Authorized Use

• Bamlanivimab and etesevimab are 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 these drugs and regional variant frequency.
  • 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.1
• Bamlanivimab and etesevimab are not authorized for use in patients 2 years and older who are hospitalized due to COVID-19.2
• Bamlanivimab and etesevimab are not authorized for use in patients, regardless of age, who:
  • 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 bamlanivimab and etesevimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation [see Warnings and Precautions (5.3)].

1.2 POST-EXPOSURE PROPHYLAXIS

Bamlanivimab and etesevimab administered together are authorized for use under an EUA for post-exposure prophylaxis of COVID-19 in adults and pediatric individuals, including neonates, who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:

• not fully vaccinated3 or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications4) and
  • have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)5 or
  • who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons).

Limitations of Authorized Use

• Bamlanivimab and etesevimab are not authorized for post-exposure prophylaxis of COVID-19 in geographic regions where exposure is likely to have been to a non-susceptible SARS-CoV-2 variant based on available information including variant susceptibility to these drugs and regional variant frequency.
  • 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.1
• Post-exposure prophylaxis with bamlanivimab and etesevimab is not a substitute for vaccination against COVID-19.
• Bamlanivimab and etesevimab are not authorized for pre-exposure prophylaxis for prevention of COVID-19.

2.1 Patient Selection

The following medical conditions or other factors may place adults and pediatric patients, including neonates, at higher risk for progression to severe COVID-19:

• Older age (for example age ≥65 years of age)
• <1 year old
• Obesity or being overweight
• Pregnancy
• Chronic kidney disease
• Diabetes
• Immunosuppressive disease or immunosuppressive treatment
• Cardiovascular disease (including congenital heart disease) or hypertension
• Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension)
• Sickle cell disease
• Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)
• Having a medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19))

Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and authorization of bamlanivimab and etesevimab under the EUA is not limited to the medical conditions or factors listed above. For additional information on medical conditions and factors associated with increased risk for progression to severe COVID-19, see the 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.

2.2 Dosage

Treatment:

The dosage in adults (18 years and older) and pediatric patients (<18 years and weighing at least 40 kg) is bamlanivimab 700 mg and etesevimab 1,400 mg. The dosage for pediatric patients weighing less than 40 kg will vary depending on body weight:

• >20 kg to <40 kg: 350 mg bamlanivimab and 700 mg etesevimab
• >12 kg to 20 kg: 175 mg bamlanivimab and 350 mg etesevimab
• 1 kg to 12 kg: 12 mg/kg bamlanivimab and 24 mg/kg etesevimab

The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Use in Specific Populations (11.3) and Clinical Trials and Supporting Data for EUA (18.1)].

For treatment of COVID-19, bamlanivimab and etesevimab should be administered together as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset.

Post-Exposure Prophylaxis:

The dosage in adults (18 years and older) and pediatric individuals (<18 years and weighing at least 40 kg) is 700 mg bamlanivimab and 1,400 mg etesevimab administered together as a single intravenous infusion. The dosage for pediatric individuals weighing less than 40 kg will vary depending on body weight:

• >20 kg to <40 kg: 350 mg bamlanivimab and 700 mg etesevimab
• >12 kg to 20 kg: 175 mg bamlanivimab and 350 mg etesevimab
• 1 kg to 12 kg: 12 mg/kg bamlanivimab and 24 mg/kg etesevimab

The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Use in Specific Populations (11.3) and Clinical Trials and Supporting Data for EUA (18.1)]. Children were not enrolled in the post-exposure prophylaxis trial, BLAZE-2 [see Clinical Trials and Supporting Data for EUA (18.2)].

For post-exposure prophylaxis, bamlanivimab and etesevimab should be given together as soon as possible following exposure to SARS-CoV-2.

Under this EUA, bamlanivimab and etesevimab must be administered together as a single intravenous infusion.

2.3 Dosage Adjustment in Specific Populations

Pregnancy or Lactation

No dosage adjustment is recommended in pregnant or lactating women [see Use in Specific Populations (11.1, 11.2)].

