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Impact of Fostamatinib on Inflammatory Biomarkers in Hospitalized Patients With COVID-19
Raquel S Da Cruz1,2, Heather L Teague1,2, Marcos J Ramos-Benitez3
1Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD.
Objectives:
Understanding the mechanistic impact of fostamatinib, a spleen tyrosine kinase inhibitor, in severe COVID-19 using biomarkers associated with disease severity is crucial for the development of host-directed therapeutics. We analyzed samples from a randomized clinical trial to investigate the impact of fostamatinib on multiple inflammatory biomarkers associated with COVID-19 disease severity.
Design:
Secondary analyses of biomarkers from a randomized clinical trial.
Setting:
Multicenter randomized clinical trial.
Patients:
A total of 400 adults hospitalized with COVID-19 were enrolled in a phase 3 randomized clinical trial. Absolute neutrophil counts (ANCs) were analyzed across 392 patients and biomarkers were measured in 190 patients with available plasma samples.
Interventions:
Adults hospitalized with COVID-19 were randomized to receive either fostamatinib (150 mg bid) or placebo. ANCs and 24 biomarkers were assessed at day 0 and over time using a multiplexed Meso Scale Discovery assay (Meso Scale Diagnostics LLC, Rockville, MD).
Measurements And Main Results:
At day 0, participants with World Health Organization ordinal scale 5-7 had elevated ANC counts, compared with ordinal scale 4. In addition, the levels of neutrophil-associated biomarkers, inflammatory cytokines, and mediators of endothelial dysfunction at day 0 were increased in the participants who were ordinal scale 5-7 vs. ordinal scale 4. Randomization to fostamatinib compared with placebo resulted in a decrease in ANC and several neutrophil-associated biomarkers, pro-inflammatory cytokines, and mediators of endothelial dysfunction/tissue damage. This differential finding was also demonstrated in a subgroup of patients (n = 85) with a hypoinflammatory phenotype.
Limitations:
Missing plasma samples and neutral phase 3 trial results.
Conclusions:
Randomization to fostamatinib resulted in lower neutrophil counts and levels of circulating biomarkers in hospitalized patients with COVID-19; however, the observed impact of fostamatinib was modest compared with prior studies.
