Gen-1124 / GEn1E Lifesci - LARVOL DELTA

A Study to Assess the Pharmacokinetics of GEn-1124 After Single Oral Dosing in Healthy Subjects (clinicaltrials.gov) - P1 | N=6 | Recruiting | Sponsor: GEn1E Lifesciences | Not yet recruiting ➔ Recruiting

Enrollment open

A Study of GEn-1124 in Subjects With Acute Respiratory Distress Syndrome (ARDS) (clinicaltrials.gov) - P2 | N=52 | Recruiting | Sponsor: GEn1E Lifesciences | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases

A Study to Assess the Pharmacokinetics of GEn-1124 After Single Oral Dosing in Healthy Subjects (clinicaltrials.gov) - P1 | N=6 | Not yet recruiting | Sponsor: GEn1E Lifesciences

New P1 trial

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 (ATS 2025) - P2 | "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"

Clinical • P1 data • PK/PD data • Acute Respiratory Distress Syndrome • Fibrosis • Immunology • Infectious Disease • Influenza • Metabolic Disorders • ANGPTL3 • C1QA • CXCL10 • CXCL11 • CXCL12 • FADD • FGF2 • HSPB1 • IGFBP1 • IL10 • IL17A • IL17RA • IL18 • IL1B • IL6 • MUC13 • S100P • TNFA • TPSAB1

Novel Compounds Targeting the Mitogen-activated Protein Kinase (MAPK)-activated Protein Kinase-2 (MK2) Binding Site in P38alpha MAPK Exert Distinct Anti-inflammatory Effects on Gene Expression in TNFalpha-stimulated Endothelial Cells (ATS 2025) - "One of these compounds, GEn-1124, which is currently in a Phase II clinical trial in ARDS, exerts effects on gene expression distinct from the classic p38alpha catalytic inhibitor, SB203580, including inhibiting death receptor signaling and increasing anti-inflammatory cyclic-AMP and protein kinase A signaling... Small molecules targeting the p38alpha MK2-binding site exert greater anti-inflammatory effects than the p38alpha catalytic inhibitor, SB203580. The distinct effect profiles of these novel compounds relate to how they interact with the p38alpha target and can be specifically matched to disease pathogenesis to develop disease-specific therapeutics."

Acute Respiratory Distress Syndrome • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • ADAMTS1 • CSF2 • CXCL5 • CXCL8 • IL15 • IL1A • IL6 • MAPK14 • STAT5 • TNFA • TRAF1

Novel Compounds Targeting the Mitogen-activated Protein Kinase (MAPK)-activated Protein Kinase-2 (MK2) Binding Site in P38alpha MAPK Exhibit Distinct Biological Effect Profiles (ATS 2025) - "One of these compounds, GEn-1124, reduced mortality in mouse models of acute lung injury (ALI) and is currently in Phase II clinical testing in ARDS... These results demonstrate how the strategy of targeting p38alpha substrate binding sites can generate compounds with variable biologic effect profiles that can be exploited to develop disease-specific, and possibly personalized, therapeutics. The negative correlation of compound effects on baseline barrier function and inhibition of thrombin-induced permeability and gene expression suggests independent mechanisms of action for these effects."

Acute Lung Injury • Acute Respiratory Distress Syndrome • Respiratory Diseases • MAPK14 • TNFA

First-in-class mitogen-activated protein kinase (MAPK) p38α: MAPK-activated protein kinase 2 dual signal modulator with anti-inflammatory and endothelial-stabilizing properties. (PubMed, J Pharmacol Exp Ther) - "To overcome its limited aqueous solubility and p38α binding affinity, we designed an analog of UM101, GEn-1124, with improved aqueous solubility, stability, and p38α-binding affinity...SIGNIFICANCE STATEMENT: We describe a novel analog of our first-in-class small molecule modulator of p38α/MK2 signaling targeted to a pocket near the glutamate-aspartate-containing substrate binding domain of p38α, which destabilizes the p38α:MK2 complex without blocking p38 catalytic activity or ablating downstream signaling. The result is a rebalancing of downstream proinflammatory and anti-inflammatory signaling, yielding anti-inflammatory, endothelial-stabilizing, and lung-protective effects with therapeutic potential in acute respiratory distress syndrome."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Influenza • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases

First-in-Class Mitogen-Activated Protein Kinase p38α: MAPK-Activated Protein Kinase-2 (MK2) Dual Signal Modulator with Anti-inflammatory and Endothelial-stabilizing Properties. (PubMed, J Pharmacol Exp Ther) - "To overcome its limited aqueous solubility and p38a binding affinity, we designed an analog of UM101, GEn-1124, with improved aqueous solubility, stability, and p38a binding affinity...Significance Statement We describe an analog of our first-in-class small molecule modulator of p38a/MK2 signaling targeted to a pocket near the ED substrate binding domain of p38a, which destabilizes the p38a:MK2 complex without blocking p38 catalytic activity or ablating downstream signaling. The result is a rebalancing of downstream pro- and anti-inflammatory signaling, yielding anti-inflammatory, endothelial-stabilizing, and lung-protective effects with therapeutic potential in ARDS."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Developmental Disorders • Infectious Disease • Inflammation • Influenza • Pneumonia • Respiratory Diseases

