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

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。肝纤维化是由I型胶原在肝实质过度沉积引起的，发生在大多数类型的肝损伤的晚期，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准确估计。对于一种非侵入性的方法来分期和监测疾病，仍然有大量的医学需求没有得到满足，因为黄金标准的肝活检是侵入性的，容易受到抽样误差的影响，不适合于疾病监测。我们的目标是通过进一步优化和开发我们的先进原型探针CM-65来推动一种非侵入性的肝纤维化成像方法进入临床，CM-65是一种基于Gd的磁共振成像(MRI)造影剂，专门结合I型胶原来成像纤维化。这种新的试剂在与纤维组织结合时提供了显著和持续的信号强度增加，我们提供了临床前的动物数据，证明了利用胶原特异性Gd试剂进行MRI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的胶原靶向纤维化成像探针，该探针优化了体内与纤维化的结合 该药物具有安全性和药代动力学特征，适合最终转化为人体临床试验。在第一阶段(目标1)，我们将确定新的探针，类似于我们的先导化合物CM-65，具有更高的胶原亲和力和改进的Gd消除。在这一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，该化合物的安全性将得到进一步评估。将在两个正交的疾病动物模型中充分评估这一开发候选对象通过MRI非侵入性分期纤维化的能力。

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.