Efficacy and Safety of SARS-CoV-2 Neutralizing Antibody JS016 in Hospitalized Chinese Patients with COVID-19: a Phase 2/3, Multicenter, Randomized, Open-Label, Controlled Trial

Run Dong, Li Jiang, Ting Yang, Changsong Wang, Yi Zhang, Xu Chen, Jianfeng Xie, Yuanbin Guo, Li Weng, Yan Kang, Kaijiang Yu, Haibo Qiu, Bin Du, China Critical Care Clinical Trials Group (CCCCTG), Run Dong, Li Jiang, Ting Yang, Changsong Wang, Yi Zhang, Xu Chen, Jianfeng Xie, Yuanbin Guo, Li Weng, Yan Kang, Kaijiang Yu, Haibo Qiu, Bin Du, China Critical Care Clinical Trials Group (CCCCTG)

Abstract

Recombinant human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibody JS016 showed neutralizing and therapeutic effects in preclinical studies. The clinical efficacy and safety of the therapy needed to be evaluated. In this phase 2/3, multicenter, randomized, open-label, controlled trial, hospitalized patients with moderate or severe coronavirus disease 2019 (COVID-19) were randomly assigned in a 1:1 ratio to receive standard care or standard care plus a single intravenous infusion of JS016. The primary outcome was a six-level ordinal scale of clinical status on day 28 since randomization. Secondary outcomes include adverse events, 28-day mortality, ventilator-free days within 28 days, length of hospital stay, and negative conversion rate of SARS-CoV-2 nucleic acid on day 14. A total of 199 patients were randomized, and 197 (99 in the JS016 group and 98 in the control group) were analyzed. Most patients, 95 (96%) in the JS016 group and 97 (99%) in the control group were in the best category on day 28 since randomization. The odds ratio of being in a better clinical status was 0.31 (95% confidence interval [CI], 0.03 to 3.19; P = 0.33). Few adverse events occurred in both groups (3% in the JS016 group and 1% in the control group, respectively; P = 0.34). SARS-CoV-2 neutralizing antibody JS016 did not show clinical efficacy among hospitalized Chinese patients with moderate to severe COVID-19 disease. Further studies are needed to assess the efficacy of the neutralizing antibody to prevent disease deterioration and its benefits among groups of patients specified by disease course and severity. (This study has been registered at ClinicalTrials.gov under identifier NCT04931238.).

Keywords: COVID-19; JS016; SARS-CoV-2; neutralizing antibodies.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1
FIG 1
Distribution of ordinal scores over time since randomization. The 6-level ordinal scale of clinical status was defined as follows: a score of 1 indicated not hospitalized; 2, hospitalized without supplemental oxygen; 3, hospitalized with supplemental oxygen; 4, hospitalized with noninvasive ventilation or high flow nasal cannula; 5, hospitalized with invasive ventilation or ECMO; and 6, death.

References

    1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou C-Q, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang C-L, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu S-Q, Luo J, Ye CJ, Zhu SY, Zhong NS, Covid-19 CMTEG. 2020. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 382:1708–1720. 10.1056/NEJMoa2002032.
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. 2020. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 323:1061–1069. 10.1001/jama.2020.1585.
    1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. 2020. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395:1054–1062. 10.1016/S0140-6736(20)30566-3.
    1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497–506. 10.1016/S0140-6736(20)30183-5.
    1. Ruan Q, Yang K, Wang W, Jiang L, Song J. 2020. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan. China Intensive Care Medicine 368:1–3.
    1. Feng Y, Ling Y, Bai T, Xie Y, Huang J, Li J, Xiong W, Yang D, Chen R, Lu F, Lu Y, Liu X, Chen Y, Li X, Li Y, Summah HD, Lin H, Yan J, Zhou M, Lu H, Qu J. 2020. COVID-19 with Different Severity: a Multi-center Study of Clinical Features. Am J Respir Crit Care Med 201:1380–1388. 10.1164/rccm.202002-0445OC.
    1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. 2020. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395:507–513. 10.1016/S0140-6736(20)30211-7.
    1. Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, Merson L, Lee J, Plotkin D, Sigfrid L, Halpin S, Jackson C, Gamble C, Horby PW, Nguyen-Van-Tam JS, Ho A, Russell CD, Dunning J, Openshaw PJ, Baillie JK, Semple MG, Investigators I, ISARIC4C investigators. 2020. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 369:m1985. 10.1136/bmj.m1985.