Pediatric Use

No dosage adjustment is recommended in pediatric patients <18 years who weigh at least 40 kg. For pediatric patients weighing less than 40 kg, dosage adjustment on the basis of body weight is required [see Dosage and Administration (2.4)]. The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Use in Specific Populations (11.3) and Clinical Trials and Supporting Data for EUA (18.1)]. Children were not enrolled in the post-exposure prophylaxis trial, BLAZE-2 [see Clinical Trials and Supporting Data for EUA (18.2)].

Geriatric Use

No dosage adjustment is recommended in geriatric patients [see Use in Specific Populations (11.4)].

Renal Impairment

No dosage adjustment is recommended in patients with renal impairment [see Use in Specific Populations (11.5)].

Hepatic Impairment

No dosage adjustment is recommended in patients with mild hepatic impairment. Bamlanivimab and etesevimab has not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (11.6)].

2.4 Dose Preparation and Administration

5.1 Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of bamlanivimab and etesevimab. 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, occurring during the infusion and up to 24 hours after the infusion, have been observed with administration of bamlanivimab and etesevimab together. These reactions may be severe or life threatening.

Signs and symptoms of infusion related reactions may include [see Overall Safety Summary (6.1)]:

• 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.

Consider slowing or stopping the infusion and administer appropriate medications and/or supportive care if an infusion-related reaction occurs.

Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of bamlanivimab and etesevimab under Emergency Use Authorization.

5.2 Clinical Worsening After Bamlanivimab and Etesevimab Administration

Clinical worsening of COVID-19 after administration of bamlanivimab and etesevimab together 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 bamlanivimab and etesevimab use or were due to progression of COVID-19.

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

Treatment with bamlanivimab and etesevimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore,

• Bamlanivimab and etesevimab are not authorized for use in patients 2 years and older who are hospitalized due to COVID-192,
• Bamlanivimab and etesevimab are not authorized for use in patients, regardless of age, who:
  • 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 [see Limitations of Authorized Use (1.1)].

6.1 Clinical Trials Experience

11.1 Pregnancy

11.2 Lactation

11.3 Pediatric Use

Bamlanivimab and etesevimab administered together are authorized for the treatment of mild to moderate COVID-19 and post-exposure prophylaxis for prevention of COVID-19 in pediatric patients, including neonates [see Authorized Use (1)]. Given the similar course of COVID-19, the authorization of bamlanivimab and etesevimab for treatment and post-exposure prophylaxis in younger pediatric patients, including neonates, is supported by safety and efficacy data in adolescents and adults, together with additional pharmacokinetic and safety data from the clinical trial in pediatric patients studying bamlanivimab and etesevimab for the treatment of mild to moderate COVID-19.

Use of bamlanivimab and etesevimab in pediatric patients is based on analyses of data from BLAZE-1 in subjects aged 10 months to 18 years of age [see Clinical Pharmacology (14.3) and Clinical Trials and Supporting Data for EUA (18.1)]. No dosage adjustment is recommended in pediatric patients 12-18 years of age who weigh at least 40 kg. Pediatric patients weighing less than 40 kg should be dosed on the basis of body weight [see Dosage and Administration (2.2, 2.4)]. The recommended dosing regimen for pediatric patients ≤12 kg is predicted based on pharmacokinetic modeling and simulation [see Clinical Pharmacology (14.3)]. The youngest participant in the pediatric clinical trial for treatment was 10 months of age and weighed 8.6 kg [see Clinical Trials and Supporting Data for EUA (18.1)]. Safety in pediatric patients was similar to what was observed in adults [see Clinical Trial Experience (6.1)]. Children were not enrolled in the post-exposure prophylaxis trial, BLAZE-2 [see Clinical Trials and Supporting Data for EUA (18.2)].

11.4 Geriatric Use

Of the 1141 patients receiving bamlanivimab and etesevimab in BLAZE-1, 30% were 65 years of age and older and 10% were 75 years of age and older. Based on population PK analyses, there is no difference in PK of bamlanivimab or etesevimab in geriatric patients compared to younger patients [see Clinical Trial Results and Supporting Data for EUA (18.1)].

