EARLY LENZILUMAB TREATMENT OF COVID-19 PATIENTS USING C-REACTIVE PROTEIN AS A BIOMARKER IMPROVES EFFICACY: RESULTS FROM THE PHASE 3 ‘LIVE-AIR’ TRIAL
Authors: Temesgen Zelalem , Kelley Colleen F. , Cerasoli Franklin , Kilcoyne Adrian , Chappell Dale , Durrant Cameron , Ahmed Omar , Chappell Gabrielle , Catterson Victoria M. , Polk Christopher , Badley Andrew D. , Marconi Vincent C. ,   the LIVE-AIR Study Group
Published: January 2022

ABSTRACTObjectiveThe LIVE-AIR trial demonstrated that the anti-GM-CSF monoclonal antibody, lenzilumab improved the likelihood of survival without invasive mechanical ventilation (SWOV) in COVID-19 patients; with greatest effect in those with baseline CRP below the median baseline value of 79 mg/L. Similar to GM-CSF, C-reactive protein (CRP) levels are correlated with COVID-19 severity. This current analysis assessed the utility of baseline CRP levels to guide treatment with lenzilumab.DesignLIVE-AIR was a phase 3, double-blind, placebo-controlled trial. Participants were randomized 1:1 and stratified according to age and disease severity, to receive lenzilumab or placebo on Day 0, were followed through Day 28.SettingSecondary and tertiary care hospitals in the US and Brazil.Participants520 hospitalized COVID-19 participants with SpO2≤ 94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included.InterventionsLenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir.Main outcome measuresA multi-variate logistic regression analysis assessed key baseline risk factors for progression to IMV or death. The primary endpoint, SWOV, and key secondary endpoints were analyzed according to baseline CRP levels in all participants with CRP values.ResultsThe multi-variate analysis demonstrated that elevated baseline plasma CRP was the most predictive feature for progression to IMV or death. SWOV was achieved in 152 (90%; 95%CI: 85to 94) lenzilumab and 183 (79%; 72 to 84) placebo participants with baseline CRP<150 mg/L and its likelihood was greater with lenzilumab than placebo (HR: 2.54; 95%CI, 1.46 to 4.41; p=0.0009) but not in participants with CRP≥150 mg/L at baseline. CRP as a covariate in the overall analysis demonstrated a statistically significant interaction with lenzilumab treatment (p=0.044). Grade ≥ 3 adverse events in participants with baseline CRP<150 mg/L were reported in 18% and 28% in lenzilumab or placebo, respectively. No treatment-emergent serious adverse events were attributable to lenzilumab.ConclusionThese finding suggest that COVID-19 participants with low baseline CRP levels achieve the greatest clinical benefit from lenzilumab and that baseline CRP levels may be a useful biomarker to guide therapeutic intervention.Trial RegistrationClinicalTrials.govNCT04351152WHAT IS ALREADY KNOWN ON THIS TOPICGM-CSF is one of the early upstream mediators and orchestrators of the hyperinflammatory immune response following SARS-CoV-2 infection. Baseline levels of GM-CSF and CRP have each been shown to correlate with COVID-19 disease progression. Increases in CRP are driven by elevations of IL-6 during the hyperinflammatory response following SARS-CoV-2 infection. In the phase 3, randomized, double-blind, placebo-controlled LIVE-AIR study, GM-CSF neutralization with lenzilumab significantly improved the likelihood of survival without invasive mechanical ventilation (SWOV, primary endpoint, also referred to as ventilator-free survival) vs. placebo (HR:1.54; 95% CI, 1.02 to 2.32; p=0.0403), which included standard supportive care including corticosteroids and remdesivir. No treatment-emergent serious adverse events attributable to lenzilumab have been reported to date.WHAT THIS STUDY ADDSA comprehensive analysis of LIVE -AIR CRP data provides evidence for the utility of baseline CRP to predict progression to IMV and death. Baseline CRP was identified to be the strongest predictor of SWOV in this study. Patients with baseline CRP<150 mg/L represented 78% of the study population and demonstrated the greatest clinical benefit with lenzilumab, including SWOV through day 28 (HR: 2.54; 95%CI; 1.46-4.41; nominal p=0.0009). A biomarker-driven approach using baseline CRP levels to guide therapeutic intervention may improve outcomes in those hospitalized with COVID-19. Participants with baseline CRP levels above 150 mg/L were described as experiencing COVID-19-associated hyperinflammation and were at risk of imminent escalation of respiratory support or death. Elevated baseline plasma CRP was the most predictive feature for progression to IMV or death (OR, 0.15; 95%CI, 0.07-0.29; nominal p<0.001). These findings suggest that baseline CRP may be a useful biomarker in determining which participants may be most successfully treated with lenzilumab.