COVID-19 associated chronic ARDS successfully treated with lenzilumab

Background:Myeloid hyperinflammation leading to T-cell immune suppression and lymphocytopenia is a hallmark of severe COVID-19. Granulocyte macrophage-colony stimulating factor (GM-CSF) neutralization may prevent myeloid driven T-cell suppression leading to increased lymphocyte counts in patients with COVID-19. Given the dual mechanism of action, lenzilumab (anti-human GM-CSF monoclonal antibody) may reduce myeloid driven hyperinflammation and improve CD8+ antiviral T-cell responses directed at SARS-Cov-2 reducing the morbidity, mortality, need for invasive mechanical ventilation (IMV) and duration of hospitalization.Methods:Hospitalized subject with confirmed COVID-19 pneumonia and established risk factors for poor outcomes was treated in the ICU for 12 weeks using standard supportive care for chronic acute respiratory distress syndrome (ARDS). An emergency single-use investigational new drug application (IND) was approved for lenzilumab 600 mg, administered intravenously every eight hours for a total of three doses. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded through duration of hospitalization.Results:77-year-old Caucasian male with past medical history of severe chronic obstructive pulmonary disease (COPD) with emphysema, coronary artery disease, type II diabetes, and obstructive sleep apnea admitted to ICU with fever, shortness of breath and confirmed SARS-CoV-2 infection. Patient was treated with standard supportive care including corticosteroids. Over the course of his ICU stay, the patient developed ARDS and on week 13, and after several unsuccessful attempts at oxygen weaning, lenzilumab was administered via emergency single use IND. One-week post lenzulimab therapy, oxygen demands decreased, lymphopenia appeared to improve and sixteen days post lenzulimab therapy, the patient was discharged home on 4L nasal cannula. No infusion-related or systemic side effects were noted.Conclusion:In a case of COVID-19 with multiple co-morbidities, refractory to corticosteroids, and deteriorating for several months, GM-CSF neutralization with lenzilumab appeared to reduce oxygen requirements, improve lymphopenia and accelerate time to recovery/discharge in a COVID-19 subject. A randomized, double-blind, placebo-controlled phase 3 clinical trial is ongoing to validate these findings (NCT04351152).

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First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe and Critical COVID-19 Pneumonia

10.1101/2020.06.08.20125369 ◽

2020 ◽

Cited By ~ 5

Author(s):

Zelalem Temesgen ◽

Mariam Assi ◽

Paschalis Vergidis ◽

Stacey A. Rizza ◽

Philippe R. Bauer ◽

...

Keyword(s):

Adverse Events ◽

Myeloid Cells ◽

Patient Characteristics ◽

Cytokine Storm ◽

Gm Csf ◽

Cytokine Analysis ◽

Single Use ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Poor Outcomes

ABSTRACTBackgroundIn COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe and critical COVID-19 pneumonia.MethodsHospitalized 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 IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report.ResultsTwelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe and critical COVID-19 pneumonia.ConclusionsIn high-risk COVID-19 patients with severe and critical pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.

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Abstract 17471: Outcome of Acute Myocardial Injury in COVID-19 Patients

Circulation ◽

10.1161/circ.142.suppl_3.17471 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Magdi Zordok ◽

Muhammad Etiwy ◽

Shruti Hegde ◽

Michael Maysky

Keyword(s):

Myocardial Injury ◽

Average Length ◽

Invasive Mechanical Ventilation ◽

Morbidity And Mortality ◽

Hospital Death ◽

Chronic Obstructive ◽

High Morbidity ◽

Elevated Troponin ◽

Obstructive Sleep ◽

Acute Myocardial Injury

Background: Acute myocardial injury has been reported in approximately 20% of patients with Coronavirus disease 2019 (COVID-19). Little is known about the outcome of this subset of patients. We are testing the hypothesis of higher morbidity and mortality in patients with COVID-19 who have acute myocardial injury. Methods: In this retrospective study, we analyzed data from patients admitted to Steward Healthcare hospitals in Massachusetts between March 22 and April 24, who tested positive for COVID-19 confirmed by serology and found to have elevated troponin levels (>0.01). The sociodemographic information, clinical data, and outcomes of these critically ill patients were retrospectively extracted from the medical records. The primary outcome was in-hospital death. Data were analyzed using JMP statistical analysis software. Results: Two hundred eighty-three COVID-19 positive patients were found to have troponin levels >0.01 on admission. Of these 183 patients (64.6%) were males, 49.1% were Caucasian and 32.1% were African Americans. The mean age of the patients was 70.7 ± 13.8. The prevalence of comorbid conditions was as follows: hypertension, 69.7%; hyperlipidemia, 46.9%; diabetes mellitus, 42.6%; chronic kidney disease, 28.3%; heart failure, 19.3%; atrial fibrillation, 22.1%; coronary artery disease, 17.1%; cerebrovascular accident, 10.2%; obesity, 38%; chronic obstructive pulmonary disease or asthma 20.8%, obstructive sleep apnea, 4.9%. One hundred thirty-seven patients (48.4%) noted to have acute kidney injury on presentation,128 (45.2%) required ICU level of care, 41% required invasive mechanical ventilation for a mean of 10.4 ± 7.9 days, and 38.8% required vasopressors. The average length of stay (LOS) in the medical intensive care unit and the hospital was 11.5 ± 8.3 days and 11.4 ± 9.5 days respectively. The overall in-hospital mortality rate was 45.6%. Conclusion: Patients with COVID-19 and elevated Troponin levels had high morbidity and mortality