11.5 Renal Impairment

Bamlanivimab and etesevimab are not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of bamlanivimab or etesevimab.

11.6 Hepatic Impairment

Based on population PK analysis, there is no difference in PK of bamlanivimab or etesevimab in patients with mild hepatic impairment compared to patients with normal hepatic function. Bamlanivimab and etesevimab have not been studied in patients with moderate or severe hepatic impairment.

11.7 Other Specific Populations

Based on population PK analysis, the PK of bamlanivimab and etesevimab was not affected by sex, race, or disease severity. Body weight had no clinically relevant effect on the PK of bamlanivimab and etesevimab in adults with COVID-19 over the body weight range of 41 kg to 173 kg.

Bamlanivimab

Bamlanivimab is a human immunoglobulin G-1 (IgG1 variant) monoclonal antibody consisting of 2 identical light chain polypeptides composed of 214 amino acids each and 2 identical heavy chain polypeptides composed of 455 amino acids produced by a Chinese Hamster Ovary (CHO) cell line and molecular weight of 146 kDa.

Bamlanivimab injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution in a vial for intravenous infusion.

Each mL contains 35 mg of bamlanivimab, and L-histidine (0.4 mg), L-histidine hydrochloride monohydrate (0.6 mg), sodium chloride (2.9 mg), sucrose (60 mg), polysorbate 80 (0.5 mg), and Water for Injection. The bamlanivimab solution has a pH range of 5.5-6.5.

Etesevimab

Etesevimab is a human IgG1 variant monoclonal antibody (mAb) consisting of 2 identical light chain polypeptides composed of 216 amino acids each and 2 identical heavy chain polypeptides composed of 449 amino acids produced by a Chinese Hamster Ovary (CHO) cell line and molecular weight of 145 kDa.

Etesevimab injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution in a vial for intravenous infusion.

Each mL contains 35 mg of etesevimab, L-histidine (1.55 mg), L-histidine hydrochloride monohydrate (2.10 mg), sucrose (80.4 mg), polysorbate 80 (0.5 mg), and Water for injection. The etesevimab solution has a pH range of 5.5.-6.5.

14.1 Mechanism of Action

Bamlanivimab is a recombinant neutralizing human IgG1ϰ monoclonal antibody (mAb) to the spike protein of SARS-CoV-2 and is unmodified in the Fc region. Bamlanivimab binds the spike protein with a dissociation constant KD = 0.071 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.17 nM (0.025 μg/mL).

Etesevimab is a recombinant neutralizing human IgG1ϰ mAb to the spike protein of SARS-CoV-2, with amino acid substitutions in the Fc region (L234A, L235A) to reduce effector function. Etesevimab binds the spike protein with a dissociation constant KD = 6.45 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.32 nM (0.046 μg/mL).

Bamlanivimab and etesevimab bind to different but overlapping epitopes in the receptor binding domain (RBD) of the S-protein. Using both antibodies together is expected to reduce the risk of viral resistance.

14.2 Pharmacodynamics

A flat exposure-response relationship for efficacy was identified for bamlanivimab and etesevimab administered together within the dose range of 700 mg bamlanivimab and 1,400 mg etesevimab to 2,800 mg bamlanivimab and 2,800 mg etesevimab (4 and 2 times the authorized dose, respectively), based on clinical data and pharmacokinetic/pharmacodynamic modeling.

For post-exposure prophylaxis of COVID-19, a dose of 700 mg bamlanivimab and 1,400 mg etesevimab was supported based on clinical data and pharmacokinetic/pharmacodynamic modeling.

14.3 Pharmacokinetics

A summary of PK parameters of bamlanivimab and etesevimab following administration of a single dose of 700 mg bamlanivimab and 1,400 mg etesevimab is provided in Table 3. There is no change in PK of bamlanivimab or etesevimab administered alone or together suggesting there is no interaction between the two antibodies. There were no differences in PK of etesevimab between mild/moderate ambulatory participants and healthy participants.

