Short-Term (16-week) Treatment of Acute Coronary Syndrome
Introduction
A-002 (varespladib methyl) is an orally administered, once-daily, inhibitor of the IIa, V and X forms of the sPLA2 enzyme that has demonstrated potent anti-inflammatory, lipid-lowering and lipid-modulating treatment effects in multiple clinical studies. A total of 1,107 patients and healthy volunteers in 15 clinical studies have been exposed to A-002. The administration of A-002 was generally safe and well-tolerated in studies where patients were exposed to a maximum of 48 weeks of therapy. A-002 has been studied in combination with atorvastatin in a Phase 2b study in acute coronary syndrome patients and two earlier Phase 2 studies in stable coronary artery disease patients, the majority of whom were on statin therapy.
Patients experiencing an acute coronary syndrome suffer from significant inflammatory activity and abnormal lipid profiles. sPLA2 enzymes act to directly amplify inflammation and abnormally modify lipids.
We believe that A-002 is one of only a few novel drugs in development with the potential to offer, through a unique mechanism, anti-inflammatory activity, as measured by reductions in sPLA2, CRP and IL-6, lipid-lowering, as measured by LDL, and lipid modulating activity beyond that achievable with statin therapy alone. Furthermore, because of their complementary mechanisms, we believe that the combination of statins and A-002 can provide synergistic anti-inflammatory and lipid-lowering benefits. Additionally, we have preliminary data to suggest that A-002 may be synergistic with other cardiovascular therapeutic regimens, such as niacin.
sPLA2 in the Cardiovascular Disease
Background
Acute coronary syndrome, or heart attack, is defined as any group of clinical signs and symptoms related to acute myocardial ischemia, or heart muscle damage. Acute coronary syndrome is characterized by chest pain due to insufficient blood supply to the heart muscle as a result of coronary artery disease. For patient who experienced a previous acute coronary syndrome event, the risk of developing secondary Major Adverse Cardiovascular Event (MACE) is significantly increased immediately following the initial event.
Patients experiencing acute coronary syndrome suffer from significant inflammatory activity and abnormal lipid profiles. sPLA2 enzymes act to directly amplify inflammation and abnormally modify lipids. A-002, or varespladib, when combined with lipid-lowering therapies, is one of only a few drugs in development with the potential to offer a unique and synergistic approach targeting inflammation, elevated lipid levels, and atherosclerosis as part of physician-directed standard of care.
Epidemiology
Coronary artery disease (CAD) is the most common cause of death in the western world and a major cause of hospital admissions. According to the American Heart Association, over 18 million people in the United States have experienced an acute coronary syndrome and an estimated 1.5 million Americans will have a new or recurrent heart attack. In addition, the American Heart Association estimates that worldwide, cardiovascular disease kills an estimated 17.5 million people each year. According to British Heart Foundation statistics, CAD, which often leads to acute coronary syndrome, or heart attacks, accounts for 1.9 million deaths in Europe annually.
The American Heart Association estimates that for people over the age of forty, 20% of them will die within one year following an initial heart attack, and over one-third of them will die within the first five years of an initial heart attack. These numbers are expected to increase given an aging population, as well as the rising epidemics of diabetes and obesity, two conditions known to increase the risk of acute coronary syndrome.
Disease Management
Current therapeutic treatments for coronary artery disease include a variety of medications such as aspirin, statins, anti-platelets, and anti-coagulant therapies, as well as interventional procedures. Medications are used to offer both acute and chronic benefits to patients. For patients presented with acute coronary syndrome, therapeutics are administered quickly to improve blood flow to the heart and limit the risk associated with continued ischemia and thrombosis.
Inflammation in Cardiovascular Disease
In patients experiencing an acute coronary syndrome, the relationship between higher levels of inflammation, as measured by CRP, sPLA2 and IL-6, and increased risk for MACE has been demonstrated extensively. In numerous clinical studies with a variety of therapeutic interventions, reductions in CRP have been correlated with reductions in subsequent MACE. CRP is the most commonly used marker of inflammation. It has been independently and strongly correlated with adverse cardiovascular outcomes in multiple clinical studies. Although a causative role for CRP has not been established, inflammation is known to promote acute coronary syndrome, and CRP may play a direct role in both vascular inflammation as well as plaque rupture.
Statins reduce the level of CRP and other markers of inflammation in patients with stable coronary artery disease. In April 2001, the Journal of the American Medical Association published results from the MIRACL study describing the effect of statins in acute coronary syndrome, where inflammation is greatly elevated. 3,086 patients were randomized within 96 hours of their index event to treatment with high-dose atorvastatin or placebo. Atorvastatin significantly reduced secondary MACE after 16 weeks. A second paper from the same study, published in Circulation in 2003, described the rapid decline of inflammatory markers in patients on statin treatment that was associated with reduced MACE. After 16 weeks, atorvastatin reduced CRP levels by 34%.
More recently, in 2005, the New England Journal of Medicine published data from the PROVE-IT study. A total of 3,745 patients were randomized to either intensive statin therapy with 80 mg atorvastatin or moderate statin therapy with 40 mg pravastatin. Patients with low CRP or LDL-C had fewer MACE than those with higher levels of either CRP or LDL-C. Patients who had both LDL-C < 70 mg/dL and CRP < 1 mg/L had the fewest number of secondary events overall.
LDL Cholesterol in Cardiovascular Disease
The direct relationship between lower LDL-C levels and reduced risk for major cardiovascular events has been consistently demonstrated for over a decade in 18 outcome studies involving over 119,000 patients. Results from large clinical outcome studies demonstrate achieving incrementally lower LDL-C levels reduces the risk of future cardiovascular events and provides continued patient benefit. As a result, the lipid treatment guidelines have been revised to establish more aggressive LDL-C treatment goals over time.
The most recent guidelines from the National Cholesterol Education Program’s Adult Treatment Panel III, or NCEP ATP III, updated in 2004 advocate treatment goals for LDL-C below 100 mg/dL for high-risk patients and 70 mg/dL for very high-risk patients. Given the breadth of more recent clinical data available, future treatment guidelines from the NCEP will likely establish new LDL-C treatment goals that apply the 70 mg/dL standard, or lower, to a broader population of at risk patients. Patients enrolled in our FRANCIS Phase 2b clinical study and our planned Phase 3 acute coronary syndrome study (VISTA-16) represent high-risk patients as defined by the NCEP.
Addressing Inflammation and LDL in Cardiovascular Disease
In order to achieve these more aggressive LDL-C targets, doctors prescribe other approved lipid-lowering therapies such as cholesterol absorption inhibitors, nicotinic acid and fish oils in combination with statins to further reduce LDL-C. Still, many acute coronary syndrome patients who represent the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guideline categories of high-risk and very high-risk do not achieve these recommended lipid goals despite maximum lipid-lowering therapies. Moreover, substantial residual risk remains even among the group of patients that do achieve these aggressive LDL-C goals, suggesting additional biological mechanisms, including inflammation, may be relevant. This is exemplified in a November 2008 publication in the New England Journal of Medicine that detailed the results from a 17,000 patient, multinational, primary prevention study named JUPITER. The study randomized patients with relatively normal levels of LDL-C, but elevated levels of inflammation based on CRP to statin or placebo therapy. The JUPITER study was stopped early because those patients randomized to statin therapy demonstrated a statistically significant reduction in CRP, which also translated to a statistically significant reduction in cardiovascular events versus those on placebo. The reduction in events was well in excess of that which would be predicted from historical data evaluating LDL-C reductions alone. While these results were generated in a primary prevention setting, the benefits of reducing inflammation may prove to be more meaningful in settings where patients are in a hyper-inflammatory state, such as following an acute coronary syndrome.
As a result of these studies, it is postulated that there is substantial need for novel therapies that provide meaningful reductions in inflammation while also improving LDL-C levels in high-risk cardiovascular patients beyond the benefits of statin therapy. Therefore, targeting inflammation and elevated LDL-C with sPLA2 inhibition during the early phase of an acute coronary syndrome will further improve patient outcomes.
sPLA2 and A-002 in Cardiovascular Disease
Elevated levels of sPLA2 have been implicated in a variety of acute inflammatory related cardiovascular diseases, including acute coronary syndrome, as well as in chronic disease settings such as stable coronary artery disease. We believe that A-002 is one of only a few novel drugs in development with the potential to offer, through a unique mechanism, anti-inflammatory activity, as measured by reductions in sPLA2 , CRP and IL-6, lipid-lowering, as measured by LDL-C, and lipid-modulating activity beyond that achievable with statin therapy alone. Furthermore, because of their complementary mechanisms, the combination of statins and A-002 can provide synergistic anti-inflammatory and lipid-lowering benefits. Further, we have preliminary data to suggest that A-002 may be synergistic with other cardiovascular therapeutic regimens, such as niacin.
Phase 2 Studies in Acute Coronary Syndrome and Stable Coronary Artery Disease
Clinical results from our Phase 2b (“FRANCIS”) clinical study enrolling 625 acute coronary syndrome patients and two Phase 2 clinical studies (“PLASMA” and “PLASMA-2”) enrolling 534 stable coronary artery disease patients demonstrated statistically significant reductions in LDL, a known predictor of cardiovascular risk. Reductions in LDL were greater when used in combination with commonly prescribed statin therapies. In addition, rapid and sustained anti-inflammatory activity was also evident as sPLA2 concentrations were statistically significantly reduced from baseline levels throughout dosing in all clinical studies. In our Phase 2b FRANCIS clinical study, CRP and IL-6, both independent predictors of cardiovascular risk, were lower at all time points among A-002 treated patients as compared to those on 80 mg of atorvastatin alone.
Nonclinical Studies
To date, over 150 preclinical pharmacology and toxicology studies have been completed with A-002 and A-001, including two-year rat and mouse carcinogenicity studies, one-year primate study, and three-month rat stud in combination with atorvastatin.
Current Phase 3 Study
We are preparing to begin a pivotal Phase 3 clinical study named VISTA-16 (Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks) for A-002 in combination with HMG-CoA reductase inhibitor, or statin, therapy for short-term (16-week) treatment of patients experiencing an acute coronary syndrome. The Phase 3 clinical study is designed to evaluate a 16-week therapy with A-002 in combination with statins for the prevention of secondary major adverse coronary events in patients who have recently experienced an acute coronary syndrome. The VISTA-16 study is expected to enroll patients with similar characteristics to patients in the Phase 2b FRANCIS acute coronary syndrome clinical study.
For information about the Phase 3 VISTA-16 clinical trial‚ please visit the VISTA-16 Clinical Trial Site.
