Antiviral and immunomodulatory effect of zapnometinib in animal models and hospitalized COVID-19 patients

Yvonne Fuell^1,2Lara Maria Schüssele^1,2Hazem Hamza^1,2,3Helen Hoffmann^1,2Martin Bauer¹Stephan Stenglein¹Oliver Pötz⁴Andreas Steinhilber⁴Viktoria Anselm⁴Mark W Delany⁵Judith M.A. van den Brand⁶Geert van Amerongen⁷Leon de Waal⁸Stephan Pleschka⁹Stephan Ludwig¹⁰Oliver Planz^2*

• ¹Atriva Therapeutics GmbH, Tuebingen, Germany
• ²Institute of Immunology;, University Hospital and Faculty of Medicine, University of Tübingen, Tübingen, Germany
• ³Virology Laboratory, Environmental Research Division, National Research Centre, Cairo, Egypt
• ⁴SIGNATOPE GmbH,, Reutlingen, Germany
• ⁵Division of Pathology, Faculty of Veterinary Medicine Utrecht,, Utrecht, Netherlands
• ⁶Division of Pathology, Faculty of Veterinary Medicine Utrecht, Utrecht, Netherlands
• ⁷Viroclinics-DDL, Cerba Research Company, Schaijk, the Netherlands, Schaijk, Netherlands
• ⁸Viroclinics-DDL, Cerba Research Company,, Schaijk, Netherlands
• ⁹Institute of Medical Virology, Justus Liebig University, Giessen, Germany
• ¹⁰Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Muenster, Germany

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 hospitalised 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 analysed via ELISA and RT-qPCR. Alterations in T and B cells from COVID-19 patients were analysed using flow cytometry. Biomarker analysis in hamster serum was conducted to monitor potential toxic effects. Results: Zapnometinib reduced SARS-CoV-2 viral load in hospitalised COVID-19 patients, in the hamster model and in various highly pathogenic coronaviruses in vitro. Pro-inflammatory cytokines and chemokines decreased in COVID-19 patients, in a lung injury mouse model, and in vitro 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 favourable antiviral and immunomodulatory properties.