Bamlanivimab and etesevimab are expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies.

Antiviral Activity

The cell culture neutralization activity of bamlanivimab and of etesevimab against SARS-CoV-2 was measured in a dose-response model quantifying plaque reduction using cultured Vero E6 cells. Bamlanivimab, etesevimab and a 1:1 (weight/weight) ratio of bamlanivimab and etesevimab together neutralized the USA/WA/1/2020 isolate of SARS-CoV-2 with estimated EC50 values = 0.14 nM (0.02 μg/mL), 0.97 nM (0.14 μg/mL) and 0.14 nM (0.02 μg/mL), respectively.

Bamlanivimab demonstrated antibody-dependent cell-mediated cytotoxicity on reporter Jurkat cells expressing FcγRIIIa following engagement with target cells expressing spike protein. Bamlanivimab did not elicit complement-dependent cytotoxicity activity in cell-based assays.

Etesevimab did not demonstrate detectable antibody-dependent cell-mediated cytotoxicity on Jurkat reporter cells expressing FcγRIIIa. Etesevimab did not elicit complement-dependent cytotoxicity activity in cell-based assays.

Antibody Dependent Enhancement (ADE) of Infection

The risk that bamlanivimab and etesevimab could mediate viral uptake and replication by immune cells was studied in THP-1 and Raji cell lines and primary human macrophages. In general, experiments with bamlanivimab, with etesevimab, and with bamlanivimab and etesevimab together did not demonstrate productive viral infection in immune cells exposed to SARS-CoV-2 at concentrations of mAb(s) down to at least 100-fold below the respective EC50 value(s).

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 (Table 5). 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 US jurisdictions can be accessed on the following CDC website: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html.

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. 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, and 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. Retention of susceptibility to the other antibody alone was observed, with the exception of the E484D and Q493R substitution. 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 1,054-fold, respectively in a pseudotyped VLP assay.

Evaluation of susceptibility of variants identified through global surveillance in subjects treated with bamlanivimab and etesevimab is ongoing. Pseudotyped VLP evaluation of amino acid substitutions identified in global surveillance showed that the V483A substitution reduced susceptibility to bamlanivimab 48-fold, but activity was maintained with etesevimab, and with bamlanivimab and etesevimab together. N501Y and N501T substitutions reduced susceptibility to etesevimab approximately 5-fold and 20-fold, respectively. Activity against variants with N501Y or N501T substitutions was maintained with bamlanivimab alone, and with bamlanivimab and etesevimab together.

Bamlanivimab and etesevimab together retained activity against a SARS-CoV-2 B.1.1.7 lineage (Alpha; UK origin) virus and related pseudotyped VLPs expressing the spike protein found in the B.1.1.7 variant (Tables 5 and 6). SARS-CoV-2 B.1.351 lineage (Beta; South Africa origin) virus and related pseudotyped VLPs expressing spike proteins from B.1.351 lineage or substitutions K417N + E484K + N501Y found in this lineage had reduced susceptibility to bamlanivimab and etesevimab together of >324, 431-fold or >45-fold, respectively. Pseudotyped VLPs expressing spike protein from the P.1 lineage (Gamma; Brazil origin) or K417T + E484K + N501Y found in the P.1 lineage had reduced susceptibility to bamlanivimab and etesevimab together of 252-fold or >3,351-fold, respectively.

