Indications

As of January 24, 2022, the United States Food and Drug Associated (FDA) fact sheet for the drug bamlanivimab states that "due to the high frequency of the Omicron variant, bamlanivimab and etesevimab, administered together, are not currently authorized for use in any U.S. region because of markedly reduced activity against the Omicron variant. These drugs may not be administered for treatment or post-exposure prevention of COVID-19 under the Emergency Use Authorization until further notice by the Agency." This topic is for historical purposes only to review this therapy's indications, mechanism, and administration when it was first developed.

Bamlanivimab is a monoclonal antibody (mAb) directed against the spike protein (S-Protein) of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Bamlanivimab, or LY-COV555, was derived from the convalescent plasma of patients with coronavirus disease 2019 (COVID-19).[1] It is 1 of the potent neutralizing antibodies approved by the Food and Drug Administration (FDA) under Emergency Use Authorization (EUA) in August 2021 to be used in combination with etesivimab (another mAb against S-protein of SARS-CoV-2).[2] The other neutralizing antibodies available are casirivimab and imdevimab, used in combination therapy.[3][4][5] The other novel agent in this class is sotrovimab.[6]

The FDA has approved the administration of the combination drug as treatment and post-exposure prophylaxis in patients meeting the following criteria:

Treatment

• Mild to moderate COVID-19, at higher risk of progression to severe disease, including hospitalization or death
• Patients with Direct SARS-CoV-2 Viral test positive results and within 10 days of symptom onset
• Adults and pediatric population, including neonates, meeting the above 2 criteria

Post-Exposure Prophylaxis

• Exposed to an individual infected with SARS-CoV-2 defined by close contact criteria as per Centers for Disease Control and Prevention (CDC) or at high risk for exposure in the same institutional setting due to the occurrence of SARS-CoV-2 in that setting, such as a nursing home or prisons.
• At higher risk of progression to severe disease, including hospitalization or death
• Not fully vaccinated or not expected to have adequate response to complete vaccination. For example - patients with immunocompromising conditions, including those on immunosuppressive drugs.
• CDC describes close contact with an infected individual as being within 6 feet for at least 15 minutes, direct physical contact, droplet exposure, or providing care at home to an infected individual.

The following patient population qualifies as high-risk individuals:

1. Age ≥ 65 years or <1 year
2. Body mass index (BMI): Adults - BMI > 25 kg/m²; age 12 to 17 years - BMI ≥ 85th percentile for age and sex
3. Pregnancy
4. Diabetes
5. Cardiovascular disease, including hypertension, congenital heart disease
6. Lung disease - moderate to severe asthma, chronic obstructive pulmonary disease (COPD), Interstitial lung disease (ILD), cystic fibrosis, and pulmonary hypertension
7. Chronic kidney disease
8. Neurodevelopmental disorders
9. Immunocompromised state including cancer, organ transplant, HIV, individuals on immunosuppressive treatment
10. Sickle cell disease
11. Dependence on medical-related technology, like tracheostomy, gastrostomy, or positive pressure ventilation unrelated to COVID-19[2]

Due to emerging variants, the FDA has authorized the combination drug to be used only in the states and territories where the data shows that resistance to the variants is < 5%. Healthcare providers should check the FDA website regularly for updates regarding this medication.

Mechanism of Action

SARS-CoV-2 is a single-stranded enveloped RNA virus. The outer surface comprises the envelope, membrane, and many glycosylated S-proteins. The virus binds to the host cell's angiotensin-converting enzyme 2 (ACE-2) receptor via S-protein. The S-protein comprises 2 subunits, S1 and S2. With the help of the receptor-binding domain (RBD) of the S1 subunit, the virus binds to the ACE-2 receptor found in cells of the respiratory system, gastrointestinal system, and endothelium.[7][8]

Bamlanivimab is a neutralizing immunoglobulin G1 variant mAb to the spike protein of SARS-CoV-2. It comprises 2 identical light and heavy chain polypeptides composed of 214 and 455 amino acids, respectively. This antibody blocks S-protein attachment to human ACE-2 receptors, preventing subsequent viral entry and replication (see Image. Bamlanivimab Mechanism of Action). The drug binds an epitope on RBD in both open and closed confrontation, which led this mAb to be potentially used as a monotherapy in phase 2 of the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial.[8] Bamlanivimab also showed antibody-dependent cell-mediated cytotoxicity on reporter cells following engagement with target cells that express spike protein in the in-vitro study. This study also revealed enhanced viral clearance via an intrinsic immune response and the mAb infusion. However, with emerging variants and resistance, the FDA revoked the EUA for monotherapy in April 2021. The EUA for combination therapy of bamlanivimab and etesevimab was reinstated in August 2021 with the caveat of unauthorizing the use of the combination therapy where the frequency of resistance to the variants exceeds 5%.

