Bamlanivimab
Introduction to Bamlanivimab
Bamlanivimab (LY-CoV555) is a neutralizing IgG1 monoclonal antibody directed against the spike protein of SARS-CoV-2. It was developed by AbCellera Biologics and Eli Lilly and Company as a potential treatment for COVID-19. Key points include:
- Discovered from convalescent plasma of a COVID-19 survivor
- Designed to block viral attachment and entry into human cells
- Initially granted Emergency Use Authorization (EUA) by the FDA in November 2020
- EUA was later revoked in April 2021 due to the prevalence of resistant variants
- Continues to be studied in combination with other antibodies (e.g., etesevimab)
Bamlanivimab represents an important milestone in the rapid development of targeted therapies for COVID-19, demonstrating the potential of monoclonal antibody treatments in emerging infectious diseases.
Mechanism of Action
Bamlanivimab's mechanism of action involves several key steps:
- Spike Protein Binding: Bamlanivimab binds with high affinity to the receptor binding domain (RBD) of the S1 subunit of the SARS-CoV-2 spike protein.
- ACE2 Receptor Blocking: This binding prevents the spike protein from attaching to the human ACE2 receptor, which is the primary entry point for the virus into human cells.
- Viral Entry Inhibition: By blocking the interaction between the virus and the ACE2 receptor, bamlanivimab effectively neutralizes the virus and prevents it from entering and infecting human cells.
- Fc-mediated Effector Functions: As an IgG1 antibody, bamlanivimab may also engage in Fc-mediated effector functions, potentially enhancing viral clearance through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).
Important characteristics of bamlanivimab's mechanism include:
- High specificity for the SARS-CoV-2 spike protein, minimizing off-target effects
- Potential to reduce viral load and associated inflammation
- Ability to neutralize the virus before it can establish a foothold in the body
- Vulnerability to mutations in the spike protein, which can lead to resistance
Indications and Usage
During its period of Emergency Use Authorization (EUA), bamlanivimab was indicated for:
- Treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg)
- Patients at high risk for progressing to severe COVID-19 and/or hospitalization
High-risk factors included, but were not limited to:
- Age ≥ 65 years
- BMI ≥ 35 kg/m²
- Chronic kidney disease
- Diabetes
- Immunosuppressive disease
- Currently receiving immunosuppressive treatment
- Age ≥ 55 years AND have cardiovascular disease, hypertension, or chronic respiratory diseases
Important considerations for use:
- To be administered as soon as possible after a positive viral test for SARS-CoV-2 and within 10 days of symptom onset
- Not authorized for patients hospitalized due to COVID-19
- Not authorized for patients requiring oxygen therapy due to COVID-19
- May be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation
After the EUA revocation, bamlanivimab is no longer authorized for use as monotherapy but continues to be studied in combination with other antibodies.
Clinical Pharmacology
Pharmacokinetics:
- Absorption: Intravenous administration results in 100% bioavailability
- Distribution:
- Mean volume of distribution: 2.68 L
- Limited distribution to tissues due to large molecular size
- Metabolism: Expected to be degraded into small peptides and amino acids via catabolic pathways, similar to endogenous IgG
- Elimination:
- Clearance: 0.27 L/day
- Elimination half-life: Approximately 17.6 days
Pharmacodynamics:
- Dose-dependent reduction in viral load observed in clinical studies
- Potential for reduced efficacy against certain SARS-CoV-2 variants
Immunogenicity:
- Treatment-emergent anti-bamlanivimab antibodies observed in a small percentage of patients
- Clinical significance of these antibodies not fully determined
Dosage and Administration
When authorized under EUA, the recommended dosage for bamlanivimab was:
- 700 mg administered as a single intravenous infusion
Administration details:
- Administer as soon as possible after positive SARS-CoV-2 test and within 10 days of symptom onset
- Dilute in 250 mL of 0.9% Sodium Chloride Injection
- Administer via pump or gravity over at least 60 minutes
- Do not administer as an intravenous push or bolus
Preparation and handling:
- Solution should appear clear to opalescent and colorless to slightly yellow to slightly brown
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration
- Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light
Monitoring:
- Clinically monitor patients during administration
- Observe patients for at least 1 hour after infusion is complete
Clinical Efficacy
The efficacy of bamlanivimab was primarily evaluated in the BLAZE-1 trial, a randomized, double-blind, placebo-controlled clinical study:
- Study population: 452 outpatients with mild to moderate COVID-19
- Primary endpoint: Change in viral load from baseline to day 11
Key efficacy results:
- Significant reduction in viral load at day 11 compared to placebo
- Reduced COVID-19-related hospitalizations or emergency room visits within 28 days after treatment (1.6% for bamlanivimab vs 6.3% for placebo)
- Faster symptom resolution in treated patients
Limitations and considerations:
- Efficacy varied depending on the viral variant
- Decreased neutralization potency against certain emerging variants led to the revocation of its EUA for monotherapy
- Ongoing studies focus on combination therapy with other monoclonal antibodies to address variant concerns
While initial results were promising, the emergence of resistant variants highlighted the need for ongoing evaluation and potential combination strategies in antibody-based COVID-19 treatments.
