What is the place in therapy for monoclonal antibodies in outpatients with COVID-19?

The coronavirus 2019 (COVID-19) pandemic has led to the need for rapid development of new agents to overcome challenges related to this novel virus. The primary emphasis early in the pandemic was a search for treatments for the most severely ill patients, and agents such as remdesivir, convalescent plasma, and methylprednisolone were shown to be beneficial.1,2 As hospital beds became increasingly limited, there has been a shift to find treatments for prevention of hospitalization in mild-to-moderate COVID-19 cases, but few therapies have been successful. However, bamlanivimab (alone and in combination with etesevimab) and the combination of casirivimab and imdevimab have shown some benefit in the outpatient setting.3,4

Bamlanivimab and casirivimab/imdevimab are intravenous (IV) IgG1κ monoclonal antibodies that target the receptor-binding domain of the COVID-19 spike protein.3,4 They prevent viral entry into human cells through the angiotensin-converting enzyme 2 (ACE2) receptor.5,6 Both agents have received authorization for emergency use in treatment of mild-to-moderate COVID-19. Bamlanivimab received emergency authorization (EUA) from the FDA on November 9, 2020 and casirivimab/imdevimab received authorization on November 21, 2020. Both monoclonal antibodies are authorized for patients who have tested positive for COVID-19, are not hospitalized due to COVID-19, don’t require supplemental oxygen for COVID-19, and are high-risk adult and pediatric patients at least 12 years of age weighing at least 40 kilograms. On February 9, 2021 an additional EUA was issued for the combination of bamlanivimab with etesevimab in the same population as previous EUAs.7 Individuals are considered high-risk for COVID-19 complications if they meet at least 1 of the criteria:3,4,8

  • A body mass index (BMI) >35
  • Chronic kidney disease
  • Diabetes
  • Immunosuppressive disease
  • Immunosuppressive treatment
  • ≥65 years of age
  • ≥55 years of age and have at least 1 of the following:
    • Cardiovascular disease
    • Hypertension
    • Chronic obstructive pulmonary disease/other chronic respiratory disease
  • 12 to 17 years of age and have at least 1 of the following:
    • BMI ≥85th percentile for their age and gender based on CDC growth charts
    • Sickle cell disease
    • Congenital or acquired heart disease
    • Neurodevelopmental disorders
    • A medical-related technological dependence (e.g., tracheostomy, gastrostomy, or positive pressure ventilation [not related to COVID-19)]
    • Asthma, reactive airway or other chronic respiratory disease that requires daily medication for control

These agents can only be given in settings in which healthcare providers have immediate access to medications to treat severe infusion reaction.3,4,7 Bamlanivimab is given as a single IV infusion of 700 mg over at least 1 hour. Etesevimab can only be administered in conjunction with bamlanivimab at a dose of 1400 mg. Similarly, casirivimab/imdevimab is a single IV infusion of 1200 mg of casirivimab and 1200 mg of imdevimab together over at least 1 hour. Both need to be administered as soon as possible after a positive COVID-19 test and within 10 days of symptom onset. After infusion, patients should continue to be monitored for at least 1 hour. Despite receiving treatment, patients should be advised to continue to self-isolate and continue use of infection control measures.

BLAZE-1 and REGN-COV2 trials

The BLAZE-1 trial is a phase 2/3, randomized, double-blind, placebo-controlled, single-dose trial with interim results to justify the EUA of bamlanivimab (LY-CoV555) for COVID-19.9 The trial was designed to evaluate the efficacy and safety of bamlanivimab in patients recently diagnosed with mild or moderate COVID-19 in the outpatient setting. Non-hospitalized individuals with mild to moderate COVID-19 were randomized to receive either placebo, a single 700 mg IV bamlanivimab dose, a single 2800 mg IV bamlanivimab dose, or a single 7000 mg IV dose of bamlanivimab. Individuals were excluded if they had serious COVID-19 disease, currently required or were anticipated to need mechanical ventilation, had another suspected or confirmed infection other than COVID-19, and if they were pregnant. The primary outcome of the trial was mean change from baseline in the viral load at day 11. The secondary outcomes included change from baseline to day 11 in viral load, proportion of individuals who experienced COVID-19-related hospitalization, change in total symptom score, and safety assessment of adverse events (AEs) and serious adverse events (SAEs).

