Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19

Abstract

Background: Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life.

Objective: To assess the safety and efficacy of amubarvimab plus romlusevimab.

Design: Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410).

Setting: Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines.

Patients: Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression.

Intervention: Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo.

Measurements: Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death.

Results: Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P < 0.001), with no severe infusion reactions or drug-related serious adverse events.

Limitation: The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants.

Conclusion: Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease.

Primary funding source: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Visual Abstract.. Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19

In an international National Institutes of Health–sponsored trial of combination SARS-CoV-2 neutralizing antibodies, investigators determined not only overall efficacy and safety but also whether there was a benefit of administration more than 5 days after symptom onset.

Figure 1.. CONSORT flow diagram.

In this platform trial, participants randomly assigned to a placebo for other agents in phase 2 evaluation may be included in the control group for evaluating amubarvimab plus romlusevimab during phase 2. For amubarvimab plus romlusevimab, there was only 1 participant in the randomized population who received placebo corresponding to a different agent. The safety analysis population included 405 participants who initiated amubarvimab plus romlusevimab (including 8 randomly assigned to placebo) and 402 who initiated placebo. Details of the screened population are not shown in the CONSORT diagram, as screening was broad for evaluating multiple investigational agents in parallel and not specific to each agent. CONSORT = Consolidated Standards of Reporting Trials; mITT = modified intention to treat.

Figure 2.. Cumulative proportion of death or hospitalizations through day 28.

Cumulative proportion of death or hospitalization is estimated by the Kaplan–Meier method. The first occurrence of either death or hospitalization is considered as the event. Hospitalization is defined as ≥24 h of acute care, in a hospital or similar acute care facility, including emergency rooms or temporary facilities instituted to address medical needs of those with severe COVID-19 during the COVID-19 pandemic, through day 28. Deaths from any cause through day 28 are included.

Appendix Figure.. Death or hospitalization through day 28 by Delta versus non-Delta COVID-19 variant.

Analyses include modified intention to treat persons enrolled in U.S. sites only. Cumulative proportion of death or hospitalization is estimated by the Kaplan–Meier method. The first occurrence of either death or hospitalization is considered as the event. Hospitalization is defined as ≥24 h of acute care, in a hospital or similar acute care facility, including emergency rooms or temporary facilities instituted to address medical needs of those with severe COVID-19 during the COVID-19 pandemic, through day 28. Deaths from any cause through day 28 are included.