In a recent phase 3 study published The Lancet Respiratory Medicine, scientists assessed the potential of tixagevimab–cilgavimab for treating hospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients.
Study: Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial. Image Credit: ustas7777777/Shutterstock
Background
Despite advancements in standard management, including dexamethasone, additional immune modulators, remdesivir, and anticoagulants, mortality is still prevalent among hospitalized CoV disease 2019 (COVID-19) patients. Existing reports indicate that when administered early to at-risk outpatients with SARS-CoV-2 infection, neutralizing monoclonal antibodies bind selectively to SARS-CoV-2 spike (S) protein, decrease viral replication in animal models and in vitro, and limit clinical progression and hospitalization.
In the RECOVERY study, administration of the monoclonal antibody cocktail casirivimab-imdevimab to hospitalized SARS-CoV-2-seronegative patients significantly decreased death rates. On the other hand, SARS-CoV-2 Omicron variants exhibit complete resistance to this monoclonal antibody combination and diminished sensitivity to others.
Tixagevimab-cilgavimab, a mixture of two monoclonal antibodies with a half-life of about 90 days, precluded symptomatic COVID-19 when used as pre-exposure prophylaxis. Besides, when given during early SARS-CoV-2 infection, it decreased hospitalizations by more than 50% in non-hospitalized subjects and retained antiviral efficacy against Omicron variants.
About the study
In the current double-blind, randomized, placebo-controlled, phase 3 study, the researchers compared tixagevimab–cilgavimab against placebo in hospitalized SARS-CoV-2 patients treated with remdesivir and other routine therapy.
Adults with SARS-CoV-2 symptoms lasting about 12 days and hospitalized for COVID-19 at 81 locations in the United States of America (USA), Singapore, Europe, and Uganda were assigned randomly in a 1:1 ratio to receive a tixagevimab (300mg)-cilgavimab (300mg) combination intravenously or a placebo along with remdesivir and other conventional care.
If patients required extracorporeal membrane oxygenation, invasive mechanical ventilation, mechanical circulatory support, vasopressor therapy, or new kidney replacement therapy due to acute organ failure, they were excluded from the study. While study volunteers, site study personnel, clinical providers, and scientists were masked regarding the research assignments, an unmasked pharmacist prepared the investigation drug.
The key outcome of the research was the duration of sustainable COVID-19 recovery up to day 90, which was outlined as 14 successive days at home following discharge from the hospital, with co-primary assessments for the entire cohort and patients negative for neutralizing antibody at entry. The modified intention-to-treat population, which consisted of patients who received a full or partial tixagevimab-cilgavimab infusion or placebo, was used for the efficacy and safety examinations. NCT04501978 was the study's registration number with ClinicalTrials.gov, and participant follow-up is underway.
Results
The study results demonstrated that 1455 patients were assigned randomly between 10 February and 30 September 2021 for the research. The primary modified intention-to-treat population included 1417 patients. Among them, 710 were infused with tixagevimab–cilgavimab and 707 with placebo.
At day 90 in the complete cohort, the estimated cumulative incidence of persistent SARS-CoV-2 recovery was 89% and 86% for tixagevimab-cilgavimab and placebo cohort subjects, respectively. Across the seronegative subset, the results were comparable.
Compared to the placebo group, which had a mortality rate of 12%, the tixagevimab-cilgavimab group's death rate was 9%. The aggregate safety outcome ensued in 178, i.e., 25%, of the tixagevimab-cilgavimab group volunteers and 212, i.e., 30%, of the placebo cohort participants. Furthermore, 34, i.e., 5%, of subjects in the tixagevimab-cilgavimab arm and 38, i.e., 5%, of those in the placebo cohort experienced significant adverse reactions.
Overall, the authors noted that while the tixagevimab-cilgavimab combination did not enhance the primary outcome of time to persisting recovery, it was safe and death was lower among COVID-19 hospitalized patients receiving remdesivir and other conventional therapy.
Conclusions
The study findings demonstrated that across hospitalized COVID-19 patients receiving remdesivir and other traditional therapy, tixagevimab-cilgavimab did not enhance the primary goal of durable patient recovery. However, it was safe and resulted in a clinically significant reduction in death, i.e., 30%.
Patients who needed non-invasive mechanical ventilation or high-flow oxygen at study entry and those with the SARS-CoV-2 Delta variant infection had a numerically higher mortality signal. There were no variations in efficacy or safety research results with initial endogenous neutralizing antibody serostatus, unlike some earlier monoclonal antibody investigations.
Taken together, the present work illustrated that hospitalized COVID-19 patients might experience higher clinical advantages with a single intravenous dosage of tixagevimab-cilgavimab in addition to contemporary standard management. Since the mortality decrease seen in this trial was a secondary objective, further validation is needed. The team mentioned that antibody screening may not be necessary to deliver this treatment because baseline serostatus was not correlated to safety or efficacy outcomes.
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