Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19

Michael Dougan, Ajay Nirula, Masoud Azizad, Bharat Mocherla, Robert L Gottlieb, Peter Chen, Corey Hebert, Russell Perry, Joseph Boscia, Barry Heller, Jason Morris, Chad Crystal, Awawu Igbinadolor, Gregory Huhn, Jose Cardona, Imad Shawa, Princy Kumar, Andrew C Adams, Jacob Van Naarden, Kenneth L Custer, Michael Durante, Gerard Oakley, Andrew E Schade, Timothy R Holzer, Philip J Ebert, Richard E Higgs, Nicole L Kallewaard, Janelle Sabo, Dipak R Patel, Matan C Dabora, Paul Klekotka, Lei Shen, Daniel M Skovronsky, BLAZE-1 Investigators, Faisal Amin, Masoud Azizad, Katherine Belden, Joseph Boscia, Yevgeniy Bukhman, Jose Cardona, Peter Chen, Paul Cook, Chad Crystal, Mike Dougan, William Fischer, Jeffrey Glassberg, Robert L Gottlieb, Corey Herbert, Howard Huang, Gregory Huhn, Jeffery Kingsley, Princy Kumar, Anuj Malik, Carlos Malvestutto, Patrick Milligan, Bharat Mocherla, Ramesh Mohseni, Jason Morris, Ramesh Nathan, David Pitrak, Joshua Purow, Mayur Ramesh, Yessica Sachdeva, Adam Schwartz, Imad Shawa, Nader Sobh, Valentina Stosor, Charles Thompson, Omesh Verma, Erica Kaufman West, David Wheeler, Michael Winnie, Brian Zeno, Keri Sullivan, Kathryn Hall, Lisa Nakatani, Fahed Bitar, Julie Toven, Haydee Gutierrez, Monica Brown, Thomas Johnson, Tayler Flores, Justin Palarca, Evelyn Flores, Chase Miller, Leslie Silva, Dana Forte, Del Gardner, Beth Moreno, Erlie Lopez, Nicole Martini, Kelly Beck, Jesse Hawkins, Valarie Maldonado, Lorna Duff, Tina Martinez, Joanna Bachowska, Sandra Barcena, Damon Murray, Jane Filus, James Fajardo, Theresa Reyes, Joanna Salvador, John S Garrett, Marcus Holmes, Cedric Spak, Sarah Burris, Rebecca Baker, Solomon Bassett, Emily Brock, Giselle Carino, Laura Clariday, Tanqunisha Coleman, Allyson Davis, Mariana Hurutado-Rodriguez, Allyson Fowlks, Nazia Iram, Janet Jerrow, Felecia Jones, Tina Jones, Kiara Leonard, Erica Lusk, Katalin Martits-Chalangari, Chintal Patel, Shannon Perez, Noelia Ramirez, Raven Robert, Dianna Robinson, Madison Ryan, Samantha Villa, Samantha Wang, Aaron D Killian, Adriana Soliz Palacios, Edilia J Solia, Bryan Youree, Nathan Albright, Asifa Ashraf, Abhishek Avirineni, Dipesh Bista, Andrew Darwin, Sathishkumar Seeliyur Duraiswamy, Shovendra Gautam, Ezmina Lalani, Sherly Mathew, Cheryl McDonald, Diana Moise, Jack Ni, Whitney Nwagbara, Ijeoma Nwelue, Aaron Oubre, Huma Paika, Vivek Ramarathnam, Nida Rasheed, Jacelyn Baldridge, Sharon Brown, Theresa Cheyne, Sandra Garcia, Kristina Perez, Felicity Vaughan, Decolia Washington, Natalia Wiemann, Elizabeth Berihun, Sierra Mullen, Sunaina Rao, Theresa Yarger, Steven Davis, Robert Engle, Blake Johnson, Alyssa Boudreau, Robin Buckner, Krizia Duque, Brittany Garcia, Jon Thammavong, Mary Wallace, Julia Cullen, Susan Ferdosian, Hemangini Joshi, Chad Samuelson, Alice Stacey, Amy C Thomas, MaryAnn Tran, William Tobleman, Nordelle Bent, Theresa Quezada, Carmen Sutton, Emily Zoelle, Anders Berg, Emad Bayoumi, Antonina Caudill, Gregg Clapham, Jeremy Falk, David Frishberg, Billy Gellepis, Lisa Herrera, Niree Hindoyan, Carissa Huynh, Susan Jackman, Harneet Jawanda, Elizabeth Kissell, Yuri Matusov, Shaunt Mehdikhani, Tanyalak Parimon, Ethan Pascual, Victor Tapson, Sam Torbati, Tanzira Zaman, Timothy Wynter, Joel Ebuh, Dennisse Galdamez, Britney Greer, Deisy Espinoza, Herman Davis, Meredith Benfield, Tara Shetley, Carita Barefoot, Polly Turner, Janet Bourque, Melissa Comeaux, David Guillory, Brandi Ingalls, Codie Lee, Sam Liprie, Summer Moss, Page Prather, Kira Rice, Kevin Hanson, Javier Nazar, Ema Burcheci, Pavel Codreanu, Sherry Alboucq, Sophia Bixler, Mitchell Kennedy, Bryan McKay, Jack O'Donnell, Hillary Thoreson, Hilda Yousefi, Gregory Lang, Anhaita Jamula, Jenay Hanson, Kinsey Grey, Krista Gross, Jennifer Norton, Suvi Gross, Maria Carrillo, Shalynn Fields, Benjamin Karsai, Syed Mehdi, Chioma B Ejiogu, Coty Coffee, Stephen Epner, Tracy Everett, Kimberly Forbes, Sybil Hosek, Matthew Itterra, Kody Keckler, Karen Kroc, Mark Mycyk, Robert Needleman, Heather Prescaro, Monina Quindipan, Daniel Pineda, Karel Reyes, Kristin Mounce, Tara Simon, Stepahanie Alford, Kathleen Kioussopoulos, Tricia Kunz, Kelly