C-reactive protein as a biomarker for improved efficacy of lenzilumab in Covid-19 patients: results from the LIVE-AIR trial

ABSTRACT

BackgroundThe hyperinflammatory cytokine storm (CS) of COVID-19 is mediated by GM-CSF leading to release of downstream inflammatory chemokines, cytokines, and markers of systemic inflammation (C-reactive protein, CRP). The LIVE-AIR study demonstrated that lenzilumab, an anti-GM-CSF monoclonal antibody in patients hospitalized with COVID-19, safely improved the likelihood of achieving the primary endpoint, survival without ventilation (SWOV) by 1.54-fold (HR 1.54;95%CI 1.02–2.32, p=0.0403) compared with placebo. An exploratory analysis in patients with CRP<150 mg/L and age<85 years was conducted to determine lenzilumab efficacy when administered prior to advanced inflammation.MethodsLIVE-AIR was a phase 3 randomized, double-blind, placebo-controlled trial. Patients with COVID-19 (n=520), >18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation (IMV), were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Participants were followed through Day 28 following treatment.ResultsOverall, baseline demographics were comparable between treatment groups male, 64.7%;mean age, 60.5 years;mean BMI, 32.5 kg/m2;median CRP, 79 mg/L;CRP was <150 mg/L in 78% of participants. Participants received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab (n=159) improved the likelihood of SWOV by 3.04-fold in participants with CRP<150 mg/L and age<85 years (3.04;1.68–5.51, nominal p=0.0003) compared with placebo (n=178). Response to lenzilumab was observed in the first through third quartiles of baseline CRP (<41 mg/L, HR8.33;41<79 mg/L, HR1.60;79<137 mg/L, HR 2.12;>137 mg/L, HR 1.17). The incidence of IMV, ECMO, or death was reduced (OR 0.31;95%CI 0.15–0.63, p=0.002) and mortality was improved by 2.22-fold (OR 2.22;95%CI 1.07–4.67, p=0.034). In these participants, lenzilumab decreased CRP as early as Day 2 following treatment, compared with placebo which was further decreased by 38% on Day 28 compared with placebo (24.4±3.4 mg/L vs 39.1±4.9 mg/L).ConclusionLenzilumab significantly improved SWOV in hospitalized, hypoxic participants with COVID-19 pneumonia with the greatest benefits in SWOV and survival in patients with CRP<150 mg/L and age <85 years. Inhibition of GM-CSF, an orchestrator of CS, early in the hyperinflammatory response improved outcomes in COVID-19. NCT04351152