NOS Inhibitor Therapy for Cardiogenic Shock

DESCRIPTION (provided by applicant): This is a Fast-track Phase I application from ArgiNOx Inc. to develop a novel pharmacotherapy that may save lives of tens of thousands of patients that develop cardiogenic shock each year in the USA. Cardiogenic shock is lethal in an estimated 60 percent of cases, and occurs in approx. 8 percent of all patients that enter hospital emergency rooms following acute myocardial infarction (MI). Published and submitted findings by Dr. Cotter, a co-investigator in the present study, suggest that ANO-1020, an inhibitor of nitric oxide (NO) biosynthesis, can reduce the mortality of cardiogenic shock by up to 50 percent. This result is consistent with the knowledge that cardiac ischemia-reperfusion can trigger overproduction of NO, leading to a futile cascade of myocardial depression and vasodilatation. A Phase I feasibility study will test whether ANO-1020 treatment can significantly improve cardiovascular function in a cohort of 10 patients with cardiogenic shock. Patients included in this study will have been admitted to the ICU with an acute MI and not have had myocardial contractility restored, despite coronary revascularization and i.v. infusion of dopamine at a maximally-acceptable rate. The primary goal of Phase I will be to assess the extent to which low-dose ANO-1020 administration improves cardiovascular function in these patients. Phase I will also provide key pharmacokinetic information on plasma drug levels and mechanistic insight into the basis for any observed cardiovascular benefit. Achievement of clear and measurable performance milestones in Phase I will trigger the progression to a Phase II study. Phase II will be a randomized, double-blind clinical trial involving 30 cardiogenic shock patients that will test whether the cardiovascular improvement obtained with ANO-1020 treatment is significant and safe, relative to placebo. If cardiovascular benefit and safety of ANO-1020 are affirmed by Phase II studies, ArgiNOx will aggressively seek FDA approval for a planned Phase III clinical trial, assessing the 30-day all cause mortality benefit of ANO-1020 in a group of 630 patients worldwide. All studies will be performed by a highly experienced team of clinical investigators, led by Dr. Judith Hochman, coordinator of the largest team of clinical investigators to complete a cardiogenic shock trial to date. Scientists at ArgiNOx were first to administer an NO synthase inhibitor to a mammal, immediately recognizing the profound importance of NO as a key regulator of the cardiovascular system. ArgiNOx and its Advisory Board have extensive experience in the emerging field of NO biology (this includes two Scientific Advisors who were awarded Nobel Prizes for relevant discoveries), including significant first-hand clinical experience with the cardiovascular actions of ANO-1020 in critically ill patients. Over 30 issued US patents and foreign counterparts have been awarded to the ArgiNOx founding scientists for pioneering discoveries covering the present indication and mode of NO synthesis inhibition, as well as other related methods, compositions and uses for NO synthase inhibitors. Success of ANO-1020 in the proposed studies will reveal major clinical and commercialization potential.