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脏疾病的患病率。由实质中I型胶原过度沉积引起的肝纤维化发生在大多数类型的肝损伤的晚期，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。对于分期和监测疾病的非侵入性方法，仍然存在大量未满足的医疗需求，因为金标准肝活检是侵入性的，易受采样误差的影响，并且不适合于疾病监测。我们的目标是通过进一步优化和开发我们的先进原型探头CM-65，一种基于钆（Gd）的磁共振成像（MRI）造影剂，可特异性结合I型胶原蛋白以成像纤维化，从而将一种非侵入性方法用于临床肝纤维化成像。这种新的代理商提供了一个显着的和持久的信号强度增加时，绑定到纤维化组织，我们目前的临床前动物数据证明MRI的可行性，以确定和阶段纤维化与胶原蛋白特异性Gd为基础的代理。该I/II期申请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，该探针被优化用于体内结合纤维化蛋白。 组织，并且具有适合于最终转化为人类临床试验的安全性和药代动力学特征。在第一阶段（目标1），我们将确定新的探针，我们的领先化合物CM-65的类似物，具有更高的胶原蛋白亲和力和改善的Gd消除。在体外效价提高的门控事件后，我们将在啮齿动物肝纤维化模型中评价这些探针的安全性和有效性（目的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，并将进一步评价该化合物的安全性。将在两种正交疾病动物模型中充分评价该开发候选物通过MRI对纤维化进行非侵入性分期的能力。

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.