Pharmacologic approaches to the treatment of chronic obstructive pulmonary disease (COPD) are evolving rapidly. Thinking outside of the current comfort zone will be required if treatment of COPD is to be improved, said respiratory experts during a symposium sponsored by Forest Laboratories at Chest 2010.
Current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic despite the available therapies, said Nicola Hanania, MD, MS, Director of the Asthma Clinical Research Center, Baylor College of Medicine, Houston, TX. Furthermore, inadequate adherence to inhaled therapy is a major cause of poor clinical outcomes in the treatment of COPD, he added. “COPD is a systemic disease and a multicomponent disease,” Dr Hanania said. Novel targets of therapy would reduce local and systemic inflammation, and potentially regenerate the lung.
Ultra–Long-Acting Bronchodilators
Bronchodilators remain the cornerstone of treatment and act to control symptoms; long-acting bronchodilators represent an advance over shortacting bronchodilators in improving lung function (as measured by forced expiratory volume in 1 second [FEV1]), said Mario Cazzola, MD, Professor of Respiratory Medicine, University of Rome Tor Vergata, Italy.
“Since it has been difficult to discover novel classes of bronchodilator drugs, the logical approach has been to improve the existing bronchodilators,” Dr Cazzola said.
A once-daily bronchodilator would further improve compliance over the current long-acting agents. Other criteria for a new bronchodilator would include a fast onset of action and drug delivery through an efficient and convenient device (ie, a breathactuated device with effective feedback to indicate successful inhalation), Dr Cazzola said. Several ultra–longacting beta-agonists (LABAs) are currently under development for COPD.
Indacaterol is one candidate as an ultra-LABA. In preclinical models, indacaterol demonstrated a rapid onset of action that correlated with high intrinsic efficacy and a 24-hour duration of action.
Its 24-hour duration of bronchodilation may be a result of its retention in the raft domain of the lipid membrane, Dr Cazzola ex plained. Lipid rafts are areas of cell membranes where beta2-receptors are held together in close contact with signaling molecules and effectors.
In clinical trials of adult patients with COPD, 12 weeks of therapy with indacaterol proved to be superior to tiotropium, formoterol, and to salmeterol in trough FEV1 levels compared with placebo.
Indacaterol was also superior to its comparators on measures of healthrelated quality of life, symptoms of breathlessness, and percentage of days without the use of rescue medication, and it was associated with an increase in the time to a first exacerbation during 1 year compared with placebo.
Carmoterol is another ultra-LABA under investigation. After 14 days of treatment, a 4-μg dose of carmoterol increased peak FEV1 by a mean of approximately 110 mL (placeboadjusted), compared with an increase of 80 mL with salmeterol. Yet another investigational agent in this class, vilanterol trifenatate, produced dose-dependent increases in trough FEV1 as high as 160 mL compared with placebo.
Olodaterol is not as advanced in its development; in preclinical studies, it demonstrated a fast onset of and a long duration of action, Dr Cazzola said.
Attacking Inflammation
Ideal future options for COPD should address the multiple components of the disease, which include, among others, mucous hypersecretion, mucosal damage, inflammation, and loss of alveolar attachments, according to Dr Hanania. Ideally, new therapies would blunt proinflammatory cells, modify disease progression, be compatible with other therapies, and be simple to administer.
In addition to improved treatment, “we should not forget the delivery system,” Dr Hanania said. More effective anti-inflammatory therapy is needed, he said. Phosphodiesterase (PDE) 4 inhibitors have anti-inflammatory action in COPD, and there is strong scientific rationale for their use in COPD, said Dr Hanania. Most PDE 4 inhibitors in development are administered systemically, but some inhaled formulations are in the works, he said.
Roflumilast is the oral PDE 4 inhibitor that is furthest along in development; it inhibits PDE 4 activity in proinflammatory cells and is approved for use in the European Union but not yet in North America.
Roflumilast has been shown to reduce the rate of moderate-to-severe COPD exacerbations before or during the use of bronchodilator agents. When used in combination with a long-acting bronchodilator or long-acting muscarinic antagonist in patients with moderate-to-severe COPD, it has also demonstrated an improvement in lung function. Some inhaled macrolide antibiotics are currently being investigated for the treatment of COPD, according to Dr Hanania. The macrolide antibiotic erythromycin may also act as an antiinflammatory agent to reduce the number of exacerbations in COPD, and studies with macrolides are ongoing, he said.
Relaxing Smooth Muscles
Long-acting antimuscarinic agents also are in development, some in combination with ultra–long-acting bronchodilators, and combinations of inhaled corticosteroids and ultra–longacting bronchodilators are being tested clinically, Dr Cazzola said.
Aclidinium bromide is a new muscarinic antagonist in development. A twice-daily inhaled agent delivered via a dry powder inhaler, it is being investigated for maintenance treatment of COPD.
In placebo-controlled studies it provided long-lasting bronchodilation and was associated with improvements in FEV1 and other measures of lung function. It has a faster rate of onset of the smooth-muscle–relaxing activity than tiotrop ium bromide, the current muscarinic antagonist on the market.
Targeting Oxidative Stress
Because oxidative stress is known to occur in COPD, agents that target reactive oxygen species—the superoxide dismutase inhibitors—hold prom ise in the treatment of COPD, said Irfan Rahman, MSc, PhD, Associate Professor of Environmental Medicine, Lung Biology and Disease Program, Univer sity of Rochester Medical Center, NY.
Antioxidant therapy may affect important outcomes in COPD, such as helping to overcome steroid resistance, mucous hypersecretion, and inflammation. Antioxidants may have a role in combination with antiinflammatory agents, bronchodilators, and other COPD treatments, Dr Rahman said.