Dual anti-viral and immunomodulatory activity of the CXCR4 inhibitor Balixafortide (POL6326) in preclinical in vitro and in vivo SARS-CoV2 infection models

Balixafortide (POL6326) is a potent, selective inhibitor of the chemokine receptor CXCR4 currently in PhIII for treatment of advanced metastatic HER2-negative breast cancer patients in combination with eribulin (NCT03786094). Clinical proof-of-concept has been demonstrated in a PhI single arm dose-escalation trial (NCT01837095) Recently, CXCR4-positive lung 'bystander' T cells and neutrophils of Covid-19 patients were correlated with disease progression and fatal outcome1, 2. Consequently, CXCR4 inhibition has been suggested to have favourable effects on the prevention and treatment of acute respiratory distress syndrome and associated cytokine storm, lung fibrosis and unbalanced angiogenesis in the SARS-CoV-2 infected lung In vitro, balixafortide displayed a dose-dependent cell-protective effect in a SARS-CoV-2 induced cytopathic effect assay (CPE) in an EC50 range of 10 μM. Head-to-head comparison with remdesivir and time-of-virus addition studies suggest a different mode of action of balixafortide The activity of Balixafortide on SARS-CoV-2 infection was investigated in vivo in the free choice diet-induced obese hamster, a model that also develops nonalcoholic steatohepatitis and heart failure with preserved ejection fraction3. Balixafortide was subcutaneously administered 20mg/kg twice daily for 10 days after SARS-CoV-2 infection Upon balixafortide treatment, significantly less infectious SARS-CoV-2 particles were found on day 4 post infection, and a lower total viral load at day 10. Balixafortide statistically reduced CXCL10 gene expression (- 40% compared to vehicle) at day 4. Elevated CXCL10 in conjunction with IL-6 is a key feature in COVID-19 disease generating a vicious circle resulting in a cytokine storm. In addition, balixafortide treatment led to a marked reduction (-40% compared to vehicle) of ISG15 gene expression in the lung on day 10. Elevated free ISG15 is associated with immune pathology in viral infection. There was no loss in body weight compared to vehicle control and no balixafortide-related mortality suggesting that balixafortide is well-tolerated The data suggest a favourable dual activity of balixafortide based on the reduction of both, viral load and inflammatory driving factors of COVID- 19 disease.