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: 8731205
• 负责人: Himashinie Diyabalanage
• 金额: $ 64.12万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731205
• 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发病率的急剧增加正在增加慢性肝病的患病率。由于 I 型胶原蛋白在实质中过度沉积而引起的肝纤维化，发生在大多数类型的肝损伤的晚期阶段，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、监测和治疗决策依赖于对纤维化程度的精确估计。由于金标准肝活检是侵入性的，容易出现采样误差且不适合疾病监测，因此对无创分期和监测疾病的方法仍有大量未满足的医疗需求。我们的目标是通过进一步优化和开发我们先进的原型探针 CM-65，将肝纤维化成像的非侵入性方法推向临床，CM-65 是一种基于钆 (Gd) 的磁共振成像 (MRI) 造影剂，可与类型特异性结合我用胶原蛋白来成像纤维化。这种新型药物与纤维化组织结合时，信号强度显着且持续增加，我们提供的临床前动物数据证明了 MRI 使用胶原蛋白特异性钆基药物识别和分期纤维化的可行性。这一 I/II 期应用的目标是鉴定和临床前开发一种新型胶原蛋白靶向纤维化成像探针，该探针针对体内与纤维化的结合进行了优化 组织，并且具有适合最终转化为人体临床试验的安全性和药代动力学特征。在第一阶段（目标 1）中，我们将鉴定新的探针，即我们的先导化合物 CM-65 的类似物，具有更高的胶原亲和力和改进的 Gd 消除。在体外效力提高的门控事件之后，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有效性（目标 2）。安全性和有效性的初步体内筛选将用于确定临床开发候选药物，并将进一步评估该化合物的安全性。该开发候选药物通过 MRI 无创分期纤维化的能力将在两个正交动物疾病模型中得到充分评估。