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Anti-SARS-CoV-2 Monoclonal Antibodies

Last reviewed: January 28, 2022

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Overview 

Monoclonal antibodies are a type of therapeutic agent under investigation for the treatment of COVID-19. These agents are often created by identifying pathogen-specific B cells of patients who have recently recovered from an infection or by immunizing mice genetically modified to have a humanized immune system and harvesting effective antibodies from them (Marovich, June 2020). Once the B cells are identified, the genes of immune globulin heavy and light chains are recovered. These genes are then expressed to produce monoclonal antibodies. Monoclonal antibodies have singular activity against a predetermined target; they therefore differ from convalescent plasma, which consists of polyclonal antibodies in serum derived from patients who are convalescing from an infection (Marston, April 2018). Monoclonal antibodies have been developed for the treatment and prophylaxis of other viral infections, such as HIV, influenza, RSV, MERS-CoV, Ebola and Zika virus (Walker, January 2018). Of these, only monoclonal antibodies targeting RSV and Ebola have been shown to be effective in human trials (with the former having FDA approval) (Marovich, June 2020). Several products targeting the other aforementioned viruses are currently being studied in clinical trials.  

The majority of direct antiviral monoclonal antibody products under development for SARS-CoV-2 target the spike protein, which the virus utilizes to enter host cells (Marovich, June 2020), thus blocking viral attachment and entry into human cells. Products with FDA authorization include bamlanivimab/etesevimab (created by Eli Lilly), casirivimab/imdevimab (created by Regeneron, brand name REGEN-COV) and sotrovimab (created by Vir/GSK). Tixagevimab/cilgavimab (created by AstraZeneca, brand name Evusheld) is emergency-authorized as pre-exposure prophylaxis against COVID-19 among immunocompromised individuals or those who cannot be vaccinated or mount post-vaccination immune response. 

Efficacy of SARS-COV-2 Monoclonal Antibodies Against the Omicron Variant 

For a comprehensive listing of the efficacy of vaccines and monoclonal antibodies against SARS-CoV-2 variants of concern, please see our variants table. Briefly, there is in vitro evidence based on studies in bioengineered pseudoviruses and in some cases authentic strains of SARS-CoV-2 isolated from patients, that bamlanivimab/etesevimab (CDC;  Gruell, December 2021 – preprint, not peer-reviewed) and casirivimab/imdevimab (Wilhelm, December 2021 – preprint, not peer-reviewed) have severely reduced neutralization efficacy against the Omicron variant of SARS-CoV-2. There is also in vitro evidence that both sotrovimab and tixagevimab/cilgavimab retain neutralizing efficacy against Omicron (NIH OpenData, December 2021). 

Bamlanivimab/Etesevimab 

Eli Lilly’s monoclonal antibody bamlanivimab (also known as LY-CoV555, aka LY3819253) was originally derived from the blood of one of the first U.S. patients who recovered from COVID-19. It is a recombinant neutralizing monoclonal antibody directed against the SARS-CoV-2 spike protein. Eli Lilly’s etesevimab (LY-CoV016, aka JS016, aka LY3832479) is a monoclonal antibody directed against the SARS-CoV-2 surface spike protein’s receptor binding domain. 

