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- Tixagevimab/Cilgavimab (Evusheld)
- Previously Efficacious Monoclonal Antibodies
Last reviewed: August 4, 2022
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, thus blocking viral attachment and entry into human cells (Marovich, June 2020). Products that have received FDA authorization include bamlanivimab/etesevimab, casirivimab/imdevimab (brand name REGEN-COV) and sotrovimab. However, because the Omicron variant has become the dominant variant in the United States, bebtelovimab is the only monoclonal antibody currently recommended for use to treat COVID-19.
Additionally, tixagevimab/cilgavimab (brand name Evusheld) is emergency-authorized as pre-exposure prophylaxis against COVID-19 for immunocompromised individuals or those who cannot be vaccinated or mount post-vaccination immune response.
In February 2022, FDA issued an emergency use authorization for bebtelovimab for the treatment of mild to moderate COVID-19 in adults and certain pediatric patients over the age of 12 for whom alternative treatment options are not accessible or clinically appropriate.
Available in vitro data from both pseudotyped virus-like particle and authentic SARS-CoV-2 virus neutralization testing shows that this monoclonal antibody retains neutralization efficacy against all variants of SARS-CoV-2 except Mu. It retains efficacy against the Omicron variant of SARS-CoV-2, including BA.1.1.529, BA.1.1 and BA.2, BA.4, and BA.5 (FDA Fact Sheet for Health Care Providers, June 2022).
Clinical data for its EUA authorization came from the BLAZE-4 trial, which was performed prior to the era when Omicron was a dominant strain (50% of participants had Delta, and 29% had Alpha). BLAZE-4 was a Phase 2 study that enrolled both low risk and high risk nonhospitalized participants with mild to moderate COVID-19 and examined clinical efficacy of 175 mg bebtelovimab alone and combined with bamlanivimab/etesevimab compared to placebo in preventing hospitalization or death, when administered within 3 days of testing positive.
The study design was complex, with many arms, and included a randomized portion and an open-label portion. One notable difference between the treatment groups was that more participants in the placebo arm were seropositive at baseline than in the group receiving bamlanivimab/etesevimab/bebtelovimab together or the group receiving bebtelovimab alone (15%, 9% and 7%, respectively); all participants were unvaccinated. A nonclinical, virologic primary endpoint of persistently high viral load by day 7 was chosen.
A persistently high viral load was observed in 21%, 13% and 14% of participants in the placebo, combination monoclonal antibody and bebtelovimab groups, respectively. The secondary endpoint of COVID-19-related hospitalization or death by day 29 was observed in 1.6%, 2.4% and 1.6% of those three groups, respectively.
Tixagevimab and cilgavimab (brand name Evusheld) has been FDA-authorized for emergency use as pre-exposure prophylaxis for prevention of COVID-19 in certain adults and pediatric patients since December 2021 (with a dosing revision in February 2022).
IDSA guidelines suggest pre-exposure prophylaxis with tixagevimab/cilgavimab rather than no tixagevimab/cilgavimab 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 (conditional recommendation, low certainty of evidence).
NIH guidelines recommend tixagevimab and cilgavimab as pre-exposure prophylaxis for patients who are moderately to severely immunocompromised and may have inadequate immune response to COVID-19 vaccination (BIIa) or are not able to be fully vaccinated with any available COVID-19 vaccines due to a documented history of severe adverse reaction to a COVID-19 vaccine or any of its components (AIIa).
The product 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 variants including Omicron (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, January 2022). 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 nonsignificant 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, the FDA EUA was revised in February 2022 to increase the initial dosing of tixagevimab/cilgavimab for pre-exposure prophylaxis due to potentially decreased activity (12- to 424-fold) of tixagevimab/cilgavimab against Omicron subvariants BA.1 and BA.1.1 (while neutralization efficacy against BA.2 subvariant seems likely to be preserved). The previous dosing had been 150 mg of tixagevimab and 150 mg of cilgavimab IM q 6 months while SARS-COV-2 remains in circulation. The amended EUA increased the initial authorized dose to 300 mg of tixagevimab and 300 mg of cilgavimab.
Manufacturer AstraZeneca also plans to conduct an additional dose-ranging study of the safety, immunogenicity, and PK/PD and efficacy data on the following dosing regimens (data to come soon, but not yet available):
- 300 mg tixagevimab and 300 mg cilgavimab administered as two consecutive IM injections, followed 3 months later by EVUSHELD (150 mg tixagevimab and 150 mg cilgavimab) administered as two consecutive IM injections with subsequent redosing every 3 months.
- 600 mg tixagevimab and 600 mg cilgavimab administered as an IV infusion followed 6 months later by 300 mg tixagevimab and 300 mg cilgavimab administered as two consecutive IM injections followed by redosing every 6 months.
Individuals who have not yet received tixagevimab/cilgavimab but could benefit from it should receive 300 mg tixagevimab and 300 mg cilgavimab as their first dose. Individuals who initially received the previously authorized dose, 150 mg of tixagevimab and 150 mg of cilgavimab, should receive a second dose of 150 mg of tixagevimab and 150 mg of cilgavimab as soon as possible. Time any subsequent doses from the date of that second dose.
No safety and efficacy data exist to inform ideal timing of repeat dosing. PROVENT data seemed to suggest that tixagevimab/cilgavimab may provide effective pre-exposure prophylaxis lasting 6 months after administration, but that was for pre-Omicron variants. The FDA fact sheet notes that “because it is unclear which SARS-CoV-2 variant or Omicron subvariant will become dominant in the United States over the next few months, the recommended timing for repeat dosing cannot be provided at this time. The Fact Sheets will be revised with repeat dosing recommendations in the near future when more data are available to determine the appropriate timing of redosing (e.g., a repeat dose with 150 mg of tixagevimab and 150 mg of cilgavimab 3 months or 6 months after the prior dose).”
Notably, the monoclonal antibody combination tixagevimab/cilgavimab has also been studied at a dose of 600 mg (i.e., 300 mg of tixagevimab and 300 mg of cilgavimab) 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.
Note: Information on previously efficacious but no longer available anti-SARS-COV-2 monoclonal antibodies is provided below, but it is important to note that many do NOT retain efficacy against the currently circulating variants of SARS-CoV-2. For an up-to-date encapsulation of regional variant frequency, refer to CDC’s COVID Data Tracker for recent proportions of circulating variants based on the national genomic surveillance system. For up-to-date information on whether a given monoclonal antibody retains efficacy against a given variant and is therefore still authorized in the U.S., refer to FDA’s EUA hub.
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.
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.
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).