Administration

Bamlanivimab is authorized by the FDA when administered as an infusion in combination with etesevimab. A qualified healthcare professional should administer an aseptic technique at an infusion center. The infusion center should have access to immediate care in case of an infusion-related adverse reaction. Each drug comes in individual single-dose vials, stored at a refrigerated temperature of 2 degrees C to 8 degrees C. FDA recommends confirming the shelf life of unopened vials at the FDA website as they authorized an extension to the shelf life. Before preparation, the vials must be allowed to equilibrate to room temperature for approximately 20 minutes. Each vial is visually inspected for any discoloration or any particulate matter. The drugs should be clear to opalescent and colorless to slightly yellow. The drugs are mixed with prefilled 0.9% normal saline bag (50 ml, 100 ml, 150 ml, 250 ml) and should be used immediately for infusion. If the infusion mix cannot be used immediately, the bag can be stored at a refrigerated temperature for 24 hours and at room temperature for 7 hours.

The dose recommended for treatment and post-exposure prophylaxis is as follows:

1. Adults (≥18 years) and pediatric patients (<18 years, at least 40 kgs)= Bamlanivimab 700 mg + Etesevimab 1400 mg
2. Pediatric patients < 40 kgs based on body weight:
   • >20 kg to < 40 kgs= Bamlanivimab 350 mg + Etesevimab 700 mg
   • <12 kg to 20 kg: Bamlanivimab 175 mg + Etesevimab 350 mg
   • 1 kg to 12 kg: Bamlanivimab 12 mg/kg+ Etesevimab 24 mg/kg; The dosing regimen for this group is predicted based on pharmacokinetic modeling and simulation. The pediatric clinical trial included ages from 10 months and weighing 8.6 kgs.

For patients weighing ≥ 40 kgs and <50 kgs, extending the infusion time to at least 70 minutes is recommended to ensure safe use. For pediatric patients <18 years and weighing <40 kgs, the FDA recommends using a syringe pump and weight-based maximum infusion rate as mentioned in their Fact Sheet. No dose adjustment is necessary for geriatric, renal, or hepatic conditions. FDA also recommends providing the patient with a fact sheet regarding the information on the drugs before the infusion[2]

Adverse Effects

Limited clinical data is available for this drug therapy. Infusion-related adverse effects were noted during the BLAZE-1 trial (a randomized, placebo-controlled, double-blind study). The BLAZE-2 trial is currently ongoing, and further data is still in process.

The adverse effects were noted in 69% of cases that received the combination infusion compared to 60% of placebo cases in the BLAZE-1 trial. The most common effects were as follows:

• GI symptoms (nausea, vomiting, diarrhea, constipation, GERD)[9][10]
• Skin-rash, pruritus, utricaria
• Dizziness[10]

However, severe hypersensitivity reactions such as anaphylaxis have also been observed. Hypersensitivity reactions occurring 24 hours post-infusion have also been reported. Infusion-related reactions have been reported during and up to 24 hours post-infusion. The overall safety summary in the FDA factsheet also mentions fever, hypo/hypertension, altered mental status, pre/syncope, and cardiac (chest pain/discomfort, arrhythmias). Clinical worsening of the symptoms of COVID-19 has also been reported, with some requiring hospitalization. FDA recommends reporting any serious adverse events considered potentially related to the infusion within 7 days from the onset of the event.

Contraindications

There is no absolute contraindication for the use of bamlanivimab. However, it has not been authorized for use in the following patient population:

• Hospitalized due to COVID-19 infection
• Requiring oxygen therapy
• Requiring increased oxygen supplementation due to COVID-19 compared to baseline need due to comorbidities unrelated to COVID-19  
• Pre-exposure prophylaxis for COVID-19
• Substitution for vaccination
• Areas where resistance to combination or individual therapy for SARS-CoV-2 variants exceeds 5%[2]

Monitoring

Monitoring for Adverse Reactions

Patients should be assessed at the infusion center before the infusion. The high-risk category patients with mild to moderate COVID-19 disease are at high risk for progression to severe COVID-19 illness and may not qualify for the infusion. Those who meet the criteria for infusion should be observed for any hypersensitivity or infusion-related reaction mentioned above during the infusion time and at least 1-hour post-infusion. Patients should also be advised to watch out for symptoms for at least 7 days post-infusion.[2] As bamlanivimab is not metabolized by cytochrome 450 enzymes or renally excreted, concomitant drug interactions are unlikely.

