Mavrilimumab improves outcomes in COVID-19 pneumonia with hyperinflammation

Adding the anti-GM-CSF* receptor-α monoclonal antibody mavrilimumab to standard care (SC) improved clinical outcomes in patients with severe coronavirus disease 2019 (COVID-19) pneumonia and systemic hyperinflammation who were not under mechanical ventilation (MV), an Italian study has shown.

“[M]avrilimumab was associated with superior and earlier clinical improvements in respiratory parameters, faster resolution of inflammation, and fewer deaths [vs] SC … 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,” they stressed.

Thirty-nine patients received SC** administered by the participating hospital at the time. Of these, 13 received a single IV dose of mavrilimumab 6 mg/kg on top of SC. [Lancet Rheumatol 2020;doi.org/10.1016/ S2665-9913(20)30170-3]

Day 28 saw no deaths among those on mavrilimumab; seven died among those who had SC only (0 percent vs 27 percent; p=0.086).

All mavrilimumab recipients showed clinical improvement vs 17 in the SC arm (100 percent vs 65 percent; p=0.03), with a significantly faster mean time to improvement with mavrilimumab vs SC (8 vs 19 days; p=0.0001).

“The improvement in respiratory outcomes with mavrilimumab resulted in earlier weaning from supplemental oxygen,” they said. Only one mavrilimumab recipient progressed to MV (and eventually achieved clinical improvement within 28 days); nine progressed to MV or died in the SC arm.

Hospital stay was also shorter with mavrilimumab vs SC alone (median, 10 vs 20 days; p=0.003).

Moreover, fever resolution among febrile patients was noted at day 14 in both arms, more so among those on mavrilimumab vs SC (n=10/11 vs 11/18). Median time to resolution was faster with mavrilimumab vs SC (1 day vs 7 days; p=0.0093).

Apart from one patient who had increased C-reactive protein, white blood cells, and serum procalcitonin, mavrilimumab was generally well-tolerated with no infusion reactions. Three patients in the SC arm developed infectious complications.

Targeting hyperinflammation

Despite the small sample size, lack of randomization and placebo arm, and short follow-up period, in terms of survival, the results were, as per the researchers, “encouraging”.

The mortality rate among SC recipients correlates with other data on COVID-19 patient settings with hyperinflammation, which may worsen prognosis. [Lancet 2020;395:1054-1062; Intensive Care Med 2020;46:846-848] “[These] indirectly emphasize the cardinal role of rampant inflammation in early mortality and strengthen the rationale for immunomodulation in hyperinflammatory settings,” they explained.

“These preliminary results represent the first evidence of attenuation of hyperinflammation in COVID-19 pneumonia by inhibition of the GM-CSF pathway … [D]ampening of hyperinflammation with mavrilimumab [may] be beneficial for COVID-19,” they said.

Blocking GM-CSF signalling

Given its cardinal role in innate inflammation, GM-CSF may be a potential mediator of the cytokine storm. [Mediators Inflamm 2015;2015:568543] “[The] complex immunologic activity [of GM-CSF] has made it a potential target for the treatment of immune-mediated diseases*** … Undoubtedly, within the inflammatory cascade, this effect can be placed further upstream compared with other cytokines^#,” commented Drs Ennio Giulio Favalli and Roberto Caporali from the ASST Gaetano Pini-CTO Institute in Milan, Italy. [Lancet Rheumatol 2020;doi.org/10.1016/S2665-9913(20)30185-5]

Atypical pathogenic T helper 1-cells expressing GM-CSF have been identified in patients with more severe COVID-19, but not in those with less symptomatic patterns and in healthy controls. [Natl Sci Rev 2020;nwaa041] This, coupled with the current data, substantiate the potential role of GM-CSF in the pathogenesis of SARS-CoV-2^##-related hyperinflammation, said Favalli and Caporali.

“GM-CSF receptor blockade is certainly a potential option for the treatment of more severe subsets of COVID-19,” they said. If confirmed in more extensive randomized trials, the findings could drive re-appraisal of the role of components involved in CRS^### development, they added.