    1. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, Consortium The N-1R, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP, the Northwell COVID-19 Research Consortium. 2020. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 323:2052–2059. 10.1001/jama.2020.6775.
    1. RECOVERY Collaborative Group. 2020. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New Engl J Med 384:693–704.
    1. Shi R, Shan C, Duan X, Chen Z, Liu P, Song J, Song T, Bi X, Han C, Wu L, Gao G, Hu X, Zhang Y, Tong Z, Huang W, Liu WJ, Wu G, Zhang B, Wang L, Qi J, Feng H, Wang F-S, Wang Q, Gao GF, Yuan Z, Yan J. 2020. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 584:120–124. 10.1038/s41586-020-2381-y.
    1. Wu X, Li N, Wang G, Liu W, Yu J, Cao G, Wang J, Chen Y, Ma J, Wu J, Yang H, Mao X, He J, Yu Y, Qiu C, Li N, Yao S, Feng H, Yan J, Zhang W, Zhang J. 2021. Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in. Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study Antimicrob Agents Ch 65:e00350-21.
    1. Baral PK, Yin J, James MNG. 2021. Treatment and prevention strategies for the COVID 19 pandemic: a review of immunotherapeutic approaches for neutralizing SARS-CoV-2. Int J Biol Macromol 186:490–500. 10.1016/j.ijbiomac.2021.07.013.
    1. Hurt AC, Wheatley AK. 2021. Neutralizing Antibody Therapeutics for COVID-19. Viruses 13:628. 10.3390/v13040628.
    1. Siemieniuk RA, Bartoszko JJ, Martinez JPD, Kum E, Qasim A, Zeraatkar D, Izcovich A, Mangala S, Ge L, Han MA, Agoritsas T, Arnold D, Ávila C, Chu DK, Couban R, Cusano E, Darzi AJ, Devji T, Foroutan F, Ghadimi M, Khamis A, Lamontagne F, Loeb M, Miroshnychenko A, Motaghi S, Murthy S, Mustafa RA, Rada G, Rochwerg B, Switzer C, Vandvik PO, Vernooij RW, Wang Y, Yao L, Guyatt GH, Brignardello-Petersen R. 2021. Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis. BMJ 374:n2231. 10.1136/bmj.n2231.
    1. Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, Shawa I, Adams AC, Naarden JV, Custer KL, Shen L, Durante M, Oakley G, Schade AE, Sabo J, Patel DR, Klekotka P, Skovronsky DM, BLAZE-1 Investigators. 2021. Investigators B-1. 2020. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 384:229–237. 10.1056/NEJMoa2029849.
    1. Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, Sandkovsky U, Brown SM, Knowlton KU, Self WH, Files DC, Jain MK, Benfield T, Bowdish ME, Leshnower BG, Baker JV, Jensen J-U, Gardner EM, Ginde AA, Harris ES, Johansen IS, Markowitz N, Matthay MA, Østergaard L, Chang CC, Davey VJ, Goodman A, Higgs ES, Murray DD, Murray TA, Paredes R, Parmar MKB, Phillips AN, Reilly C, Sharma S, Dewar RL, Teitelbaum M, Wentworth D, Cao H, Klekotka P, Babiker AG, Gelijns AC, Kan VL, Polizzotto MN, Thompson BT, Lane HC, Neaton JD, ACTIVE-3/TICO Bamlanivimab Study Group. 2021. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med 384:905–914.
    1. Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, Shawa I, Kumar P, Adams AC, Naarden JV, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Klekotka P, Shen L, Skovronsky DM. 2021. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19. JAMA 325:632–644. 10.1001/jama.2021.0202.
    1. Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, Hebert C, Perry R, Boscia J, Heller B, Morris J, Crystal C, Igbinadolor A, Huhn G, Cardona J, Shawa I, Kumar P, Adams AC, Naarden JV, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Dabora MC, Klekotka P, Shen L, Skovronsky DM, Blaze-1 Investigators. 2021. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med 385:1382–1392. 10.1056/NEJMoa2102685.
