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

Clinical and economic benefits of lenzilumab plus standard of care compared with standard of care alone for the treatment of hospitalized patients with Coronavirus Disease 19 (COVID-19) from the perspective of National Health Service England

PurposeEstimate the clinical and economic benefits of lenzilumab plus standard of care (SOC) compared with SOC alone in the treatment of hospitalized COVID-19 patients from the National Health Service (NHS) England perspective. MethodsA cost calculator was developed to estimate the clinical benefits and costs of adding lenzilumab to SOC in newly hospitalized COVID-19 patients over 28 days. The LIVE-AIR trial results informed the clinical inputs: failure to achieve survival without ventilation (SWOV), mortality, time to recovery, intensive care unit (ICU) admission, and invasive mechanical ventilation (IMV) use. Base case costs included drug acquisition and administration for lenzilumab and remdesivir and hospital resource costs based on level of care required. Clinical and economic benefits per weekly cohort of newly hospitalized patients were also estimated. ResultsIn all populations examined, specified clinical outcomes were improved with lenzilumab plus SOC over SOC treatment alone. In a base case population aged <85 years with C-reactive protein (CRP) <150 mg/L, with or without remdesivir, adding lenzilumab to SOC was estimated to result in per-patient cost savings of {pound}1,162. In a weekly cohort of 4,754 newly hospitalized patients, addition of lenzilumab to SOC could result in 599 IMV uses avoided, 352 additional lives saved, and over {pound}5.5 million in cost savings. Scenario results for per-patient cost savings included: 1) aged <85 years, CRP <150 mg/L, and receiving remdesivir ({pound}3,127); 2) Black patients with CRP <150 mg/L ({pound}9,977); and 3) Black patients from the full population ({pound}2,369). Conversely, in the full mITT population, results estimated additional cost of {pound}4,005 per patient. ConclusionFindings support clinical benefits for SWOV, mortality, time to recovery, time in ICU, time on IMV, and ventilator use, and an economic benefit from the NHS England perspective when adding lenzilumab to SOC for hospitalized COVID-19 patients.

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.

Clinical Benefits and Budget Impact of Lenzilumab plus Standard of Care Compared with Standard of Care Alone for the Treatment of Hospitalized Patients with COVID-19 in the United States from the Hospital Perspective

AimsThe study estimated the clinical benefits and budget impact of lenzilumab plus standard of care (SOC) compared with SOC alone in the treatment of hospitalized COVID-19 patients from the United States hospital perspective. Materials and MethodsAn economic model was developed to estimate the clinical benefits and costs for an average newly hospitalized COVID-19 patient, with a 28-day time horizon for the index hospitalization. Clinical outcomes from the LIVE-AIR trial included failure to achieve survival without ventilation (SWOV), mortality, time to recovery, intensive care unit (ICU) admission, and invasive mechanical ventilation (IMV) use. Base case costs included drug acquisition and administration for lenzilumab and hospital resource costs based on the level of care required. The inclusion of 1-year rehospitalization costs was examined in a scenario analysis. ResultsIn the base case and all scenarios, treatment with lenzilumab plus SOC improved all specified clinical outcomes over SOC alone. Adding lenzilumab to SOC was also estimated to result in cost savings of $3,190 per patient in a population aged <85 years with CRP <150 mg/L and receiving remdesivir (base case). Per-patient cost savings were also estimated in the following scenarios: 1) aged <85 years with CRP <150 mg/L, with or without remdesivir ($1,858); 2) Black and African American patients with CRP <150 mg/L ($13,154); and 3) Black and African American patients from the full population ($2,763). In the full mITT population, a budget impact of $4,952 was estimated. When adding rehospitalization costs to the index hospitalization, a total per-patient cost savings of $5,154 was estimated. ConclusionsThe results highlight the clinical benefits for SWOV, ventilator use, time to recovery, mortality, time in ICU, and time on IMV, in addition to a favorable budget impact from the United States hospital perspective associated with adding lenzilumab to SOC for patients with COVID-19 pneumonia.