Abstract Rationale GEn-1124 is a 1st-in-class, novel, p38α:MK2 dual signal modulator with anti-inflammatory and endothelial-stabilizing properties. GEn-1124 reduced mortality in both bacterial and influenza models of acute respiratory distress syndrome (ARDS). The purpose was to study the proteomic analysis of GEn-1124 after lipopolysaccharide challenge of blood of subjects receiving GEn-1124 or placebo after multiple dosing for 6 days in a multiple ascending dose study of 24 subjects (NCT04728061). Methods 1536 biomarkers were analyzed from blood stimulated with 50 ng/mL lipopolysaccharide (LPS) for 6 hours ex vivo using the O-link™ platform. Relative protein quantification, normalization, and log2 transformation was completed with NPX software. The change from pre-dose baseline values for Days 2 through 6 were used to calculate an area under the curve (AUC) for each dose level and for each panel. The AUC for each protein was then compared for statistical significance (p 0.05) for each dose level and each protein vs. its matching placebo value using an unpaired t-test. The AUC values that were up regulated or down regulated were plotted for each dose level vs its placebo value. A difference of 1 for AUC signifies an approximately 2-fold change in the drug NPX protein value vs. placebo. Results GEn-1124 consistently significantly decreased pro-inflammatory cytokines: TNFα, IL-6, IL1β and others. In addition, GEn-1124 either increased or had no effect on anti-inflammatory cytokines, including IL-10. In addition, protein signatures for GEn-1124 point to a decrease in neutrophil activation, decrease in inflammation, reduced vascular leakage, endothelium and epithelium stabilization, reduced fibrosis, reduced apoptosis, and reduced activation in the complement and coagulation pathways (Figure). These protein signatures are important in many diseases of inflammation including ARDS, host-directed responses to viral/bacterial infections, influenza, sepsis, acute kidney injury, meningitis, encephalitis, acute ischemic stroke, and acute coronary syndrome among other diseases. Also, GEn-1124’s protein signature from Olink point to treatments for chronic neurological diseases like tauopathies which are responsible for frontotemporal dementia, Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy, among others. Further work is ongoing to study GEn-1124’s unique protein signatures to match various diseases of inflammation. Figure: Volcano plot of up- (red) or down- (blue) regulated proteins after dosing with GEn-1124 vs. placebo. Conclusions GEn-1124 is a novel 1st-in-class dual signal modulator with good safety, PK, PD, and a biological effect profile predicted to benefit in many inflammatory diseases and neurodegenerative diseases. A Phase 2 study in ARDS patients is currently underway (NCT05795465). This abstract is funded by: GEn1E Lifesciences Inc.
Lal et al. (Fri,) studied this question.