Traverse Biosciences Inc. is a pre-clinical stage drug development company working to commercialize new chemical entities which act to resolve inflammatory conditions through pleiotropic host-modulation of pathologically unrestrained matrix metalloproteinases (MMPs) and pro-inflammatory cytokines. The company's lead drug candidate, TRB-N0224, is a proprietary chemically modified curcumin developed by the co-inventor of Periostat(R) and Oracea(R), currently the only FDA-approved MMP inhibitors. Periodontal disease is a chronic inflammatory condition involving interactions between oral bacterial products, numerous cell populations in the host tissues, and inflammatory mediators, such as cytokines, chemokines, arachidonic acid metabolites and proteolytic enzymes (including matrix metalloproteinases), which collectively contribute to tissue destruction and bone resorption. The Centers for Disease Control (CDC) estimates that the prevalence of periodontitis in U.S. adults aged 30 years and older is 47.2% (64.7M), and the prevalence of mild, moderate, and severe periodontitis is 8.7% (11.9M), 30.0% (41.1M), and 8.5% (11.7M), respectively. Periodontal disease has also been associated with other chronic conditions such as heart disease, diabetes, and various cancers. Most current drug therapies are primarily focused on the management of the microbial biofilm, not taking into account the central role of inflammation in causing tissue damage, which makes this therapy only partly effective. TRB-N0224 exhibits pleiotropic anti-inflammatory effects as a broad-spectrum MMP modulator, as well as an inhibitor of pro-inflammatory cytokines such as IL1-b, TNF-a, and IL-6, likely through interruption of the NF-kB pathway. TRB-N0224 acts to resolve inflammation via a multi-target, host-modulatory approach that overcomes the challenges of redundancy, compensation and necessity exhibited by the immune system Curcumin was chosen as a parent structure because it also has a 1,3-diketo moiety similar to that of the tetracyclines, and chemical modifications were pursued to overcome limited clinical use of curcumin due to its insolubility, rapid metabolism and modest biological activity. Our long-term goal is to develop an effective inhibitor of inducible MMPs with minimal side effects and toxicity that will significantly reduce the complications associated with periodontal disease. The objective here, which is the next step in the pursuit of our goal, is to test the efficacy of our lead compound, TRB-N0224, in a LPS-induced rat model of periodontal disease. Our Phase I Hypothesis is that administration of TRB-N0224 will protect alveolar bone from MMP damage in a LPS-induced rat model of periodontal disease, and lower the gingival tissue and serum levels of pro- inflammatory mediators. Our specific aims are to evaluate the effectiveness of our lead compound, TRB- N0224, to prevent and treat periodontal disease using a LPS-induced rat model. Bone loss will be determined by measuring the distance from a fixed anatomical landmark, the cemento-enamel junction, to the alveolar bone crest, and levels/activity of MMPs and inflammatory cytokines will also be assessed. Successful completion of Phase I will allow us to pursue Phase II funding to support pre-clinical testing of TRB-N0224, utilizing a clinically applicable canine model of periodontal disease. We hope to commercialize TRB-N0224 as an FDA-approved pharmaceutical intervention for the treatment of periodontal disease in an orally-administer (i.e. systemic) formulation, and intend to pursue pre-clinical and clinical development to demonstrate the safety and efficacy of this lead drug candidate.
Public Health Relevance Statement: Public Health Relevance: The Centers for Disease Control (CDC) estimates that the prevalence of periodontitis in U.S. adults aged 30 years and older is 47.2% (64.7M), and the prevalence of mild, moderate, and severe periodontitis is 8.7% (11.9M), 30.0% (41.1M), and 8.5% (11.7M), respectively. Periodontal disease has also been associated with other chronic conditions such as heart disease, diabetes, and various cancers. This proposed project is directly relevant to the public health, since it is to develop a promising new drug candidate for the treatment of this critical unmet medical need. Moreover, the drug candidate has also shown promise in a variety of other disease areas related to chronic inflammation, demonstrating the potential for broad application and societal benefit if proven to be both safe and effective.
Project Terms: Accounting; Active Sites; Adult; Adverse effects; aged; alveolar bone; Alveolar Bone Loss; analog; Anti-inflammatory; Anti-Inflammatory Agents; Arachidonic Acids; Area; Attenuated; Biological; bone loss; Bone Matrix; Bone Resorption; Canis familiaris; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; chemokine; Chronic; Cleaved cell; Clinical; Collagen; commercial application; Connective Tissue; Curcumin; cytokine; Degenerative polyarthritis; Dental Enamel; Development; Diabetes Mellitus; Disease; drug candidate; drug development; Drug Formulations; Effectiveness; efficacy testing; Elastin; Enzymes; Evaluation; Exhibits; FDA approved; Financial compensation; Funding; Gelatin; Gingiva; Gingivitis; Goals; Heart Diseases; Immune system; Inflammation; Inflammation Mediators; Inflammatory; inhibitor/antagonist; Interleukin-1; Interleukin-6; Interruption; Intervention; Knowledge; Lead; Left; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Medical; Metabolism; Microbial Biofilms; Modeling; Modification; Molecular; NF-kappa B; Oral; Outcome; Parents; Pathway interactions; Peptide Hydrolases; Periodontal Diseases; Periodontitis; Periostat; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; phenylamide; Physiological; Population; pre-clinical; Prevalence; prevent; Preventive Intervention; Property; Proteoglycan; public health medicine (field); public health relevance; Rattus; research clinical testing; Role; Safety; Serum; Staging; Structure; Tetracyclines; Tissues; Toxic effect; Tumor Necrosis Factor-Beta; Work; Zinc
