LENZILUMAB OUTCOMES ACCORDING TO RACE OF COVID-19 PARTICIPANTS IN THE LIVE-AIR PHASE 3 TRIAL

RATIONALEThe hyperinflammatory immune response of COVID-19, in part orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF) can lead to respiratory failure and death with disparities in outcomes between racial subgroups. In the LIVE-AIR trial, the GM-CSF neutralizing antibody lenzilumab improved survival without mechanical ventilation (SWOV) in COVID-19. OBJECTIVEAn analysis of outcomes was performed to determine differences between Black/African American (B/AA) and White participants in LIVE-AIR. METHODSLIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial. Participants hospitalized with COVID-19 pneumonia were randomized 1:1 to receive lenzilumab (1800 mg total) or placebo in addition to standard of care, including remdesivir and/or corticosteroids. MEASUREMENTS AND MAIN RESULTSLenzilumab, compared to placebo, numerically improved the likelihood of SWOV (primary endpoint) in B/AA (n=71; 86.8% vs 70.9%; HR, 2.68; 95% confidence interval [CI], 0.88-8.11; p=0.0814) and White (n=343; 85.1% vs 80.8%; HR, 1.41; 95%CI, 0.85-2.35, p=0.182) participants. A statistically significant improvement in SWOV was observed in B/AA (HR: 8.9; 95%CI: 1.08, 73.09; p=0.0418) and White (HR: 2.32; 95%CI: 1.17, 4.61; p=0.0166) participants with baseline CRP<150 mg/L. Lenzilumab numerically, but not statistically, improved secondary endpoints of IMV, ECMO or mortality; ventilator-free days; ICU days and time to recovery in either race while ventilator-free days, ICU days, and time to recovery were statistically improved in B/AA participants with baseline CRP<150 mg/L. Lenzilumab was well tolerated without differences in serious adverse events regardless of race. CONCLUSIONLenzilumab significantly improved SWOV and some key secondary outcomes in B/AA COVID-19 participants with baseline CRP<150 mg/L. NCT04351152

EARLY LENZILUMAB TREATMENT OF COVID-19 PATIENTS USING C-REACTIVE PROTEIN AS A BIOMARKER IMPROVES EFFICACY: RESULTS FROM THE PHASE 3 LIVE-AIR TRIAL

ObjectiveThe LIVE-AIR trial demonstrated that the anti-GM-CSF monoclonal antibody, lenzilumab improved the likelihood of survival without invasive mechanical ventilation (SWOV) in COVID-19 patients; with greatest effect in those with baseline CRP below the median baseline value of 79 mg/L. Similar to GM-CSF, C-reactive protein (CRP) levels are correlated with COVID-19 severity. This current analysis assessed the utility of baseline CRP levels to guide treatment with lenzilumab. DesignLIVE-AIR was a phase 3, double-blind, placebo-controlled trial. Participants were randomized 1:1 and stratified according to age and disease severity, to receive lenzilumab or placebo on Day 0, were followed through Day 28. SettingSecondary and tertiary care hospitals in the US and Brazil. Participants520 hospitalized COVID-19 participants with SpO2[≤] 94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included. InterventionsLenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir. Main outcome measuresA multi-variate logistic regression analysis assessed key baseline risk factors for progression to IMV or death. The primary endpoint, SWOV, and key secondary endpoints were analyzed according to baseline CRP levels in all participants with CRP values. ResultsThe multi-variate analysis demonstrated that elevated baseline plasma CRP was the most predictive feature for progression to IMV or death. SWOV was achieved in 152 (90%; 95%CI: 85to 94) lenzilumab and 183 (79%; 72 to 84) placebo participants with baseline CRP<150 mg/L and its likelihood was greater with lenzilumab than placebo (HR: 2.54; 95%CI, 1.46 to 4.41; p=0.0009) but not in participants with CRP[≥]150 mg/L at baseline. CRP as a covariate in the overall analysis demonstrated a statistically significant interaction with lenzilumab treatment (p=0.044). Grade [≥] 3 adverse events in participants with baseline CRP<150 mg/L were reported in 18% and 28% in lenzilumab or placebo, respectively. No treatment-emergent serious adverse events were attributable to lenzilumab. ConclusionThese finding suggest that COVID-19 participants with low baseline CRP levels achieve the greatest clinical benefit from lenzilumab and that baseline CRP levels may be a useful biomarker to guide therapeutic intervention. Trial RegistrationClinicalTrials.gov NCT04351152 WHAT IS ALREADY KNOWN ON THIS TOPICGM-CSF is one of the early upstream mediators and orchestrators of the hyperinflammatory immune response following SARS-CoV-2 infection. Baseline levels of GM-CSF and CRP have each been shown to correlate with COVID-19 disease progression. Increases in CRP are driven by elevations of IL-6 during the hyperinflammatory response following SARS-CoV-2 infection. In the phase 3, randomized, double-blind, placebo-controlled LIVE-AIR study, GM-CSF neutralization with lenzilumab significantly improved the likelihood of survival without invasive mechanical ventilation (SWOV, primary endpoint, also referred to as ventilator-free survival) vs. placebo (HR:1.54; 95% CI, 1.02 to 2.32; p=0.0403), which included standard supportive care including corticosteroids and remdesivir. No treatment-emergent serious adverse events attributable to lenzilumab have been reported to date. WHAT THIS STUDY ADDSA comprehensive analysis of LIVE -AIR CRP data provides evidence for the utility of baseline CRP to predict progression to IMV and death. Baseline CRP was identified to be the strongest predictor of SWOV in this study. Patients with baseline CRP<150 mg/L represented 78% of the study population and demonstrated the greatest clinical benefit with lenzilumab, including SWOV through day 28 (HR: 2.54; 95%CI; 1.46-4.41; nominal p=0.0009). A biomarker-driven approach using baseline CRP levels to guide therapeutic intervention may improve outcomes in those hospitalized with COVID-19. Participants with baseline CRP levels above 150 mg/L were described as experiencing COVID-19-associated hyperinflammation and were at risk of imminent escalation of respiratory support or death. Elevated baseline plasma CRP was the most predictive feature for progression to IMV or death (OR, 0.15; 95%CI, 0.07-0.29; nominal p<0.001). These findings suggest that baseline CRP may be a useful biomarker in determining which participants may be most successfully treated with lenzilumab.

LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL

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(R) 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

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

BackgroundIn 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.

Augmented Curation of Unstructured Clinical Notes from a Massive EHR System Reveals Specific Phenotypic Signature of Impending COVID-19 Diagnosis

Understanding temporal dynamics of COVID-19 patient symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVIDpos; n=2,317) versus COVID-19-negative (COVIDneg; n=74,850) patients for the week preceding the PCR testing date, we identify anosmia/dysgeusia (27.1-fold), fever/chills (2.6-fold), respiratory difficulty (2.2-fold), cough (2.2-fold), myalgia/arthralgia (2-fold), and diarrhea (1.4-fold) as significantly amplified in COVIDpos over COVIDneg patients. The combination of cough and fever/chills has 4.2-fold amplification in COVIDpos patients during the week prior to PCR testing, and along with anosmia/dysgeusia, constitutes the earliest EHR-derived signature of COVID-19. This study introduces an Augmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis.