Optimization of Efficacy and Safety Pharamacology of Fibrosis Imaging Agent CM-65

纤维化显像剂CM-65的疗效和安全性药理学优化

• 批准号: 8626513
• 负责人: Thomas James McMurry
• 金额: $ 57.93万
• 依托单位: COLLAGEN MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626513
• 关键词: Acute; Affinity; Alcoholic Liver Diseases; Animal Disease Models; Animals; Autopsy; Binding; Biochemical Markers; Biodistribution; Biological Markers; Blood; CCL4 gene; Carbon Tetrachloride; Chelating Agents; Clinic; Clinical; Clinical Trials; Collagen; Collagen Type I; Contrast Media; Data; Deposition; Detection; Development; Diabetes Mellitus; Discrimination; Disease; Dose; Drug Kinetics; Event; Fibrosis; Gadolinium; Gadolinium DTPA; Goals; Gold; Hepatitis C; Histology; Human; Hydroxyproline; Image; In Vitro; Incidence; Lead; Ligation; Liver Fibrosis; Liver diseases; Magnetic Resonance Imaging; Measurement; Medical; Metabolic; Metabolic syndrome; Methods; Modeling; Monitor; Mus; Obesity; Patients; Phase; Prevalence; Rattus; Resolution; Risk; Rodent Model; Safety; Sampling Errors; Series; Signal Transduction; Specificity; Staging; Tissues; Toxic effect; Translations; analog; animal data; base; bile duct; chronic liver disease; gadolinium oxide; imaging probe; improved; in vivo; liver biopsy; liver injury; nonalcoholic steatohepatitis; nonhuman primate; novel; outcome forecast; pre-clinical; prototype

DESCRIPTION (provided by applicant): Dramatic increases in the incidence of obesity, diabetes, and the metabolic syndrome are increasing the prevalence of chronic liver diseases. Liver fibrosis arising from an excessive deposition of type I collagen in the parenchyma, occurs in advanced stages of most types of liver injury such as hepatitis C, alcoholic liver disease and nonalcoholic steatohepatitis. Prognosis, surveillance, and treatment decisions in patients with chronic liver disease rely on a precise estimation of the degree of fibrosis. There remains a large unmet medical need for a noninvasive method to stage and monitor disease, as the gold standard liver biopsy is invasive, subject to sampling error and not suitable for disease monitoring. We aim to advance a non-invasive method to image liver fibrosis into the clinic by further optimizing and developing our advanced prototype probe, CM-65, a gadolinium (Gd)-based magnetic resonance imaging (MRI) contrast agent that binds specifically to type I collagen to image fibrosis. This novel agent provides a conspicuous and persistent increase in signal intensity when bound to fibrotic tissue, and we present preclinical animal data demonstrating the feasibility of MRI to identify and stage fibrosis with a collagen specific Gd-based agent. The goal of this Phase I/II application is identification and preclinical development of a new collagen-targeted fibrosis imaging probe that is optimized for in vivo binding to fibrotic tissue and that has a safety and pharmacokinetic profile suitable for ultimate translation to human clinical trials. In Phase I (Aim 1) we will identify new probes, analogs of our lead compound CM-65, with higher collagen affinity and improved Gd elimination. After this gating event of improved in vitro potency, we will evaluate these probes for safety and efficacy in rodent models of liver fibrosis (Aim 2). Primary in vivo screens of safety and efficacy will be used to identify a clinical development candidate and the safety of this compound will be further evaluated. The ability of this development candidate to noninvasively stage fibrosis by MRI will be fully evaluated in two orthogonal animal models of disease.

描述（由申请人提供）：肥胖，糖尿病和代谢综合征的发生率的急剧增加正在增加慢性肝病的患病率。肝纤维化是由实质中I型胶原蛋白过度沉积产生的，发生在大多数类型的肝炎的晚期阶段，例如丙型肝炎，酒精性肝病和非酒精性脂肪性肝炎。慢性肝病患者的预后，监测和治疗决策取决于纤维化程度的精确估计。由于黄金标准肝活检具有侵入性，但要遭受采样误差，并且不适合疾病监测，因此仍然需要对疾病进行非侵入性方法的未满足医学需求。我们旨在通过进一步优化和开发我们的先进原型探针CM-65（基于gd）的gadolinium（GD）基于磁共振成像（MRI）对比剂，将我们的先进原型探针CM-65（MRI）对比剂进一步优化和开发，将非侵入性方法提高到诊所中，该探针特异性结合了I型胶原型胶原蛋白纤维化。当与纤维化组织结合时，这种新型药物提供了信号强度的显着且持续的增加，我们提供了临床前动物数据，证明了MRI可与基于胶原蛋白的基于GD的剂鉴定和分期纤维化的可行性。 I/II阶段应用的目的是鉴定和临床前开发新的胶原蛋白靶向纤维化成像探针，该探针可在体内与纤维化结合进行优化 组织具有安全性和药代动力学特征，适合于最终转化为人类临床试验。在第一阶段（AIM 1）中，我们将确定具有较高胶原蛋白亲和力和改善GD消除的铅化合物CM-65的新探针，类似物。在这一提高体外效力的门控事件之后，我们将评估这些探针在肝纤维化啮齿动物模型中的安全性和功效（AIM 2）。将使用安全性和功效的主要体内筛选来识别临床发育候选者，该化合物的安全将得到进一步评估。在两种正交动物模型的疾病模型中，将对这种发育候选者通过MRI进行非侵入性纤维化的能力进行全面评估。