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Easing Inflammation

New immune modulators will be easier to swallow—and pay for.

Sometimes firefighters do more damage than the blaze itself—especially if they flood a room for what turns out to be a scorched bagel. The body’s fire service is its white blood cells, the leukocytes, which rush to respond to chemical alarms from damaged tissues. And like overzealous firefighters, leukocytes extinguishing cells can batter surrounding tissue in the process. The rush of leukocytes contributes to inflammation, leading to disease in its own right. In Crohn’s disease, for instance, the villi in the small intestine become so misshapen that patients can no longer absorb nutrients from food. Plaque psoriasis causes unseemly, itchy scales. Arthritis twists joints beyond function.

Easing Inflammation; Copyright © 2004 Acumen Sciences, LLC, All Rights Reserved.Fighting inflammation is a multibillion-dollar business. Drugs ranging from aspirin to Pfizer’s Celebrex ease the pain and swelling of arthritis, but they do nothing to protect inflamed tissue from leukocytes. Doing that means interfering with the alarm signal that summons the leukocytes. Protein drugs like Enbrel from Amgen, Humira from Abbott Laboratories, and Remicade from Centocor work by removing from the bloodstream one of the main links in transmitting the cry for help, a protein called tumor necrosis factor, or TNF, that is released by damaged tissue and that activates wider chemical signaling.

This strategy is effective—it stops the destruction of joints and may even allow healing to begin—but these protein drugs are expensive and cannot be taken orally. Insurers are loath to pay for them, and patients hate injections. “The problem is that society cannot pay for treatment costing $15,000 per year,” says Marc Feldmann, whose work unraveling the role of TNF won him the 2003 Albert Lasker Award for Clinical Medical Research. His solution, as well as that of many drug companies, is not to tackle TNF directly but to block its manufacture or activity inside cells, using small molecules that can be administered orally.

Most small molecules designed to stop TNF’s actions have been aimed at an enzyme called p38 MAP kinase, which promotes the production of TNF, as well as interleukin-1 and cycloöxygenase-2 (COX-2), two other proteins that stimulate inflammation. Many analysts believe that Johnson & Johnson’s recent $2.4 billion acquisition of Scios, a Silicon Valley biotech firm, was motivated by the potential of its p38 inhibitor, which is currently in Phase II trials. But p38 MAP kinase is found in every cell of the body, mostly doing good, not harm, so attacking it has draw backs, especially as such drugs are likely to hit other kinases besides p38. Most p38 inhibitors that have made it to clinical trials have failed.

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1  Including COX, LOX, and PAF.

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