Impact of Fostamatinib on Inflammatory Biomarkers in Hospitalized Patients With COVID-19
Raquel S. Da Cruz, Heather L. Teague, Marcos J. Ramos-Benitez, Sonya J. Malavez-Cajigas, Trenton Williams, Rui Miao, Xin Tian, Gefei Lin, Laurence W. Busse, Akram Khan, Ari Moskowitz, David N. Hager, Todd W. Rice, Adit A. Ginde, Nicole M. Iovine, Peter Chen, Basmah Safdar, Kevin W. Gibbs, Ali Javaheri, Marjolein de Wit, Michelle Harkins, Kris Hudock, Lisa H. Merck, Aaron Barksdale, Jeffrey M. Sturek, Harry Schrager, Nathan I. Shapiro, Michael Lanspa, Estelle Harris, Subhashini Sellers, Andrew J. Goodwin, Mark A. Tidswell, Michael R. Filbin, Matthew S. Shotwell, Matthew W. Semler, Wesley H. Self, Sean P. Collins, Jeffrey R. Strich,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 (
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.