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40. Lenzilumab Efficacy and Safety in Newly Hospitalized COVID-19 Subjects: Results From a Phase 3 Randomized Double-Blind Placebo-Controlled Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.040 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S29-S29

Author(s):

Zelalem Temesgem ◽

Charles Burger ◽

Jason Baker ◽

Christopher Polk ◽

Claudia R Libertin ◽

...

Keyword(s):

Research Study ◽

Controlled Trial ◽

Invasive Mechanical Ventilation ◽

Scientific Research ◽

Research Support ◽

Phase 3 ◽

Double Blind ◽

Gm Csf ◽

Study Investigator ◽

Research Grant

Abstract Background Severe coronavirus disease 2019 (COVID-19) often results from the immune-mediated cytokine storm, triggered by granulocyte macrophage-colony stimulating factor (GM-CSF), potentially leading to respiratory failure and death. Lenzilumab, a novel anti-human GM-CSF monoclonal antibody, neutralizes GM-CSF and demonstrated potential to improve clinical outcomes in a matched case-cohort study of patients with severe COVID-19 pneumonia. This Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to improve the likelihood of survival without invasive mechanical ventilation (SWOV), beyond available treatments. Methods Hypoxic patients, hospitalized with COVID-19 (n=520), requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized on Day 0 to receive lenzilumab (1800mg, n=261) or placebo (n=259), and available treatments, including remdesivir and/or corticosteroids; and were followed through Day 28. Results Baseline demographics were comparable between groups: male, 64.7%; mean age, 60.5 years; median CRP, 79.0 mg/L. Patients across both groups received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the primary endpoint, likelihood of SWOV in the mITT population, by 1.54-fold (HR: 1.54; 95%CI: 1.02-2.32, p=0.0403). Lenzilumab improved SWOV by 1.91-fold (nominal p=0.0073) and 1.92-fold (nominal p=0.0067) in patients receiving remdesivir or remdesivir and corticosteroids, respectively. A key secondary endpoint of incidence of IMV, ECMO or death was also improved in patients receiving remdesivir (p=0.020) or remdesivir and corticosteroids (p=0.0180). Treatment-emergent serious adverse events were similar across both groups. Conclusion Lenzilumab significantly improved SWOV in hypoxic COVID-19 patients upon hospitalization, with the greatest benefit observed in patients receiving treatment with remdesivir and corticosteroids. NCT04351152 Disclosures Zelalem Temesgem, MD, Humanigen, Inc (Grant/Research Support) Jason Baker, MD, Humanigen, Inc (Grant/Research Support) Christopher Polk, MD, Atea (Research Grant or Support)Gilead (Advisor or Review Panel member, Research Grant or Support)Humanigen (Research Grant or Support)Regeneron (Research Grant or Support) Claudia R. Libertin, MD, Gilead (Grant/Research Support) Colleen F. Kelley, MD, MPH, Gilead Sciences (Individual(s) Involved: Self): Grant/Research Support; Moderna (Individual(s) Involved: Self): Grant/Research Support; Novavax (Individual(s) Involved: Self): Grant/Research Support; Viiv (Individual(s) Involved: Self): Grant/Research Support Vincent Marconi, MD, Bayer (Consultant, Scientific Research Study Investigator)Eli Lilly (Consultant, Scientific Research Study Investigator)Gilead Sciences (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator) Victoria Catterson, PhD, Humanigen, Inc (Consultant) William Aronstein, MD, PhD, Humanigen, Inc (Consultant) Cameron Durrant, MD, Humanigen, Inc (Employee) Dale Chappell, MD, Humanigen, Inc (Employee) Omar Ahmed, PharmD, Humanigen, Inc (Employee) Gabrielle Chappell, MSc, Humanigen, Inc (Consultant) Andrew Badley, M.D., AbbVie (Consultant) for the LIVE-AIR Study Group, n/a, Humanigen, Inc (Grant/Research Support)

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