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 | Global Health | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.175.212.130. Please contact the publisher to request reinstatement.
1.
Berlin  DA, Gulick  RM, Martinez  FJ.  Severe Covid-19.   N Engl J Med. 2020;383(25):2451-2460. doi:10.1056/NEJMcp2009575PubMedGoogle ScholarCrossref
2.
Wu  C, Chen  X, Cai  Y,  et al.  Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.   JAMA Intern Med. 2020;180(7):934-943. doi:10.1001/jamainternmed.2020.0994PubMedGoogle ScholarCrossref
3.
Williamson  EJ, Walker  AJ, Bhaskaran  K,  et al.  Factors associated with COVID-19-related death using OpenSAFELY.   Nature. 2020;584(7821):430-436. doi:10.1038/s41586-020-2521-4PubMedGoogle ScholarCrossref
4.
Wang  Y, Zhang  D, Du  G,  et al.  Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.   Lancet. 2020;395(10236):1569-1578. doi:10.1016/S0140-6736(20)31022-9 PubMedGoogle ScholarCrossref
5.
Beigel  JH, Tomashek  KM, Dodd  LE,  et al; ACTT-1 Study Group Members.  Remdesivir for the treatment of Covid-19—final report.   N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764PubMedGoogle ScholarCrossref
6.
Prescott  HC, Rice  TW.  Corticosteroids in COVID-19 ARDS: evidence and hope during the pandemic.   JAMA. 2020;324(13):1292-1295. doi:10.1001/jama.2020.16747PubMedGoogle ScholarCrossref
7.
Li  L, Zhang  W, Hu  Y,  et al.  Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.   JAMA. 2020;324(5):460-470. Published correction appears in JAMA. 2020;324(5):519. doi:10.1001/jama.2020.10044PubMedGoogle ScholarCrossref
8.
Renn  A, Fu  Y, Hu  X, Hall  MD, Simeonov  A.  Fruitful neutralizing antibody pipeline brings hope to defeat SARS-Cov-2.   Trends Pharmacol Sci. 2020;41(11):815-829. doi:10.1016/j.tips.2020.07.004PubMedGoogle ScholarCrossref
9.
Chen  P, Nirula  A, Heller  B,  et al; for the BLAZE-1 Investigators.  SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19.   N Engl J Med. Published online October 28, 2020. doi:10.1056/NEJMoa2029849 Google Scholar
10.
US Food and Drug Administration. FDA issues Emergency Use Authorization for convalescent plasma as potential promising COVID–19 treatment, another achievement in administration’s fight against pandemic. Published August 23, 2020. Accessed December 22, 2020. https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment
11.
US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibody for treatment of COVID-19. Published November 9, 2020. Accessed December 22, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibody-treatment-covid-19
12.
US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibodies for treatment of COVID-19. Published November 21, 2020. Accessed December 22, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19
13.
Jones  BE, Brown-Augsburger  PL, Corbett  KS,  et al.  LY-CoV555, a rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model of SARS-CoV-2 infection.   bioRxiv. Published online October 9, 2020. doi:10.1101/2020.09.30.318972 Google Scholar
14.
Shi  R, Shan  C, Duan  X,  et al.  A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2.   Nature. 2020;584(7819):120-124. doi:10.1038/s41586-020-2381-y PubMedGoogle ScholarCrossref
15.
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.abd0831PubMedGoogle ScholarCrossref
16.
Huang  C, Wang  Y, Li  X,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5 PubMedGoogle ScholarCrossref
17.
Garg  S, Kim  L, Whitaker  M,  et al.  Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 States, March 1-30, 2020.   MMWR Morb Mortal Wkly Rep. 2020;69:458-464.Google ScholarCrossref
18.
Petrilli  CM, Jones  SA, Yang  J,  et al.  Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.   BMJ. 2020;369:m1966. doi:10.1136/bmj.m1966PubMedGoogle ScholarCrossref
19.
Ko  JY, Danielson  ML, Town  M,  et al; COVID-NET Surveillance Team.  Risk factors for COVID-19-associated hospitalization: COVID-19-associated hospitalization surveillance network and behavioral risk factor surveillance system.   Clin Infect Dis. Published online September 18, 2020. doi:10.1093/cid/ciaa1419 PubMedGoogle Scholar
20.
Joyner  MJ, Wright  RS, Fairweather  D,  et al.  Early safety indicators of COVID-19 convalescent plasma in 5000 patients.   J Clin Invest. 2020;130(9):4791-4797. doi:10.1172/JCI140200PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    5 Comments for this article
    EXPAND ALL
    Expanding Combinations Will Improve Efficacy
    Jianshe Yang, PhD, MM | Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
    This paper reports that bamlanivimab alone had limited capacity to neutralize antispike antigens without a significant difference from placebo when treating outpatients with mild to moderate coronavirus disease 2019 [1]. The effect was improved when bamlanivimab was combined with f etesevimab, another distinct mAbextracted from the convalescent serum of a COVID-19 patient from China. Single use of etesevimab had outcomes similar to those of Bamlanivimab [2].

