Antiviral and immunomodulatory effect of zapnometinib in animal models and hospitalized COVID-19 patients
Yvonne Füll, Lara M. Schüssele, Hazem Hamza, Helen Hoffmann, Martín W. Bauer, Stephan Stenglein, Oliver Pötz, Andreas Steinhilber, Viktoria Anselm, Mark W. Delany, Judith M. A. van den Brand, Geert van Amerongen, Leon de Waal, Stephan Pleschka, Stephan Ludwig, Oliver Planz
Abstract
Introduction: In severe COVID-19, direct-acting antiviral drugs were not effective in hyperinflammatory stages and steroid treatment may weaken host immunity. The MEK inhibitor zapnometinib, as a host-targeting drug, has demonstrated promising efficacy against severe acute viral infections. Proof-of-concept for the innovative approach was presented in a clinical Phase 2 trial with hospitalized COVID-19 patients. Methods: The antiviral and immunomodulatory potential of zapnometinib was investigated in samples obtained from COVID-19 patients enrolled in a Phase 2 clinical trial (RESPIRE), as well as in a SARS-CoV-2 Syrian hamster model, an acute lung injury mouse model, and in cell culture. The antiviral activity of zapnometinib was assessed using viral load reduction assays and RT-qPCR. Cytokines and chemokines were analyzed via ELISA and RT-qPCR. Alterations in T and B cells from COVID-19 patients were analyzed using flow cytometry. Biomarker analysis in hamster serum was conducted to monitor potential toxic effects. Results: in primary human blood cells treated with zapnometinib. In the hamster model, zapnometinib alleviated SARS-CoV-2-mediated lung pathology. In patients with COVID-19, zapnometinib increased T and plasma B cells. Conclusion: Unlike direct-acting antivirals, zapnometinib's dual effect highlights its therapeutic potential in the treatment of severe acute viral infections, with favorable antiviral and immunomodulatory properties.