PROJECT SUMMARY In the U.S., over 20,000 heart transplants are needed each year, but fewer than 4,000 procedures are performed despite the yearly availability of more than 12,000 donors. This gap exists because 6 hearts from every 10 organ donors are unused. The vast majority of eligible donor hearts are rejected because the transport time is limited to 4 hours. To address this unmet need, Nour Heart developed and patented the bioenergetic cardioprotective drug, Nourexal™ (Cyclocreatine Phosphate (CCrP)), which was recently granted FDA Orphan Drug Designation for “Prevention of Ischemic Injury to Enhance Cardiac Graft Recovery and Survival in Heart Transplantation” (DRU-2015-4951). CCrP enhances myocardial energy stores during ischemia, reduces cell injury, inhibits inflammation and fibrosis, and restores normal cardiac function after extended cold storage of rat and dog hearts. Further, injection of CCrP (1.2 gm/kg) into rat donors, protected hearts during harvesting and allowed prolonged storage for 22 hours with full recovery of surgically grafted hearts for 3 days. In this two-year Direct-to-Phase II SBIR project, Nour Heart, Inc. (NHI) will prepare and file an Investigational New Drug (IND) for FDA approval to initiate CCrP Phase I safety trial in human healthy volunteers. Based on the FDA response to NHI’s Pre-IND application (PIND 125867), we will: 1) produce Good Manufacturing Practice (GMP) grade CCrP and determine its Chemistry Manufacturing and Controls (CMC) (Aim 1); 2) conduct FDA- recommended, IND-enabling CCrP preclinical safety studies in rats, dogs, and human unused cadaver donors (UCDs) (Aim 2) (initial rat studies indicated that CCrP is a safe drug); 3) conduct a pilot in vivo efficacy study in pigs to confirm the ability of CCrP to safely extend cold storage time of pig hearts to 6 hours before surgically transplanting the graft into recipient pigs (Aim 3). This pig study will be overseen by Dr. O.H. Frazier at the Texas Heart Institute to test the therapeutic benefits of our patented “three-step clinical protocol” where CCrP will be administered only once to heart donors and not to recipients; and 4) prepare CCrP Phase I safety protocol, investigational brochure, as well as assemble and file Nour Heart’s IND application to the FDA for an indication for end-stage heart failure patients scheduled for heart transplantation procedures (Aim 4). We expect CCrP to be safe in rats, dogs, and human unused cadaver donors and can preserve cardiac function in the pig heart transplantation model. As a novel bioenergetic cardioprotective drug, CCrP will potentially increase the time and distance that the hearts can be transported, thus extending transplantation to eligible recipient candidates located outside the current 4-hour transport limit. Upon successful completion of this project, Nour Heart plans to commercialize CCrP by raising capital to conduct CCrP Phase I safety trial, via two venture capital groups, who have indicated interes...