HONOLULU – Current interventions for chronic obstructive pulmonary disease leave many patients with unmet needs, according to Dr. Nicola A. Hanania.
"We know from large clinical trials that current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic with current therapies," Dr. Hanania, director of the asthma clinical research center at Baylor College of Medicine, Houston, said at the annual meeting of the American College of Chest Physicians.
Dr. Nicola A. Hanania
Inadequate adherence to therapy "is a major cause of poor clinical outcomes in the treatment of COPD," he said. The cost, compliance, and safety of certain agents are issues "that we cannot ignore."
When considering a therapy for COPD, clinicians should factor in components of COPD beyond bronchoconstriction, he advised, including mucociliary dysfunction, structural changes in the airway and the lung, systemic components, and airway inflammation. "We also have to look at outcomes other than lung function including exacerbations, activity limitation, and symptoms of dyspnea," he said. "We are no more satisfied with just a drug that improves lung function but does nothing for the patient-reported outcomes."
Dr. Hanania’s "wish list" for an ideal COPD therapeutic option in the future is one that addresses the multiple components and phenotypes of COPD. He said he would like to see drugs that blunt proinflammatory cells and molecules known to be involved in COPD. "We’d also like to see drugs that could modify the disease progression and comorbid conditions," he said. Such drugs, he continued, should be well tolerated and compatible with other therapies for COPD and comorbid conditions, be simple to administer, and have the potential to improve patient adherence, he added.
Treatment approaches being studied include novel formulations of existing medications, such as the combination of ultralong-acting beta-2 agonists and long-acting antimuscarinics. Among the agents that are the most promising on this front, he said, are indacaterol plus glycopyrronium (QVA-149) and vilanterol plus GSK-573719.
Other agents in development include bifunctional muscarinic antagonist–beta-2 agonists such as GSK-961081 and THRX-200495 as well as combinations of once-daily long-acting beta-2 agonists and inhaled corticosteroids, including formoterol and mometasone (MFF258) and vilanterol and fluticasone (Relovair).
However, perhaps the most promising pharmacotherapies will be novel agents aimed at reducing local and systemic inflammation. "We know that COPD is an inflammatory disease, so we need drugs that can target inflammation right from the very beginning," Dr. Hanania explained. "Inhaled steroids are important, but they’re not as effective in COPD as they are in asthma."
Phosphodiesterase type 4 inhibitors are currently being studied in COPD. These agents reduce the activity of neutrophils, macrophages, and CD8-positive T-lymphocytes, as well as the expression of cytokines and other inflammatory mediators. Currently, the only phosphodiesterase type 4 inhibitor approved in the United States for use in patients with COPD is roflumilast (Daliresp). Several others are in development.
"We know from large clinical trials that current pharmaco-therapies do not change the natural history of COPD."
Because they target airway inflammation, p38 mitogen-activated protein kinase inhibitors are also being studied in COPD patients. However, so far clinical trials have found potential problems related to systemic side effects and toxicity, "indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure," Dr. Hanania said.
He concluded his presentation by noting that certain medications used to treat comorbidities in COPD may have beneficial effects on COPD outcomes. These include statins, ACE inhibitors, beta-blockers, peroxisome proliferator–activated receptor agonists, and macrolides. The National Heart, Lung, and Blood Institute COPD Clinical Research Network is currently conducting a prospective randomized controlled trial in 1,126 patients with severe COPD randomized to daily simvastatin (40 mg) vs. placebo for at least 1 year. The primary outcome is exacerbation of COPD. The secondary outcomes include change in forced expiratory volume in 1 second (FEV1), St. George’s Respiratory Questionnaire responses, 6-minute walk test results, BODE Index score, a combined cardiovascular end point, and serum inflammatory biomarker levels. Furthermore, a recent study showed that daily azithromycin significantly reduced exacerbations in high-risk patients.
Dr. Hanania disclosed that he has received grant support from the National Institutes of Health, the American Lung Association, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Sunovion, Novartis, Pfizer, and Forest Pharmaceuticals. He also serves as a consultant for GSK, Dey Pharmaceuticals, Sunovion, Pfizer, and Forest, and is a member of the speakers bureau for GSK, BI, AstraZeneca, and Forest.