Download consisting of diuretics to remove excess water, beta blockers and

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. There are in excess of one million hospitalizations
each year in the United States for CHF (AMA 2009).
Urocortin 2 is an endogenous peptide ligand of the CRF2 receptor present in the cardiovascular system, notably
the heart and cerebral arterial system. Urocortin 2 plays a role in the control of the hormonal, cardiovascular,
gastrointestinal, and behavioral responses to stress, and has an array of effects on the cardiovascular system and
metabolism. Based on preclinical efficacy and safety data, together with its known role in human physiology, we
believe that urocortin 2 may have positive hemodynamic effects on cardiac output and blood pressure which may
benefit patients with acute CHF.
During 2005, we completed a Phase II placebo controlled dose-escalation study to evaluate the safety,
pharmacokinetics and pharmacodynamics of two dose levels of urocortin 2 in patients with stable CHF. Results of
this study demonstrated a dose-related increase in cardiac output of up to 50% with only a modest increase (6%) in
heart rate. We completed an additional Phase II study evaluating urocortin 2 over four-hour infusions in patients
with stable CHF in the first half of 2006. The treatments were generally well tolerated without serious adverse
events, abnormalities in electrocardiograms or significant changes in renal function. Positive hemodynamic effects
were noted in virtually all patients with increases in cardiac output ranging from 6% to 54%.
During 2008, we completed the necessary preclinical work to allow for periods of infusion of urocortin 2 up to
14 days. This substantially completes all of the preclinical toxicology work required by the FDA. Further
development of urocortin 2 for CHF and other acute care cardiovascular diseases is highly dependent upon
partnering of this program.
Research Programs
Our research and development focus is on addressing diseases and disorders of the central nervous system and
endocrine system, which include therapeutic categories ranging from diabetes to stress-related disorders and
neurodegenerative diseases. Central nervous system and endocrinology drug therapies are among the largest
therapeutic categories, accounting for over $60 billion in worldwide drug sales in 2007 according to Med Ad News.
Vesicular Monoamine Transporter 2 Inhibitor (VMAT2)
VMAT2 is a protein concentrated in the human brain that is essential for the transmission of nerve impulses
between neurons. VMAT2 is primarily responsible for re-packaging and transporting monamines (dopamine,
norepinephrine, serotonin, and histamine) among nerve cells. Specifically, dopamine enables neurotransmission
among nerve cells that are involved in voluntary and involuntary motor control.
We have identified one highly selective VMAT2 inhibitor that is effective in regulating the levels of dopamine
release during nerve communication, while at the same time having minimal impact on the other monoamines
thereby reducing the likelihood of “off target” side effects. We have developed this novel compound to provide very
predictable plasma and brain concentrations and therefore allow for exposure that we expect to be well tolerated in
patients.
We believe that this clinical candidate will be effective in the management of hyperkinetic movement disorders
characterized by involuntary bodily movements as seen in patients suffering from Tardive Dyskinesia, and
Huntington’s disease. Additionally, the modulation of dopamine pathways may also be useful for patients suffering
from schizophrenia, one population at risk for Tardive Dyskinesia.
We anticipate moving this compound into Phase I clinical trials in 2009.
Glucose Dependent Insulin Secretagogues
Type II diabetes affects more than 23 million Americans (Datamonitor 2007), and is growing at epidemic
proportions world-wide. The disease is characterized by reduced ability to secrete and respond to insulin. Drugs
which can enhance the secretion of insulin in response to rising blood glucose levels can improve blood glucose
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