    We have written that mAbs hold great promise against COVID-19 [3] and speculate that SARS-CoV-2 has a  diversity of antigens that put it beyond the neutralizing capacity of single specific mAbs. Polyclonal mAbs
    for combination infusion might improve efficacy. But the cross-interaction among these different mAbs in a co-system must be demonstrated. Current studies, at most, have developed the two-mAb combinations. Further trials of three or more mAbs should be performed, especially with mAbs originating from diverse patient sources given that the varying infectious capacity of SARS-CoV-2 in patients by gender, age, BMI, race and other comorbidities.

    References

    1. 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. JAMA,2021 doi:10.1001/jama.2021.0202
    2. Shi R, Shan C, Duan X, et al. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2.  Nature. 2020;584(7819):120-124
    3. Jianshe Yang. mAbs may be the most promising candidate to bat SARS-CoV-2: a comment on “Bridging the Gap at Warp Speed-Delivering Options for Preventing and Treating Covid-19”. N Engl J Med 2020; 383:1899-1901

    Contributed by Professor JS Yang, PhD; Chengyou Jia, PhD, Professor Zhongwei Lv, MD, both in Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.
    E-mail: yangjs@impcas.ac.cn
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Monoclonal antibodies to SARS-CoV-2 to treat mild to moderate COVID-19 outpatients?
    Job Harenberg, Professor of Medicine | Heidelberg University, Germany
    Therapeutic perspectives for the treatment of SARS-CoV-2-induced COVID-19 disease receive a future-oriented perspective through the use of monoclonal antibodies. The authors have described its possible early early use to prevent rapid development of illness from local to septic viral infection.

    Since patients are usually hospitalized with severe symptoms, the limited efficacy of monoclonal antibodies may be explained by their use in relatively advanced stages of COVID-19. Mild or moderate symptoms of COVID-19 are more frequent in patients before hospitalization. The logistical challenges of treatment of outpatients are enormous but would be worthwhile and attractive for pilot projects.

    Contributed
    by emeritus Professor Job Harenberg, MD, Heidelberg University, Germany
    E-mail: j.harenberg@doasense.de
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Bamlanivimab versus Etesivimab
    Sardar Babar, MD | Singing River Hospital system
    I find it interesting that the 700 mg Bamlanivimab group showed statistically significant decreases in clinically meaningful parameters such as resolution and decrease in symptoms at day 11, whereas higher doses did not. This dose also came close to achieving statistical significance in reduction in hospitalization. This raises the question of whether the Etesevimab alone would have produced similar results to the combination.
    A trial of Etesivimab versus Bamlanivimab is called for.
    CONFLICT OF INTEREST: None Reported
    Appropriate Placebo Group?
    Pieter Cohen, MD | Harvard Medical School
    The authors report that the monoclonal combination therapy led to a statistically significant decrease in several outcomes including in COVID-19 related emergency department visits and hospitalization compared to placebo. However, this comparison may be flawed.

    As the authors describe, “patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3, 2020)” However, the outcomes of patients receiving combination therapy appear to have been compared to the outcomes of all patients receiving placebo, not just those randomized between August 22-September 3, 2020. />
    Several studies have suggested that the severity of COVID-19 has been decreasing during the course of the pandemic in the United States [1,2].  Therefore, comparing combination therapy to patients who received placebo during an earlier period of the pandemic may overestimate its effectiveness. Could the authors provide a comparison – including statistical analysis – between patients receiving combination therapy vs those receiving placebo treatment only during the comparable dates (i.e., August 22-September 3, 2020)?

