The heart of inflammation

Inflammation is a complex network of interactions that arises in response to tissue injury, regardless of the site or nature of the initiating event. Despite this virtual omnipresence of the inflammatory process throughout the body, therapeutic applications of anti-inflammatory compounds have traditionally focused on a relatively narrow set of diseases. However, new research has led to a paradigm shift that is focusing on the intersection between inflammation biology and new disease areas.

This paradigm shift already is particularly evident in cardiovascular disease. For example, Millennium Pharmaceuticals Inc. recently merged its cardiology and inflammation departments because of the overlap in biology between the two areas. In addition, several companies, including one in the most recent IPO class, have focused efforts to reprofile anti-inflammatory compounds to treat cardiovascular disease.

What is more, the clinical data are starting to back up the biological concepts. The results of recent statins trials suggest that lowering LDL doesn't necessarily correlate with the early improvement of clinical outcomes in patients with coronary artery disease (CAD), indicating that the anti-inflammatory properties of statins might be responsible. Moreover, the Phase IIb results for AtheroGenics Inc.'s AGI-1067 - perhaps the exemplar for anti-inflammatory cardiovascular drug development - showed the compound reduced atherosclerotic lesion progression.

Outside of the cardiovascular arena, there is evidence that inflammation plays a clinically relevant role in areas such as Alzheimer's disease, diabetes and obesity. But research in these fields is still developing, and thus has yet to translate into a critical mass of companies or compounds in development (see "Old School," A2 & "New(er) School," A3).

In contrast, there is a growing pipeline of compounds for cardiovascular indications that inhibit different inflammatory processes. Some inhibit the ability of blood cells to traffic to and through the atherosclerotic plaque. Others inhibit the production of cytokines, leukotrienes and reactive oxygen species, which amplify the inflammation at the vascular wall. Still other products are aimed at silencing the innate immune system's response to cardiovascular injury by inhibiting the complement system.

Setting the stage

Although it has been more than 15 years since evidence began to accumulate that cardiovascular disease is linked to inflammation, the first products resulting from these insights are just now reaching the point of clinical validation (see "Cardiovascular Pipeline," A5).

"In the late 1980s, people started to look at inflammation as a way of approaching cardiovascular disease based upon several different synergistic risk factors for the development of atherosclerosis," said Russell Medford, CEO of AtheroGenics (AGIX, Alpharetta, Ga.).

For example, both diabetes and hypertension are risk factors for developing CAD. And both conditions lead to the production of molecules that have inflammatory properties - angiotensin II in hypertension and glycosylated proteins in diabetes.

Now, the process that produces inflammation in the vessel wall is recognized as a central player in atherosclerosis. "The evidence for a local inflammatory component in atherosclerosis is strong and primarily involves infiltrating leukocytes

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