REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

David M Weinreich, Sumathi Sivapalasingam, Thomas Norton, Shazia Ali, Haitao Gao, Rafia Bhore, Bret J Musser, Yuhwen Soo, Diana Rofail, Joseph Im, Christina Perry, Cynthia Pan, Romana Hosain, Adnan Mahmood, John D Davis, Kenneth C Turner, Andrea T Hooper, Jennifer D Hamilton, Alina Baum, Christos A Kyratsous, Yunji Kim, Amanda Cook, Wendy Kampman, Anita Kohli, Yessica Sachdeva, Ximena Graber, Bari Kowal, Thomas DiCioccio, Neil Stahl, Leah Lipsich, Ned Braunstein, Gary Herman, George D Yancopoulos, Trial Investigators, Dario Altamirano, Ximena Graber, Dickson Ellington, Anita Kohli, Vicki McIntyre, Yessica Sachdeva, Mezgebe Berhe, Haley Clinton, Uriel Sandkovsky, Emma Dishner, Rahaf Al Masri, Erin Duhaime, Robinson Koilpillai, Stephanie Cassady, Jennifer Cox, Eduardo Torres, Faisal A Fakih Faisal, M Fakih, Fernando Alvarado, Daniel Layish, Jose Diaz, Augusto Focil, Griselda Rosas, Stevan Correa, Michael Bogseth, Roxana Stoici, Gualberto Perez, Joseph Pica, Enrique Villareal, Suraj Saggar, Thomas Birch, Benjamin De La Rosa, Karyna Neyra, Erina Kunwar, Jeffrey Kingsley, April Pixler, Eric Meissner, Andrew Goodwin, Deeksha Jandhyala, Nandita Nadig, Godson Oguchi, DeAndrea Duffus, Moti Ramgopal, Brenda Jacobs, Lisa Cason, Angela Trodglen, Terence Chang, Robbyn Traylor, Lenee Gordon, John McDivitt, Jennifer Killion, Rupal Amin, Shauna Basener, Timothy Lowry, Kevin Cannon, Mesha Chadwick, Jazila Mantis, Margaret Kemeny, Merjona Saliaj, Edward Cordasco, Brian Zeno, Heather Holmes, Manuel Gordillo, Rishi Bhattacharyya, Sudha Tallapragada, Annette Artau, Julie Larkin, Roberto Mercado, Michael Milam, Natan Kraitman, Sarah Temple, Lenka Offner, Rabih Loutfi, Kirk Voelker, Michael Lowry, Carl Dukes, Robert Bass, Larry Lothringer, Leonel Reyes, Adil Fatakia, Marissa Miller, Kristen Clinton, Gary Reiss, David Diemert, Afsoon Roberts, David Parenti, Hana Akselrod, Marc Siegel, Andrew Meltzer, Elissa Malkin, Julie Philley, Megan Devine, Richard Yates, Steven Hickerson, Olayemi Osiyemi, Jose A Menajovsky-Chaves, Christina Campbell, Gerard Acloque, Agustin Martinez, Thomas Campbell, Martin Krsak, Steven Johnson, Hillary Dunlevy, Joseph Bocchini, Clint Wilson, Achint Chani, Adebiyi Adepoju, Adnan Mahmood, Aisha Mortagy, Ajla Dupljak, Alison Brown, Alpana Waldron, Amanda Cook, Amy Froment, Andrea Hooper, Andrea Margiotta, Andrew Bombardier, Anne Smith, Aswani Bathula, Bari Kowal, Barry Siliverstein, Benjamin Horel, Bret Musser, Brian Bush, Brian Head, Bryan Zhu, Camille Debray, Careta Phillips, Carol Lee, Caryn Trbovic, Catherine Elliott, Chad Fish, Charlie Ni, Charlotte Lyon, Christina Perry, Christine Enciso, Christopher Caira, Christopher Chamak, Christopher Powell, Cliff Baum, Colby Burk, Cynthia Pan, David Liu, David Stein, Daya Gulabani, Deborah Leonard, Denise Bonhomme, Denise Kennedy, Derrick Bramble, Dhanalakshmi Barron, Diana Rofail, Dipinder Kaur, Dona Bianco, Donna Gambaccini, Eduardo Forleo Neto, Edward Jean-Baptiste, Ehsan Bukhari, Elizabeth Bucknam, Emily Nanna, Esther Huffman O'Keefe, Evelyn Gasparino, Georgia Bellingham, Giane Sumner, Grainne Moggan, Grainne Power, Haitao Gao, Haixia Zeng, Heath Gonzalez, Helen Kang, Hibo Noor, Ian Minns, James Donohue, Janice Austin, Janie Parrino, Jeannie Yo, Jenna McDonnell, Jennifer Hamilton, Jessica Boarder, Jing Xiao, Jingchun Yu, Joanne Malia, Joanne Tucciarone, John Strein, Jonathan Cohen, Jordan Ursino, Joseph Im, Joseph Wolken, Karen Browning, Karen Yau, Kenneth Turner, Kimberly Dornheim, Kit Chiu, Kristina McGuire, Kristy Macci, Kurt Ringleben, Kyle Foster, Lacey Douthat, Latora Knighton, Lisa Boersma, Lisa Hersh, Lisa Purcell, Lisa Sherpinsky, Lori Geissler, Marc Dickens, Marco Mancini, Martha Simpkins, Meagan O'Brien, Michael Batchelder, Michael Partridge, Michal Rozanski, Michel Tarabocchia, Michelle Wong, Mivianisse Rodriguez, Moetaz Albizem, Muriel O'Byrne, Nagendher Burra, Neena Sarkar, Nicholas Moore, Nicole Memblatt, Nikki Miocevic, Nirav Shah, Nitin Kumar, Olga Herrera, Patrick Floody, Paul D'Ambrosio, Qin Li, Rafia Bhore, Rakiyya Ali, Ramya Iyer, Ravikanth Chava, Rinol Alaj, Romana Hosain, Ruchin Gorawala, Ryan Yu, Rylee Fogarty, S Balachandra Dass, Sagarika Bollini, Samit Ganguly, Sandra DeCicco, Sara Dale, Sara Hamon, Sarah Cassimaty, Selin Somersan-Karakaya, Shane McCarthy, Sharon Henkel, Shazia Ali, Soraya Nossoughi, Steven Elkin, Sumathi Sivapalasingam, Susan Irvin, Tami Min, Ted Burczynski, Theresa Devins, Thomas Norton, Travis Bernardo, Vinh Nuce, Wilson