Pharmacokinetics, Pharmacodynamics and Safety of GEn-1124, a Next-generation Non-catalyticp38α:mk2 Dual Signal Modulator in Phase 1 Study With Endothelial Stabilizing, Anti-inflammatory, and Lung-protective Activities for the Treatment of ARDS

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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 pharmacokinetics (PK), pharmacodynamics (PD), and safety of GEn-1124 in 48 healthy subjects (NCT05795465). Methods: GEn-1124 was studied in a double blind, placebo-controlled single ascending (SAD) and multiple ascending dose (MAD) study, with 24 subjects in the SAD cohort from 50 mg to 450 mg administered as a single 2-hour IV infusion and 24 subjects in the MAD cohort from 225 mg to 900 mg administered as 2-hour IV infusions given twice daily (8 hour interval) for 5 days and one dose on Day 6. Safety and PK data were collected. 1536 biomarkers from blood stimulated ex vivo with 50 ng/mL lipopolysaccharide (LPS) for 6 hours was measured using the O-link™ platform. Results: GEn-1124 had dose-proportional PK in the SAD/MAD study up to the 900 mg BID dose with a half-life of 3 hours. Steady-state was reached rapidly. GEn-1124 was well tolerated, with the majority of adverse events (AEs) being mild and all resolved by the end of the study. There was one serious AE related to an underlying glucose-6 phosphate dehydrogenase (G6PD) deficiency which was resolved.The O-link analysis demonstrated a lung-protective biological effect profile of GEn-1124 that included: 1.Decreased inflammatory signaling TNFα, IL6, IL1β, IFNɣ, TANK, CXCL10, CXCL11, CXCL12, and CASP1. 2.Increased or no change in anti-inflammatory IL-10 expression.3.Reduced vascular leak and decreased HSPB1, IL1β, VEGFA, and HNMT.4.Enhanced endothelial stabilization and decreased S100P, ANGPTL4, ANGPTL3, and VEGFA.5.Reduced epithelial dysfunction and decreased MUC13, IL18, and IL17RA. 6.Reduced apoptosis/necrosis S100P and FADD. 7.Reduced fibrosis FGF2, IGFBP1, VEGFA, and TPSAB1. 8.Reduced complement and coagulation pathway activation (C1QA, C2, F7, and F9). PK/PD modeling was conducted to obtain an effective concentration (IC90) of 0.6 μg/mL. An efficacious dose of 500 to 750 mg BID ( 8 hour interval) is predicted to cover this IC90 throughout the day (Figure 1). 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 ARDS. A Phase 2 study in ARDS patients is currently underway (NCT05795465). Figure 1: PK Profiles of 500mg and 750mg BID Dose with Predicted IC90 (Efficacious Dose) coverage

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