Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial

Abstract

Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with CO...

Stimulating severe COVID-19: the potential role of GM-CSF antagonism

“…In The Lancet Respiratory Medicine , Zelalem Temesgen and colleagues 6 report on a multicentre, placebo-controlled clinical trial of hospitalised patients with COVID-19, showing that lenzilumab, a neutralising monoclonal antibody against GM-CSF, is associated with improved survival without invasive mechanical ventilation at 28 days. Lenzilumab is a monoclonal antibody that directly binds GM-CSF and is being tested for conditions such as chronic myelomonocytic leukaemia and B-cell lymphoma.…”

Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial

“… 25 Lenzilumab, given as a three-dose course in non-ventilated hospitalised patients, showed a benefit over standard care in the primary outcome of survival without ventilation, an effect that seemed more pronounced in patients aged 85 years or younger and with CRP concentration of less than 150 mg/L. 26 Our data suggest the effect of a single dose of namilumab on CRP concentration and WHO clinical progression score is independent of age, although this requires confirmation in larger studies. Although it is not possible to directly compare these studies given the differences in sample sizes, inclusion criteria, and study designs, the overall randomised controlled trial data suggest a benefit of GM-CSF inhibition in COVID-19.…”

Clinical and economic benefits of lenzilumab plus standard of care compared with standard of care alone for the treatment of hospitalized patients with Coronavirus Disease 19 (COVID-19) from the perspective of National Health Service England

“…In brief, eligible patients were newly hospitalized with COVID-19 pneumonia, with SpO2 ≤94% on room air and/or requiring supplemental oxygen, but not on IMV. 23 Further analyses of LIVE-AIR trial data suggested that patients aged <85 years with CRP <150 mg/L particularly benefited from . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

“…38 LIVE-AIR (NCT04351152) was a Phase 3, prospective, randomized, multicentered, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of lenzilumab or placebo (in addition to institutional standard of care [SOC] in both treatment groups) in hospitalized participants with COVID-19 pneumonia. 23 Patients must have been hospitalized with an oxygen saturation (SpO 2 ) ≤94% on room air or required supplemental oxygen but had not progressed to IMV. 23 Results from the LIVE-AIR trial showed that lenzilumab plus SOC significantly improved the likelihood of achieving survival without ventilation (SWOV) a (sometimes referred to as ventilator-free survival) by day 28 compared with placebo plus SOC.…”

“…23 Patients must have been hospitalized with an oxygen saturation (SpO 2 ) ≤94% on room air or required supplemental oxygen but had not progressed to IMV. 23 Results from the LIVE-AIR trial showed that lenzilumab plus SOC significantly improved the likelihood of achieving survival without ventilation (SWOV) a (sometimes referred to as ventilator-free survival) by day 28 compared with placebo plus SOC. 23 Additional analyses revealed that lenzilumab plus SOC had greater efficacy in patients aged <85 years with CRP levels <150 mg/L, overall and exclusively in patients receiving remdesivir, compared with placebo plus SOC, as measured by SWOV.…”