This application focuses on initial preclinical steps required to develop Poloxamer-188 (P-188) for the treatment of heart failure (HF) associated with Duchene and Becker Muscular Dystrophy (MD). Dr. Joe Metzger and colleagues (Yasuda et al., 2005) demonstrated that P-188 seals microscopic membrane tears in cardiac muscle cells from mdx mice, a MD model, prevents the influx of calcium and decreases the tension developed during passive stretch of cardiomyocytes. In mdx mice, P-188 normalized cardiac hemodynamics as evidenced by a rightward shift in PV loops indicating that cardiac muscle was able to relax more completely. Further it protected mdx mice from contraction-induced damage as dramatically evidenced by significantly improved survival of mice during a dobutamine challenge. P-188 has been in over 2000 patients clinically for treatment of vaso-occlusive crisis in sickle cell disease or for acute MI. P-188 was shown to be relatively safe and adverse effects were monitorable and reversible upon discontinuation of therapy. Here, Phrixus proposes to determine the dose-range of P- 188 over which improved hemodynamics occur (normalization of LVEDV), determine the duration of action of a single dose of P-188, and confirm the putative mechanism of action of P-188 in vivo. The dose-response study will aid in determining dosing for other development activities, such as chronic toxicology studies, and to aid in the prediction of effective dosing in clinical studies. The duration of action study will help in the design of other development activities and suggest whether or not P-188, an i.v. delivered compound, will be commercially viable as a chronic therapy. The mechanism of action study is designed to confirm that microscopic membrane tears occur in cardiomyocytes of mdx mouse hearts in vivo, and show whether or not these tears can be sealed by P- 188. The data from these experiments will form part of an IND application. Since this model and patients with MD-associated HF also have skeletal muscle membrane tears, work done in other HF models cannot be applied to MD. In Phase II of this application, Phrixus will do a GLP chronic (6 month) toxicology study of P-188 in a rodent model, and examine the effects of chronic dosing in both the mdx mouse and the GRMD dog model of muscular dystrophy (with Dr. Metzger). Phrixus will seek funding from venture capital funds for clinical development.
This project concerns the development of Poloxamer-188 for the treatment of heart failure associated with muscular dystrophy (MD) . If successful this project will result in a drug that will extend the life of many boys afflicted with MD by slowing down cardiac muscle damage and cardiac muscle wasting. It may also be used to treat a genetic form of heart failure, seen at high prevalence, in the mothers of boys with MD.
