TY - JOUR T1 - LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL JF - medRxiv DO - 10.1101/2021.05.01.21256470 SP - 2021.05.01.21256470 AU - Temesgen, Zelalem AU - Burger, Charles D. AU - Baker, Jason AU - Polk, Christopher AU - Libertin, Claudia AU - Kelley, Colleen AU - Marconi, Vincent C. AU - Orenstein, Robert AU - Durrant, Cameron AU - Chappell, Dale AU - Ahmed, Omar AU - Chappell, Gabrielle AU - Badley, Andrew D. Y1 - 2021/01/01 UR - http://medrxiv.org/content/early/2021/05/05/2021.05.01.21256470.abstract N2 - BACKGROUND Severe 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.METHODS Subjects 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.RESULTS Baseline 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 &lt;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&lt;150 mg/L and age &lt;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&lt;150 mg/L and age &lt;85 years (2.17; 1.04-4.54, nominal p=0.040).CONCLUSION Lenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRP&lt;150 mg/L and age &lt;85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab. NCT04351152Competing Interest StatementZT, CDB have no conflicts of interest; JB has received research support from Gilead and research support from Humanigen, Inc.; CP, CL, CK have no conflicts of interest; VCM has received investigator-initiated research grants (to the institution) and consultation fees (both unrelated to the current work) from Eli Lilly, Bayer, Gilead Sciences and ViiV; RO has no conflicts of interest; CD, DC, OA, GC are employees of Humanigen, Inc.; ADB is supported by grants from NIAID (grants AI110173 and AI120698) Amfar (#109593) and Mayo Clinic (HH Sheik Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). ADB is a paid consultant for Abbvie and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals, Equilium, and Excision Biotherapeutics, has received fees for speaking for Reach MD, owns equity for scientific advisory work in Zentalis and Nference, and is founder and President of Splissen therapeutics.Clinical TrialNCT04351152Funding StatementAll aspects of the LIVE-AIR phase 3 study were sponsored and funded by Humanigen, Inc.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Central IRB (ADVARRA) approval was obtained in addition to local IRB approval at each participating institution as appropriate for all aspects of this company-sponsored phase 3 clinical trial.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe authors confirm that the data supporting the findings of this study are available within the article ER -