The REGN-COV2 trial is a phase 1 to 3, randomized, double-blind, placebo-controlled trial with interim results to justify the EUA of casirivimab/imdevimab for COVID-19 in patients with mild or moderate COVID-19 in the outpatient setting.10 Individuals were randomized to either receive placebo, a 2.4 gram IV infusion of casirivimab/imdevimab, or an 8 gram IV infusion of casirivimab/imdevimab. The primary outcomes were time-weighted average change in viral load from baseline through day 7 and percentage of individuals with a COVID-19-related medical visit through day 29 following infusion. A safety analysis was also completed.

In the BLAZE-1 trial, 143 individuals were randomized to placebo and 309 individuals were randomized to bamlanivimab with 101 individuals receiving the 700 mg dose, 107 individuals receiving the 2800 mg dose, and 101 individuals receiving the 7000 mg dose.9 In the REGN-COV2 trial, 93 individuals were randomized to placebo and 182 to casirivimab/imdevimab.10 Ninety-two individuals received a 2.4 gram IV infusion, and 90 individuals received an 8 gram IV infusion. In the REGN-COV2 trial, individuals were tested for serum antibodies at baseline for stratification.

The placebo and intervention arms were relatively similar in terms of age, gender, baseline viral load, and presence of risk factors that would affect COVID-19 severity in both trials.9,10 Relevant baseline characteristics that could affect disease severity are summarized in Table 1 and viral load results can be found in Table 2.

