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

TRB-N0224（一种专有的化学改性姜黄素）治疗效果的评估

• 批准号: 8781389
• 负责人: DANIEL A. GRANDE
• 金额: $ 22.38万
• 依托单位: TRAVERSE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781389
• 关键词: Active Sites; Adult; Adverse effects; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Biological; Biomechanics; Canis familiaris; Cartilage; Cartilage Matrix; Categories; Characteristics; Chemicals; Chronic; Cleaved cell; Clinical; Collagen; Connective Tissue; Curcumin; Degenerative polyarthritis; Development; Disease; Drug Formulations; Effectiveness; Elastin; Elderly; Enzymes; Etiology; Evaluation; Exhibits; Extracellular Matrix; FDA approved; Financial compensation; Funding; Gelatin; Goals; Hand; Hip region structure; Histology; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-1; Interleukin-6; Interruption; Intervention; Joints; Knee; Knowledge; Lead; Left; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Medical; Metabolism; Modeling; Modification; NF-kappa B; Natural regeneration; Oral; Oryctolagus cuniculus; Outcome; Pain; Parents; Pathway interactions; Periostat; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Population; Preventive Intervention; Property; Proteoglycan; Public Health; Safety; Staging; Structure; Symptoms; Tetracyclines; Therapeutic; Tissues; Toxic effect; Tumor Necrosis Factor-Beta; Vertebral column; Woman; Work; Zinc; aggrecan; analog; arthropathies; articular cartilage; bone; commercial application; cytokine; disability; drug candidate; drug development; efficacy testing; foot; inhibitor/antagonist; innovation; palliative; phenylamide; pre-clinical; prevent; public health relevance; research clinical testing; skeletal disorder

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.

描述(申请人提供)：TraVerse生物科学公司是一家临床前阶段的药物开发公司，致力于将新的化学实体商业化，这些化学实体通过对病理上不受限制的基质金属蛋白酶(MMPs)和促炎细胞因子的多效性宿主调节来化解炎症状况。该公司的主要候选药物TRB-N0224是由Periostat(注册商标)和Oracea(注册商标)的共同发明人开发的一种经过化学修饰的专有姜黄素。Periostat(注册商标)和Oracea(注册商标)目前是FDA批准的唯一一种基质金属蛋白酶抑制剂。骨性关节炎是最常见的关节疾病，也是导致老年人残疾的主要原因。骨关节炎目前影响2700万美国人，其特征是关节软骨进行性破坏和细胞外基质丢失。目前的治疗方法 骨性关节炎包括止痛和抗炎化合物，以增加对日常活动的耐受性。然而，现有的治疗方法主要是姑息治疗，疗效较低，无法阻止病情进展。此外，目前的治疗方法可能会导致严重的副作用，从而限制长期使用。TRB-N0224作为一种广谱的基质金属蛋白酶调节剂，以及一种促炎症细胞因子的抑制剂，如IL-1-b、TNF-a和IL-6，显示出多效性的抗炎作用，可能是通过阻断NF-kB途径实现的。TRB-N0224通过多靶点、宿主调节的方法来消除炎症，克服了免疫系统表现出的冗余、补偿和必要性的挑战。姜黄素被选为亲本结构，因为它也具有类似于四环素的1，3-二酮结构，并且寻求化学修饰来克服由于姜黄素的不溶性、快速新陈代谢和适度的生物活性而限制其临床应用。我们的长期目标是开发一种有效的诱导型MMPs抑制剂，副作用和毒性最小，从而显着减少与骨性关节炎相关的并发症。这里的目标，也是我们追求目标的下一步，是测试我们的先导化合物TRB-N0224在损伤诱导的兔OA模型中的有效性。我们的第一阶段假设是，在损伤诱导的兔骨关节炎模型中，应用TRB-N0224可以保护关节软骨免受基质金属蛋白酶的损伤，并降低促炎介质的组织水平。我们的具体目标是(A)评估我们的先导化合物TRB-N0224在通过组织学、生物力学和聚集素含量测量的兔前交叉韧带横断模型预防骨性关节炎进展方面的有效性，以及(B)确定和测量我们的先导化合物TRB-N0224抑制与骨关节炎相关的促炎介质水平的能力。第一阶段的成功完成将使我们能够继续进行第二阶段的资金，以支持TRB-N0224的临床前测试，利用临床适用的犬骨关节炎模型。我们希望将TRB-N0224作为FDA批准的用于治疗口服和关节内制剂中的骨性关节炎的药物干预措施商业化，并打算进行临床前和临床开发，以证明这种主要候选药物的安全性和有效性。

项目成果

Exploratory study for identifying systemic biomarkers that correlate with pain response in patients with intervertebral disc disorders.

• DOI: 10.1007/s12026-015-8709-2
• 发表时间: 2015-12
• 期刊: Immunologic research
• 影响因子: 4.4
• 作者: Weber KT;Satoh S;Alipui DO;Virojanapa J;Levine M;Sison C;Quraishi S;Bloom O;Chahine NO
• 通讯作者: Chahine NO

Serum levels of the proinflammatory cytokine interleukin-6 vary based on diagnoses in individuals with lumbar intervertebral disc diseases.

• DOI: 10.1186/s13075-015-0887-8
• 发表时间: 2016-01-07
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Weber KT;Alipui DO;Sison CP;Bloom O;Quraishi S;Overby MC;Levine M;Chahine NO
• 通讯作者: Chahine NO