    1. Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, Sandkovsky U, Brown SM, Knowlton KU, Self WH, Files DC, Jain MK, Benfield T, Bowdish ME, Leshnower BG, Baker JV, Jensen J-U, Gardner EM, Ginde AA, Harris ES, Johansen IS, Markowitz N, Matthay MA, Østergaard L, Chang CC, Goodman A, Chang W, Dewar RL, Gerry NP, Higgs ES, Highbarger H, Murray DD, Murray TA, Natarajan V, Paredes R, Parmar MKB, Phillips AN, Reilly C, Rupert AW, Sharma S, Shaw-Saliba K, Sherman BT, Teitelbaum M, Wentworth D, Cao H, Klekotka P, Babiker AG, Davey VJ, Gelijns AC, Kan VL, Polizzotto MN, ACTIVE-3/TICO Bamlanivimab Study Group, et al.. 2021. Clinical and Virological Response to a Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19. Medrxiv. 10.1101/2021.07.19.21260559.
    1. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Musser BJ, Soo Y, Rofail D, Im J, Perry C, Pan C, Hosain R, Mahmood A, Davis JD, Turner KC, Hooper AT, Hamilton JD, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Kohli A, Sachdeva Y, Graber X, Kowal B, DiCioccio T, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD, Trial Investigators. 2021. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med 384:238–251. 10.1056/NEJMoa2035002.
    1. Group RC, Horby PW, Mafham M, Peto L, Campbell M, Pessoa-Amorim G, Spata E, Staplin N, Emberson JR, Prudon B, Hine P, Brown T, Green CA, Sarkar R, Desai P, Yates B, Bewick T, Tiberi S, Felton T, Baillie JK, Buch MH, Chappell LC, Day JN, Faust SN, Jaki T, Jeffery K, Juszczak E, Lim WS, Montgomery A, Mumford A, Rowan K, Thwaites G, Weinreich DM, Haynes R, Landray MJ. 2021. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Medrxiv. 10.1101/2021.06.15.21258542.
    1. Holmes EC, Hurt AC, Dobbie Z, Clinch B, Oxford JS, Piedra PA. 2021. Understanding the Impact of Resistance to Influenza Antivirals. Clin Microbiol Rev 34:e00224-20. 10.1128/CMR.00224-20.
    1. Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, Giordano S, Lanza K, Negron N, Ni M, Wei Y, Atwal GS, Murphy AJ, Stahl N, Yancopoulos GD, Kyratsous CA. 2020. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369:1014–1018. 10.1126/science.abd0831.
    1. Starr TN, Greaney AJ, Addetia A, Hannon WW, Choudhary MC, Dingens AS, Li JZ, Bloom JD. 2021. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Science 371:850–854. 10.1126/science.abf9302.
    1. Copin R, Baum A, Wloga E, Pascal KE, Giordano S, Fulton BO, Zhou A, Negron N, Lanza K, Chan N, Coppola A, Chiu J, Ni M, Wei Y, Atwal GS, Hernandez AR, Saotome K, Zhou Y, Franklin MC, Hooper AT, McCarthy S, Hamon S, Hamilton JD, Staples HM, Alfson K, Carrion R, Ali S, Norton T, Somersan-Karakaya S, Sivapalasingam S, Herman GA, Weinreich DM, Lipsich L, Stahl N, Murphy AJ, Yancopoulos GD, Kyratsous CA. 2021. The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies. Cell 184:3949–3961.e11. 10.1016/j.cell.2021.06.002.
    1. Dall'Acqua WF, Kiener PA, Wu H. 2006. Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)*. J Biol Chem 281:23514–23524. 10.1074/jbc.M604292200.
    1. Bian H, Zheng Z-H, Wei D, Wen A, Zhang Z, Lian J-Q, Kang W-Z, Hao C-Q, Wang J, Xie R-H, Dong K, Xia J-L, Miao J-L, Kang W, Li G, Zhang D, Zhang M, Sun X-X, Ding L, Zhang K, Jia J, Ding J, Li Z, Jia Y, Liu L-N, Zhang Z, Gao Z-W, Du H, Yao N, Wang Q, Wang K, Geng J-J, Wang B, Guo T, Chen R, Zhu Y-M, Wang L-J, He Q, Yao R-R, Shi Y, Yang X-M, Zhou J-S, Ma Y-N, Wang Y-T, Liang X, Huo F, Wang Z, Zhang Y, Yang X, Zhang Y, et al.. 2021. Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase. Signal Transduct Target Ther 6:194. 10.1038/s41392-021-00603-6.