Underwood, Chanda Beckner, Michael Dougan, Ajay Nirula, Masoud Azizad, Bharat Mocherla, Robert L Gottlieb, Peter Chen, Corey Hebert, Russell Perry, Joseph Boscia, Barry Heller, Jason Morris, Chad Crystal, Awawu Igbinadolor, Gregory Huhn, Jose Cardona, Imad Shawa, Princy Kumar, Andrew C Adams, Jacob Van Naarden, Kenneth L Custer, Michael Durante, Gerard Oakley, Andrew E Schade, Timothy R Holzer, Philip J Ebert, Richard E Higgs, Nicole L Kallewaard, Janelle Sabo, Dipak R Patel, Matan C Dabora, Paul Klekotka, Lei Shen, Daniel M Skovronsky, BLAZE-1 Investigators, Faisal Amin, Masoud Azizad, Katherine Belden, Joseph Boscia, Yevgeniy Bukhman, Jose Cardona, Peter Chen, Paul Cook, Chad Crystal, Mike Dougan, William Fischer, Jeffrey Glassberg, Robert L Gottlieb, Corey Herbert, Howard Huang, Gregory Huhn, Jeffery Kingsley, Princy Kumar, Anuj Malik, Carlos Malvestutto, Patrick Milligan, Bharat Mocherla, Ramesh Mohseni, Jason Morris, Ramesh Nathan, David Pitrak, Joshua Purow, Mayur Ramesh, Yessica Sachdeva, Adam Schwartz, Imad Shawa, Nader Sobh, Valentina Stosor, Charles Thompson, Omesh Verma, Erica Kaufman West, David Wheeler, Michael Winnie, Brian Zeno, Keri Sullivan, Kathryn Hall, Lisa Nakatani, Fahed Bitar, Julie Toven, Haydee Gutierrez, Monica Brown, Thomas Johnson, Tayler Flores, Justin Palarca, Evelyn Flores, Chase Miller, Leslie Silva, Dana Forte, Del Gardner, Beth Moreno, Erlie Lopez, Nicole Martini, Kelly Beck, Jesse Hawkins, Valarie Maldonado, Lorna Duff, Tina Martinez, Joanna Bachowska, Sandra Barcena, Damon Murray, Jane Filus, James Fajardo, Theresa Reyes, Joanna Salvador, John S Garrett, Marcus Holmes, Cedric Spak, Sarah Burris, Rebecca Baker, Solomon Bassett, Emily Brock, Giselle Carino, Laura Clariday, Tanqunisha Coleman, Allyson Davis, Mariana Hurutado-Rodriguez, Allyson Fowlks, Nazia Iram, Janet Jerrow, Felecia Jones, Tina Jones, Kiara Leonard, Erica Lusk, Katalin Martits-Chalangari, Chintal Patel, Shannon Perez, Noelia Ramirez, Raven Robert, Dianna Robinson, Madison Ryan, Samantha Villa, Samantha Wang, Aaron D Killian, Adriana Soliz Palacios, Edilia J Solia, Bryan Youree, Nathan Albright, Asifa Ashraf, Abhishek Avirineni, Dipesh Bista, Andrew Darwin, Sathishkumar Seeliyur Duraiswamy, Shovendra Gautam, Ezmina Lalani, Sherly Mathew, Cheryl McDonald, Diana Moise, Jack Ni, Whitney Nwagbara, Ijeoma Nwelue, Aaron Oubre, Huma Paika, Vivek Ramarathnam, Nida Rasheed, Jacelyn Baldridge, Sharon Brown, Theresa Cheyne, Sandra Garcia, Kristina Perez, Felicity Vaughan, Decolia Washington, Natalia Wiemann, Elizabeth Berihun, Sierra Mullen, Sunaina Rao, Theresa Yarger, Steven Davis, Robert Engle, Blake Johnson, Alyssa Boudreau, Robin Buckner, Krizia Duque, Brittany Garcia, Jon Thammavong, Mary Wallace, Julia Cullen, Susan Ferdosian, Hemangini Joshi, Chad Samuelson, Alice Stacey, Amy C Thomas, MaryAnn Tran, William Tobleman, Nordelle Bent, Theresa Quezada, Carmen Sutton, Emily Zoelle, Anders Berg, Emad Bayoumi, Antonina Caudill, Gregg Clapham, Jeremy Falk, David Frishberg, Billy Gellepis, Lisa Herrera, Niree Hindoyan, Carissa Huynh, Susan Jackman, Harneet Jawanda, Elizabeth Kissell, Yuri Matusov, Shaunt Mehdikhani, Tanyalak Parimon, Ethan Pascual, Victor Tapson, Sam Torbati, Tanzira Zaman, Timothy Wynter, Joel Ebuh, Dennisse Galdamez, Britney Greer, Deisy Espinoza, Herman Davis, Meredith Benfield, Tara Shetley, Carita Barefoot, Polly Turner, Janet Bourque, Melissa Comeaux, David Guillory, Brandi Ingalls, Codie Lee, Sam Liprie, Summer Moss, Page Prather, Kira Rice, Kevin Hanson, Javier Nazar, Ema Burcheci, Pavel Codreanu, Sherry Alboucq, Sophia Bixler, Mitchell Kennedy, Bryan McKay, Jack O'Donnell, Hillary Thoreson, Hilda Yousefi, Gregory Lang, Anhaita Jamula, Jenay Hanson, Kinsey Grey, Krista Gross, Jennifer Norton, Suvi Gross, Maria Carrillo, Shalynn Fields, Benjamin Karsai, Syed Mehdi, Chioma B Ejiogu, Coty Coffee, Stephen Epner, Tracy Everett, Kimberly Forbes, Sybil Hosek, Matthew Itterra, Kody Keckler, Karen Kroc, Mark Mycyk, Robert Needleman, Heather Prescaro, Monina Quindipan, Daniel Pineda, Karel Reyes, Kristin Mounce, Tara Simon, Stepahanie Alford, Kathleen Kioussopoulos, Tricia Kunz, Kelly Underwood, Chanda Beckner

