Urocortin 2Need for New Drugs for Congestive Heart Failure (CHF)Congestive heart failure (CHF) is a condition where the heart cannot pump enough blood to supply all of the body’s organs or avoid fluid build up in the lungs. It is a result of narrowing of the arteries combined with high blood pressure, which results in increased respiration as well as edema from water retention. In the case of acute symptomology, CHF patients will eventually experience a rapid deterioration and require urgent treatment in the hospital. According to 2011 data from the American Heart Association, over 6 million people experience CHF and about 670,000 new cases are diagnosed each year in the United States. CHF becomes more prevalent with age and the number of cases is expected to grow as the overall age of the population increases. Current treatment options include a cocktail of drugs consisting of diuretics to remove excess water, beta blockers and digitalis to improve heart muscle contraction, and/or ACE inhibitors and vasodilators to expand blood vessels. According to the American Heart Association (2011), there are approximately one million hospital discharges each year in the United States for CHF. Market OpportunitiesMorbidity and mortality associated with acute CHF, especially in the months following the initial discharge from the hospital, are notoriously high and the cost to the U.S. healthcare system is more than $20 billion annually. The commercial opportunity for a new agent with a demonstrated improvement on long term morbidity and mortality associated with acute CHF is significant. Mechanism of ActionUrocortin 2 was designed to mimic the effect of the recently discovered protein urocortin 2. Urocortin 2 selectively stimulates the CRF2 receptor and can improve cardiac output with minimal increase in heart rate. It also has the potential to provide cardioprotection via a novel mechanism for regulating calcium cycling enzymes/channels in heart muscle cells. Clinical ResultsIn 2012, The Christchurch Cardioendocrine Research Group at University of Otago, Christchurch School of Medicine and Health Sciences, New Zealand, completed a pilot Phase II study of urocortin 2 in 53 patients with acute decompensated heart failure. After initial stabilization, subjects were randomized to receive a 4-hour infusion of either placebo or urocortin 2 in addition to standard-of-care treatments. Infusion of urocortin 2 was generally well tolerated and there were no treatment-related serious adverse events. The hemodynamic profile of urocortin 2 infusion was consistent with what had been established in earlier Phase I and Phase II clinical studies including improved cardiac output, reduction in peripheral vascular resistance and absence of sympathetic overstimulation. Mean arterial pressures were significantly reduced (p<0.001) from 92 +/- 3 mmHg at baseline to 80+/-3 mmHg at end of the urocortin 2 infusion (n=27) in contrast to placebo (n=26) where the mean arterial pressure was 92 +/- 3 mmHg at baseline and 89 +/- 4 mmHg at the end of the placebo infusion. Heart rates were slightly higher during urocortin 2 infusion than placebo although these remained in normal range and comparable in both groups post infusion. In the subset of subjects undergoing right heart catheterization (n=20, 10 per arm), cardiac output increased markedly by over 50% in those randomized to urocortin 2 compared to unchanging values in the placebo group (p=0.003). Additional urocortin 2 studies are being conducted by the Centre for Cardiovascular Sciences at The University of Edinburgh through a British Heart Foundation grant. A total of nine studies are to be conducted in both healthy volunteers and patients with stable CHF to determine the impact of urocortin 2 infusions on biomarkers of cardiovascular function and dysfunction. These studies began in 2010, and are expected to take several years to complete.
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