Bamlanivimab and etesevimab together and etesevimab alone retained activity against SARS-CoV-2 B.1.617.2 lineage (Delta; India origin) virus and related pseudotyped VLPs, but bamlanivimab alone had reduced activity (>1,136 and >1,868-fold, respectively). Bamlanivimab and etesevimab are expected to retain activity against B.1.617.2 sublineage AY.3 (India origin). B.1.617.2 sublineages AY.1/AY.2 (India origin) have an additional K417N substitution; pseudotyped VLPs expressing AY.1/AY.2 related spike sequence had a reduced susceptibility to bamlanivimab and etesevimab together of 1,235-fold. SARS-CoV-2 recombinant virus containing the L452R substitution present in B.1.427/B.1.429 lineages (Epsilon; USA [California] origin) and pseudotyped VLPs expressing the full-length spike protein or the L452R substitution found in this lineage showed reduced susceptibility to bamlanivimab and etesevimab together of 11-fold, 9-fold or 5-fold, respectively. Pseudotyped VLPs expressing spike protein from the B.1.617.1 lineage (Kappa; India origin) showed reduced susceptibility to bamlanivimab and etesevimab together of 6-fold; for this variant, susceptibility to etesevimab alone was maintained, but not to bamlanivimab alone (>1,030-fold reduction). Bamlanivimab and etesevimab together and etesevimab alone retained activity against pseudotyped VLPs expressing the full-length spike protein from the C.37 lineage (Lambda; Peru origin), but bamlanivimab alone had reduced activity (>2,112-fold reduction). Pseudotyped VLPs expressing spike protein from the B.1.621 lineage (Mu; Colombia origin) show reduced susceptibility to bamlanivimab and etesevimab together of 116-fold, due to susceptibility reductions to bamlanivimab (>1,863-fold) and etesevimab (17-fold) alone. Pseudotyped VLPs expressing the spike protein from the B.1.1.529/BA.1 lineage (Omicron; South Africa origin) show reduced susceptibility to bamlanivimab alone (>1,465-fold), etesevimab alone (>616-fold), and bamlanivimab and etesevimab together (>2,938-fold).

Due to the large reduction of pseudotyped VLP neutralization activity of both bamlanivimab and etesevimab against the substitutions in B.1.351 (Beta; South Africa origin), P.1 (Gamma; Brazil origin), AY.1/AY.2 (Delta [+K417N]; India origin), B.1.621 (Mu; Colombia origin), and B.1.1.529/BA.1 (Omicron; South Africa origin), it is unlikely that bamlanivimab and etesevimab together will be active against these variants.

It is unclear how small reductions in susceptibility to bamlanivimab and etesevimab seen in authentic or recombinant SARS-CoV-2 or pseudotyped VLP assays correlate with clinical outcomes.

In authentic SARS-CoV-2 assays, bamlanivimab and etesevimab together retained activity against variants of B.1.1.7 (Alpha) and B.1.617.2/AY.3 (Delta) lineages (Table 6), although bamlanivimab alone had reduced activity to B.1.617.2/AY.3 (Delta) in this assay (>1,136-fold). SARS-CoV-2 (USA/WA/1/2020 isolate) engineered to express the E484K substitution present in the B.1.526 lineage (Iota; USA [New York] origin) or the L452R substitution present in the B.1.427/B.1.429 lineage (Epsilon; USA [California] origin) showed reduced susceptibility to bamlanivimab and etesevimab together of 11-fold. Susceptibility to etesevimab alone was maintained for both isolates, but not to bamlanivimab alone (>833-fold and >1,460-fold reduction for E484K and L452R viruses, respectively). Available nonclinical and clinical PK data indicate that etesevimab at the authorized dose may retain activity against the B.1.526 variant clinically, although only very limited data are currently available from patients infected with this variant in clinical trials. Preliminary clinical evidence indicates that the administration of bamlanivimab and etesevimab together result in similar viral load reductions in participants infected with the L452R variant (Epsilon; USA [California] origin) as observed in those who were infected with bamlanivimab-sensitive strains. Of the 134 participants infected with the L452R variant at baseline in the Phase 3 portion of BLAZE-1, 3 of the 50 individuals treated with placebo (6%) and 1 of the 84 participants treated with bamlanivimab 700 mg and etesevimab 1,400 mg (1%) were hospitalized (p=0.15).

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

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%.

