Routes of
administration Oral Legal status Investigational CAS Number 172733-08-3 | ATC code none Synonyms A-002 PubChem CID 9886917 | |
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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. From 2006 to 2012, varespladib methyl was under active investigation by Anthera Pharmaceuticals as a potential therapy for several inflammatory diseases, including acute coronary syndrome. In March 2012, Anthera halted further investigation of varespladib per a recommendation from an independent Data Safety Monitoring Board.
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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.
History
Varespladib methyl was originally developed jointly by Eli Lilly and Company and Shionogi & Co., Ltd., and was acquired by Anthera Pharmaceuticals in 2006.
A Phase II study 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 C-reactive proteins (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 initiated 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 insufficient efficacy. On November 18, 2013, an excess of myocardial infarctions, and of the composite endpoint of cardiovascular mortality, myocardial infarctions and stroke in the VISTA-16 study were reported.