Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19
Background: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS+IMD).
Methods: In this phase I/II/III, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.0 g CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus. Results: 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met: in seronegative patients, the least-squares mean difference (CAS+IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log 10 copies/mL (95% CI, -0.51 to -0.05; P=.0172). The primary clinical analysis of death or mechanical ventilation (death/MV) from day 6-29 in patients with high viral load had a strong positive trend but did not reach significance. CAS+IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2-74.0). No safety concerns were noted.
Conclusions: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS+IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients.
Notes Forest plot shows relative risk and relative risk reduction with 95% CIs for CAS+IMD combined dose analysis (2.4 g and 8.0 g) versus placebo. Parameters examined include death within 28 days, discharge alive from hospital from days 1 to 29, and death or mechanical ventilation from days 1 to 29. For all populations, the mFAS was comprised of patients who tested positive for SARS-CoV-2 at baseline. Populations analyzed include patients who tested negative for all SARS-CoV-2 antibodies at baseline (seronegative mFAS), patients who tested positive for any SARS-CoV-2 antibody at baseline (seropositive mFAS), those with borderline, inconclusive or missing baseline serology (other), and the overall population regardless of serostatus (overall mFAS). For the proportion of death within 28 days and the proportion of death or mechanical ventilation with 28 days, the lower bounds of the CI of the relative risk reduction were -342.0% and -241.0%, respectively, which are presented as "NA" in the figure . Abbreviations: CAS+IMD, casirivimab and imdevimab; CI, confidence interval; mFAS, modified full analysis set; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Baum, Fulton, Wloga, Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies, Science
Copin, Baum, Wloga, The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies, Cell
Goyal, Choi, Pinheiro, Clinical characteristics of Covid-19 in New York City, N Engl J Med
Group, Lundgren, Grund, A neutralizing monoclonal antibody for hospitalized patients with Covid-19, N Engl J Med
Group, Lundgren, Grund, Clinical and virological response to a neutralizing monoclonal antibody for hospitalized patients with COVID-19, medRxiv
Guan, Ni, Hu, Clinical characteristics of coronavirus disease 2019 in China, N Engl J Med
Hansen, Baum, Pascal, Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail, Science
Horby, Lim, Dexamethasone in hospitalized patients with Covid-19, N Engl J Med
Li, Zhang, Hu, Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial, JAMA
Marconi, Ramanan, De Bono, Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial, Lancet Respir Med
O'brien, Forleo-Neto, Musser, Subcutaneous REGEN-COV antibody combination for Covid-19 prevention, medRxiv
O'brien, Forleo-Neto, Musser, Subcutaneous REGEN-COV antibody combination to prevent Covid-19, N Engl J Med
Plains, Center, Plains, Ny, Schelker et al., Former employee of Regeneron Pharmaceuticals
Richardson, Hirsch, Narasimhan, Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area, JAMA
Rosas, Brau, Waters, Tocilizumab in hospitalized patients with severe Covid-19 pneumonia, N Engl J Med
Sharun, Tiwari, Dhama, Emran, Rabaan et al., Emerging SARS-CoV-2 variants: impact on vaccine efficacy and neutralizing antibodies, Hum Vaccin Immunother
Verderese, Stepanova, Lam, Neutralizing monoclonal antibody treatment reduces hospitalization for mild and moderate COVID-19: A real-world experience, Clin Infect Dis
Weinreich, Sivapalasingam, Norton, REGEN-COV antibody combination and outcomes in outpatients with Covid-19, N Engl J Med
Weinreich, Sivapalasingam, Norton, REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19, N Engl J Med