deCODE trials unique atherosclerosis compound

DG041 is a novel, orally-administered small molecule, which has been shown in preclinical studies to be a selective and potent antagonist of the EP3 receptor for prostaglandin E2 (PGE2), inhibiting human platelet aggregation in a dose-dependent manner. deCODE selected EP3 as a target in PAOD through its population genetics research, which linked variations in the gene encoding EP3 to increased risk of the disease.

EP3 receptors may also be important modulators of pain transmission. The company are planning to evaluate the potential of compounds targeting EP3 as alternatives to COX-2 inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of chronic pain.

deCODE are thought to be the only company that had developed a specific compound to target the product of a gene isolated in a common disease.

The very nature of atherosclerosis means that there is a shortage of effective treatment of this disorder, also known as peripheral arterial occlusive disease (PAOD). It affects over 10 per cent of the adult population in the industrialised world and one in five people over the age of 70.

The initial symptoms of PAOD include pain in the legs while walking or exercising, due to the narrowing by atherosclerotic plaques of one or more major arteries in the legs. The reduction of blood flow leads to insufficient oxygenation of muscle tissue. As the disease worsens it can lead to tissue damage, ulceration and gangrene, and in extreme cases may require the amputation of the affected limb.

Kari Stefansson, CEO of deCODE genetics said: "DG041 is the second compound we have entered into clinical trials, and the most advanced to have been developed entirely from our own target and drug discovery capabilities. By targeting the protein made by a major disease gene, we are in a position to manipulate the key biological pathway involved in the disease."​

deCODE​ identified common versions of the gene encoding EP3 (the PTGER3 gene) that confer increase in risk of PAOD. These variants are believed to increase susceptibility to the disease through heightened expression of EP3. Functional analysis underscores the important role of EP3 in modulating the biology of the platelet and the vessel wall.

Binding of PGE2 to EP3 is known to increase platelet aggregation, and EP3 is expressed in smooth muscle cells found in atherosclerotic plaques. In preclinical in vitro studies DG041 has been shown to inhibit human platelet aggregation induced by PGE2, and to do so in a dose- dependent manner. In mice, DG041 has been shown to protect against intravascular coagulation in a model based on prostanoid-induced platelet activation. DG041 has been shown to have minimal effect on bleeding time in animal studies.

The lack of treatments signifies a potentially lucrative opportunity within the market. GlaxoSmithKline are currently looking into the enzyme Lp-PLA2 (lipoprotein-associated phospholipase A2), which researchers hypothesised that the enzymatic action of Lp-PLA2 yielded substances that caused inflammation, so-called inflammatory mediators. Results of a newly published study that links these mediators to ischemic stroke and coronary heart disease (CHD) appear in the February 8, 2005 issue 1 of Circulation.​

Sankyo's CS-505, a drug developed for the treatment of arteriosclerosis has high expectations placed on it. CS-505 itself is a novel new drug displaying a unique mechanism of action that leads to its status as a first-in-class drug.

CS-505 is an anti-arteriosclerotic cholesterol acyltransferase (ACAT) inhibitor that has been shown to reduce progression of atherosclerosis in animal models by preventing cholesterol ester accumulation in macrophages. Research has shown that there may be potential synergy for atherosclerosis regression when used with other lipid lowering agents, mainly statins. Such is the hope of this compound, regulatory submission are planned in the fourth quarter of 2006.