GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Cohort Study

Abstract

Objective: To assess the efficacy and safety of lenzilumab in patients with severe coronavirus disease 2019 (COVID-19) pneumonia.

Methods: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use investigational new drug application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. We also identified a cohort of patients matched to the lenzilumab patients for age, sex, and disease severity. Study dates were March 13, 2020, to June 18, 2020. All patients were followed through hospital discharge or death.

Results: Twelve patients were treated with lenzilumab; 27 patients comprised the matched control cohort (untreated). Clinical improvement, defined as improvement of at least 2 points on the 8-point ordinal clinical endpoints scale, was observed in 11 of 12 (91.7%) patients treated with lenzilumab and 22 of 27 (81.5%) untreated patients. The time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort with a median of 5 days versus 11 days (P=.006). Similarly, the proportion of patients with acute respiratory distress syndrome (oxygen saturation/fraction of inspired oxygen<315 mm Hg) was significantly reduced over time when treated with lenzilumab compared with untreated (P<.001). Significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) were observed in patients who received lenzilumab, but not in untreated patients. Cytokine analysis showed a reduction in inflammatory myeloid cells 2 days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab.

Conclusion: In high-risk COVID-19 patients with severe pneumonia, granulocyte-macrophage colony-stimulating factor neutralization with lenzilumab was safe and associated with faster improvement in clinical outcomes, including oxygenation, and greater reductions in inflammatory markers compared with a matched control cohort of patients hospitalized with severe COVID-19 pneumonia. A randomized, placebo-controlled clinical trial to validate these findings is ongoing (NCT04351152).

Copyright © 2020. Published by Elsevier Inc.

Figures

Figure 1

Clinical outcome measures of patients with severe coronavirus disease 2019 pneumonia (lenzilumab-treated patients versus controls). A, Cumulative percentage of patients with at least a 2-point improvement in the 8-point ordinal clinical endpoint scale estimated by Kaplan-Meier curve and compared by log-rank test. B, Mechanical ventilator-free survival estimated by Kaplan-Meier curve and compared by log-rank test.

Figure 2

Measurement of oxygenation status of patients treated with lenzilumab versus controls. A, Change in mean oxygen saturation (SpO2)/fraction of inspired oxygen (Fio2) ratio displayed at baseline (day 0) through day 14 post-therapy and compared by repeated measures analysis of variance (ANOVA). B, Percentage of patients with acute respiratory distress syndrome (defined as SpO2/Fio2 <315 mm Hg) and compared by repeated measures ANOVA.

Figure 3

Lenzilumab treatment results in improved inflammatory cytokines in a patient with severe coronavirus disease 2019 pneumonia. Inflammatory cytokine levels on day 1 and day 2 post-lenzilumab treatment (∗=P<.05, ∗∗=P<.01). FLT-3L = fms-related tyrosine kinase 3 ligand; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; GRO = growth-regulated oncogene; IFNγ = interferon gamma; IL = interleukin; MDC = macrophage-derived chemokine.

Figure 4

Proposed mechanim for granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralization in coronavirus disease 2019 – associated cytokine storm. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects monocytes/macrophages direcly via the angiotensin-converting enzyme 2 (ACE-2) receptors and through antibody-dependent enhancement. Infection with SARS-CoV-2–induced a T-cell response through the activation of ThGM and Th17 cells. Granulocyte-macrophage colony-stimulating factor production by ThGM cells further stimulated monocytes and initiates an immune hyper-inflammatory response. Activated monocytes result in production of myeloid derived cytokines, propagation of cytokine storm, trafficking of blood derived monocytes to the lungs, acute respiratory distress syndrome (ARDS), and respiratory failure. Granulocyte-macrophage colony-stimulating factor – activated monocytes induce T-cell death and result in lymphopenia and worse clinical outcomes. CCR2 = C-C chemokine receptor type 2; FcR = interferon; IFN = interferon; IL = interleukin; MCP-1 = monocyte chemoattractant protein-1; MIG = monokine induced by gamma; MIP-1α = macrophage inflammatory protein-1α; ROS = reactive oxygen species; TNFα = tumor necrosis factor α; VEGF = vascular endothelial growth factor.