Respiratory diseases are a major cause of morbidity and mortality in this country for both adults and children. More than 360,000 people die each year from lung disease, which represents one out of every seven deaths each year.

Twenty-five million people in this country suffer from chronic lung disease. The two most common chronic lung disorders are chronic obstructive pulmonary disease (COPD), which also encompasses emphysema and chronic bronchitis, and asthma. The economic burden of these two conditions is in the range of 40 billion dollars in direct and indirect costs each year. Much of these direct costs are directly related to the frequent hospitalizations experienced by subjects with COPD and asthma. Thus, for chronic lung conditions such as COPD, treatments that improve lung function can have tremendous impact on health care costs. For example, any treatment that can effectively reduce the frequency of COPD exacerbations will translate into an improvement in lung function, increased patient satisfaction (through an improved quality of life and decrease in dyspnea) and a reduction of hospitalization rates.

Statistics on the most costly respiratory disorders are as follows:

Condition	Prevalence (US)
COPD	6.5 million
Emphysema	3 million
Chronic Bronchitis	9 million
Asthma	17.4 million adults 8.6 million children
Pneumonia	5.1 million (incidence/year)
Acute Respiratory Distress Syndrome	20,000 cases/year

COPD is the leading cause of mortality in subjects with lung disease and is the fourth leading cause of death in this country. Other lung conditions that are characterized by high morbidity and mortality include the acute respiratory distress syndrome (ARDS), pneumonia, influenza and cystic fibrosis. It is important to realize that it is the mortality rate of COPD combined with that of these other lung disorders that results in lung disease being the third most common cause of death in the U.S. today.

Chronic obstructive pulmonary disease (COPD) is caused by smoking in 80% to 90% of the cases. There is no effective treatment for this disorder. Currently the best means of preventing the progression of COPD is through the cessation of smoking and aggressive prevention and treatment of acute exacerbations of COPD and pneumonia. Use of short-acting bronchodilators, available anticholinergic inhalers and steroid inhalers has not been shown to improve pulmonary function over time. Most of these medications are currently used for the temporary reduction of symptoms, such as wheezing and shortness of breath, in COPD subjects.

However, there seems to be data on newer anticholinergic agents and currently available long-acting bronchodilators that is more promising. For example, the new generation antimuscarinic agent tiotropium, inhaled once daily, seems to provide improvement in dyspnea, reduction in exacerbations of COPD and reduction in hospital admission rates for COPD exacerbations. Tiotropium may exert such positive effects through both bronchodilator and anti-inflammatory effects.

Long-acting beta-2 agonists, such as salmeterol and formoterol, also seem to have additional anti-inflammatory effects in COPD as well as in asthma. In this regard, salmeterol has been shown to improve lung function after long term treatment of COPD subjects. In addition, the combined use of salmeterol and inhaled corticosteroids improves the management of asthmatic subjects.

The beneficial effect of tiotropium and salmeterol complements several lines of evidence that suggest that it is the inflammatory response in the lungs of subjects with COPD that promotes deterioration of lung function over time. It is important to note that the inflammatory response in COPD is resistant to corticosteroids. Furthermore, since short-acting bronchodilator drugs do not possess a strong anti-inflammatory component, research has been very active in identifying alternative anti-inflammatory agents for the management of chronic lung disorders where inflammation plays an important role (such as COPD and asthma).

To complicate matters, the inflammatory response in COPD differs markedly from that of asthma with differences in inflammatory cells, cytokines, and the remodelling that takes place in the lung due to the inflammation. There are currently more than 60 drugs in the drug development pipeline for the management of chronic obstructive pulmonary disease (COPD) and/or asthma. Most of these are new formulations of currently used inhalers or modified versions of available drugs.

The anti-inflammatory agents that are currently being evaluated in COPD include agents that act on tachykinin receptors (NK1, NK2 and NK3). These may be beneficial in both COPD and asthma as both groups of subjects have been found to have elevated tachykinin levels in their airways; moreover, airway inflammation seems to upregulate tachykinin receptors. GlaxoSmithKline is evaluating SB 223412 as a tachykinin receptor antagonist; it is in phase I development for the treatment of COPD and cough. DNK 333 is a dual NK1/NK2 antagonist in phase II trials for Asthma and COPD.

Other anti-inflammatory agents in the drug development pipeline include interleukin-8 inhibitors (ABX-IL-8; Abgenix), leukotriene inhibitors (for example, LTB019). In addition, phosphodiesterase 4 inhibitors look promising in early clinical studies; for example, Ariflo (GlaxoSmithKline) is in phase III trials for subjects with moderate-severe COPD and has demonstrated significantly improved pulmonary function and exercise tolerance. Finally, nuclear factor-kappa B inhibitors and p38 MAP kinase inhibitors may also be effective. SB281832 is a p38 inhibitor in phase I trials.

Other active areas in drug development in the field of lung disease include the evaluation of anti-fibrotic drugs in the management of pulmonary fibrosis. Avonex, already a standard treatment in multiple sclerosis, is being evaluated in phase II trials in pulmonary fibrosis; similarly, Deskar (Marnac) is being evaluated in phase II trials for this indication. Development of natural and artificial elastase inhibitors has the potential to offer therapy to patients with alpha-1-antitrypsin deficiency as well as those who suffer from acute lung injury and ARDS. Alpha Therapeutic is conducting phase III trials to evaluate the effect of administering alpha-1-proteinase to subjects with hereditary emphysema; Sivelestat is a neutrophil elastase inhibitor that has been submitted for regulatory review in Japan by Ono Pharmaceuticals.

Future developments in the field of respiratory disorders will include drugs that stimulate alveolar repair, gene profiling to identify smokers at highest risk for the development of COPD, and increasingly sophisticated anti-inflammatory control that can be used to prevent the deterioration of lung function. For the millions of subjects with chronic pulmonary disease, the strides in the drug development arena present a welcome front against potentially progressive pulmonary disability.