Thetis plans to investigate TP-317, an innovative and potential first in-class therapeutic agent, as an oral therapy for the induction and maintenance of remission of intestinal inflammation symptoms in ulcerative colitis (UC) patients. While the precise etiology of UC is unknown, it is thought to result from an inappropriate inflammatory response to commensal gut bacteria in genetically susceptible individuals. Current treatment regimens for treatment of UC can be: 1) excessively broad in scope, inducing a pan-suppression of host immunity and a predisposition to infection and malignancy, and 2) not uniformly effective or durable, as evidenced by the high percentage of complications of the disease. Novel oral agents that are safe and effective for the induction and maintenance of UC remission would represent a major improvement in treatment options. TP-317 is a unique derivative of Resolvin E1 (RvE1), a metabolite of the omega-3 fatty acid, eicosapentaenoic acid (EPA). RvE1 is part of the resolvin family of specialized proresolving mediators (SPMs), a group of enzymatically hydroxylated metabolites derived from EPA. SPMs, including RvE1, are particularly important for maintaining immunological homeostasis in the gastrointestinal (GI) tract, which is constantly exposed to bacterial antigens and other inflammatory stimuli. By delivering RvE1 to the intestinal mucosa, TP- 317 has prospects to promote the resolution of inflammation, accelerate intestinal tissue repair and minimize exposure to potentially harmful inflammation without sacrificing host-protective functions of the innate immune system. RvE1 has been shown in several well-designed studies to be effective in treating UC in animal models. Through innovative medicinal chemistry, Thetis has developed proprietary technology to convert bioactive lipids into solid, stable, small molecule active pharmaceutical ingredients (APIs). Using this technology, Thetis chemically transforms RvE1 into TP-317, an innovative NME with pharmaceutical and IP credentials that represents a novel approach to immunoresolution-based therapeutics for UC. TP-317 offers several key advantages including (1) rapid dissociation in aqueous solution to deliver RvE1 as the natural material that is an endogenous mediator regulating inflammatory processes; (2) an anticipated favorable safety profile with prospects for minimal off-target effects; and (3) favorable physico-chemical properties that make TP-317 amenable to formulation as a tablet or capsule for oral administration. Phase 1 of this SBIR Fast Track will demonstrate the efficacy of oral TP-317 for the treatment of UC (Specific Aim #1) and characterize the pharmacokinetics of oral TP-317 (Specific Aim #2). Phase 2 of this project will include initial characterization of TP-317 safety and toleration (Specific Aim #3), synthesis and qualification of TP-317 for use in GLP studies (Specific Aim # 4), and conduct of full GLP toxicology and safety pharmacology studies (Specific Aim #5). On completion of this Fast-track SBIR project, Thetis will be in a position to complete CMC activities and subsequently prepare and submit an IND filing to initiate Phase I clinical studies.
Public Health Relevance Statement: NARRATIVE Ulcerative colitis (UC) is a growing global health problem affecting between 1.2 and 20.3 cases per 100,000 people in the US alone, and is a growing and significant unmet medical concern. Oral agents that are safe and effective for the induction and maintenance of UC remission are in dire need as additional treatment options, and to limit the use of drugs with potentially severe side effects. Thetis plans to investigate TP-317, an innovative and potential first in-class therapeutic agent, as an oral therapy for the induction and maintenance of remission of intestinal inflammation symptoms in UC patients. .
Project Terms: ADME Study; Adverse effects; Affect; Animal Model; Antibodies; aqueous; Bacteria; Bacterial Antigens; base; Biological Assay; Canis familiaris; capsule; Chemicals; Chronic; clinical development; Clinical Research; Colitis; Development; Disease; Disease remission; Dissociation; Dose; Drug Kinetics; Drug usage; Eicosapentaenoic Acid; Etiology; Exposure to; Family; Formulation; Future; Gastrointestinal tract structure; global health; Homeostasis; Immune system; Immunity; Immunologics; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory disease of the intestine; Inflammatory Response; innate immune function; innovation; Intestinal Mucosa; Intestines; Lipids; Maintenance; Malignant Neoplasms; Mediator of activation protein; Medical; Modeling; Mus; Neoadjuvant Therapy; No-Observed-Adverse-Effect Level; novel; novel strategies; Omega-3 Fatty Acids; Oral; Oral Administration; parenteral administration; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Phase; Positioning Attribute; Predisposition; Process; Property; Protocols documentation; Rattus; Research Design; Resolution; Risk; Safety; screening; Series; Small Business Innovation Research Grant; small molecule; Sodium Dextran Sulfate; Solid; Stimulus; Symbiosis; Symptoms; Tablets; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; tissue repair; Toxicology; Treatment Protocols; Ulcerative Colitis
