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Preclinical study shows ilomastat potential to cut tobacco smoke-related lung damage by 96%

ALAMEDA, CALIF., September 29, 2003 -- Arriva Pharmaceuticals announced the results of an animal model study showing the effects of an inhaled protease inhibitor, ilomastat, on the development of emphysema due to cigarette smoking.

The work was presented by Dr. Philip Pemberton, Vice President, Research and Development of Arriva, at the 13th Congress of the European Respiratory Society in Vienna, Austria. The study showed that lung degeneration caused by cigarette smoke could be reduced by up to 96% using this strategy.

Since this model is widely recognized by specialists as reproducing most characteristics of the disease as it occurs in humans, the study gives rise to very real hopes for the clinical treatment of this widespread disease. Recent estimates show that the global frequency of smoking-related chronic obstructive pulmonary disease (COPD) accounts for up to $20 billion in healthcare costs annually.

Researchers have known for many years that inhalation of cigarette smoke, which attacks the bronchial airways, leads the body to recruit large numbers of immune-response cells, especially macrophages and neutrophils. These cells are very abundant in the finer extensions of the bronchi (bronchioles) and the alveolar walls, precisely where emphysema, that characteristic smoker's disease, tends to develop.

The inflammatory cells then secrete enzymes that can damage the connective tissue that makes up the structure of the lung. These enzymes, called proteases, are able to break up other proteins; this is true particularly of the so-called matrix metalloproteases (MMPs). These proteases, especially MMP-9, are suspected of destroying the elastic tissue of the bronchioles and alveolar walls in smokers, leading to COPD in a large proportion of such individuals. In normal circumstances, these proteases are not present at such high levels in the lungs and a natural balance develops between destructive proteases and inhibitors, also locally produced, which protect the lung tissue from harm. However, the inflammation caused by smoking causes a rise in the level of destructive proteases, thereby upsetting the delicate natural balance and leading to lung damage.

Many research teams have thus sought to re-establish the natural balance, even where the subject smokes, by developing protease inhibitors, and ilomastat, the synthetic enzyme inhibitor at the center of the Arriva work presented in Vienna, is especially promising.

The results presented in Vienna showed that low doses of inhaled ilomastat could limit inflammatory cell accumulation in lung tissue, especially accumulation of macrophages and neutrophils, thus also reducing the level of destructive MMPs. In particular, the results indicate that Ilomastat reduces lung damage proportionately to the dose inhaled and by as much as 96% when compared to the damage found in control mice that were not treated with ilomastat.

While other protease inhibitors have been tested on animals for bronchial anti-inflammatory effect, including a Pfizer molecule tested on guinea-pigs by means of daily subcutaneous injections of 20 mg per kg, the experiment presented in Vienna by Arriva and its collaborators is particularly original because of the way the inhibitor is administered. "To my knowledge, these inhibitors have all been administered orally or injected at relatively high doses," explained Dr. Pemberton. "In this regard, our approach, using direct delivery of the drug to the lung, is unique, and allows the use of much lower levels of the inhibitor."

Dr. Philip J. Barr, Arriva's Chief Scientific Officer and a co-author of the work commented, "These results are all the more promising since, to date, there is no treatment capable of stopping the progressive destruction of the alveolar walls characteristically found in emphysema, for which smoking is the main culprit. This result complements clinical studies we are carrying out in human subjects, where we are also delivering a protease inhibitor with a view to ameliorating the lung degeneration seen in the hereditary form of emphysema."

Source: Arriva Pharmaceuticals

Posted: September 2003