CHRONIC OBSTRUCTIVE PULMONARY DISEASE(COPD)

What is chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is a progressive, irreversible restriction of breathing, associated with abnormal inflammation of the lung in response to noxious particles or gases. People with COPD may have chronic bronchitis, emphysema and/or chronic asthma and there is therefore variability in its symptoms. These typically include long-standing cough, sputum production and breathlessness. Smoking is by far the most significant risk factor for developing COPD, followed by exposure to occupational dusts and chemicals and air pollution. A rare hereditary deficiency in alpha-1-antitrypsin may lead to the development of emphysema, but other genetic factors have not been found to be directly responsible for causing COPD. Although COPD shows a steady progression over years, acute exacerbations, about half of them caused by bacterial infection, are common and worsen the outlook for those affected.

Who does COPD affect and how much does it cost?

Around 80 per cent of people diagnosed with COPD smoke, or have smoked. The disease is mainly diagnosed in middle age, because many people do not go to a doctor until their symptoms (usually breathlessness) become troublesome. This may be only after many years of disease progression. About 900,000 people have been diagnosed in England and Wales, but surveys show that many people with reduced lung function go undetected. The Chief Medical Officer has estimated that as many as three million people in the UK may be affected by COPD.

COPD was recorded as the underlying cause of over 23,000 deaths in England and Wales in 2004, but the total number of COPD-related deaths is certainly larger than this. COPD has been estimated to cost the health service over £800 million per year and to have caused 24 million lost working days a year.

Present treatments and shortcomings

No medication has been shown to halt or reverse disease progression in COPD, and the resulting lung damage is permanent. Treatment is aimed at controlling symptoms in a step-wise approach and preventing acute exacerbations. COPD is classified as mild, moderate or severe according to the degree of airflow restriction. Stopping smoking is vital for all those with COPD and is the only intervention that may slow disease progression. Nicotine replacement therapy (with chewing gum, skin patches, lozenges, etc) and treatment with bupropion (Zyban, GSK) are the two main medical options for stopping smoking and are best used together with behavioural support.

Short-acting inhaled bronchodilators (beta₂-adrenoreceptor agonists or anticholinergics) are used to relax the airways on an as needed basis in mild COPD. In moderate disease, long-acting bronchodilators are used instead, either singly or in combination. In more severe COPD, an inhaled long-acting bronchodilator may be combined with an inhaled corticosteroid. Such a combination has been shown to reduce overall death rates significantly and to reduce the number of acute exacerbations.

Long-term administration of oxygen may be needed in more advanced COPD and can be effective in preventing the progression of complications such as raised blood pressure in the lungs, as well as in relieving symptoms of breathlessness. Antibiotics are prescribed during acute exacerbations if there are signs of infection. Vaccination against influenza and streptococcal pneumonia is also recommended, especially in the elderly, and has been shown to reduce death rates.

Pulmonary rehabilitation - a programme of gentle exercise training and advice on lung health and living with COPD - is helpful for many people with moderate to severe breathing difficulties. It is usually run on an outpatient basis by a hospital, although not all hospitals are yet able to provide it. With the help of trained health professionals, participants are able to increase their activity levels, cope better with breathlessness and gain more control over their condition. They will be encouraged to continue exercising after completing the programme. Rehabilitation can also reduce the risks of hospital admission and death associated with acute exacerbations of COPD.

The short-acting beta2 agonists salbutamol (Airomir, IVAX), terbutaline (Bricanyl, AstraZeneca), or the anticholinergic ipratropium bromide (Atrovent, Boehringer Ingelheim) are the usual starting point of therapy in mild COPD. Long-acting agents used in more advanced disease are the beta2 agonists salmeterol (Serevent, GSK) and formoterol (Foradil, Novartis and Oxis, AstraZeneca) and the long-acting anticholinergic tiotropium (Spiriva, Boehringer Ingelheim). Bronchodilators are generally less effective in improving lung function in COPD than in asthma. A fixed combination of short-acting inhaled medications used in mild to moderate COPD is salbutamol + ipratropium (Combivent, Boehringer Ingelheim). The two combination products containing a beta2 agonist and a corticosteroid indicated for use in advanced disease are budesonide + formoterol (Symbicort, AstraZeneca) and salmeterol + fluticasone (Seretide, GSK). In advanced disease not controlled by these inhaled medications, the oral bronchodilator theophylline (Slo-Phyllin, Merck Pharmaceuticals) may be given, but its many interactions with other medicines and high risk of side-effects mean that it is usually reserved for difficult-to-treat cases.

