Dataset Information

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).

SUBMITTER: Temesgen Z

PROVIDER: S-EPMC7470718 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Coronavirus disease 2019 (COVID-19) results from SARS-CoV-2-induced hyperinflammatory immune response, orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF increases interleukin-6 (IL-6) levels, ultimately leading to increased C-reactive protein (CRP). The LIVE-AIR trial demonstrated that lenzilumab, the GM-CSF neutralizing antibody, improved the likelihood of survival without invasive mechanical ventilation (IMV) in hospitalized COVID-19 patients requiring supplemental oxygen but not IMV. This sub-analysis correlated levels of cytokines before and after lenzilumab treatment. Methods LIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial (NCT04351152). Patients hospitalized with COVID-19 pneumonia, requiring only supplemental oxygen, were randomized to receive lenzilumab (1800 mg in three equally divided doses of 600 mg, q8h) or placebo IV infusion, in addition to standard of care which included remdesivir and corticosteroids. Blood taken at baseline (BL) and subsequent to treatment through day 10 (D10) were obtained and analyzed by high sensitivity enzyme immunoassay for GM-CSF, IL-6, and CRP. Results Baseline IL-6 levels (Loge-transformed for all cytokines and biomarkers) were linearly correlated with higher baseline GM-CSF levels (slope=0.60, p< 0.001). Baseline CRP levels were linearly correlated with higher baseline IL-6 levels (slope=0.29, p < 0.001). GM-CSF levels decreased with lenzilumab treatment on day 1 (D1) which persisted through D10 (Table). In contrast, GM-CSF increased with placebo treatment. IL-6 levels decreased only with lenzilumab treatment. CRP following lenzilumab or placebo treatment decreased on D1 to similar levels and further decreased on D10 only with lenzilumab treatment. Cytokine Levels Associated with Lenzilumab Treatment Conclusion Lenzilumab decreased GM-CSF as well as downstream cytokines and systemic biomarkers of inflammation during the hyperinflammatory immune response of COVD-19. Disclosures Dale Chappell, MD, MBA, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Adrian Kilcoyne, MD, Humanigen, Inc: Employee Frank Cerasoli, PhD, Humanigen, Inc: Advisor/Consultant John Lukas, PhD, Humanigen, Inc: Advisor/Consultant Cameron Durrant, MD, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Zelalem Temesgen, MD, Gilead: unrestricted educational grant (to the institution)|Humanigen, Inc: Grant/Research Support|Merck: unrestricted educational grant (to the institution)|ViiV: Advisor/Consultant Christopher Polk, MD, Gilead: Advisor/Consultant Jason Baker, MD, Gilead: Grant/Research Support|Humanigen, Inc: Grant/Research Support Vincent Marconi, MD, Gilead: Grant/Research Support.