Table 1. Baseline characteristics of patients in BLAZE-1 and REGN-COV2.9,10
 
BLAZE-1 Trial
REGN-COV2 Trial
Intervention Arm n=309Placebo Arm
n=143

Intervention Arm n=182
Placebo Arm
n=92

n (%)
n (%)
n (%)
n (%)
Race
White: 269 (88.2)
Black: 22 (7.2)
White: 120 (87)
Black: 7 (5.1)
White: 152 (84)
Black: 21 (12)
White: 72 (77)
Black: 14 (15)
BMI
>30 to <40: 112 (36.8)
>40: 24 (7.9)
>30 to <40: 56 (40.3)
>40: 9 (6.5)
30.51 ± 6.874a29.73 ± 7.149 a
Risk Factors for Severe COVID-19
215 (69.6)
95 (66.4)
118 (65)b58 (62)b
Mild Disease
232 (75.1)
113 (79)
NR
NR
Moderate Disease
77 (24.9)
30 (21)
NR
NR
a Data presented as mean ± standard deviation.
b Patients with at least 1 risk factor for hospitalization.
Abbreviations: BMI, body mass index; COVID-19, coronavirus 2019; NR, not reported.
Table 2. Viral load outcomes in BLAZE-1 and REGN-COV2 trials.9,10
Trial
Viral Load
Intervention Arm
(n=309)
Placebo Arm (n=143)
Difference (95% CI)
BLAZE-1 Trial
Mean change from baseline to day 3700 mg: -1.27-0.85
700 mg: -0.42 (-0.89 to 0.06)
2800 mg: -1.52800 mg: -0.64 (-1.11 to -0.17)
7000 mg: -1.277000 mg: -0.42 (-0.9 to 0.06)
Overall: -1.35Overall: -0.49 (-0.87 to
-0.11)
Mean change from baseline to day 7 700 mg: -2.82
 -2.56
700 mg: -0.25 (-0.73 to 0.23)
2800 mg: -3.01
2800 mg: -0.45 (-0.92 to 0.03)
7000 mg: -2.857000 mg: -0.28 (-0.77 to 0.20)
Overall: -2.90Overall: -0.33 (-0.72 to 0.06)
Mean change from baseline to day 11
700 mg: -3.67
 -3.47700 mg: -0.20 (-0.66 to 0.25)
2800 mg: -4.002800 mg: -0.53 (-0.98 to -0.08)
7000 mg: -3.38
7000 mg: 0.09 (-0.37 to 0.55)
Overall: -3.70Overall: -0.22 (-0.60 to 0.15)
REGN-COV2 Trial
Viral Load
Intervention Arm
Placebo Arm
Difference (95% CI)
Serum antibody negative: LSM change – log10 copies/mL through day 7n=69
n=28
2.4 g: -1.89 ± 0.18-1.37 ± 0.202.4 mg: -0.52 (-1.04 to 0.00)
8 g: -1.96 ± 0.188 mg: -0.60 (-1.12 to
-0.08)
Overall: -1.94 ±0.13Overall: -0.56 (-1.02 to
-0.11)
Serum antibody positive: LSM change – log10 copies/mL through day 7n=56n=37
2.4 g: -1.24 ± 0.19-1.24 ± 0.162.4 mg: 0.00 (-0.48 to 0.49)
8 g: -1.63 ± 0.208 mg: -0.39 (-0.89 to 0.11)
Overall: -1.45 ± 0.13Overall: -0.21 (-0.62 to 0.20)
Unknown antibody status: LSM change – log10 copies/mL through day 7n=18
n=13 
2.4 g: -0.95 ± 0.56
-1.49 ± 0.632.4 mg: 0.54 (-1.20 to 2.28)
8 g: -1.98 ± 0.608 mg: -0.49 (-2.27 to 1.30)
Overall: -1.43 ± 0.44Overall: 0.06 (-1.51 to 1.63)
Full analysis set: LSM change – log10 copies/mL through day 7
n=143
n=78
2.4 g: -1.6 ± 0.14-1.34 ± 0.132.4 mg: -0.25 (-0.6 to 0.1)
8 g: -1.90 ± 0.148 mg: -0.56 (-0.91 to -0.21)
Overall: -1.74 ± 0.11Overall: -0.41 (-0.71 to -0.10)
Abbreviations: CI, confidence interval; LSM, least squares mean.

Clinical outcomes

When all bamlanivimab doses were pooled in the BLAZE-1 study, the incidence of hospitalization was 1.6% compared with 6.3% among patients treated with placebo.9 A post-hoc analysis of patients 65 years of age or older and those with a BMI of at least 35 kg/m2 found 4% of patients treated with bamlanivimab were hospitalized compared with 15% of those treated with placebo. Total symptoms scores had greater improvement from baseline to days 7 to 11 in patients treated with bamlanivimab than placebo.

In the REGN-COV2 trial, 6% of participants that received casirivimab/imdevimab and were serum antibody negative had at least 1 medical visit within 29 days of infusion compared with 15% of those who received placebo.10 Fewer patients who were serum antibody positive at baseline were hospitalized within 29 days of treatment and the groups were similar (1% in the treatment group and 2% in placebo).

In the BLAZE-1 trial, there were no SAEs in the intervention arm, but there was a single SAE in the placebo arm.9 In the REGN-COV2 trial, there was 1 individual in the intervention arm out of 176 individuals that experienced an SAE (2 of 93 in the placebo group).10 Infusion reactions were rare in both studies.

Bamlanivimab combination therapy

As part of the BLAZE-1 trial bamlanivimab was also evaluated with an adjunct monoclonal antibody, etesevimab, to overcome possible resistance.8,11 One hundred twelve patients received combination therapy (2800 mg bamlanivimab and 2800 mg etesevimab) with baseline characteristics similar to the monotherapy and placebo groups.11 Individuals in the combination group had a significant decrease from baseline in viral load at day 11 compared to placebo. Combination therapy had a greater rate of virus clearance at day 7, 11, and 15 compared to any bamlanivimab monotherapy dose. Hospitalization rates were similar between the monotherapy and combination therapy arms. Combination therapy also lowered total symptom score at day 11, but the number of individuals in the combination group who had improvement in symptoms at day 11 was not significantly better than placebo.