Caldwell, Yanmei Tian, Yasmin Khan, David M Weinreich, Sumathi Sivapalasingam, Thomas Norton, Shazia Ali, Haitao Gao, Rafia Bhore, Bret J Musser, Yuhwen Soo, Diana Rofail, Joseph Im, Christina Perry, Cynthia Pan, Romana Hosain, Adnan Mahmood, John D Davis, Kenneth C Turner, Andrea T Hooper, Jennifer D Hamilton, Alina Baum, Christos A Kyratsous, Yunji Kim, Amanda Cook, Wendy Kampman, Anita Kohli, Yessica Sachdeva, Ximena Graber, Bari Kowal, Thomas DiCioccio, Neil Stahl, Leah Lipsich, Ned Braunstein, Gary Herman, George D Yancopoulos, Trial Investigators, Dario Altamirano, Ximena Graber, Dickson Ellington, Anita Kohli, Vicki McIntyre, Yessica Sachdeva, Mezgebe Berhe, Haley Clinton, Uriel Sandkovsky, Emma Dishner, Rahaf Al Masri, Erin Duhaime, Robinson Koilpillai, Stephanie Cassady, Jennifer Cox, Eduardo Torres, Faisal A Fakih Faisal, M Fakih, Fernando Alvarado, Daniel Layish, Jose Diaz, Augusto Focil, Griselda Rosas, Stevan Correa, Michael Bogseth, Roxana Stoici, Gualberto Perez, Joseph Pica, Enrique Villareal, Suraj Saggar, Thomas Birch, Benjamin De La Rosa, Karyna Neyra, Erina Kunwar, Jeffrey Kingsley, April Pixler, Eric Meissner, Andrew Goodwin, Deeksha Jandhyala, Nandita Nadig, Godson Oguchi, DeAndrea Duffus, Moti Ramgopal, Brenda Jacobs, Lisa Cason, Angela Trodglen, Terence Chang, Robbyn Traylor, Lenee Gordon, John McDivitt, Jennifer Killion, Rupal Amin, Shauna Basener, Timothy Lowry, Kevin Cannon, Mesha Chadwick, Jazila Mantis, Margaret Kemeny, Merjona Saliaj, Edward Cordasco, Brian Zeno, Heather Holmes, Manuel Gordillo, Rishi Bhattacharyya, Sudha Tallapragada, Annette Artau, Julie Larkin, Roberto Mercado, Michael Milam, Natan Kraitman, Sarah Temple, Lenka Offner, Rabih Loutfi, Kirk Voelker, Michael Lowry, Carl Dukes, Robert Bass, Larry Lothringer, Leonel Reyes, Adil Fatakia, Marissa Miller, Kristen Clinton, Gary Reiss, David Diemert, Afsoon Roberts, David Parenti, Hana Akselrod, Marc Siegel, Andrew Meltzer, Elissa Malkin, Julie Philley, Megan Devine, Richard Yates, Steven Hickerson, Olayemi Osiyemi, Jose A Menajovsky-Chaves, Christina Campbell, Gerard Acloque, Agustin Martinez, Thomas Campbell, Martin Krsak, Steven Johnson, Hillary Dunlevy, Joseph Bocchini, Clint Wilson, Achint Chani, Adebiyi Adepoju, Adnan Mahmood, Aisha Mortagy, Ajla Dupljak, Alison Brown, Alpana Waldron, Amanda Cook, Amy Froment, Andrea Hooper, Andrea Margiotta, Andrew Bombardier, Anne Smith, Aswani Bathula, Bari Kowal, Barry Siliverstein, Benjamin Horel, Bret Musser, Brian Bush, Brian Head, Bryan Zhu, Camille Debray, Careta Phillips, Carol Lee, Caryn Trbovic, Catherine Elliott, Chad Fish, Charlie Ni, Charlotte Lyon, Christina Perry, Christine Enciso, Christopher Caira, Christopher Chamak, Christopher Powell, Cliff Baum, Colby Burk, Cynthia Pan, David Liu, David Stein, Daya Gulabani, Deborah Leonard, Denise Bonhomme, Denise Kennedy, Derrick Bramble, Dhanalakshmi Barron, Diana Rofail, Dipinder Kaur, Dona Bianco, Donna Gambaccini, Eduardo Forleo Neto, Edward Jean-Baptiste, Ehsan Bukhari, Elizabeth Bucknam, Emily Nanna, Esther Huffman O'Keefe, Evelyn Gasparino, Georgia Bellingham, Giane Sumner, Grainne Moggan, Grainne Power, Haitao Gao, Haixia Zeng, Heath Gonzalez, Helen Kang, Hibo Noor, Ian Minns, James Donohue, Janice Austin, Janie Parrino, Jeannie Yo, Jenna McDonnell, Jennifer Hamilton, Jessica Boarder, Jing Xiao, Jingchun Yu, Joanne Malia, Joanne Tucciarone, John Strein, Jonathan Cohen, Jordan Ursino, Joseph Im, Joseph Wolken, Karen Browning, Karen Yau, Kenneth Turner, Kimberly Dornheim, Kit Chiu, Kristina McGuire, Kristy Macci, Kurt Ringleben, Kyle Foster, Lacey Douthat, Latora Knighton, Lisa Boersma, Lisa Hersh, Lisa Purcell, Lisa Sherpinsky, Lori Geissler, Marc Dickens, Marco Mancini, Martha Simpkins, Meagan O'Brien, Michael Batchelder, Michael Partridge, Michal Rozanski, Michel Tarabocchia, Michelle Wong, Mivianisse Rodriguez, Moetaz Albizem, Muriel O'Byrne, Nagendher Burra, Neena Sarkar, Nicholas Moore, Nicole Memblatt, Nikki Miocevic, Nirav Shah, Nitin Kumar, Olga Herrera, Patrick Floody, Paul D'Ambrosio, Qin Li, Rafia Bhore, Rakiyya Ali, Ramya Iyer, Ravikanth Chava, Rinol Alaj, Romana Hosain, Ruchin Gorawala, Ryan Yu, Rylee Fogarty, S Balachandra Dass, Sagarika Bollini, Samit Ganguly, Sandra DeCicco, Sara Dale, Sara Hamon, Sarah Cassimaty, Selin Somersan-Karakaya, Shane McCarthy, Sharon Henkel, Shazia Ali, Soraya Nossoughi, Steven Elkin, Sumathi Sivapalasingam, Susan Irvin, Tami Min, Ted Burczynski, Theresa Devins, Thomas Norton, Travis Bernardo, Vinh Nuce, Wilson Caldwell, Yanmei Tian, Yasmin Khan