However, in outpatients, two double-blind, randomized, controlled trials of REGEN-COV (trials 2067 and 20145; also see Weinreich, January 2021, an interim analysis) have recently released results via press release. In study 20145 (N=803), an outpatient dose-ranging virologic efficacy trial of REGEN-COV among low-risk outpatients with asymptomatic or mild symptomatic COVID-19, there was comparable viral load drop among all dose levels, including the subcutaneously dosed groups, through day 7 (without a dose-response effect). In the large outpatient study of the impact of REGEN-COV on clinical outcomes among high-risk patients with COVID-19 (N=4,567), there was a significant reduction in COVID-related hospitalization or death of 71.3% (1.3% vs. 4.6%; p<0.0001) in the 2,400 mg group and 70.4% (1.0% vs. 3.2%) in the 1,200 mg group, as compared to placebo. The effect was strongest among those with baseline SARS-CoV-2 viral load above 1 million and negative SARS-CoV-2 antibodies. Likewise, the time to symptom resolution was faster with both doses than placebo, with a median of 10 versus 14 days to clinical improvement (p<0.0001). In a large safety database of participants from these two trials (N=6,334), no serious safety signal of concern was observed, and severe adverse events were less frequent in the combined monoclonal antibody group than in the placebo group (1.4% vs. 4%).  The large, Phase 3 U.K. NHS RECOVERY trial then evaluated REGEN-COV in a very large (N=9,785) group of patients hospitalized with COVID-19, and found that, among participants who were seronegative for SARS-CoV-2 at baseline, there was a significant mortality benefit from receiving the combination of casirivimab and imdevimab (REGEN-COV), as compared to standard of care (see Key Literature, below).  

REGEN-COV has also been studied as a “passive vaccine” in study 2069 to prevent infection among household contacts of patients with known COVID. Final Phase 3 results are forthcoming and showed a reduction in symptomatic (SARS-CoV-2 PCR+) infections from 8/233 (3.6%) in placebo to 0/186 (0%) in REGEN-COV group (p<0.01). There was also a reduction in SARS-CoV-2 PCR+ infections of any symptom degree with a high (above 10,000) viral load, from 13/212 (6.1%) in the placebo group to 0/179 (0%) in the REGEN-COV group (p<0.001).   

In November 2020, FDA granted emergency use authorization for both bamlanivimab and the combination of casirivimab and imdevimab in outpatients with mild to moderate COVID-19 who are at high risk for severe COVID-19. These approvals were based on interim analyses of outpatient randomized controlled trials, which showed a reduction in COVID-19 related hospitalization or emergency room visits with the use of these monoclonal products. Following these two trials, the randomized controlled ACTIV-3 study of bamlanivimab in hospitalized COVID-19 patients without end-organ failure showed little additional impact on sustained recovery over 90 days when compared to placebo plus standard of care, which included remdesivir and corticosteroids (Gottlieb, January 2021). The study was stopped by the data safety and monitoring board for futility after 314 participants had been enrolled.   

Casirivimab/Imdevimab 

Regeneron’s REGEN-COV (previously known as REGN-CoV2 or REGEN-CoV2) consists of two antibodies that bind to different regions of the SARS-CoV-2 spike protein receptor binding domain: casirivimab (REGN10933) and imdevimab (REGN10987). In October 2020, an independent data monitoring committee recommended halting a study examining the use of casirivimab plus imdevimab in hospitalized patients requiring high-flow oxygen or mechanical ventilation, due to a potential safety signal and an unfavorable risk/benefit profile.   

However, in outpatients, two double-blind, randomized, controlled trials of REGEN-COV (trials 2067 and 20145; also see Weinreich, 2021, an interim analysis) have recently released results via press release. In study 20145 (N=803), an outpatient dose-ranging virologic efficacy trial of REGEN-COV among low-risk outpatients with asymptomatic or mild symptomatic COVID-19, there was comparable viral load drop among all dose levels, including the subcutaneously dosed groups, through day 7 (without a dose-response effect). In the large outpatient study of the impact of REGEN-COV on clinical outcomes among high-risk patients with COVID-19 (N=4,567), there was a significant reduction in COVID-related hospitalization or death of 71.3% (1.3% vs. 4.6%; p<0.0001) in the 2,400 mg group and 70.4% (1.0% vs. 3.2%) in the 1,200 mg group, as compared to placebo. The effect was strongest among those with baseline SARS-CoV-2 viral load above 1 million and negative SARS-CoV-2 antibodies. Likewise, the time to symptom resolution was faster with both doses than placebo, with a median of 10 versus 14 days to clinical improvement (p<0.0001). In a large safety database of participants from these two trials (N=6,334), no serious safety signal of concern was observed, and severe adverse events were less frequent in the combined monoclonal antibody group than in the placebo group (1.4% vs. 4%).  The large, Phase 3 U.K. NHS RECOVERY trial then evaluated REGEN-COV in a very large (N=9,785) group of patients hospitalized with COVID-19, and found that, among participants who were seronegative for SARS-CoV-2 at baseline, there was a significant mortality benefit from receiving the combination of casirivimab and imdevimab (REGEN-COV), as compared to standard of care (see Key Literature, below). 