Monitoring for Drug Resistance

Emerging variants that are resistant to the combination drug—the combination drug does not have activity against the Omicron variant—can potentially cause treatment failure. Updates regarding resistance trends and authorized use of combination therapy can be accessed via the U.S. Department of Health and Human Services and the CDC websites.

Toxicity

During the clinical trials, doses up to 7000 mg, 10 times the authorized bamlanivimab, were administered without any dose-limiting toxicity. In case of overdose, supportive treatment is recommended, along with monitoring of vitals and clinical status. In case of an overdose, there is no specific antidote.

Specific Populations

1. Pediatric use: Phase 2/3 of the BLAZE-1 Trial was completed in December 2021. No dosing adjustments were made to a population of 12-18 years and weighing at least 40 kg. Dosing adjustment recommendation besides this age/weight group is mentioned above.
2. Geriatric use: BLAZE- 1 Trial included 30% of age 65 and 10% 75. No pharmacokinetic differences were noted compared to the younger population.
3. Renally impairment: Renal impairment is not expected as the drug is not eliminated via urine.
4. Hepatic impairment: The drug has not been evaluated in cases of moderate or severe hepatic impairment. With mild hepatic impairment, it has been shown to have no difference compared to normal hepatic function.
5. Pregnancy: Human IgG1 antibodies can cross the placental barrier, so the drug has the potential to do the same. The FDA recommends using the drug in pregnant women if the potential benefit outweighs the risk to both the mother and the fetus. There is no sufficient data regarding birth defects secondary to drug use.
6. Lactating mothers: Bamlanivimab has a molecular weight of 146,000 Da. Because it is a very large protein, the amount of the drug in the milk is expected to be low.[11] There is no data available regarding the effect of bamlanivimab on breast milk production and breastfed infants [2]. The use of the drug should be considered on an individual basis.

Nonclinical Toxicology studies, including carcinogenesis, mutagenesis, and reproductive toxicology, have not yet been conducted.

Enhancing Healthcare Team Outcomes

Bamlanivimab has been associated with decreasing the viral load and further spreading the disease (even as monotherapy), as shown in phase 1 of the BLAZE-1 trial. The other study by Ganesh et al. at Mayo Clinic facilities from November 2020 and February 2021 revealed that bamlanivimab reduced hospitalization rate on days 14 and 21, along with lower intensive care admission and all-cause mortality.[12] However, with emerging new strains of the SARS-CoV-2 virus that are resistant to only bamlanivimab therapy, the FDA revoked the use of bamlanivimab monotherapy in April 2021.[9] Later, data from phase 2/3 (ambulatory setting) of BLAZE-1 therapy revealed that combination therapy with etesevimab has decreased the incidence of hospitalization and death in high-risk populations.[10][13] The data from phase 3 of the BLAZE-1 clinical trial revealed an accelerated decline in viral load in patients receiving the combination therapy and reduced hospitalization rate by 70%.[14] The Phase 2/3 BLAZE-1 Trial included the pediatric population; the youngest participant was 10 months old and weighed 8.6 kg. BLAZE-2 study involved a single infusion of bamlanivimab 4200 mg vs. placebo in residents and staff of a skilled nursing facility after a confirmed positive COVID-19 test. The data revealed a reduced risk of being infected by 57%, which supported post-exposure prophylaxis treatment.[15]

Primary care, Urgent, and Immediate care physicians should triage patients meeting the criteria for receiving the monoclonal antibody therapy.[13][16] Patients should only receive the infusion at a well-equipped infusion center with access to advanced health facilities in case of an adverse event. Pharmacists help in dose preparation and storage of the drug, and nurses assist in administering and monitoring the patient during and 1-hour post-infusion. Physicians and Nurses should coordinate to educate the patient regarding possible adverse effects and provide the patient with the fact sheet about the drug provided by the FDA before the drug administration. The care team and the patient should follow the directions in the fact sheet to notify of any adverse event within 7 calendar days.