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

Objective: The 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. Design: LIVE-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. Setting: Secondary and tertiary care hospitals in the US and Brazil. Participants: 520 hospitalized COVID-19 participants with SpO2[≤]94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included. Interventions: Lenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir. Main outcome measures: A 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. Results: The 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. Conclusion: These 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 Registration: ClinicalTrials.gov NCT04351152

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

BACKGROUND: Severe COVID19 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 (MCP1, IL8, IP10), cytokines (IL6, IL1), 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 <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 <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 to 2.31, p=0.041) and by 90% in the ITT population (HR: 1.90; 1.02 to 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 to 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 to 5.37, nominal p=0.0003); and by 88% in subjects hospitalized <2 days prior to randomization (1.88; 1.13 to 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 to 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<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 (preprint)

Background: In 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 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 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. Results: Twelve 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 COVID-19 pneumonia. Conclusions: In high-risk COVID-19 patients with severe pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.