REGEN-COV has also been studied as a “passive vaccine” in study 2069 to prevent infection among household contacts of patients with known COVID. Final Phase 3 results are forthcoming and showed a reduction in symptomatic (SARS-CoV-2 PCR+) infections from 8/233 (3.6%) in placebo to 0/186 (0%) in REGEN-COV group (p<0.01). There was also a reduction in SARS-CoV-2 PCR+ infections of any symptom degree with a high (above 10,000) viral load, from 13/212 (6.1%) in the placebo group to 0/179 (0%) in the REGEN-COV group (p<0.001).  

In November 2020, FDA granted emergency use authorization for both bamlanivimab and the combination of casirivimab and imdevimab in outpatients with mild to moderate COVID-19 who are at high risk for severe COVID-19. These approvals were based on interim analyses of outpatient randomized controlled trials, which showed a reduction in COVID-19 related hospitalization or emergency room visits with the use of these monoclonal products. Following these two trials, the randomized controlled ACTIV-3 study of bamlanivimab in hospitalized COVID-19 patients without end-organ failure showed little additional impact on sustained recovery over 90 days when compared to placebo plus standard of care, which included remdesivir and corticosteroids (Gottlieb, January 2021). The study was stopped by the data safety and monitoring board for futility after 314 participants had been enrolled. 

Sotrovimab 

In May 2021, FDA approved for emergency use a new monoclonal anti-SARS-CoV-2 antibody manufactured by GSK and Vir Biotechnology, sotrovimab (formerly VIR-7831), which binds to a highly conserved epitope of the receptor binding domain of viral spike protein. The approval was based on an analysis of data from the COMET-ICE study, a randomized controlled trial investigating the safety and efficacy of sotrovimab 500 mg IV given within 5 days of symptom onset in 583 nonhospitalized adults with mild to moderate SARS-CoV-2 infection. The primary endpoint, death or >24 hours of hospitalization through Day 29 after dose, was reached in 21 of 292 (7%) patients in the placebo group compared to 3 of 291 (1%) who received sotrovimab, an 85% reduction (p=0.002). Based on these results at the time of the interim analysis, an independent safety and data monitoring committee recommended stopping the study. A parallel in vitro study found that sotrovimab retains efficacy against most circulating variants. Further studies are planned by the manufacturers, including a pharmacokinetic study (COMET-PEAK) comparing venous and intramuscular sotrovimab, which could lay the groundwork for intramuscular administrations of anti-SARS-CoV-2 monoclonal antibodies, rather than intravenous infusions; this will be followed by Phase 3 trials assessing the impact of intramuscular sotrovimab on hospitalization and death in high-risk people with COVID-19 and on symptomatic infection among asymptomatically infected individuals (COMET-TAIL and COMET-STAR). 

Tixagevimab/Cilgavimab  

Another combined product with favorable results in Phase 3 testing is AZD7442, produced by AstraZeneca. It contains two monoclonal antibodies, tixagevimab (AZD8895) and cilgavimab (AZD1061), which target the receptor binding domain of the SARS-CoV-2 spike protein and appear to retain in vitro activity against emergent SARS-CoV-2 variants such as Omicron, Delta and Mu (Dong, March 2021 - preprint, not peer-reviewed). The product has been optimized for an extended half-life and longer duration of action, via reducing its ingredients’ binding to the Fc receptor and C1q complement (Loo, September 2021 - preprint, not peer-reviewed). The duration of action is 9-12 months, offering a potential protective option for, among others, patients who fail to mount a protective immune response to COVID-19 vaccination. As compared to other monoclonal antibodies requiring intravenous administration and monitoring in an infusion center, this drug is given by intramuscular administration, which confers a significant operational advantage. 

