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

描述（由申请人提供）：肥胖症、糖尿病和代谢综合征的发病率急剧增加，慢性肝病的患病率也在增加。肝纤维化是由I型胶原在实质中过度沉积引起的，发生在大多数类型肝损伤的晚期，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精确估计。由于金标准肝活检是侵入性的，容易产生采样误差，不适合疾病监测，因此对非侵入性疾病分期和监测的医学需求仍未得到满足。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，将一种无创的肝纤维化成像方法推向临床，CM-65是一种基于钆（Gd）的磁共振成像（MRI）造影剂，可以特异性地结合I型胶原蛋白来成像纤维化。当这种新型药物与纤维化组织结合时，信号强度会显著而持续地增加，我们提出了临床前动物数据，证明了MRI用胶原特异性Gd-based药物识别和分期纤维化的可行性。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，该探针可在体内与纤维化结合

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.