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

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 theparenchyma, 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 toadvance 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 improvedin 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. PUBLIC HEALTH RELEVANCE: Liver fibrosis occurs in advanced stages of mosttypes of liver injury such as hepatitis C, alcoholic liver disease and now increasingly metabolic syndrome (obesity and diabetes). The goal of this application is optimization and preclinical development of a new gadolinium-based collagen-targeted imagingprobe for noninvasive magnetic resonance imaging measurement of liver fibrosis so as to assess liver disease in patients without the need for liver biopsy.