In the Phase 3 PROVENT pre-exposure prophylaxis study and STORM CHASER post-exposure prophylaxis study, AZD7442 was examined for its ability to prevent symptomatic COVID-19. In the PROVENT trial, a 300 mg intramuscular dose of AZD7442 was compared to placebo in 5,197 participants (75% of whom had comorbidities increasing risk of severe disease) who did not have SARS-CoV-2 infection at baseline. The study found that AZD7442 lowered participants’ risk of developing symptomatic COVID-19 by 77% (95% CI, 46-90) in the treatment group as compared to the placebo group. In the STORM CHASER study, the safety and efficacy at preventing symptomatic COVID-19 of a 300 mg intramuscular dose of AZD7442 was compared to that of placebo among 1,121 unvaccinated participants with recent (≤ 8 days) exposure to an individual with laboratory-confirmed COVID-19. The primary endpoint (which was not met) was the prevention of PCR-confirmed symptomatic COVID-19 up to day 183 post treatment; participants were followed for 15 months. There was a non-significant reduction in the overall study population of the risk of symptomatic COVID-19 by 33% (95% CI, 26-65) in the treatment arm compared to placebo (rates were 3% [23/749] and 4.6% [17/372], respectively). In a pre-planned subgroup analysis among only those participants confirmed to be PCR-negative at baseline, there was a 73% reduction (95% CI, 27-90) in symptomatic COVID-19 cases in the AZD7442 treatment group compared to placebo (0.8% [6/715] and 3% [11/358] respectively). When looking only at COVID-19 cases that occurred more than 7 days after dosing (most likely to represent cases acquired while on the drug as opposed to before the drug had been given), the effect was stronger: a 92% reduction (95% CI, 32-99) in symptomatic COVID-19 cases in the treatment group as compared to placebo (0.1% [1/710] and 1.6% [6/353], respectively). Based on some of these findings, AstraZeneca submitted an FDA EUA application for tixagevimab/cilgavimab for pre-exposure prophylaxis of COVID-19, which was granted in December of 2021. 

Notably, tixagevimab/cilgavimab has also been studied at a dose of 600 mg for treatment of mild COVID-19. The results of the Phase 3 TACKLE trial (N=903) were announced in an October 2021 press release. This study compared a single intramuscular injection of the antibody combination to placebo among nonhospitalized people with mild or moderate symptomatic COVID-19 at high risk of progression to severe disease and found a significant decrease in progression to severe COVID-19 disease or death. Participants were required to have been symptomatic for ≤ 7 days prior to receipt of the study product, so all participants were early in the course of their illness. The risk of progressing to the combined endpoint of severe COVID-19 or death was 4.4% (18/407) in the tixagevimab/cilgavimab group and 8.9% (37/415) in the placebo group, conferring a 50% decrease in risk among tixagevimab/cilgavimab recipients. In a subgroup of participants who received the study product within 5 days of symptom onset, the benefit was even greater, with a risk of progression to severe illness or death of 3.5% (9/253) in the tixagevimab/cilgavimab arm and 10.8% (27/251) in the placebo arm, for a 67% risk reduction. The ACTIV-3 trial led by NIH is also studying tixagevimab/cilgavimab as treatment for hospitalized patients with COVID-19. The current EUA, however, is only for COVID-19 pre-exposure prophylaxis. 

Bebtelovimab

In February 2022, FDA emergency-authorized bebtelovimab for the treatment of mild to moderate COVID-19 in adults and certain pediatric patients for whom alternative treatment options are not accessible or clinically appropriate.

This section will be updated soon with further information.