Eli Lilly is also conducting the BLAZE-4 trial assessing the safety and efficacy of bamlanivimab alone, 700 mg of bamlanivimab/1400 mg etesevimab, and 700 mg of bamlanivimab/500 mg VIR-7831 (another monoclonal antibody being studied for COVID-19) versus placebo in COVID-19 patients.12,13 Eli Lilly plans to explore lower doses of bamlanivimab in combination with other monoclonal antibodies to maximize available supply and reduce the burden on healthcare systems.

Use in hospitalized patients

Although bamlanivimab has shown efficacy in outpatients, it has not shown significant benefit when used for hospitalized patients.14 In the hospital setting, bamlanivimab was studied with supportive care including remdesivir, glucocorticoids, and other supplemental treatment. Compared to placebo, the study found that bamlanivimab did not significantly improve symptoms and did not provide significant improvement in terms of mortality, SAEs, and clinical grade 3 or 4 adverse events through day 5 from their initial infusion. Based on these finding, bamlanivimab should not be used in patients hospitalized for COVID-19. Casirivimab/imdevimab is currently being studied in hospitalized patients, but results are still being collected with study completion expected in April.15

COVID-19 prevention trials

Eli Lilly is currently completing a phase 3 trial (BLAZE-2) to evaluate the efficacy and safety of bamlanivimab for COVID-19 prevention in skilled nursing and assisted living facility residents and staff.16 A total of 1097 individuals are included in the study with 965 participants (299 residents and 666 staff members) testing negative for COVID-19 and 132 participants (41 residents and 91 staff members) testing positive for COVID-19 at baseline. Participants either received 4200 mg of bamlanivimab or placebo. The manufacturer has reported that there was a significantly lower frequency of symptomatic COVID-19 in the treatment arm compared to placebo (odds ratio 0.43, p=0.00021). For residents, there was a significant decrease in symptomatic COVID-19 in the treatment arm compared to placebo with an 80% lower risk of contracting symptomatic COVID-19 compared to those that received placebo. There were 4 deaths due to COVID-19 in individuals that tested negative and 4 in individuals that tested positive.17 Investigators will also be assessing efficacy and safety of combination therapy with bamlanivimab and etesevimab similar to the BLAZE-1 trial.

Casirivimab/imdevimab is also being studied for COVID-19 prevention; however, the patient population being studied is household exposure contacts.18,19 Approximately 400 subjects who were COVID-19 negative but had a household contact with COVID-19 were enrolled and randomized to receive either casirivimab/imdevimab 1.2 g as a subcutaneous injection or placebo. Interim results reported that casirivimab/imdevimab prevented 100% of symptomatic infections (8/223 in placebo group vs 0/186 in the treatment group) and lowered the overall infection rate by approximately 50% (23/223 in placebo group vs 10/186 in the treatment group). There was 1 death and 1 COVID-19-related hospitalization in the placebo group compared to none in the drug group.

Other monoclonal antibodies for COVID-19

There are several monoclonal antibodies being studied in the ACTIV-2, ACTIV-3, and ACTIV-5 trials.20,21 These trials are sponsored by the National Institute of Allergy and Infectious Diseases and are currently enrolling patients and/or analyzing results. The ACTIV-2 trial is designed to compare the effects of monotherapy bamlanivimab and combination BRII-196 and BRII-198 versus placebo in the outpatient setting. The ACTIV-3 trial is designed to compare the benefit of monotherapy bamlanivimab, monotherapy VIR-7831, and combination BRII-196 and BRII-198 versus remdesivir in patients hospitalized for COVID-19. The ACTIV-5 trial is designed to compare the benefit of monotherapy risankizumab and monotherapy lenzilumab versus remdesivir and placebo in hospitalized patients. Other monoclonal antibodies being studied include BGB-DXP593, CT-P59, and leronlimab.22-26