Abstract

Background: Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications.

Methods: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19-related hospitalization or death from any cause by day 29.

Results: A total of 1035 patients underwent randomization and received an infusion of bamlanivimab-etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab-etesevimab group had a Covid-19-related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, -4.8 percentage points; 95% confidence interval [CI], -7.4 to -2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab-etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19-related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, -1.20; 95% CI, -1.46 to -0.94; P<0.001).

Conclusions: Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19-related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.).

Copyright © 2021 Massachusetts Medical Society.

Figures

Figure 1. Enrollment and Trial Design.
Figure 1. Enrollment and Trial Design.
CDC denotes Centers for Disease Control and Prevention, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.
Figure 2. Kaplan–Meier Estimate of the Time…
Figure 2. Kaplan–Meier Estimate of the Time to Hospitalization among High-Risk Patients Who Received Bamlanivimab–Etesevimab or Placebo.
The inset shows the same data on an enlarged y axis. Tick marks indicate censored data.
Figure 3. Effect of Bamlanivimab–Etesevimab on Viral…
Figure 3. Effect of Bamlanivimab–Etesevimab on Viral Load (Days 1–11).
The mean change in the viral load from baseline to day 11 after the initiation of bamlanivimab–etesevimab or placebo is shown. The viral load was calculated from the cycle-threshold value on reverse-transcriptase–polymerase-chain-reaction assay. The error bars indicate 95% confidence intervals.