 

Guidelines 

FDA Criteria for Use of Monoclonals  

A revised FDA EUA expanded the criteria that may place an individual at higher risk for severe COVID-19 and thus become eligible for anti-SARS-CoV-2 monoclonal antibodies, stating that health care providers should consider the use of monoclonals in individuals with the following characteristics: 

  • BMI >25 kg/m2, or if under 18 years, with BMI ≥85th percentile for their age and sex. 
  • History of solid organ or bone marrow transplant, or cardiovascular disease, cancer, chronic kidney disease or chronic obstructive pulmonary disease. 
  • Older age (for example, age ≥65 years of age). 
  • 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]). 

FDA Authorizations for Monoclonals 

Bamlanivimab & Etesevimab 

The FDA EUA for the combination of bamlanivimab and etesevimab authorizes their use for: 

  • Treatment of mild to moderate COVID-19 in nonhospitalized adults and children at least 12 years of age who have positive direct viral testing for SARS-CoV-2 and are at high risk of progression to severe COVID-19 who:  
    • Do not require supplemental oxygen treatment. 
    • Are within 10 days of symptom onset.  
  • Post-exposure prophylaxis of COVID-19 in adults and children over 12 years of age at high risk for progression to severe COVID-19 who are:  
    • Not fully vaccinated or not expected to have an immune response to vaccination AND ARE EITHER 
    • Exposed (within 6 feet distance for at least 15 minutes) to a SARS-CoV-2-infected person OR 
    • At high risk for SARS-CoV-2 exposure due to COVID-19 cases in others sharing the same institutional environment.  

HHS has at times paused all distribution of bamlanivimab/etesevimab in the United States due to concerns about a lack of effectiveness of the product against variants of concern circulating in the United States. For the latest updates on distribution and allocations of bamlanivimab/ etesevimab, see the HHS website. 

Casirivimab & Imdevimab 

The FDA EUA for REGEN-COV (casirivimab and imdevimab) authorizes its use for: 

  • Treatment of mild to moderate COVID-19 in nonhospitalized adults and children at least 12 years of age who are at high risk of progression to severe COVID-19.
    • Dosage of 600 mg of casirivimab and 600 mg of imdevimab in a single-vial coformulation OR as single vials to be administered together, as a single IV infusion or by subcutaneous injection. 
    • To be given within 10 days of symptom onset.
  • Post-exposure prophylaxis of COVID-19 in adults and children over 12 years of age at high risk for progression to severe COVID-19, who are:  
    • Not fully vaccinated or not expected to have an immune response to vaccination AND ARE EITHER
    • Exposed (within 6 feet distance for at least 15 minutes) to a SARS-CoV-2-infected person OR
    • At high risk for SARS-CoV-2 exposure due to COVID-19 cases in others sharing the same institutional environment.
    • Dosage of 600 mg casirivimab and 600 mg imdevimab (by subcutaneous injection or IV infusion) followed by subsequent repeat administrations of 300 mg casirivimab and 300 mg imdevimab every 4 weeks for the duration of the ongoing exposure. 

The revised EUA for REGEN-COV specifies:

  • Subcutaneous injection as an alternative route of administration when intravenous infusion is not feasible and would lead to delay in treatment. 

Sotrovimab 

FDA’s EUA authorizes sotrovimab for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg), with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death. 

Tixagevimab/cilgavimab  

FDA’s EUA authorizes tixagevimab/cilgavimab for the pre-exposure prevention of COVID-19 among individuals 12 years and older who have moderate to severe immune suppression, may not mount a response to COVID-19 vaccination or for whom vaccination is contraindicated. 

IDSA Guidelines on Monoclonals 

Pre-Exposure Prophylaxis  
In moderately or severely immunocompromised individuals at increased risk for inadequate immune response to COVID-19 vaccine or for whom COVID-19 vaccine is not recommended due to a documented serious adverse reaction to the vaccine, the IDSA guideline panel suggests pre-exposure prophylaxis with tixagevimab/cilgavimab rather than no tixagevimab/cilgavimab (conditional recommendation, low certainty of evidence).  

Post-Exposure Prophylaxis 
In persons exposed to COVID-19 who are at high risk for progression to severe COVID-19, IDSA guidelines suggest post-exposure casirivimab/imdevimab rather than no casirivimab/imdevimab (conditional recommendation; low certainty of evidence). 

