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Monoclonal Lenzilumab Cuts Need
for Ventilation in Phase 3 COVID Trial
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IDWeek, September 29-October 3, 2021
Mark Mascolini
Lenzilumab, a monoclonal antibody, significantly cut the need for mechanical ventilation in hypoxic COVID-19 inpatients enrolled in a US phase 3, double-blind, placebo-controlled trial [1]. The significant improvement with lenzilumab occurred both in people also receiving remdesivir and in those also receiving remdesivir and corticosteroids.
The immune-mediated cytokine storm that drives advanced COVID-19 gets triggered by granulocyte macrophage-colony stimulating factor (GM-CSF), a cytokine that helps make white blood cells. Research shows that GM-CSF levels correlate with severity of COVID-19.
Lenzilumab is an antihuman GM-CSF monoclonal antibody that neutralizes GM-CSF. A 39-person matched case-cohort study of people with severe COVID-19 pneumonia found significantly shorter time to clinical improvement with versus without lenzilumab (5 versus 11 days, P = 0.006) and significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) [2].
The phase 3 trial, LIVE-AIR, enrolled 520 COVID inpatients requiring supplemental oxygen but not invasive mechanical ventilation [3]. Everyone had virologically confirmed SARS-CoV-2 infection. Researchers randomized participants to receive 600 mg of lenzilumab every 8 hours for a total dose of 1800 mg on day 0 or to receive placebo. All participants could also receive available anti-COVID therapies including remdesivir, corticosteroids, convalescent plasma, and hydroxychloroquine with or without azithromycin. Follow-up lasted through day 60 with the primary endpoint, survival without ventilation, on day 28.
Among 479 treated people, 236 got lenzilumab and 243 placebo. The lenzilumab and placebo groups did not differ substantially in sex (overall 64.7% male), average age (60.5 years), or race/ethnicity (71.6% white, 14.8% black, 38.6% Hispanic). Median C-reactive protein was similar in the two groups (79 mg/L overall). Similar proportions in the two groups received corticosteroids (93.7% overall), remdesivir (72.4%), or both therapies (69.1%).
In the modified intention-to-treat population, Kaplan-Meier analysis determined that 84.4% (95% confidence interval [CI] 79.1 to 88.5) receiving lenzilumab achieved survival without mechanical ventilation, compared with 77.9% (95% CI 72.1 to 82.6) receiving placebo. Chances of survival without ventilation were about 50% greater in people receiving lenzilumab (hazard ratio [HR] 1.54, 95% CI 1.02 to 2.32, P = 0.040). Chances of survival without ventilation were almost doubled in lenzilumab recipients also getting remdesivir (HR 1.91, 95% CI 1.19 to 3.05, P = 0.0073) or remdesivir and corticosteroids (HR 1.92, 95% CI 1.20 to 3.07, P = 0.0067).
Compared with the placebo group, the lenzilumab group had a significantly lower incidence of invasive mechanical ventilation, extracorporeal membrane oxygenation, or death whether taking remdesivir (P = 0.02) or remdesivir and corticosteroids (P = 0.018). People receiving lenzilumab spent fewer days in the intensive care unit (5.4 vs 6.6), although this difference did not reach statistical significance (P = 0.16).
The rate of any grade 3 or worse adverse event was modestly lower with lenzilumab than with placebo (26.7% vs 32.7%). The same small difference between the lenzilumab group and the placebo group held true for respiratory, thoracic, and mediastinal disorders (25.1% vs 27.6%) and cardiac disorders (5.9% vs 5.4%). The researchers attributed no serious adverse events to lenzilumab, including infusion-related reactions. And the lenzilumab and placebo groups did not differ in lab values, hematologic measures, creatinine readings, or liver function tests.
The ongoing ACTIV-5/BET-B platform trial is recruiting participants to further evaluate lenzilumab for COVID-19 [4].
References
1. Temesgen Z, Burger C, Baker J, et al. Lenzilumab efficacy and safety in newly hospitalized COVID-19 subjects: results from a phase 3 randomized double-blind placebo-controlled trial. IDWeek, September 29-October 3, 2021. Abstract 40.
2. Temesgen Z, Assi M, Shweta FNU, et al. GM-CSF neutralization with lenzilumab in severe COVID-19 pneumonia: a case-cohort study. Mayo Clin Proc. 2020;95:2382-2394. doi: 10.1016/j.mayocp.2020.08.038.
3. ClinicalTrials.gov. Phase 3 study to evaluate efficacy and safety of lenzilumab in patients with COVID-19. ClinicalTrials.gov identifier NCT04351152. https://clinicaltrials.gov/ct2/show/NCT04351152
4. ClinicalTrials.gov. ACTIV-5 / Big Effect Trial (BET-B) for the Treatment of COVID-19. ClinicalTrials.gov identifier NCT04583969. https://www.clinicaltrials.gov/ct2/show/NCT04583969
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