A Study of GEn-1124 in Subjects With Acute Respiratory Distress Syndrome (ARDS) (clinicaltrials.gov) - P2 | N=52 | Recruiting | Sponsor: GEn1E Lifesciences | Trial completion date: Jul 2024 ➔ Dec 2025 | Trial primary completion date: May 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases • IL10 • IL1B • IL6 • TNFA

Novel Next-generation Non-catalytic P38alpha/MK2 Immunomodulators With Endothelial-barrier-stabilizing and Anti-inflammatory Activity (ATS 2024) - "A next-generation analog with modifications on the first and third ring, GEn1124, has improved anti-inflammatory and endothelial barrier-stabilizing activity, is lung protective in mouse models of influenza and ARDS, and is currently in a Phase II clinical trial in ARDS... We have developed two novel next-generation analogs of the noncatalytic p38akpha/MK2 inhibitor UM101 that demonstrate anti-inflammatory actions and endothelial barrier-stabilizing activity greater than the parent compound."

Immunomodulating • Acute Respiratory Distress Syndrome • Infectious Disease • Influenza • Respiratory Diseases • CSF2 • CXCL5 • DUSP1 • DUSP2 • MAPK14 • TNFA

The Novel Mechanism of Action of GEn-1124, A Next-generation Non-catalytic P38alpha/MK2 Signal Modifier With Endothelial-barrier-stabilizing, Anti-inflammatory, and Lung-protective Activities (ATS 2024) - P2 | "Following cell activation, p38 is phosphorylated then translocates into the nucleus where it phosphorylates MK2. There the complex of p38:MK2 is rapidly exported to the cytoplasm, thereby ending anti-inflammatory intranuclear p38 signaling and increasing pro-inflammatory cytoplasmic MK2 signaling. GEn-1124 modifies the p38alpha/MK2 signal in a novel way, through disruption of the p38:MK2 complex, leading to dissocation and nuclear export of MK2 without p38."

Acute Respiratory Distress Syndrome • Infectious Disease • Influenza • Pulmonary Disease • Respiratory Diseases • MAPK14 • SPR

Identification of Small Molecules Targeting One of the P38alpha MAPK Substate-docking Domains With Endothelial-Barrier-Function-stabilizing and Immunomodulatory Activity (ATS 2023) - "Introduction: Using Computer-aided drug design (CADD), we identified a small molecule, UM101, targeted to the ED substrate-docking domain of p38alpha MAPK and developed a second-generation UM101 analog, GEn-1124 with improved lung-protective activity... Using our strategy of targeting the substrate-docking domains of p38alpha, we have identified additional lead compounds with endothelial barrier-stabilizing, lung-protective activity, and novel anti-inflammatory activities."

Immunomodulating • Acute Lung Injury • Immune Modulation • Infectious Disease • Influenza • Respiratory Diseases • CXCL3 • DUSP1 • IL7 • MAPK11 • MAPK14 • SOCS2 • TNFA

A Novel Non-catalytic p38alpha/MK2 Pathway Modulator Mitigates Acute Lung Injury and Improves Survival in a Mouse Influenza Model (ATS 2023) - "The novel selective p38alpha/MK2 immunomodulator, GEn1124, is effective treatment for influenza pneumonia and acute lung injury in mice."

Preclinical • Acute Lung Injury • Immune Modulation • Infectious Disease • Influenza • Pneumonia • Respiratory Diseases • MAPK14

A Novel Next-generation Non-catalytic P38alpha/MK2 Immunomodulator With Endothelial-Barrier-Stabilizing and Anti-inflammatory Activity Mitigates LPS-induced Acute Lung Injury (ALI) (ATS 2023) - "The novel p38alpha/MK2 modulator, GEn-1124, exerts lung-protective effects that improve survival in the mouse LPS-induced ALI model."

Immunomodulating • Acute Lung Injury • Immune Modulation • Respiratory Diseases • CSF2 • CXCL10 • DUSP4 • MAPK14 • TLR2 • TNFA • VCAM1

A Study of GEn-1124 in Subjects With Acute Respiratory Distress Syndrome (ARDS) (clinicaltrials.gov) - P2 | N=52 | Recruiting | Sponsor: GEn1E Lifesciences | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases

A Study of GEn-1124 in Subjects With Acute Respiratory Distress Syndrome (ARDS) (clinicaltrials.gov) - P2 | N=52 | Not yet recruiting | Sponsor: GEn1E Lifesciences

New P2 trial • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases