Proof of concept and dose response of CAM-6019 for HFrEF patients

PROJECT SUMMARY The leading cause of mortality worldwide is cardiovascular disease. Ischemic or non-ischemic cardiac events, such as myocardial infarction (MI), hypertension, or genetic disorders lead to a chronic deficit between cardiac capacity and an individuals’ demands, termed chronic heart failure (CHF)/heart failure (HF). Of US patients, 6.2 million had heart failure in 2016, with this number estimated to reach over 8 million between 2028 and 2030. The current standard of care for patients with cardiovascular disease is focused on secondary prevention, either by managing risk factors prior to development of HF or preventing further deterioration in diagnosed patients by managing their symptoms (e.g. reducing hypertension). Unfortunately, the mammalian adult heart does not regenerate, so there is no replacement for cardiomyocytes after cell death. Currently, there is no approved regenerative/reparative therapy that may improve HF patients’ cardiac function and reduce mortality. In this application, we propose an innovative therapy, based on the mechanisms of endogenous neonatal cardiac regeneration, that is designed to protect the cardiac tissue, reduce adverse remodeling, and allow for cardiac regeneration. Lessons learned from comparing neonatal, regenerating hearts to adult non-regenerating ones revealed a conserved protein, Agrin, that is sufficient and essential for cardiac regeneration. Utilizing recombinant human Agrin (rhAgrin; CAM-6019) and introducing it to the injured heart leads to improvement in cardiac function and reduction of scar tissue in several preclinical models of acute myocardial infarction and HF, which suggest it as a new promising regenerative therapeutic approach to improve HF patients’ quality of life and reduce morbidity and mortality. In this SBIR Direct to Phase II project, we aim to conduct pre-clinical studies required to demonstrate CAM-6019 efficacy and dose response in treating HF. Porcine studies will allow Velakor to submit an IND for CAM-6019 as a treatment for HF patients and promote HF clinical trials in humans. In these Phase II studies, we will: 1) establish the efficacy and dose response (defining the ideal dose for future clinical trials) of CAM-6019 in the pig HF model, and 2) evaluate the effect of CAM-6019 on biomarkers which indicate that CAM-6019 is indeed affecting the heart. In these studies, we will administer our drug intravenously and use imaging, histology (echocardiography and cMRI) and plasma biomarkers to determine the drug’s impact on the heart. Conducting these studies will allow us to demonstrate how CAM-6019 improves heart function and allows for reverse remodeling of the heart, define the relevant dose levels for clinical trials as well as identify a bloodborne biomarker that will indicate a positive effect of CAM-6019 on adverse remodeling. Clinical trials resulting from these studies would support the drug approval, potentially reducing the burden of HF healthcare by reducing morbidity and mortality.