• In the Phase 3 portion of BLAZE-1, treatment-emergent variants were observed in 9.0% (42/467) of patients treated with bamlanivimab 2,800 mg and etesevimab 2,800 mg together, in 5.3% (21/394) of patients treated with bamlanivimab 700 mg and etesevimab 1,400 mg together, and in 4.0% (27/674) of patients treated with placebo. 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 2,800 mg and etesevimab 2,800 mg together, bamlanivimab 700 mg and etesevimab 1,400 mg together, and placebo groups, respectively.
• 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. While these variants had reduced susceptibility to either bamlanivimab OR etesevimab compared to wild-type in a pseudotyped VSV VLP or authentic virus assay they still retained susceptibility to the other antibody in the combination.
• There were also observations of variants with reduced susceptibility (≥5-fold) to both bamlanivimab and etesevimab and to bamlanivimab + etesevimab tested together: E484D (n=1; 145-fold reduction to bamlanivimab + etesevimab tested together at a molar ratio of 1:2), Q493K/R (n=9; 584-fold and 1,054-fold reduction to bamlanivimab + 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.
• 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 1,656-fold reduction in susceptibility to bamlanivimab + etesevimab together (1:2 molar ratio).
• Additional treatment-emergent substitutions in patients treated with bamlanivimab and etesevimab together, with no phenotypic data, include D405del, D420G, C480R, G485D, S494L, and P499L. The impact of these substitutions on susceptibility is not currently known.
• In a subgroup of 53 pediatric subjects who were infected with a B.1.617.2 (Delta)-related variant, which has reduced susceptibility to bamlanivimab (>1,136-fold), the following treatment-emergent substitutions with reduced susceptibility to etesevimab were detected: D420A (n=2), N460T (n=1), N460Y (n=1). Three of these four subjects had high viral load (>5.27 log10) on Day 7.
• Additional treatment-emergent substitutions with no phenotypic data detected in other pediatric subjects who were infected with a B.1.617.2 (Delta)-related variant at an allele fraction of ≥50% included: F347C, V401L, G431S and I434V.

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.

Immune Response Attenuation

There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.

Antiviral Activity In Vivo

Prophylactic administration of bamlanivimab to female Rhesus macaques (n=3 or 4 per group) resulted in 1 to 4 log10 decreases in viral genomic RNA and viral replication (sub-genomic RNA) in bronchoalveolar lavage samples relative to control animals, but less of an impact on viral RNA in throat and nasal swabs following SARS-CoV-2 inoculation.

Prophylactic or therapeutic administration of etesevimab to male Rhesus macaques (n=3 per group) resulted in approximately 4 or 3 log10 average decreases, respectively, in viral genomic RNA in oropharyngeal swabs at Day 4 post infection relative to control animals.

The applicability of these findings to a prophylaxis or treatment setting is not known.

18.1 Treatment of Mild to Moderate COVID-19 (BLAZE-1)

18.2 Post-Exposure Prophylaxis of COVID-19 (BLAZE-2)

The data supporting this EUA for post-exposure prophylaxis of COVID-19 are based on the final analysis of Part 1 of the Phase 3 trial BLAZE-2 (NCT04497987). The database lock occurred after all enrolled subjects completed Day 57. BLAZE-2 Part 1 is a randomized, double-blind, placebo-controlled study evaluating bamlanivimab alone for prevention of COVID-19 in residents and staff of skilled nursing facilities following a confirmed reported case of SARS-CoV-2 infection at the facility. No pediatric participants were enrolled.

All participants in Part 1 were randomized and treated with a single infusion of bamlanivimab 4,200 mg or placebo. Results of baseline testing for SARS-CoV-2 were not known until after the therapy was administered. Those with a positive baseline SARS-CoV-2 RT-PCR test were included in the Treatment Population (N=132) and those with a negative test were included in the Prevention Population (N=966). Individuals in these populations were also required to have a baseline negative SARS-CoV-2 serology test; those who tested positive were only included in the overall safety population.

Data are presented for the Prevention Population only. No data were collected on the type or extent of exposure to the index case in the Prevention Population.

In the overall Prevention Population (N=484 for bamlanivimab 4,200 mg and N=482 for placebo) at baseline, the median age was 53 years (with 29% of subjects aged 65 or older); 75% of subjects were female, 89% were White, 5% were Hispanic or Latino, and 8% were Black. The baseline demographics and disease characteristics were well balanced across bamlanivimab and placebo treatment groups.

