The cardiovascular disease (CVD) market is worth approximately $100 billion today and makes up 12% of all global pharmaceutical sales. Unit sales of medicines for CVD are growing, but patent expirations for drugs such as Lipitor will hold revenues down. The advent of statins in the treatment of CVD was an incredible advance in the field, however, recent attempts to develop new products have been less successful.
In recent years, the novel target, PLA2 has become the subject of substantial research. PLA2s, or Phospholipases A2, are enzymes that catalyze the hydrolysis of fatty acid chains from phospholipids. PLA2s play important an important role in lipid metabolism and inflammatory response. There are 15 known members of the PLA2 family, ordered into four subgroups: secretory sPLA2, cytosolic cPLA2, calcium independent iPLA2, and lipoprotein associated Lp-PLA2. Much attention has been focused on sPLA2 and Lp-PLA2 due to their involvement in the production of biologically active metabolites implicated in the pathology of atherosclerosis. In the last few years, cPLA2 has also come under increased scrutiny.
In independent studies, activity of sPLA2 and Lp-PLA2 have been shown to be predictive biomarkers of an increased risk for coronary heart disease. This correlation combined with current understanding of the enzymes’ roles in vascular biology have made them prime targets for pharmacologic intervention.
The most advanced compounds targeting secretory PLA2 are from Anthera Pharmaceuticals (ANTH). Anthera licensed a set of potent and specific sPLA2 inhibitors from Eli Lilly (LLY) in 2006. The compounds, LY333010, a prodrug of LY315920, are now called A002 and A001, respectively.
In a Phase II trial, treatment with A002 resulted in a mean 84% reduction in sPLA2 levels, 15% reduction in LDL, and 20% reduction in the inflammatory biomarker, C-reactive protein (CRP). Anthera has begun enrollment of up to 6500 patients in a pivotal study called VISTA-16. The trial will attempt to determine if a 16 week treatment of A002 plus Lipitor helps prevent the occurrence of major adverse coronary events in patients who have recently experienced an acute coronary syndrome. It is anticipated to complete in 2012.
Meanwhile, GlaxoSmithKline (GSK) is placing its bet on Lp-PLA2. In the Phase II setting, GSK’s inhibitor, darapladib, showed 59% inhibition of Lp-PLA2 activity, but had no significant effect on levels of CRP. It did, however, reduce expansion of the necrotic core of plaques in coronary arteries. Two large Phase III trials are now underway for darapladib in two different patient populations.
The first study, termed STABILITY, was initiated in 2008 and enrolled 15,000 patients with chronic congestive heart failure; it is a long-term study intended to determine if darapladib combined with standard of care helps prevent major adverse cardiovascular events (MACE) and is expected to last three years. The second study, SOLID-TIMI 52, began in 2009 and will enroll 11,500 patients with acute coronary syndrone; the objective of the study is to determine if darapladib plus standard of care helps prevent a first occurrence of MACE. Unlike patients on Anthera’s VISTA-16 study, patients on this study will likely be dosed for two more years. Total time for completion of this trial is anticipated to take more than 3.5 years.
As you can see, GSK has put considerable resources on Lp-PLA2 inhibition. Behind darapladib, it also has a follow-on compound, rilapladib, now in Phase II trials.
Some of the most recent research is on inhibition of cytosolic PLA2 due to its key role in the production of pro-inflammatory prostaglandins and leukotrienes. There is nothing in the clinic yet, but it is an area of significant interest. Wyeth (WYE) - now Pfizer (PFE) - has its own cPLA2 inhibitors.
Specific inhibition of PLA2 is a compelling new mechanism for down-regulating inflammation in the treatment of cardiovascular disease. But so far, there is no definitive data to show this will result in a real benefit for the patient. Results to-date, though intriguing, only show the compounds are modulating their targets, with some hints of therapeutic effects. Pre-clinical data looks good and the targets are validated risk factors - the rest is a leap of faith.
Disclosure: Author long ANTH