This Administrative Supplement is for Aim 2C (boldface font) that is focused on testing efficacy of a protein inhibitor of galectin-3 in an ischemia/reperfusion (I/R) miniswine model of myocardial infarction (MI). In the Specific Aims for the Phase II project (Aims 2-4 shown below) we are testing efficacy in animal models of MI, performing pharmacokinetics and toxicology, and developing GLP/GMP manufacturing processes.
Aim 2. To better understand efficacy of Gal-3C therapy in animal models. 2A. Determine efficacy and optimal dosage of Gal-3C in rat I/R MI model. 2B. Determine efficacy of Gal-3C in comparison to mineralocorticoid receptor antagonist (MRA) and in combination with ARB in rat I/R MI model. 2C. Determine efficacy of Gal-3C in miniswine I/R model of MI.
Aim 3. To develop GLP/GMP production methods and a formulation for Gal-3C.
Aim 4. To perform pharmacokinetic studies and acute/subacute toxicology in rats. In Phase I, we found that in rats treated with our protein inhibitor of galectin-3 there was a very statistically significant reduction (P < 0.001) in left ventricular end diastolic volume (EDV) at 56 days, but no improvement at 28 days. The response to injury takes a longer time in larger animals. Based on our Phase I results, we will increase total treatment and observation period to 3 months (90 days) in the miniswine I/R model to detect a reduction in EDV. There is a greater likelihood today that in Phase II clinical trials FDA would accept infarct size, which can be determined from cardiac magnetic resonance (CMR), as a surrogate endpoint rather than only LV volume and ejection fraction, which can be quantified by echocardiography, than there was when we submitted the Fast Track application two years ago. Thus, in analysis of the miniswine, we will use CMR imaging, which that can determine primary infarct size as well as ejection fraction and EDV because in filing an Investigational New Drug application these data could better inform FDA regarding the potential efficacy in humans.
The overall goal of this project is to develop a protein inhibitor of galectin-3 as a biologic to prevent and treat harmful remodeling after myocardial infarction and, thereby, improve cardiac function and reduce mortality from subsequent heart failure. Myocardial infarction is the most common cause of cardiac morbidity and mortality in the western world. The annual incidence in the United States is 610,000 new attacks and 325,000 recurrent attacks. Because current standard practice of minimizing time from onset of myocardial infarction to re-opening of the blocked artery has greatly reduced the incidence of death from acute myocardial infarction, heart failure subsequent to myocardial infarction has become the main mortality associated with coronary events.
