(Laurie Barclay, MD, February 2003)

Chronic obstructive pulmonary disease (COPD) is characterized by obstruction to air flow. It includes emphysema and chronic bronchitis, which frequently coexist. In the U.S., COPD is the fourth leading cause of death, and it claims the lives of more than 100,000 each year. At death, approximately 8.8 million people have chronic bronchitis and 2.8 million have emphysema. More men than women have emphysema, but the condition is increasing among women. National costs for COPD each year exceed $30.4 billion, including healthcare costs of $14.7 billion and indirect costs of $15.7 billion.

Smoking causes 80-90% of COPD cases, although frequent lung infections and exposure to certain industrial pollutants may also be responsible. Smokers are 10 times more likely than nonsmokers to die of COPD. Alpha-1 antitrypsin deficiency-related emphysema is an inherited condition responsible for =<5% of emphysema cases in the U.S.

Symptoms of COPD are gradually progressive, beginning with mild dyspnea and occasional cough, followed by chronic cough productive of clear, colorless sputum. As the disease progresses, coughing becomes more frequent, breathing becomes more labored, and eventually death may ensue from inadequate oxygenation. Shortness of breath and associated symptoms often disable COPD suffers during their peak productive years.

COPD causes the walls of the small airways to thicken and the alveoli to lose their elasticity. In chronic bronchitis, the bronchial lining becomes inflamed and eventually scarred, further narrowing the airway. Mucus plugs may block the airway altogether. Air continues to enter alveoli during inhalation, but it is often unable to escape during exhalation because the air passages collapse. As COPD progresses, many small pulmonary blood vessels are destroyed, while hypoxia causes the remaining vessels to constrict. Resultant right heart failure and cor pulmonale may cause fatigue, cardiac arrhythmias, edema, and secondary polycythemia.

The mainstay of approved treatments for COPD is bronchodilator therapy, including sympathomimetics, parasympathomimetics, and methylxanthines. Corticosteroids lessen inflammation of the airway walls, and are often used in conjuction with bronchodilators. Depending on complications of COPD, antibiotics and diuretics may be indicated. Combination drugs containing varying amounts of sympathomimetics, methylxanthines, expectorants, and sedatives are widely available, but may be problematic, as it is difficult to adjust the dose of methylxanthines without increasing adverse effects from the other ingredients.

In May 2002, the European Federation of Asthma and Allergy Associations issued a patient manifesto calling for healthcare professionals to educate asthma patients that a symptom-free life is possible, and to help them adjust the dose of their own medication depending on symptom control.

CenterWatch had identified a pipeline of 17 drugs in various stages of development for COPD. Furthest along is Seretide (Advair), for which GlaxoSmithKline has submitted an NDA. This combination inhaler consists of the beta-2 agonist salmeterol and the corticosteroid fluticasone. The rationale behind combination drugs is to improve compliance, as patients with COPD want better control of their condition, but are often unwilling to use multiple drugs and inhalers.

Another combination inhaler is Symbicort, in phase III testing in Europe by AstraZeneca. It contains budesonide (Pulmicort®), a corticosteroid, and formoterol (Oxis®), a long-acting beta-2 agonist bronchodilator. Oxis is also available alone as a dry powder in the Turbuhaler® inhalation device. Both products have been widely tested in asthma.

As of February 2003, AstraZeneca has successfully completed the Mutual Recognition Procedure in the European Union for the treatment of COPD with Oxis Turbuhaler as maintenance therapy, with additional doses as required, up to a maximum total daily dose of 36 micrograms. Bronchodilation with Oxis begins within minutes, as rapidly as with salbutamol, and is sustained for at least 12 hours, as long as with salmeterol.

In seven clinical trials involving 2,416 patients, Oxis was an effective maintenance treatment for COPD, and additional doses could be added as needed for symptom relief. In one study of 657 patients, six months of maintenance therapy with Oxis, 9 micrograms twice daily, led to improved lung function, symptom relief, and reduced use of beta-2-agonists for symptom flares.

Another formoterol product is (R,R)-formoterol, a single-isomer bronchodilator in phase III development by Sepracor. In phase II testing, once-daily inhalation was tolerated as well as other beta-agonists, and it significantly improved FEV(1) immediately after dosing, with a duration of action of up to 24 hours.

Serevent (salmeterol xinafoate) is a long-acting, orally inhaled beta-2-adrenergic receptor agonist in phase III testing for COPD by GlaxoSmithKline. Its mechanism of action is to increase cyclic AMP via stimulation of adenyl cyclase, which relaxes bronchial muscle and inhibits release of hypersensitivity mediators. Like other beta-2-agonists, Serevent has come under close scrutiny for possibly increasing morbidity and mortality in asthma, but the preponderance of evidence suggests that it is safe as well as effective. However, pending the results of large cohort studies and ongoing surveillance, patients who use Serevent should be well-educated on its proper use and should be followed carefully.

An alternate approach to bronchodilation is through localized anticholinergic activity, as is the case with Spiriva (tiotropium bromide), in phase III testing by Boehringer Ingelheim. Spiriva has been approved by the Medicinal Evaluation Board in Den Haag, Netherlands for maintenance treatment in COPD. Tiotropium bromide, a new chemical structurally related to ipratropium bromide (Atrovent), is a long-acting inhaled antimuscarinic bronchodilator administered once daily with the HandiHaler inhalation device.

In a six-month study involving 623 COPD patients, those receiving tiotropium had significantly improved lung function measured by FEV1 compared with patients receiving either placebo or salmeterol. Breathlessness and health-related quality of life were also better than in patients receiving placebo. Tiotropium maintained its effectiveness during the course of the study. As would be expected from an anticholinergic drug, the most common side effect was dry mouth.

The selective phosphodiesterase (PDE-4) inhibitors are useful in COPD primarily by reducing release of inflammation mediators. Roflumilast, in phase III testing by Altana, is a highly potent and selective orally administered PDE-4 inhibitor. When tested in asthma, its anti-inflammatory actions significantly decreased late responses to allergen, but it did not act as a bronchodilator.

Ariflo(cilomilast; SB 207499), a phase III product of GlaxoSmithKline, is also an oral PDE-IV inhibitor. In a 6-week, randomized, dose-ranging study in 424 patients with COPD, Ariflo 15 mg twice daily significantly improved FEV1, FVC and peak expiratory flow compared with placebo. Quality of life measures and serious adverse events did not differ significantly between the groups.

Other novel treatment approaches to COPD are in earlier phases of development. Milkhaus Laboratory has completed phase II testing of HP-3, a nucleic acid medication in an oral formulation which works to break up sputum. Phase II testing is underway for talnetant (SB 223412), a tachykinin (NK3) receptor antagonist from GlaxoSmithKline, and ZD4407, a 5-lipoxygenase inhibitor from AstraZeneca.

Pharmaceutical companies developing drugs which will ultimately prove to be useful in COPD can draw on their experience with similar products in asthma. Relaxation of bronchial smooth muscle, inhibition of inflammation mediators, and breakup of mucus plugs may all be effective, while improving selectivity of adrenergic or anticholinergic action increases safety. Offering anti-inflammatory drugs and bronchodilators in combination inhalers may improve symptom control by increasing patient compliance.