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The results with lenzilumab on SWOV demonstrate that impeding GM-CSF signaling early in CS is required to prevent COVID-19 disease progression to IMV or death. This is further supported by an 88% improvement in SWOV in subjects hospitalized < 2 days. The results herein with lenzilumab confirm results from prior clinical trials targeting GM-CSF but are differentiated by patient selection, timing of intervention, and dosing strategy. Mavrilimumab, a monoclonal antibody that acts as a GM-CSF alpha-receptor antagonist demonstrated non-significant trends of 48% improvement in survival without requirement for supplemental oxygen.27 Otilimab, a monoclonal antibody targeting circulating GM-CSF in ventilated subjects, was reported in a non-peer-reviewed disclosure of results from its phase 2b COVID-19 study (NCT04376684) to not meet its primary endpoint of improvement in the proportion of COVID-19 subjects who were alive and free of respiratory failure 28 days; however, in pre-planned analysis of subjects aged at least 70 years, which comprised 22% of the entire patient population, 65.1% were alive and free of respiratory failure, compared to 45.9% of subjects who received the standard of care.28 The results of all three trials of GM-CSF antagonism suggest the central role of GM-CSF in CS of COVID-19 that has been recently demonstrated through network analysis of cytokine profiles from COVID-19 subjects.10 This analysis associated IL-6, CXCL10, but in particular GM-CSF, to markers of endothelial injury and thrombosis early in COVID-19, in severe cases, in hospitalized subjects and those with risk factors for severe disease, and uniquely elevated in fatal COVID-19. The results herein with lenzilumab more completely define the central role of GM-CSF in COVID-19, identified subjects more likely to receive benefit from lenzilumab and underscores the necessity to target GM-CSF early during the emerging hyperinflammatory stage in order to ameliorate CS induced by COVID-19.

The findings of the network analysis and the anti-GM-CSF approaches listed above, including the robust response to lenzilumab particularly in subjects with CRP levels <150 mg/L and age<85, helps explain the limited efficacy of other anti-cytokine approaches that target cytokines downstream of myeloid cell activation in the CS cascade (i.e., IL-6, TNF?, IL-10). Results from clinical trials with anti-IL-6 agents are mixed and mostly negative.22,29-33. Targeting single downstream mediators of CS, such as IL-6, may render therapy clinically ineffective as other key, redundant cytokines continue to promote tissue damage or are even compensatory upregulated in the absence of IL-6 signaling. Alternatively, it is possible that targeting IL-6 is more effective later in the disease course as evidenced by tocilizumab wherein benefit appears to be derived in more critically ill subjects recently admitted to the ICU.22