Recently, Kintor Pharma scientists published results of a study titled " Inhibitory Effects of GT0918 on Acute Lung Injury and the Molecular Mechanisms of Anti-inflammatory Response " in the preprint journal bioRxiv. The study demonstrated that pruxelutamide (GT0918) is an effective therapeutic drug for severe COVID-19 patients, in addition to mild to moderate COVID-19 patients treatment.

doi:https://doi.org/10.1101/2022.06.29.498191

The Kintor team found that pruxelutamide could reduce cytokine release and suppress inflammatory responses through inhibiting NF-κB signaling and activating NRF2. Therefore, pruxelutamide exhibits potentials in regulating immune system function, maintaining immune homeostasis, and reducing the risk of cytokine release storm (CRS), acute respiratory distress syndrome (ARDS) and tissue damage.

The COVID-19 pandemic has been a global public health crisis since early 2020. Scientists around the world have made great efforts in developing vaccines and drugs against COVID-19. However, the unexpected emergence of SARS-CoV-2 virus variants, which carry multiple mutations on the spike protein receptor binding domain, may be resistant to existing treatments such as neutralizing antibodies or vaccines. Oral drugs are especially necessary for the world to defeat the pandemic apart from vaccines and neutralizing antibodies.

Pruxelutamide, an oral therapeutic drug, independently developed by Kintor Pharma, has been showing to accelerate viral clearance and recovery rate in COVID-19 patients with mild to moderate symptoms by blocking SARS-CoV-2 infiltrating into host cells though down-regulating ACE2 and TMPRSS2 expressions. Clinical studies have shown that pruxelutamide reduced mortality rate and shortened hospital stay in COVID-19 inpatients. Moreover, Pruxelutamide exhibits protective efficacy in severe COVID-19 patients in critical care.

In the present study, the team conducted lipopolysaccharide (LPS) and Poly(I:C) induced model to explore the immune regulation mechanism of pruxelutamide.

Specifically, in vitro experiments with various kinds of immune cells (lines) showed that pruxelutamide down-regulated LPS-induced IL-6 and TNF-α expression and secretion in a dose-dependent manner. Previous clinical data suggest that upregulation of TNF-α and IL-6 in patients with COVID-19 often predicts poor prognosis. These pro-inflammatory factors are quickly eliminated in mild-to-moderate patients, but their delayed and continued elevation can lead to cytokine release syndrome (CRS). CRS can induce a series of side effects, such as severe lung injury and acute respiratory distress syndrome (ARDS), is a common characteristic in severe COVID-19 patients. Pruxelutamide decreased the levels of these proinflammatory cytokines in a dose-dependent manner and protected against CRS-induced severe clinical COVID-19 outcomes. Further analysis indicated pruxelutamide down-regulated the activation of p65 by decreasing phosphorylation of IκBα, in a dose-dependent manner, suggesting pruxelutamide inhibited the expression of proinflammatory cytokines through NF-κB signaling.

Moreover, by screening of more than 200 transcription factors, the team found the binding activity of NRF2 was enhanced with pruxelutamide treatment. It was found that pruxelutamide could up-regulate the level of NRF2 protein and enhanced the signal response of NRF2, suggesting another important mechanism of pruxelutamide in immune regulation.

Meanwhile, in vivo data in LPS and Poly I:C induced acute lung injury model showed that, treated with pruxelutamide, proinflammatory cytokines in alveolar lavage fluid of mice were decreased , less inflammatory infiltration in lung tissue was observed , and alveolar structure was normalized. These results suggest that pruxelutamide can reduce acute lung injury in mice by reducing the level of proinflammatory factors and maintaining immune homeostasis.

In conclusion, this study demonstrated the immune regulation mechanism of pruxelutamide. Pruxelutamide is not only effective for treatment of mild to moderate COVID-19 patients, but also an effective therapeutic drug for severe COVID-19 patients by reducing the risk of cytokine storm and acute respiratory distress.