What's in the development pipeline?

Development of new long-acting beta2 agonists and anticholinergics continues. Several new beta2 agonists for potential once-a-day dosing are in development, including indacaterol (Novartis, Phase 3), carmoterol (Chiesi, Phase 2), and several agents in development by GSK (159797, 159802, 597901, 642444 and 678007).

Once-daily anticholinergics in development include LAS34273 (Almirall) in Phase 3 trial and NVA237 (Novartis), at Phase 2. In addition, Novartis has QAT370 at Phase 1 and GSK has compound 233705 in Phase 2. Interestingly, GSK is conducting Phase 1 studies on a compound (961081) that combines the activities of a beta2 agonist and an anticholinergic in a single molecule.

Several new steroids are in Phase 2 development. GSK has compounds 685698 and 799943 in combination with a long-acting beta2 agonist, while Topigen is studying TPI 1020 - a nitric oxide releasing analogue of budesonide. Nitric oxide relaxes smooth muscle, and TPI 1020 has been shown to be superior to budesonide in protecting against narrowing of the airways. In addition, Epigenesis Pharma is studying EPI-12323, which does not provoke the adverse effects associated with glucocorticoids, such as Cushing's syndrome, brittle bones, etc. It has a long duration of action, making it suitable for once-a-day use.

A completely different approach is being developed in studies of inhibitors of the enzyme phosphodiesterase-4 (PDE-4). This enzyme controls the activity of neutrophils, monocytes and macrophages, as well smooth muscle and cells lining the airways, all of which are involved in the damaging inflammatory over-reaction to smoke and dusts seen in COPD. Inhibiting this enzyme should enable inflammation to be reduced. Unlike steroids and beta2 agonists, PDE-4 inhibitors are often given by mouth. Two such inhibitors are at an advanced stage: cilomilast (Ariflo, GSK) has completed trials and roflumilast (Daxas, Nycomed) is in Phase 3 trial. These compounds may provoke some gastrointestinal side-effects, although these mostly decrease after the initial stages of treatment. GSK has an inhaled PDE-4 inhibitor (256066) in Phase 1 trial that may be a suitable alternative. Other PDE-4 inhibitors are being developed by Ono Pharma (ONO-6126, Phase 2), and Forest Labs (Oglemilast, Phase 1).

Other new treatments are based on inhibiting other mediators of the inflammatory response in COPD. Leukotriene B4 and other substances are released during the inflammatory response and can irreversibly damage lung structures. Interfering with such processes, or with the recruitment or function of the inflammatory cells, offers a new approach to treating COPD. Targets include:

• Interleukin-1β (ACZ885, Novartis, Phase 1),
• Leukotriene B₄ (amelubant, Boehringer Ingelheim, Phase 2),
• CXCR2 receptors (Schering-Plough, Phase 2)
• Neurokinins (CS-003, Daiichi-Sankyo, Phase 2)
• p38 mitogen-activated protein kinase (681323 and 856553 GSK, Phase 2).

Finally, a variety of new medicines are being developed with the aim of improving the success rate of smoking cessation. Pfizer has varenicline (Champix) and sanofi-aventis's rimonabant (Acomplia) has completed Phase 3 trials. Sanofi-aventis also has SSR 591813 C 55 Chronic Obstructive Pulmonary Disease COPD) Figure 2: Exercise-based pulmonary rehabilitation has significant benefits in COPD (Dianicline) in Phase 3 trial. GSK has a compound (468816) for this use in Phase 2 study.

Three vaccine-based approaches are also being explored and these have appeared promising in early trials. Celtic Pharma has TA-NIC at Phase 1. Nabi Biopharmaceuticals' NicVAX is expected to enter Phase 2 trial shortly, while the third vaccine, CYT002-NicQb (Cytos Biotechnology), has already completed Phase 2 studies.

The longer-term future

COPD is now the focus of quite extensive research activity, both on smoking cessation and the treatment of its symptoms, but development of a therapy that actually changes the progression of the condition will probably require a more thorough understanding of the very complex processes involved in inflammation. Equally critical are improvements in diagnostic screening that are needed to identify the large number of people who are believed to be affected by COPD but are so far undiagnosed. Nevertheless, prospects for those identified early in the progress of the disease will probably improve significantly as newer therapies become available.

FOR FURTHER INFORMATION CONTACT:

The British Lung Foundation
73-75 Goswell Road
London, EC1V 7ER
Phone: 0845 850 5020 (Helpline)
Website: www.lunguk.org