Treatment 
Among ambulatory care patients with mild to moderate COVID-19 at high risk for progression to severe disease,  IDSA guidelines suggest bamlanivimab/etesevimab, casirivimab/imdevimab or sotrovimab rather than no neutralizing antibody treatment (conditional recommendation, moderate certainty of evidence) in unvaccinated outpatients with mild to moderate COVID-19 who are at high risk for progression to severe disease.  

  • Patients with mild to moderate COVID-19 who are at high risk of progression to severe disease admitted to the hospital for reasons other than COVID-19 may also receive bamlanivimab/etesevimab or casirivimab/imdevimab or sotrovimab. 
  • Local variant susceptibility may be considered in the choice of the most appropriate neutralizing antibody therapy. 
  • There are limited data on efficacy of bamlanivimab/etesevimab or casirivimab/imdevimab in high-risk patients under 18 years of age. 
  • There are limited data on the use of monoclonals to prevent disease progression among individuals fully vaccinated against COVID-19. 

Among hospitalized patients with severe COVID-19, IDSA recommends against bamlanivimab monotherapy (strong recommendation, moderate certainty of evidence). 

NIH Guidelines on Monoclonals 

NIH guidelines recommend the use of bamlanivimab 700 mg plus etesevimab 1,400 mg for outpatients with mild to moderate COVID-19 who are at high risk of clinical progression. NIH recommends against the use of bamlanivimab 700 mg plus etesevimab 1,400 mg for patients who are hospitalized because of COVID-19, except in a clinical trial. However, they state the combination should be considered for persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 but who otherwise meet EUA criteria.  

  


Key Literature
 

RECOVERY Trial: Casirivimab and Imdevimab in Patients Admitted to Hospital With COVID-19 (Horby, June 2021 – preprint, not peer-reviewed). 

Patient population: 

  • 3,153 (32%) seronegative patients, 5,272 (54%) seropositive patients and 1,360 (14%) patients with unknown baseline antibody status. 
  • Randomized (1:1) to either standard of care OR usual care plus a single intravenous dose of REGEN-COV 8 g (including the combination of casirivimab 4 g and imdevimab 4 g). 

Primary endpoint: 

  • Death within 28 days. 

Key findings: 

  • Among seronegative patients: 396 (24%) of 1,633 patients allocated to REGEN-COV and 451 (30%) of 1,520 patients allocated to standard of care died within 28 days (rate ratio 0.80; 95% CI, 0.70-0.91; p=0.0010). 
  • In an analysis with all randomized patients, which did not take into account baseline serostatus, 944 (20%) of 4,839 patients allocated to REGEN-COV and 1,026 (21%) of 4,946 patients allocated to standard of care died within 28 days (rate ratio, 0.94; 95% CI, 0.86-1.03; p=0.17).  
  • The effect of REGEN-COV on mortality was significantly different between seronegative and seropositive patients (p value for heterogeneity, 0.001). 
  • No evidence that mortality effect varied depending on concomitant receipt of azithromycin, colchicine or aspirin (all interaction p values >0.1). 
  • Among seronegative patients not on invasive mechanical ventilation at baseline, there was a lower risk of the composite secondary outcome of invasive mechanical ventilation or death in the REGEN-COV group than in the standard of care group (30% vs. 37%; risk ratio, 0.83; 95% CI, 0.75-0.92).  
  • This was not seen in the overall study population (24% vs. 25%; risk ratio, 0.96; 95% CI, 0.90-1.04). 

Limitations: 

  • Scalable and low-cost options for ascertaining SARS-CoV-2 spike antibody serostatus are not available across all clinical settings. 
  • Open label (participants and clinicians aware of their randomization assignment). 
  • Data on duration of symptoms prior to receipt of product was not provided (but arguably, documenting a positive SARS-CoV-2 PCR and negative anti-spike antibody is tantamount to early disease). 

 

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