The primary endpoint (cases of symptomatic COVID-19 by Day 57) was assessed after all participants in the Prevention Population reached 8 weeks of follow-up, and analysis were adjusted for facility, sex, and role within facility (resident/staff). There were 114 cases of symptomatic COVID-19, with a lower frequency occurring in participants treated with bamlanivimab as compared to placebo (residents and staff; adjusted odds ratio 0.43; p<0.001) reducing the risk of being infected with COVID-19 by up to 57%. As a supplementary analysis, the time to symptomatic COVID-19 is shown for each arm in Figure 2. Four COVID-19-related deaths were reported in the overall Prevention Population; all occurred in the placebo arm (0.8%). No COVID-19-related deaths occurred in the bamlanivimab arm.

Figure 2: Time to symptomatic COVID-19 in the overall prevention population (residents and staff).

For the pre-specified subgroup of nursing home residents, there were 45 cases of symptomatic COVID-19, with a lower frequency in those treated with bamlanivimab versus placebo (adjusted odds ratio 0.20; p<0.001), reducing the risk of being infected with COVID-19 by up to 80%. The time to symptomatic COVID-19 in nursing home residents is shown by treatment arm in Figure 3. In this same cohort of residents within the Prevention Population, 6 deaths due to any cause occurred in residents treated with placebo (4.3%) and 5 deaths due to any cause occurred in residents treated with bamlanivimab (3.1%).

Figure 3: Time to symptomatic COVID-19 in residents only.

For the post-hoc subgroup of patients who met the high risk criteria (all residents and all high risk staff7), there were 75 cases of symptomatic COVID-19, with a lower frequency in those treated with bamlanivimab versus placebo (adjusted odds ratio 0.28; nominal p<0.001), reducing the risk of being infected with COVID-19 by up to 72%.

For the post-hoc subgroup of staff who did not meet high risk criteria, there were 39 cases of symptomatic COVID-19, with less evidence of a preventative effect for bamlanivimab versus placebo (adjusted odds ratio 0.64; nominal p=0.26).

7

All high risk participants in the Prevention Population were either residents in a skilled nursing or assisted living facility, or staff in a skilled nursing or assisted living facility who satisfied at least 1 of the following at the time of screening: were ≥65 years of age, had a BMI ≥35, had CKD, had diabetes, had immunosuppressive disease, were currently receiving immunosuppressive treatment, OR were ≥55 years of age AND had cardiovascular disease, OR hypertension, OR COPD or other chronic respiratory disease.

How Supplied

UNDER THIS EUA, BAMLANIVIMAB AND ETESEVIMAB MUST BE ADMINISTERED TOGETHER.

Bamlanivimab

Bamlanivimab injection is a sterile, preservative-free clear to opalescent and colorless to slightly yellow to slightly brown solution supplied in a vial.

Etesevimab

Etesevimab injection is a sterile, preservative-free clear to opalescent and colorless to slightly yellow to slightly brown solution supplied in a vial.

Bamlanivimab and etesevimab are supplied as:

Storage and Handling

Bamlanivimab is preservative-free. Discard unused portion.

Etesevimab is preservative-free. Discard unused portion.

Store unopened vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

FDA has authorized an extension to the shelf-life (i.e., expiration date) of both bamlanivimab and etesevimab following a thorough review of data submitted by Eli Lilly and Company. The extension applies to all unopened vials of bamlanivimab and etesevimab that have been held in accordance with storage conditions. Confirm the shelf-life of unopened vials of bamlanivimab and etesevimab by batch number at the FDA EUA website under the Drug and Biological Therapeutic Products bamlanivimab and etesevimab. This site includes a complete listing of extended expiration dates by batch number. If the batch number on the vial/carton is not included in this listing, the product is labeled with the correct expiration date.

DO NOT FREEZE, SHAKE, OR EXPOSE TO DIRECT LIGHT.

The prepared infusion solution is intended to be used immediately. If immediate administration is not possible, store infusion solution in the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours and at room temperature (20°C to 25°C [68°F to 77°F]) and for up to 7 hours, including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature prior to administration.