Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a myelopoietic growth factor and pro-inflammatory cytokine that plays a central role in a broad range of immune-mediated diseases. GM-CSF, which is secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and fibroblasts, regulates macrophage number and function. It acts as a pro-inflammatory signal, prompting macrophages to launch an immune cascade that ultimately results in tissue damage.^1,2 GM-CSF is believed to be a key driver of lung inflammation in severe and critical COVID-19 pneumonia, operating upstream of other pro-inflammatory cytokines and chemokines.^1-6 Anti-GM-CSF monoclonal antibodies (mAbs) may mitigate inflammation by inhibiting this signaling axis upstream and thus minimizing downstream production of numerous pro-inflammatory mediators involved in the pathogenesis of COVID-19.⁷ Gimsilumab, lenzilumab, namilumab, and otilimab target GM-CSF directly, neutralizing the biological function of GM-CSF by blocking the interaction of GM-CSF with its cell surface receptor.^1,8,9 Mavrilimumab targets the alpha subunit of the GM-CSF receptor, blocking intracellular signaling of GM-CSF.^8,10 None of these agents are currently FDA approved for any indication.

Recommendation

• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of GM-CSF inhibitors for the treatment of hospitalized patients with COVID-19.

Rationale

Clinical data are lacking to definitively establish the potential benefits and risks associated with the use of GM-CSF inhibitors in patients with COVID-19. Data from a double-blind randomized controlled trial of lenzilumab did show a significant improvement in the primary endpoint of ventilator-free survival through Day 28 among those who received the GM-CSF inhibitor.¹¹ However, preliminary data from a large, double-blind randomized trial of otilimab (primary endpoint: alive and free of respiratory failure at Day 28) and published results of a small, double-blind, randomized trial of mavrilimumab (primary endpoint: proportion alive and off supplemental oxygen at Day 14) did not show a survival benefit for the GM-CSF inhibitors compared to placebo.^12-14 The study populations differed; the lenzilumab and mavrilimumab studies primarily included patients on room air or low-flow oxygen and excluded patients receiving mechanical ventilation, whereas the otilimab study included only patients receiving high-flow oxygen, noninvasive ventilation, or mechanical ventilation. Lenzilumab and mavrilimumab continue to be investigated, whereas clinical development of otilimab for the treatment of COVID-19 has ceased.

Clinical Data for COVID-19

Lenzilumab, mavrilimumab, namilumab, and otilimab have been evaluated in clinical trials in hospitalized adults with SARS-CoV-2 pneumonia.^12-15 Clinical data are not yet published for gimsilumab. The Panel’s recommendations are based on the results of the available clinical studies. Selected clinical data on the use of anti-GM-CSF mAbs for the treatment of COVID-19 are summarized in Table 5e.

Clinical Trials

See ClinicalTrials.gov for a list of ongoing clinical trials that are evaluating the use of GM-CSF inhibitors for the treatment of COVID-19.

Adverse Effects

The primary risks associated with GM-CSF inhibitors being reported and evaluated are related to bacterial infection. Other adverse events that have been reported with these agents include acute kidney injury and elevated liver transaminases.¹⁰ Autoimmune pulmonary alveolar proteinosis has been associated with a high-titer of anti-GM-CSF auto-antibodies.¹⁶

Considerations in Pregnancy

Pregnant patients have been excluded from clinical trials evaluating GM-CSF inhibitors for the treatment of COVID-19. There is insufficient evidence to recommend for or against their use in pregnant individuals with COVID-19.

Considerations in Children

There are no data on the use of GM-CSF inhibitors in children.