Adverse Effects
Based on clinical trial data, bamlanivimab was generally well-tolerated. However, the following adverse effects were reported:
Common adverse reactions (incidence ≥ 1%):
- Nausea (3%)
- Dizziness (3%)
- Headache (3%)
- Pruritus (2%)
- Diarrhea (1%)
- Vomiting (1%)
Serious adverse events:
- Hypersensitivity reactions, including anaphylaxis (rare)
- Infusion-related reactions (observed in 1.3% of patients)
Infusion-related reactions may include:
- Fever
- Chills
- Dizziness
- Pruritis
- Flushing
- Angioedema
It's important to note that due to the emergency nature of the drug's authorization and use, the full safety profile may not have been completely characterized. Ongoing pharmacovigilance is crucial for monoclonal antibody therapies like bamlanivimab.
Precautions and Contraindications
Contraindications:
- Known hypersensitivity to any ingredient in bamlanivimab
Warnings and Precautions:
- Hypersensitivity Reactions:
- Serious hypersensitivity reactions, including anaphylaxis, have been observed
- 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:
- Monitor patients for infusion-related reactions
- If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care
- Clinical Worsening After Bamlanivimab Administration:
- Clinical worsening of COVID-19 after administration has been reported
- May include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrhythmia, fatigue, and altered mental status
- Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19:
- Not authorized for use in patients hospitalized due to COVID-19
- Monoclonal antibodies may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation
Risk of Viral Resistance:
- There is a potential risk of treatment failure due to the development of viral variants that are resistant to bamlanivimab
- Healthcare providers should consider the prevalence of SARS-CoV-2 variants in their area when considering treatment options
Drug Interactions
Bamlanivimab has a low potential for drug-drug interactions due to its nature as a monoclonal antibody:
- Not metabolized by cytochrome P450 enzymes
- Eliminated via catabolism into small peptides and amino acids
Considerations:
- No formal drug interaction studies have been conducted
- Unlikely to have significant pharmacokinetic interactions with medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes
Potential interactions:
- May interfere with the development of immunity to SARS-CoV-2
- Vaccination with live-attenuated COVID-19 vaccines should be delayed for at least 90 days after bamlanivimab administration
While direct drug interactions are limited, healthcare providers should consider the overall treatment regimen and potential immunological effects when administering bamlanivimab.
Use in Special Populations
Pregnancy:
- Limited data available on use in pregnant women
- Animal reproductive toxicity studies have not been conducted
- Potential benefits may outweigh risks in pregnant women
- Consider the mother's clinical condition and the potential effects on the fetus when making treatment decisions
Lactation:
- No data on the presence of bamlanivimab in human or animal milk, effects on the breastfed infant, or effects on milk production
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for bamlanivimab
Pediatric Use:
- Safety and effectiveness have not been assessed in pediatric patients under 12 years of age
- The dosage for pediatric patients 12 years of age and older, weighing at least 40 kg, is the same as that for adults
Geriatric Use:
- Of the 465 patients who received bamlanivimab in clinical trials, 11% were 65 years of age and older
- No overall differences in safety or effectiveness observed between these patients and younger patients
Renal Impairment:
- No dosage adjustment recommended in patients with renal impairment
- Bamlanivimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure
Hepatic Impairment:
- No dosage adjustment recommended in patients with mild hepatic impairment
- Bamlanivimab has not been studied in patients with moderate or severe hepatic impairment
Regulatory Status and Development
Emergency Use Authorization (EUA):
- Initially granted EUA by the FDA on November 9, 2020
- EUA revoked on April 16, 2021 due to sustained increase of SARS-CoV-2 viral variants resistant to bamlanivimab alone
Ongoing Development:
- Continued study in combination with other monoclonal antibodies, particularly etesevimab
- Evaluation of effectiveness against emerging SARS-CoV-2 variants
- Investigation of potential use in post-exposure prophylaxis
Global Use:
- Various countries have granted emergency or conditional use authorizations
- Availability and use may vary based on local SARS-CoV-2 variant prevalence
Future Directions:
- Potential development of second-generation antibodies with broader variant coverage
- Exploration of subcutaneous administration for easier outpatient use
- Long-term safety and efficacy studies in various patient populations