Conclusion

Bamlanivimab, casirivimab/imdevimab, and bamlanivimab/etesevimab have been granted EUA by the FDA. Authorization is for outpatients with confirmed COVID-19 infections who are considered to be at high-risk for severe COVID-19. At the time of writing this article, they are only authorized to be given in settings that are capable of handling severe infusion reactions which may limit access to these medications. Another limitation to access is the short timeframe for drug administration between symptom onset and treatment. A patient must have a test completed, resulted positive for COVID-19, and have an appointment scheduled to receive treatment all before 10 days pass from their first symptoms. Given that not every facility is able to offer these agents and many patients have transportation barriers to care, this can sometimes make it nearly impossible for some patients to receive these drugs.

Another concern with these products is the limited evidence. Given the small sample size and interim analyses, it is difficult to draw definite conclusions on the efficacy and safety of these products. None of these drugs have established long-term safety data in COVID-19 patients. In addition, the majority of patients were white which limits applicability to other races.

Despite the limitations of the available evidence, bamlanivimab (with or without etesevimab) and casirivimab/imdevimab are currently the only available treatment options for outpatients with mild to moderate COVID-19 symptoms. Also, these agents have shown the ability to improve symptoms and reduce hospitalizations in patients at high risk of severe COVID-19. Given these benefits and the current limited options, these agents have a place in therapy in reducing the burden on healthcare systems and preventing some patients from developing severe complications.

