Humanigen Inc (fka HGENQ)

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Stimulating severe COVID-19: the potential role of GM-CSF antagonism

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00539-7/fulltext#%20

One of the key components of the detrimental hyperinflammatory response in COVID-19 is granulocyte-macrophage colony-stimulating factor (GM-CSF), which is an immunomodulatory cytokine that might help to clear respiratory microbes by stimulating alveolar macrophages, but when in excess can cause damage. Its concentrations are low or undetectable in healthy individuals, yet many conditions can cause a rapid increase its concentration.1 Increased circulating concentrations of GM-CSF have been described in patients with COVID-19 compared with healthy controls.2 In the later stages of lung disease in COVID-19, excessive GM-CSF production can contribute to the dysregulated immune response in severe COVID-19,3 in which, upstream of IL-1 and IL-6, activated T cells target neutrophils and macrophages.4 Agents that interfere with its actions have high plausibility for benefit, not just in COVID-19, but in other acute inflammatory conditions, such as acute respiratory distress syndrome or sepsis.5

In The Lancet Respiratory Medicine, Zelalem Temesgen and colleagues6 report on a multicentre, placebo-controlled clinical trial of hospitalised patients with COVID-19, showing that lenzilumab, a neutralising monoclonal antibody against GM-CSF, is associated with improved survival without invasive mechanical ventilation at 28 days. Lenzilumab is a monoclonal antibody that directly binds GM-CSF and is being tested for conditions such as chronic myelomonocytic leukaemia and B-cell lymphoma.

Of 520 randomly assigned patients who were hypoxic or who required oxygen, but who did not require invasive mechanical ventilation, 479 patients were included in the modified intention-to-treat analysis. Patients in the lenzilumab group showed a 6% absolute increase in survival without ventilation at 28 days compared with the placebo group (198 [84%] of 236 patients vs 190 [78%] of 243 patients; hazard ratio [HR] 1·54 [95% CI 1·02–2·32], p=0·040). This difference on the outcome of survival without ventilation was primarily driven by more patients in the placebo group requiring invasive ventilation (49 [20%] patients) than those in the lenzilumab group (26 [11%] patients; HR 0·52 [0·32–0·82], p=0·0059). Key secondary outcomes, such as mortality, ventilator-free days, intensive care unit days, or recovery time, along with adverse events were not significantly different between the two groups.

This study population had lower baseline C-reactive protein (CRP) concentrations than the cohorts in RECOVERY and REMAP-CAP—trials where IL-6-targeted therapy has shown the largest benefit.7, 8 Exploratory sensitivity analyses suggested greater benefit of lenzilumab in patients with CRP concentrations less than the median value of 79 mg/L; further study of a CRP-guided approach, possibly targeting patients with lower CRP concentrations, earlier in their disease course, or of a different disease phenotype, could therefore be warranted. Whether biomarker-driven immunotherapy with stratification of patients can guide individualised use of immunomodulatory treatments in COVID-19 needs to be explored.