Lenzilumab Efficacy and Safety in Newly Hospitalized Covid-19 Subjects: Results From the Live-Air Phase 3 Randomized Double-Blind Placebo-Controlled Trial

Abstract

BACKGROUNDSevere COVID-19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM-CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-6, IL-1), and other markers of systemic inflammation (CRP, D-dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered® anti-human GM-CSF monoclonal antibody that directly binds GM-CSF and prevents signaling through its receptor. The LIVE-AIR Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator-free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19.METHODSSubjects with COVID-19 (n=520), ≥18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment.RESULTSBaseline demographics were comparable between the two treatment groups: male, 64.7%; mean age, 60.5 years; mean BMI, 32.5 kg/m2; mean CRP, 98.36 mg/L; CRP was <150 mg/L in 77.9% of subjects. The most common comorbidities were obesity (55.1%), diabetes (53.4%), chronic kidney disease (14.0%), and coronary artery disease (13.6%). Subjects received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the likelihood of SWOV by 54% in the mITT population (HR: 1.54; 95%CI: 1.02-2.31, p=0.041) and by 90% in the ITT population (HR: 1.90; 1.02-3.52, nominal p=0.043) compared to placebo. SWOV also relatively improved by 92% in subjects who received both corticosteroids and remdesivir (1.92; 1.20-3.07, nominal p=0.0067); by 2.96-fold in subjects with CRP<150 mg/L and age <85 years (2.96; 1.63–5.37, nominal p=0.0003); and by 88% in subjects hospitalized ≤2 days prior to randomization (1.88; 1.13-3.12, nominal p=0.015). Survival was improved by 2.17-fold in subjects with CRP<150 mg/L and age <85 years (2.17; 1.04-4.54, nominal p=0.040).CONCLUSIONLenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRP<150 mg/L and age <85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab. NCT04351152

Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy

“…In addition, it was demonstrated that GM-CSF neutralization with lenzilumab results in the reduction of neuro-inflammation and cytokine release syndrome in a primary acute lymphoblastic leukemia patient-derived xenograft model following chimeric antigen receptor T-cell therapy [ 138 ]. Furthermore, a phase ΙΙΙ trial is underway, investigating the potential use of lenzilumab to improve the likelihood of ventilator-free survival beyond standard supportive care, in hospitalized patients with severe SARS-CoV-2 [ 139 ]. Along the same line, recent evidence from studies of human and transplant mouse melanomas implicate CSF1 induction as a CD8+ T-cell–dependent adaptive resistance mechanism and demonstrate that simultaneous CSF1R targeting might be beneficial in melanomas refractory to immune checkpoint blockade and potentially, in other T-cell–based therapies [ 140 ].…”

Early treatment with inhaled GM-CSF improves oxygenation and anti-viral immunity in COVID-19 induced lung injury – a randomized clinical trial

“…Indeed, given the known role of GM-CSF in emergency myelopoiesis and CAR-T cell associated cytokine release syndrome 75 , and the observation of increased numbers of GM-CSF producing T cells 31 and higher serum concentrations 45 of GM-CSF in some patients with COVID-19, blockade of systemic GM-CSF or its receptor was also proposed as a strategy to dampen hyperinflammation in severe COVID-19. At least six randomized clinical trials have been launched since the beginning of the pandemic 46 , one of which already reported promising results on a preprint server 76 , while another did not show benefit and was prematurely halted 77 . Major differences in outcome of GM-CSF interventions might depend on timing of intervention, but also on the route of administration.…”

Antibodies to watch in 2022

“…Initiated in May 2020 and completed in March 2021, the LIVE-AIR trial assessed the potential for lenzilumab to improve the likelihood of ventilator-free survival beyond standard supportive care in hospitalized subjects with severe COVID-19. 37 The study enrolled 520 adult patients who experienced blood oxygen saturation of less than or equal to 94%, or required low-flow supplemental oxygen, or high-flow oxygen support, or non-invasive positive pressure ventilation; and were hospitalized but did not require invasive mechanical ventilation. Patients were randomized to receive three infusions of either 600 mg lenzilumab or placebo, with each 1-h infusion separated by 8 h over a 24-h period.…”