    References

    1. Asch DA, Sheils NE, Islam MN, Chen Y, Werner RM, Buresh J, Doshi JA. Variation in US Hospital Mortality Rates for Patients Admitted With COVID-19 During the First 6 Months of the Pandemic. JAMA internal medicine. 2020 Dec 22.
    2. Anesi GL, Jablonski J, Harhay MO, Atkins JH, Bajaj J, Baston C, Brennan PJ, Candeloro CL, Catalano LM, Cereda MF, Chandler JM. Characteristics, Outcomes, and Trends of Patients With COVID-19–Related Critical Illness at a Learning Health System in the United States. Annals of internal medicine. 2021 Jan 19.
    CONFLICT OF INTEREST: Dr. Cohen reports receiving compensation from UptoDate for co-authoring a chapter on the outpatient management of COVID-19.
    READ MORE
    Historical vs. Randomized Controls for Bamlanivimab-Etesevimab in BLAZE-1
    Jolanta Piszczek, BSc Pharm, Pharm D, MSc | Vancouver Island Health Authority
    In the interim analysis of BLAZE-1, Chen et al report that 143 patients were randomized to receive placebo, and 309 received one of the three doses of bamlanivimab monotherapy. [1] These participants were randomized between June 17 and August 21, 2020. On August 21, as per the history of changes log on clinicaltrials.gov for BLAZE-1 (NCT04427501), the combination arm of bamlanivimab-etesevimab was added, and patients were recruited into this arm from August 22 to September 2, 2020.

    In the final analysis of BLAZE-1 [2], the number of patients who received the combination therapy between August 22 and
    September 2 was reported as N=112, but the number of patients who received placebo was N=156, meaning that only an additional 13 patients received placebo after August 21, 2020.

    Based on these numbers, the 112 patients who received combination therapy were evaluated not through a randomized trial methodology, but rather mainly by comparing them with historical controls. These therapies were given sequentially and the result favoring bamlanivimab-etesevimab over placebo is subject to the same bias present in non-randomized studies, including non-contemporaneous bias that is essential to control for in a rapidly evolving pandemic.

    While the final analysis of BLAZE-1 is thought-provoking, it does not provide the high standard of evidence afforded by a randomized controlled trial.

    References

    1. Chen P, Nirula A, Heller B, et al; for the BLAZE-1 Investigators. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19.  N Engl J Med. Published online October 28, 2020. doi:10.1056/NEJMoa2029849

    2. 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. 2021;325(7):632–644. doi:10.1001/jama.2021.0202
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    January 21, 2021

    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

    Author Affiliations
    • 1Baylor University Medical Center and Baylor Scott and White Research Institute, Dallas, Texas
    • 2Eli Lilly and Company, Indianapolis, Indiana
    • 3Department of Medicine, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • 4Vitalink Research, Union, South Carolina
    • 5Long Beach Clinical Trials, Long Beach, California
    • 6Imperial Health, Lake Charles, Louisiana
    • 7Cook County Health, Chicago, Illinois
    • 8Indago Research, Hialeah, Florida
    • 9Las Vegas Medical Research Center, Las Vegas, Nevada
    • 10Feinberg School of Medicine, Northwestern University, Chicago, Illinois
    • 11Franciscan Health, Greenwood, Indiana
    • 12Georgetown University, Washington, DC
    JAMA. 2021;325(7):632-644. doi:10.1001/jama.2021.0202
    Key Points

    Questions  What is the effect of early treatment with antispike neutralizing antibodies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in outpatients with mild to moderate coronavirus disease 2019 (COVID-19)?

    Findings  In the phase 2 portion of a randomized phase 2/3 clinical trial with 577 patients, there was no significant difference in change in viral load with 3 different doses of bamlanivimab monotherapy compared with placebo; treatment with a combination of bamlanivimab and etesevimab significantly decreased SARS-CoV-2 log viral load at day 11 compared with placebo (between-group difference, –0.57 [95% CI, –1.00 to –0.14], P = .01).

    Meaning  Treatment with bamlanivimab and etesevimab combination therapy, but not bamlanivimab monotherapy, resulted in a reduction in SARS-CoV-2 log viral load at day 11 in patients with mild to moderate COVID-19.

    Abstract

    Importance  Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.

    Objective  To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.

    Design, Setting, and Participants  The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020.

    Interventions  Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).

    Main Outcomes and Measures  The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19–related hospitalization, an emergency department [ED] visit, or death at day 29).

    Results  Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was –3.72 for 700 mg, –4.08 for 2800 mg, –3.49 for 7000 mg, –4.37 for combination treatment, and –3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, –0.35 to 0.52; P = .69) for 700 mg, –0.27 (95% CI, –0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, –0.13 to 0.76; P = .16) for 7000 mg, and –0.57 (95% CI, –1.00 to –0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19–related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment.

    Conclusions and Relevance  Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.

    Trial Registration  ClinicalTrials.gov Identifier: NCT04427501

    ×