References

    1. 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;384:229-237.
    1. Cates J, Lucero-Obusan C, Dahl RM, et al. Risk for in-hospital complications associated with COVID-19 and influenza — Veterans Health Administration, United States, October 1, 2018–May 31, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1528-1534.
    1. Ejaz H, Alsrhani A, Zafar A, et al. COVID-19 and comorbidities: deleterious impact on infected patients. J Infect Public Health 2020;13:1833-1839.
    1. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-1720.
    1. Piroth L, Cottenet J, Mariet A-S, et al. Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study. Lancet Respir Med 2021;9:251-259.
    1. Xie J, Tong Z, Guan X, Du B, Qiu H. Clinical characteristics of patients who died of coronavirus disease 2019 in China. JAMA Netw Open 2020;3(4):e205619-e205619.
    1. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-1062.
    1. Chidambaram V, Tun NL, Haque WZ, et al. Factors associated with disease severity and mortality among patients with COVID-19: a systematic review and meta-analysis. PLoS One 2020;15(11):e0241541-e0241541.
    1. Chen R, Liang W, Jiang M, et al. Risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in China. Chest 2020;158:97-105.
    1. Gosain R, Abdou Y, Singh A, Rana N, Puzanov I, Ernstoff MS. COVID-19 and cancer: a comprehensive review. Curr Oncol Rep 2020;22:53-53.
    1. 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.
    1. Kim L, Whitaker M, O’Halloran A, et al. Hospitalization rates and characteristics of children aged <18 years hospitalized with laboratory-confirmed COVID-19 — COVID-NET, 14 states, March 1–July 25, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1081-1088.
    1. Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). June 30, 2020. ().
    1. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med 2020;383:2451-2460.
    1. Carfì A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA 2020;324:603-605.
    1. Del Rio C, Collins LF, Malani P. Long-term health consequences of COVID-19. JAMA 2020;324:1723-1724.
    1. Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation. J Med Virol 2021;93:1013-1022.
    1. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without Azithromycin in mild-to-moderate Covid-19. N Engl J Med 2020;383:2041-2052.
    1. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 — final report. N Engl J Med 2020;383:1813-1826.
    1. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384:693-704.
    1. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. August 12, 2020. (). preprint.
    1. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021;384:20-30.
    1. Roche. Roche provides an update on the phase III COVACTA Trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 associated pneumonia. July 29, 2020. ().
    1. FDA takes key action in fight against COVID-19 by issuing emergency use authorization for first COVID-19 vaccine. News release of the Food and Drug Administration Silver Spring, MD, December 11, 2020. ().
    1. FDA takes additional action in fight against COVID-19 by issuing emergency use authorization for second COVID-19 vaccine. News release of the Food and Drug Administration Silver Spring, MD, December 18, 2020. ().
    1. Marston HD, Paules CI, Fauci AS. Monoclonal antibodies for emerging infectious diseases — borrowing from history. N Engl J Med 2018;378:1469-1472.
    1. 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. October 1, 2020. (). preprint.
    1. Shi R, Shan C, Duan X, et al. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 2020;584:120-124.
    1. Benton DJ, Wrobel AG, Xu P, et al. Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion. Nature 2020;588:327-330.
    1. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-454.
    1. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibody for treatment of COVID-19. News release of the Food and Drug Administration, Silver Spring, MD, November 9, 2020. ().
    1. Coronavirus (COVID-19) Update: FDA authorizes monoclonal antibodies for treatment of COVID-19. News release of the Food and Drug Administration, Silver Spring, MD, February 9, 2021. ().
    1. Centers for Disease Control and Prevention. People at increased risk: and other people who need to take extra precautions. April 20, 2021. ().
    1. Centers for Disease Control and Prevention. Clinical growth charts ().
    1. Food and Drug Administration. COVID-19: developing drugs and biological products for treatment or prevention. May 2020. ().
    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: a randomized clinical trial. JAMA 2021;325:632-644.
    1. Zhou D, Dejnirattisai W, Supasa P, et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 2021;184(9):2348.e6-2361.e6.
    1. Chen RE, Zhang X, Case JB, et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat Med 2021;27:717-726.
    1. Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA) of bamlanivimab and etesevimab. Indianapolis: Eli Lilly, February 2021. ().

Source: PubMed

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