Phospholipases may not be targets of choice for medicinal chemistry, but two inhibitors are now in clinical development for atherosclerosis

By Editorial Board member Dr Keith Suckling

Phospholipases do not appear high on the list of major druggable target types. There are significant challenges in medicinal chemistry to provide specificity and in enzymology to generate data that can support chemistry for reactions that take place at a lipid-water interface at which active concentrations of compounds are difficult to define. So it is perhaps surprising that there are now two phospholipase inhibitors in clinical development for the treatment of atherosclerosis - surprising because of the chemical challenges but also because the final proof of efficacy in patients requires extended outcome studies in around 16,000 subjects.

The first of these compounds is darapladib (GSK) for which Phase 2 results were presented last year [1]. Darapladib inhibits the enzyme known as lipoprotein-associated phospholipase A2. As the name suggests, this phospholipase is found in the circulation associated with LDL and is thought to catalyse the hydrolysis of oxidised phospholipids. The products of the hydrolysis promote the expression of adhesion molecules on the artery wall and chemokines in macrophages and so promote the development of the vulnerable plaque. Inhibition of this process would therefore be expected to be of benefit and recent studies in a pig model support this concept [2] and some of the Phase 2 data are consistent with it too. This mechanism would be expected to have a similar overall effect on the pathogenesis of atherosclerosis to a chemokine receptor antagonist, for example CCR2. Importantly this approach does not reduce plasma LDL, and is not expected to.

Other forms of phospholipase have been implicated in atherogenesis in recent years and in particular those known as secretory phospholipases [3], of which the Group V enzymes have been of particular interest. Animal data also supports a role for these enzymes in atherogenesis [4], but the mechanism is different. In this case the phospholipase modifies HDL and LDL particles making the former less able to support reverse cholesterol transport and the latter more susceptible to oxidation. Very recently Phase 2 data have been reported of the effects of an sPLA2 inhibitor, varespladib (A-002, Anthera Pharmaceuticals) [5]. This compound inhibits a range of sPLA2 s (sPLA2-IIa>sPLA2-X>sPLA2-V) and, in contrast to darapladib, does have an effect on plasma LDL concentration and also on hsCRP. Recent animal data are consistent with an effect of varespladib on atherogenesis in the mouse [6]

It is important to recognize that the effects of these two phospholipase inhibitors on the process of atherogenesis are quite different and as a result, at least in Phase 2, they require different end points to be studied. If this is not borne clearly in mind there is a danger of serious confusion amongst non-experts. In this respect we should no more talk about phospholipase inhibitors as a class than we might about PPAR agonists: there are so many differences. Nevertheless, for both mechanisms, it is necessary to show that they improve outcomes in patients, and at this point the differences are not important. A large outcome study is beginning for darapladib (STABILITY) with around 15,000 patients [7].

By Keith Suckling, PhD, Editorial Board member of Expert Opinion on Investigational Drugs

Reference List

1. Serruys P.W., Garcia-Garcia H.M., Buszman P., Erne P., Verheye S., Aschermann M., Duckers H., Bleie O., Dudek D., Botker H.E. et al. (2008). Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118: 1172-1182.
2. Wilensky R.L., Shi Y., Mohler E.R., III, Hamamdzic D., Burgert M.E., Li J., Postle A., Fenning R.S., Bollinger J.G., Hoffman B.E. et al. (2008). Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 14: 1059-1066.
3. Kimura-Matsumoto M., Ishikawa Y., Komiyama K., Tsuruta T., Murakami M., Masuda S., Akasaka Y., Ito K., Ishiguro S., Morita H. et al. (2008). Expression of secretory phospholipase A2s in human atherosclerosis development. Atherosclerosis 196: 81-91.
4. Boyanovsky B., Zack M., Forrest K., and Webb N.R. (2009). The Capacity of Group V sPLA2 to Increase Atherogenicity of ApoE-/- and LDLR-/- Mouse LDL In Vitro Predicts its Atherogenic Role In Vivo. Arterioscler Thromb Vasc Biol ATVBAHA.
5. Rosenson RS, Hislop C, McConnell D, Elliot, M, Stasiv U, et al. (2009). Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial. Lancet 373: 649-658.
6. Fraser H., Hislop C., Christie R.M., Rick H.L., Reidy C.A., Chouinard M.L., Eacho P.I., Gould K.E., and Trias J. (2009). Varespladib (A-002), a Secretory Phospholipase A2 Inhibitor, Reduces Atherosclerosis and Aneurysm Formation in ApoE-/- Mice. J Cardiovasc Pharmacol.53, 60-65
7. GSK Press release: http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10144.htm