References

  1. Daou F, Abou-Sleymane G, Badro DA, et al. The history, efficacy, and safety of potential therapeutics: a narrative overview of the complex life of COVID-19. Int J Environ Res Public Health. 2021;18(3):955. doi: 10.3390/ijerph18030955
  2. Abubakar AR, Sani IH, Godman B, et al. Systematic review on the therapeutic options for COVID-19: clinical evidence of drug efficacy and implications. Infect Drug Resist. 2020;13:4673-4695. doi: 10.2147/IDR.S289037
  3. Fact sheet for health care providers emergency use authorization (EUA) of bamlanivimab. Food and Drug Administration. Updated November 9, 2020. Accessed January 29, 2021. https://www.fda.gov/media/143603/download
  4. Fact sheet for health care providers emergency use authorization (EUA) of casirivimab and imdevimab. Food and Drug Administration. Updated November 21, 2020. Accessed January 29, 2021. https://www.fda.gov/media/143892/download
  5. Baum A, Fulton BO, Wloga E, et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science. 2020;369(6506):1014-1018. doi: 10.1126/science.abd0831
  6. Hansen J, Baum A, Pascal KE, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 2020;369(6506):1010-1014. doi: 10.1126/science.abd0827
  7. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibodies for treatment of COVID-19. Food and Drug Administration. Updated February 9, 2021. Accessed February 11, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19-0
  8. People with certain medical conditions. Centers for Disease Control and Prevention. Updated December 29, 2020. Accessed January 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html
  9. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2021;384(3):229-237. doi: 10.1056/NEJMoa2029849
  10. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2021;384(3):238-251. doi: 10.1056/NEJMoa2035002
  11. Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. Published online January 21, 2021. doi: 10.1001/jama.2021.0202
  12. New data show treatment with Lilly’s neutralizing antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) together reduced risk of COVID-19 hospitalizations and death by 70 percent. Eli Lilly. Updated January 26, 2021. Accessed January 29, 2021. https://investor.lilly.com/news-releases/news-release-details/new-data-show-treatment-lillys-neutralizing-antibodies
  13. Lilly, VIR Biotechnology and GSK announce first patient dosed in expanded BLAZE-4 trial evaluating bamlanivimab (LY-CoV555) with VIR-7831 (GSK4182136) for COVID-19. GlaxoSmithKline. Updated January 27, 2021. Accessed January 29, 2021. https://www.gsk.com/en-gb/media/press-releases/lilly-vir-biotechnology-and-gsk-announce-first-patient-dosed-in-expanded-blaze-4-trial/
  14. Lundgren JD, Grund B, Barkauskas CE, et al. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med. Published online December 22, 2020. doi: 10.1056/NEJMoa2033130
  15. Safety, tolerability, and efficacy of anti-spike (S) SARS-CoV-2 monoclonal antibodies for hospitalized adult patients with COVID-19. Clinicaltrials.gov. Updated January 15, 2021. Accessed February 1, 2021.https://clinicaltrials.gov/ct2/show/NCT04426695
  16. Lilly’s neutralizing antibody bamlanivimab (LY-CoV555) prevented COVID-19 at nursing homes in the BLAZE-2 trial, reducing risk by up to 80 percent for residents. Eli Lilly. Updated January 21, 2021. Accessed January 29, 2021. https://investor.lilly.com/news-releases/news-release-details/lillys-neutralizing-antibody-bamlanivimab-ly-cov555-prevented
  17. A study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in preventing SARS-CoV-2 infection and COVID-19 in nursing home residents and staff (BLAZE-2). gov. Updated January 22, 2021. Accessed January 29, 2021. https://clinicaltrials.gov/ct2/show/study/NCT04497987
  18. Regeneron reports positive interim D]data with REGEN-COV antibody cocktail used as passive vaccine to prevent COVID-19. Regeneron Newsroom. January 26, 2021. Accessed January 31, 2021. https://newsroom.regeneron.com/news-releases/news-release-details/regeneron-reports-positive-interim-data-regen-covtm-antibody
  19. A phase 3, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of anti-spike SARS-CoV-2 monoclonal antibodies in preventing SARS-CoV-2 infection in household contacts of individuals infected with SARS-CoV-2. ClinicalTrials.gov identifier: NCT04452318. Updated January 25, 2021. Accessed February 2, 2021. https://clinicaltrials.gov/ct2/show/NCT04452318
  20. Kaplon H, Reichert JM. Antibodies to watch in 2021. MAbs. 2021;13(1):1860476. doi: 10.1080/19420862.2020.1860476
  21. COVID-19 therapeutics prioritized for testing in clinical trials. National Institutes of Health. Updated January 22, 2021. Accessed February 2, 2021. https://www.nih.gov/research-training/medical-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials
  22. Starr TN, Greaney AJ, Addetia A, et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Science. Published online January 2021. doi: 10.1126/science.abf9302
  23. Tuccori M, Ferraro S, Convertino I, et al. Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline. MAbs. 2020;12(1):1854149. doi:10.1080/19420862.2020.1854149
  24. Patterson BK, Seethamraju H, Dhody K, et al. CCR5 inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8 T-cells, and decreases SARS-CoV2 RNA in plasma by day 14. Int J Infect Dis. Published online November 2020. doi: 1016/j.ijid.2020.10.101
  25. UPDATE – impressive results from CytoDyn’s phase 2 COVID-19 trial. Updated July 21, 2020. Accessed January 29, 2021. https://www.cytodyn.com/newsroom/press-releases/detail/453/update—impressive-results-from-cytodyns-phase-2.
  26. FDA resumes eIND approval for severe-to-critical COVID-19 patients use of Vyrologix™ (leronlimab) following full enrollment in CytoDyn’s phase 3 trial. Global Newswire. Updated December 22, 2020. Accessed January 29, 2021.https://www.globenewswire.com/news-release/2020/12/22/2149221/0/en/FDA-Resumes-eIND-Approval-for-Severe-to-Critical-COVID-19-Patients-Use-of-Vyrologix-leronlimab-Following-Full-Enrollment-in-CytoDyn-s-Phase-3-Trial.html

Prepared by:
Alex Thorp, PharmD
PGY1 Pharmacy Resident
University of Illinois at Chicago College of Pharmacy, Rockford Campus

March 2021

The information presented is current as February 11, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.