Inhibiting granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling may offer a therapeutic benefit in patients suffering from severe coronavirus disease 2019 (COVID-19) pneumonia and systemic hyperinflammation, according to a study published in The Lancet Rheumatology.
Preliminary findings suggest treatment with mavrilimumab, an experimental GM-CSF inhibitor, led to “superior and earlier clinical improvements in respiratory parameters, faster resolution of inflammation, and fewer deaths compared with standard care,” in a small cohort of non-mechanically ventilated patients with COVID-19-related severe pneumonia, hypoxia and hyperinflammation, said Giacomo De Luca, IRCCS San Raffaele Scientific Institute, Milan, Italy, and colleagues.
The authors noted that ligand binding to GM-CSF receptor-α (GM-CSFRα) activates multiple pro-inflammatory pathways and, in macrophages and neutrophils, leads to greater secretion of pro-inflammatory cytokines, including TNF, IL-1, IL-6, IL-23 and IL-12, as well as stimulation of several downstream signalling pathways, such as JAK2–STAT5, MAPK and PI3K, all of which influence activation and differentiation of myeloid cells. Mavrilimumab is a monoclonal antibody (human isoform lgG4) that binds to GM-CSFRα and disrupts downstream signalling.
The prospective study included non-mechanically ventilated patients aged 18 years or older who were admitted to San Raffaele Hospital, Milan, Italy, with severe COVID-19 pneumonia. Patients had acute lung injury, defined as PaO2/FiO2 of 300 mm Hg or less, bilateral pulmonary infiltrates, and no clinical evidence of left atrial hypertension. They also had hyperinflammation, defined as elevation of serum inflammation markers C-reactive protein (CRP) to 100 mg/L or more (normal range <6 mg/L) or ferritin to 900 μg/L or more (normal range 30–400 μg/L), in the presence of any increase in lactate dehydrogenase (normal range 125–220 U/L).
Exclusion criteria were management (including mechanical ventilation) in the intensive care unit, evidence of bacterial infection, and concomitant administration of other immunosuppressive biological agents or corticosteroids.
All patients who were admitted to hospital with COVID-19 pneumonia received on admission treatment with oral hydroxychloroquine (200 mg twice a day), intravenous azithromycin (500 mg once daily until patient tested negative for urine antigen for Legionella pneumophila), oral lopinavir–ritonavir (400 mg and 100 mg, respectively, twice a day), and respiratory support with supplemental oxygen or non-invasive ventilation with continuous positive airway pressure.
Between March 17 and April 15, 2020, 13 patients (median age 57 years [IQR 52–58], 12 [92%] men) received mavrilimumab, administered intravenously as a single dose of 6 mg/kg, in addition to standard management, while 26 patients (median age 60 [IQR 53–67], 17 [65%] men) in the control group received standard care. The control cohort consisted of consecutive contemporaneous patients who received local standard of care, but were not treated with mavrilimumab for various reasons, including no drug availability or shortage of the drug, or even absence of patient consent.
The study’s main outcome was time to clinical improvement, defined as improvement of two or more points on the seven-point ordinal scale of clinical status, while other outcomes included the proportion of patients achieving clinical improvement, survival, mechanical ventilation-free survival, and time to fever resolution.
During the 28-day follow-up, none of the mavrilimumab-treated patients died, whereas seven (27%) patients in the control group died (p=0.086). At day 28, all patients in the mavrilimumab arm of the study and 17 (65%) control patients exhibited clinical improvement (p=0.030), with earlier improvement seen with mavrilimumab over control (mean time to improvement 8 days [IQR 5 to 11] vs 19 days [11 to >28], p=0.0001). Accordingly, the drug was linked to earlier hospital discharge than was standard care (median 10 days [IQR 9 to 12] vs 20 days [12 to >28] days, p=0.0030).
One (8%) patient in the mavrilimumab group progressed to mechanical ventilation compared with nine (35%) in the control group who progressed to mechanical ventilation or died (p=0.14). The mavrilimumab-treated patient who progressed to mechanical ventilation achieved clinical improvement within the 28-day observation period.
The median increase in PaO2/FiO2 from baseline was higher in the mavrilimumab arm than for controls (275 mm Hg [IQR 202 to 313] vs 175 mm Hg [–63 to 287]). The improvement in respiratory function in patients treated with mavrilimumab was parallelled by reduction in serum CRP (last available median CRP 8 mg/L [6–28] vs 52 mg/L [14–141] in the control group; p=0.0068), corresponding to a CRP decline of at least 75% in 11 (85%) patients in the mavrilimumab group and 11 (44%) of 25 patients with post-baseline assessments in the control group (p=0.035).
Meanwhile, by day 14, fever resolved in ten (91%) of 11 febrile patients in the mavrilimumab group, compared with 11 (61%) of 18 febrile patients in the control group (p=0.18). Fever resolution was also faster in mavrilimumab recipients versus controls (median time to resolution 1 day [IQR 1 to 2] vs 7 days [3 to >14], p=0·0093).
In terms of safety, the authors said mavrilimumab was well tolerated, with no infusion reactions and no cases of neutropenia. An increase in CRP, white blood cells, and serum procalcitonin was observed in one mavrilimumab-treated patient, who was admitted to the ICU 3 days after infusion. Meanwhile, 3 (12%) patients in the control group developed infectious complications.
“These data suggest that administration of mavrilimumab in patients admitted to hospital with COVID-19 pneumonia and hyperinflammation improved clinical outcomes compared with local standard care only,” the authors said. “Several anticytokine biological agents have the potential to dampen detrimental inflammation in COVID-19. However, we theorised that inhibition of inflammatory cascades upstream could yield robust results. Mavrilimumab inhibits a cardinal pathway of granulocytes and myeloid cells upstream, thus quenching downstream production of myriad pro-inflammatory mediators involved in the pathogenesis of COVID-19.”
They added “this is the first evaluation of a novel therapeutic strategy in a setting overwhelmed by the COVID-19 pandemic, in order to tackle cogent and immediate clinical needs.”
One limitation of the study was that, as it prioritised quick access to a potentially life-saving medication over investigational setup, patients could not be randomly assigned to receive mavrilimumab or the institutional standard of care, thus introducing risks for selection bias, treatment bias, or placebo effect. In addition, other clinical variables besides mavrilimumab treatment might have affected clinical outcomes, despite the matching of baseline demographics and clinical characteristics.
Further, the authors noted that the relatively short follow-up of 28 days is also limited for longer-term efficacy and safety conclusions, even though near-term results with respect to the survival of patients treated with mavrilimumab were “encouraging.” They said further testing in controlled trials is warranted, and multicentre, double-blind, randomised, placebo-controlled studies are planned on the basis of the signal obtained in this trial.