Thetis plans to investigate TP-317, an innovative and potential first in-class therapeutic agent, as a therapy for the treatment of eosinophilic esophagitis (EoE), a chronic, atopic disease characterized by eosinophilic inflammation and tissue remodeling of the esophagus. Although the pathogenesis of EoE is not completely understood, recent evidence suggests that it results from an inappropriate immune response to food allergens in genetically-predisposed individuals. The defining histopathological feature of EoE is a dense eosinophilic infiltrate within the esophageal epithelium. If left untreated, EoE results in esophageal fibrosis and dysfunction that can significantly reduce patient quality of life. While currently-available therapies can effectively treat symptoms, they are associated with potentially serious side effects, such as infection, adrenal insufficiency and malnutrition, which can be particularly problematic for pediatric patients. Thus, EoE represents a significant unmet medical need for which new treatment strategies are needed. To address this unmet need, Thetis is developing TP-317, a unique derivative of Resolvin E1 (RvE1). RvE1 is part of a family known as specialized proresolving mediators (SPMs), a group of enzymatically hydroxylated metabolites derived from eicosapentaenoic acid. SPMs, including RvE1, are particularly important for maintaining immunological homeostasis in the gastrointestinal (GI) tract, which is constantly exposed to allergens and other inflammatory stimuli. Delivering RvE1 to the esophagus has the potential to promote the resolution of inflammation, accelerate intestinal tissue repair and minimize exposure to harmful inflammation without sacrificing host-protective functions of the innate immune system. RvE1âs inflammation-resolving properties have been validated in animal models of many inflammatory disease, including several models with pathophysiological features similar to human EoE. These studies have revealed that RvE1 promotes the resolution of inflammation by acting on many of the same pathways implicated in EoE pathogenesis. When administered prophylactically, RvE1 has been shown to potently inhibit the induction of allergic inflammation, in part by limiting the recruitment and activation of eosinophils. Importantly, Thetis has recently completed a series of preclinical studies demonstrating the ability of TP-317 to counter-regulate pathologic processes implicated in EoE, including eosinophil infiltration of the mucosa and inflammation-associated fibrosis. Using its proprietary technology platform, Thetis has chemically transformed RvE1 into TP-317, a novel salt of RvE1 that overcomes some of the key barriers that have inhibited the development of an RvE1-based agent. This SBIR Phase 1 program, conducted in collaboration with leading EoE expert Dr. Glenn Furuta (University of Colorado, Denver), will demonstrate the efficacy of TP-317 in an animal model of EoE. On completion of this project, Thetis will have demonstrated proof of concept for TP-317 in EoE and will be in a position to initiate key IND-enabling studies through a Phase 2 program.
Public Health Relevance Statement: NARRATIVE Eosinophilic esophagitis (EoE) is a growing global health problem affecting between 9.7 and 56.7 cases per 100,000 people in the US alone, and treatment are associated with significant side effects. EoE patients are in dire need of safe and effective treatment options. Thetis plans to investigate TP-317, an innovative and potential first in-class therapeutic agent, as a therapy for the treatment of EoE.
Project Terms: Abdominal Pain; active method; Address; Adrenal Cortex Hormones; Adrenal gland hypofunction; Adult; Affect; Allergens; Allergic inflammation; Animal Model; aqueous; Bacterial Antigens; base; Chemicals; Child; Chronic; Clinical; Clinical Trials; Collaborations; Colorado; Country; Data; Deglutition Disorders; Desire for food; Development; Direct Costs; Disease; Dissociation; Dose; Drug Kinetics; effective therapy; Eicosapentaenoic Acid; eosinophil; Eosinophilic Esophagitis; Eosinophilic Infiltrate; eosinophilic inflammation; Epithelium; Esophageal; Esophageal mucous membrane; Esophageal Tissue; Esophagus; Exposure to; Failure to Thrive; Family; feeding; Fibrosis; Food; food allergen; food avoidance; Formulation; Functional disorder; Gastrointestinal tract structure; Genetic Predisposition to Disease; global health; Growth and Development function; Homeostasis; Human; Iatrogenesis; IL5 gene; immune function; Immune response; Immunologics; Impairment; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammatory; innate immune function; Innate Immune System; innovation; Intellectual Property; Intestines; Intraperitoneal Injections; Investigational Drugs; Lead; Left; Life; Malnutrition; Mediator of activation protein; Medical; Modeling; Molecular; mouse model; Mucositis; novel; Oils; Omega-3 Fatty Acids; Oral; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; pediatric patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; phase 2 study; Positioning Attribute; preclinical study; Prevalence; prevent; programs; Property; prophylactic; Protocols documentation; Public Health; Quality of life; recruit; Recurrence; Reporting; Resolution; Resources; Retrospective Studies; Risk; Safety; Series; side effect; Small Business Innovation Research Grant; Sodium Chloride; Stimulus; symptom treatment; Symptoms; Technology; Therapeutic Agents; therapeutic development; tissue repair; Tissues; Toxicology; treatment strategy; United States; Universities; Vomitin
