Varespladib methyl

Varespladib methyl (also known as A-002, formerly LY333013 and S-3013) is a secretory phospholipase A2 (sPLA2) inhibitor formerly under development by Anthera Pharmaceuticals as a treatment for acute coronary syndrome (ACS). Varespladib methyl is an orally bioavailable prodrug of the molecule varespladib. It is currently under active investigation in a Phase III clinical trial called VISTA-16.

Mechanism
Increased levels of sPLA2 have been observed in patients with cardiovascular disease, and may lead to both acute and chronic disease manifestations by promoting vascular inflammation. Plasma levels of sPLA2 can predict coronary events in patients who recently suffered an ACS as well as in those with stable coronary artery disease.

Furthermore, sPLA2 remodels lipoproteins, notably low-density lipoproteins (LDL) and their receptors, which are responsible for removing cholesterol from the body. This remodeling can lead to increased deposition of LDL and cholesterol in the artery wall. In combination with chronic vascular inflammation, these deposits lead to atherosclerosis.

Varespladib inhibits the IIA, V and X isoforms of sPLA2 to reduce inflammation, lower and modulate lipid levels, and reduce levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both indicators of inflammation.

Clinical Development
Varespladib methyl was originally developed jointly by Eli Lilly and Company and Shionogi & Co., Ltd., and was acquired by Anthera Pharmaceuticals in 2005.

A Phase II study by Anthera successfully demonstrated selective sPLA2 inhibition as well as statistically significant anti-inflammatory responses and reductions in LDL cholesterol levels. Two other Phase II trials, conducted in patients with coronary artery disease, found significant decreases in sPLA2 and LDL cholesterol levels, as well as CRP and other inflammatory biomarkers. Varespladib methyl has also been shown to further reduce LDL and inflammatory biomarker levels when administered in conjunction with a cholesterol lowering statin therapy.

In 2010, a Phase III study entitled VISTA-16 was launched to evaluate the safety and efficacy of short-term treatment with varespladib methyl in subjects with ACS. The trial was halted in March 2012 due to lack of efficacy. On November 18, 2013, JAMA reported an excess of myocardial infarctions, and of the composite endpoint of cardiovascular mortality, myocardial infarctions and stroke in the VISTA-16 study.. See: doi:10.1001/jama.2013.282836