Abstract

Background: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.

Methods: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.

Results: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.

Conclusions: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).

Copyright © 2020 Massachusetts Medical Society.

Figures

Figure 1. Screening, Randomization, and Treatment.
Figure 1. Screening, Randomization, and Treatment.
One patient underwent randomization in error, and Regeneron requested that the patient withdraw from the trial. Four patients in the low-dose REGN-COV2 group withdrew consent: one patient could not participate in the follow-up period, one patient could not have blood drawn and an intravenous line placed, and two patients withdrew consent with no additional information available. Three patients in the high-dose REGN-COV2 group withdrew consent: one patient could not participate in the follow-up period, one patient could not have blood drawn and an intravenous line placed, and one withdrew consent with no additional information available.
Figure 2. SARS-CoV-2 Viral Load over Time.
Figure 2. SARS-CoV-2 Viral Load over Time.
Shown is the change in mean viral load (in log10 copies per milliliter) from baseline at each visit through day 7 in the overall population (modified full analysis set, which excluded patients who tested negative for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] by qualitative reverse-transcriptase polymerase chain reaction at baseline) and in groups defined according to baseline antibody status and baseline viral load. 𝙸 bars in Panel C indicate the standard error. The least-squares mean difference between the groups in the time-weighted average change in viral load (TWA LS mean) from baseline through day 7, expressed as log10 copies per milliliter, was based on analysis-of-covariance models with treatment group, risk factor, and baseline antibody status as fixed effects and baseline viral load and treatment group–by–baseline viral load as covariates. The lower limit of detection (dashed line) is 714 copies per milliliter (2.85 log10 copies per milliliter).

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