    1. Planas D, Veyer D, Baidaliuk A, Staropoli I, Guivel-Benhassine F, Rajah MM, Planchais C, Porrot F, Robillard N, Puech J, Prot M, Gallais F, Gantner P, Velay A, Guen JL, Kassis-Chikhani N, Edriss D, Belec L, Seve A, Courtellemont L, Péré H, Hocqueloux L, Fafi-Kremer S, Prazuck T, Mouquet H, Bruel T, Simon-Lorière E, Rey FA, Schwartz O. 2021. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature 596:276–280. 10.1038/s41586-021-03777-9.
    1. Wang P, Nair MS, Liu L, Iketani S, Luo Y, Guo Y, Wang M, Yu J, Zhang B, Kwong PD, Graham BS, Mascola JR, Chang JY, Yin MT, Sobieszczyk M, Kyratsous CA, Shapiro L, Sheng Z, Huang Y, Ho DD. 2021. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593:130–135. 10.1038/s41586-021-03398-2.
    1. Wang R, Zhang Q, Ge J, Ren W, Zhang R, Lan J, Ju B, Su B, Yu F, Chen P, Liao H, Feng Y, Li X, Shi X, Zhang Z, Zhang F, Ding Q, Zhang T, Wang X, Zhang L. 2021. SARS-CoV-2 variants resist antibody neutralization and broaden host ACE2 usage. BioRxiv. 10.1101/2021.03.09.434497.
    1. Chen RE, Winkler ES, Case JB, Aziati ID, Bricker TL, Joshi A, Darling TL, Ying B, Errico JM, Shrihari S, VanBlargan LA, Xie X, Gilchuk P, Zost SJ, Droit L, Liu Z, Stumpf S, Wang D, Handley SA, Stine WB, Shi P-Y, Davis-Gardner ME, Suthar MS, Knight MG, Andino R, Chiu CY, Ellebedy AH, Fremont DH, Whelan SPJ, Crowe JE, Purcell L, Corti D, Boon ACM, Diamond MS. 2021. In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains. Nature 596:103–108. 10.1038/s41586-021-03720-y.
    1. Wang P, Casner RG, Nair MS, Wang M, Yu J, Cerutti G, Liu L, Kwong PD, Huang Y, Shapiro L, Ho DD. 2021. Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization. Cell Host Microbe 29:747–751.e4. 10.1016/j.chom.2021.04.007.
    1. Beigel JH, Tebas P, Elie-Turenne M-C, Bajwa E, Bell TE, Cairns CB, Shoham S, Deville JG, Feucht E, Feinberg J, Luke T, Raviprakash K, Danko J, O’Neil D, Metcalf JA, King K, Burgess TH, Aga E, Lane HC, Hughes MD, Davey RT, Team IS, Tebas P, Quinn J, Jiang Y, Elie-Turenne M-C, Hoelle R, Iovine N, Wills RS, Pata S, Huggins M, Manukian B, Bajwa E, Holland C, Brait K, Hunt T, Stowell C, Slater A, Bell TE, Townsends M, Cairns CB, Quackenbush EB, Park YA, Jordan PG, Blanchet C, Chronowski K, Alvarez K, Shoham S, Ostrander D, Woessner T, IRC002 Study Team, et al.. 2017. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med 5:500–511. 10.1016/S2213-2600(17)30174-1.
    1. Wang Y, Fan G, Salam A, Horby P, Hayden FG, Chen C, Pan J, Zheng J, Lu B, Guo L, Wang C, Cao B. 2020. Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. J Infect Dis 221:1688–1698. 10.1093/infdis/jiz656.
    1. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, et al.. 2020. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382:1787–1799. 10.1056/NEJMoa2001282.
    1. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira DLM, Silva PGM, de BE, Tramujas L, Abreu-Silva EO, Laranjeira LN, Soares AT, Echenique LS, Pereira AJ, Freitas FGR, Gebara OCE, Dantas VCS, Furtado RHM, Milan EP, Golin NA, Cardoso FF, Maia IS, Filho CRH, Kormann APM, Amazonas RB, de Oliveira MFB, Serpa-Neto A, Falavigna M, Lopes RD, Machado FR, Berwanger O, Investigators CC-1B, Coalition Covid-19 Brazil I Investigators. 2020. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med 383:2041–2052. 10.1056/NEJMoa2019014.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe