SCCM Resource Library-Lenzilumab in Hospitalized Black/African-American COVID-19 Patients: Live-Air Phase 3 Study Results

Video Transcription

Greetings, all. I am Dr. Zelalem Tamezgan from the Division of Infectious Diseases at Mayo Clinic, Rochester, Minnesota. It is my pleasure and privilege to present, on behalf  of the investigators and the research team, Lenzilumab in hospitalized Black African American COVID-19 patients. These are my disclosures. Granulocyte macrophage colony stimulating  factor, initially described as a hematopoietic growth factor, is now understood to be a key  mediator of inflammation and tissue injury. Multiple studies have demonstrated the association  of elevated levels of GM-CSF and CRP with COVID-19 disease and its severity. Lenzilumab is a humanized GM-CSF neutralizing antibody that binds to GM-CSF and prevents its signaling  through its receptor. It has reduced immunogenicity due to its high specificity to human germline  sequences and also has high affinity and low dissociation rates. In five clinical trials,  Lenzilumab has been found to be safe and well-tolerated. LiveAIR was a phase 3 randomized, double-blind,  placebo-controlled clinical trial in adults 18 years or older with virologically confirmed SARS-CoV-2 infection and hospitalized with COVID-19 pneumonia. Participants had an oxygen  saturation rate less than or equal to 94% or required supplemental oxygen but not invasive mechanical ventilation. Patients received Lenzilumab or placebo via three intravenous  infusions administered eight hours apart. The primary endpoint was survival without ventilation,  also known as SWAV, by day 28. Data were collected through day 60. Secondary endpoints included  ventilator-free days, incidence of invasive mechanical ventilation, extracorporeal membrane oxygenation or death, duration of ICU stay, mortality, time to recovery, and safety. 528  patients were screened, 520 were randomized. There have been many reports describing the disproportionate impact of COVID-19 on Black and African-American populations. Therefore,  we performed a post-hoc analysis of the impact of Lenzilumab on COVID-19 outcomes in African  or Black American participants of the live air clinical trial. There were 38 Black or African  Americans in the Lenzilumab arm and 33 in the placebo arm. These are the baseline demographics.  Please remember that the participants were not stratified by race as part of the clinical trial  design. Age, sex, and BMI distributions were comparable between the Lenzilumab and placebo arms in the Black or African American subpopulations. A larger proportion of the Black  or African American participants in the Lenzilumab arm had baseline CRP greater than or equal to 150  milligrams per liter. Correspondingly, a larger proportion of Black or African American participants  in the placebo arm had baseline CRP values below 150 milligrams per liter. As regards comorbidities,  distribution of hypertension, diabetes, and chronic kidney disease were comparable between the two arms in the African American or Black subpopulation, but there were differences in  the distribution of the other comorbidities as outlined on this slide. The proportion of Black  or African American participants with three or more comorbidities was larger in the Lenzilumab  arm compared to the placebo arm. In the next few slides, I will present the results for the  various endpoints and compare those results in the Black or African American participants to  that of the white participants as well as the overall study population. I start with the primary  endpoint. The primary endpoint, the likelihood of achieving survival without ventilation was  achieved in the overall population with a hazard ratio of 1.54 and a p-value of 0.0403. As you can  see on this slide, the impact of Lenzilumab on the primary endpoint was clearly evident in the Black  or African American subgroup. When it comes to the secondary endpoints, while there were numeric  differences between the Lenzilumab and placebo arms, suggesting a favorable impact of Lenzilumab  on these outcomes, these differences did not reach statistical significance. When analyzing these  results within the subgroup of Black or African American and comparing them to that of the white  participants, results remain without statistical significance. However, the impact of Lenzilumab  or the magnitude of difference between the Lenzilumab and placebo arms was greater in the  Black or African American participants when compared to the white participants. These are the  results for the incidence of mechanical ventilation, extracorporeal membrane oxygenation, or death.  In the overall population, the magnitude of difference was 0.67. In the Black or African American population, 0.39. And in the white population, 0.71. Significance statistically  was not achieved in any of the populations. The same observation can be made regarding mortality.  The magnitude of the difference between the placebo and the Lenzilumab arms was greater in the Black or African American subpopulation. The same applies to ventilator-free days,  and the same applies to ICU days. We previously reported that the impact of Lenzilumab was  greatest in those individuals with baseline C-reactive protein values less than 150 milligrams per liter. This is depicted on this slide. Lenzilumab improved the likelihood of SWAV  in the overall population with a hazard ratio of 1.54 and a p-value of 0.0403. In the subpopulation  with baseline CRP less than 150 milligrams per liter, the hazard ratio was 2.54 with a p-value  of 0.0009. And in the subpopulation with CRP above 150 milligrams per liter, the hazard ratio  was 1.04 with a p-value of 0.9058. We therefore explored the impact of Lenzilumab in Black or  African American participants of the live air clinical trial with baseline CRP values below  and above 150 milligrams per liter. These are the results in patients with baseline CRP values below  150 milligrams per liter. Lenzilumab improved the likelihood of SWAV statistically significantly  in all the three populations. However, the magnitude of the difference between the Lenzilumab  and placebo arms was the greatest in the Black or African American subpopulation. This is another way  of looking at the data and comparing the likelihood of survival without ventilation in live air.  As you can see, the magnitude of the difference between Lenzilumab and placebo in the likelihood  of survival without ventilation was the largest in the Black African American subpopulation with  baseline CRP values less than 150 milligrams per liter. Lenzilumab was safe and well tolerated  in live air. There were no suspected unexpected serious adverse reactions. There were no serious  adverse events attributed to Lenzilumab. No cases of pulmonary alveolar proteinosis were reported.  There were no differences between the Lenzilumab and placebo arms in terms of laboratory parameters,  including hematology, creatinine, or liver function tests. In conclusion, Lenzilumab significantly  improved survival without the need for mechanical ventilation in hospitalized COVID-19 patients not  yet requiring mechanical ventilation. This improvement in SWAV was more marked in Black or  African American participants. Improvement in SWAV was greatest in patients with baseline CRP values  below 150 milligrams per liter. This impact of baseline CRP on SWAV was greatest in Black or  African Americans. Black or African American participants in live air had more comorbidities  compared to whites. Lenzilumab was safe and well tolerated with no serious adverse events  attributable to Lenzilumab. The improved response to Lenzilumab observed in Black or African American participants of live air requires further investigation. On behalf of the Live  Air Study Group, I thank you for the opportunity to present and share our findings. Thank you.

Video Summary

Dr. Zelalem Tamezgan from Mayo Clinic presented the findings of a clinical trial investigating the use of Lenzilumab, a neutralizing antibody, in hospitalized COVID-19 patients. The study focused on Black or African American participants and compared the impact of Lenzilumab on various endpoints to that of the overall study population. The results showed that Lenzilumab significantly improved survival without the need for mechanical ventilation, with a greater impact observed in Black or African American participants. The study also found that the improvement was greatest in patients with lower baseline levels of C-reactive protein. Lenzilumab was deemed safe and well-tolerated in the trial. Further investigation is needed to understand the observed differences in response among different populations.

Asset Subtitle

Pharmacology, Infection, Worldwide Data, 2022

Asset Caption

BACKGROUND: Black/African Americans (B/AA) are twice as likely as Whites to develop COVID-19, possibly due to disparities in healthcare access and genetics. Mutations in the angiotensin converting enzyme gene enabling greater SARS-CoV-2 replication may be overexpressed in B/AAs leading to increased viral load, morbidity, hospitalizations, and mortality. The hyperinflammatory cytokine storm accompanying SARS-CoV-2 infection is mediated by GM-CSF releasing downstream inflammatory chemokines, cytokines, and inflammatory markers including C-reactive protein (CRP), predictive of clinical worsening. This analysis of LIVE-AIR explored the efficacy of lenzilumab in its B/AA population. METHODS: LIVE-AIR was a randomized, double-blind, placebo-controlled trial of 479 (mITT population) hospitalized COVID-19. Patients, >18 years old with oxygen saturation ≤94% on room air or requiring supplemental oxygen (low-flow or high-flow), but not invasive mechanical ventilation, were randomized to receive lenzilumab (1800 mg, n=236) or placebo (n=243) via three IV infusions, every 8 hours, within 12 hours of randomization. A secondary analysis of the primary endpoint, survival without ventilation (SWOV), by race/ethnicity and baseline CRP level was assessed at Day 28. RESULTS: Participants were racially and ethnically diverse: 3.1% Asians, 14.8% B/AA, 38.6% Hispanic/Latino. The likelihood of SWOV was significantly improved by lenzilumab across races and ethnicities compared with placebo (HR: 1.54; 95% CI: 1.02, 2.32; p=0.0403; Nf479) and in patients with baseline CRP < 150 mg/L, < 85 years of age (HR 3.04; 1.68, 5.51; p=0.0003; n=337). The likelihood of SWOV in B/AAs trended higher than the overall population (HR: 2.68; 0.89-8.12; p=0.0811; n=71) and was significantly and disproportionately improved in those with baseline CRP < 150 mg/L (HR: 8.96; 1.09-73.55; p=0.0412; n=51). Serious adverse events were similar across treatment groups. CONCLUSION: In LIVE-AIR, with a B/AA representation comparable to the US population and usually under-represented in trials, lenzilumab improved the likelihood of SWOV across races and ethnicities of COVID-19 patients; however, B/AA with baseline CRP < 150 mg/L exhibited a markedly greater improvement. Biological, genetic, and social factors contributing to these differences requires further investigation.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Infection

Knowledge Area Worldwide Data

Knowledge Level Advanced

Membership Level Select

Tag Pharmacokinetics Pharmacodynamics

Tag Epidemiology Outcomes

Tag COVID-19

Year 2022

Keywords

Lenzilumab

COVID-19

clinical trial

survival

C-reactive protein

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