Evaluation of TRB-N0224, a Proprietary Chemically-Modified Curumin, for the Treat

描述（由申请人提供）：特拉弗斯生物科学公司是一家临床前药物开发公司，致力于商业化新的化学实体，通过病理不受约束的基质金属蛋白酶（MMPs）和促炎细胞因子的多效宿主调节来解决炎症状况。该公司的主要候选药物TRB-N0224是一种专有的化学改性姜黄素，由Periostat(R)和Oracea(R)的共同发明者开发，目前是fda批准的唯一MMP抑制剂。骨关节炎（OA）是最常见的关节疾病，也是老年人致残的主要原因。骨性关节炎目前影响了2700万美国人，其特征是关节软骨的进行性破坏和细胞外基质的丧失。目前的治疗方法

DESCRIPTION (provided by applicant): 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. Osteoarthritis [OA] is the most common form of joint disease and a leading cause of disability in the elderly. OA currently affects 27M Americans, and it is characterized by progressive destruction of the articular cartilage and loss of its extracellular matrix. Current treatments for OA involve pain relief and anti-inflammatory compounds to increase tolerance for daily activities. However, available therapies are primarily palliative, have low efficacy and fail to prevent progression. Moreover, current therapeutics can lead to severe side effects and consequently limit long term use. 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 tetracycline's, 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 OA. 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 an injury-induced rabbit model of OA. Our Phase I Hypothesis is that administration of TRB-N0224 will protect articular cartilage from MMP damage in an injury-induced rabbit model of osteoarthritis, and lower the tissue levels of pro-inflammatory mediators. Our specific aims are to (a) evaluate the effectiveness of our lead compound, TRB-N0224, in preventing the progression of OA using the rabbit ACL transection model, as measured by histology, biomechanics and aggrecan content, and (b) determine and measure the ability of our lead compound, TRB-N0224, to inhibit the levels of pro-inflammatory mediators associated with osteoarthritis. 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 OA. We hope to commercialize TRB-N0224 as an FDA-approved pharmaceutical intervention for the treatment of OA in both an oral and intraarticular formulations, and intend to pursue pre-clinical and clinical development to demonstrate the safety and efficacy of this lead drug candidate.