Secretory phospholipase A2 (sPLA2) enzymes are involved in the production of bioactive lipids that contribute to atherosclerosis. They are highly expressed in human and mouse atherosclerosis, and different groups of the enzyme contribute differently to atherosclerosis. A-002 (1-H-indole-3-glyoxamide, veraslpadib methyl, Anthera pharmaceuticals, CA) is a novel inhibitor of sPLA2 in humand with specificity towards sPLA2-I1A, -V and –X.
In this phase II, randomized, double-blind, placebo-controlled trial, 393 patients were randomly assigned to receive either placebo or one of four doses of A-002 for 8 weeks.The primary endpoint was the change in sPLA2-IIA concentration.348 patients reached this endpoint, and the mean sPLA2-IIA concentration was found to have fallen by 86.7% in the active treatment group, compared to just 4.8% in the placebo group (p<0.0001).Reductions in LDL cholesterol, C-reactive protein, arachidonic acid, and oxidized-LDL were also seen, even in patients already on statin therapy.This reduction was found to be dose-dependent, but one serious adverse event was seen in with the highest dose (500mg) – an exacerbation of chronic obstructive pulmonary disease.Otherwise the main side-effects of the drug included headache (n=20), nausea (n=17), and diarrhoea (n=12).
These promising initial results suggest that, by acting on a number of atherogenic pathways, sPLA2 inhibition may be able to provide substantial protection from cardiovascular disease. Despite multiple innovations in recent years, deaths from cardiovascular disease continue to rise – the development of novel treatments such as this therefore remains an important goal for drug development.
- Rosenson RS, Hislop C, McConnell D, et al. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomized, placebo-controlled trial. Lancet 2009; 373:649-658.
- Corson MA. Phospholipase A2 inhibitors in atherosclerosis: the race is on. Lancet 2009; 373: 608-610.