At the 2010 meeting of the American College of Chest Physicians, American Health & Drug Benefits asked Dr Hanania to weigh in on the current and emerging therapies for chronic obstructive pulmonary disease (COPD).
What is the current state of COPD therapy, and why are newer options needed?
We have therapy for COPD that can improve symptoms, exercise tolerance, and quality of life (QOL). The concern is that despite available therapy, many patients with COPD continue to have symptoms and exacerbations that require emergency department visits and even hospitalization.
Current therapy does not modify the cause of the disease, and this has been shown in 2 large trials—UPLIFT (Understanding Potential Long-Term Impacts on Function with Tiotropium) and TORCH (Towards a Revolution in COPD Health), which showed that although the current therapies— including long-acting bronchodilators and the long-acting bronchodilator/ inhaled corticosteroid combination— can improve frequency of exacerbations and improve QOL, they have a limited effect on the declining lung function that occurs over time with COPD, which is a major problem.
Also, available therapies have a minimal effect on mortality. COPD is now the third (up from fourth until recently) leading cause of death in the United States.1,2 In addition, some COPD medications have dose-dependent side effects.
Finally, cost is also an issue for current therapies. Many patients cannot afford using them, because they are expensive.
Has there been any breakthrough in COPD treatment in the past few years?
The biggest breakthrough is that guidelines written for COPD consider it a treatable disease. For many years we approached COPD as a disease that happens in smokers, and that we could not do much for them. We had a nihilistic attitude about treatment; we did not believe that treatment could improve outcome.
Since the past few years, with the release of the landmark trials (UPLIFT and TORCH), we know that treatment does improve outcomes, but there is still a way to go. There is still the need for more intervention.
Where do we stand with delivery systems?
Some patients, especially elderly patients, have problems with certain delivery systems. Currently, most COPD medications are delivered through the inhaled route. The inhaler devices are not all the same. Some are easier to use than others. We have metered-dose inhalers, dry powder inhalers, and nebulizers. In some patient populations, one delivery system may be better than the other. In addition to what drug we give the patient, it is important to keep in mind that the choice of delivery system plays a major role in the acceptance of the medication, as well as adherence.
Can you discuss some of the newer agents in development?
There are 4 areas of new drugs or new interventions. One is the development of drugs similar to what we have now, except in a simpler platform, such as once-daily drugs and combination therapies. Many companies are developing once-daily long-acting bronchodilators, including once-daily long-acting beta-agonists (LABAs), once-daily long-acting anticholinergic (antimuscarinic) agents (LAMAs), and a combination of these 2—what we call a LABA/LAMA combination.
Some manufacturers are looking at a combination of a once-daily LABA/ inhaled corticosteroid. The agents we have now are twice daily. The emerging drugs will be much of the same agents we have today, but with oncedaily inhaled delivery system.
Many of them are in phase 3 trials. The most advanced is indacaterol, which is a once-daily LABA. It is approved in Europe and in some countries in South America, but not in the United States. Others are in phase 2 or starting phase 3 trials, including vilanterol, olodaterol, and carmoterol.
The others are LAMAs. Probably the most advanced is aclidinium. It can be once daily or twice daily. The problem with aclidinium is that it may not be as long-acting as tiotropium, but there are other options.
The second avenue is to look at novel therapeutic targets. COPD is an inflammatory disease, and multiple pathways of inflammation can be targeted. The most advanced group of drugs in this field is the phospho diesterase (PDE) 4 inhibitors. Roflu - milast is approved in the European Union but not yet in the United States. It is still under review by the Food and Drug Administration (FDA) and may be approved early in 2011. It is an oral agent with once-daily dosing, which is an advantage.
Roflumilast has anti-inflammatory activity, but it is not a bronchodilator. It has decreased exacerbations in most of the clinical studies as a standalone therapy, but it is more impressive when added to long-acting bronchodilators. It will have to be studied as stand-alone therapy to get FDA approval, but in my mind, it will be used as an add-on therapy. The effect is very significant when added to long-acting bronchodilators.
Several drugs that target mediators of inflammation are being studied. Many of these studies so far have been disappointingly negative. For example, anti–interleukin-8 has been looked at, as well as leukotriene B4 inhibitors and anti–tumor necrosis factor-alpha inhibitors.
Several mitogen-activated protein (MAP) kinase inhibitors are in phase 2 trials; MAP kinase may play a role in chronic inflammation. The problem with these agents is potential toxicity. They are given systemically (by mouth), so inhaled versions will probably need to be developed to reduce systemic exposure.
Drugs such as antioxidants and synthetic protease inhibitors are potentially beneficial, but it is too early to tell how effective they will be. Some of them are targeting thiol (an extra- and intracellular antioxidant in the lungs) and inflammation of the alveoli. Retinoids are also being tested right now, but they are very early in development.
The third group of interest includes drugs that we use for other comorbidities, which may have an effect on COPD. There is some interest in statins in COPD; they may reduce exacerbations. They have anti-inflammatory effects and were shown in observational studies to decrease exacerbations and even mortality. STATCOPE (Prospective Randomized Placebo-Controlled Trial of Sim vastatin in the Prevention of COPD Exacerbations) is a large multicenter study that will investigate simvastatin in COPD.
Another group is prophylactic antibiotics. Inhaled antibiotics are in early development in COPD to prevent exacerbations. Inhaled levofloxacin and ciprofloxacin are 2 such antibiotics in the fluoroquinolone class.
By which mechanism would antibiotics be acting in COPD?
These are antibacterial agents— bronchial bacterial colonization is a problem in COPD that could contribute to progression of airway disease and decline in lung function, but bacterial colonization is also associated with airway inflammation, and antibiotics may also have anti-inflammatory effects.
Macrolides are another group of antibiotics being investigated in COPD; erythromycin has been shown to decrease exacerbations. A large macrolide study (with erythromycin over 1 year) has just been completed, but the data will only be presented at the 2011 meeting of the American Thoracic Society
Some studies suggest that cyclic oral antibiotics may be effective. One study showed that giving moxifloxacin for 5 days every 8 weeks on a cyclic basis decreases exacerbations compared with placebo, but we are not ready to pre scribe antibiotics to everybody with COPD.
Beta-blockers also look like they may have an effect on COPD, but it is too early to know. In one recent study, beta-blockers were associated with reductions in mortality and risk of exacerbations in COPD.
What is the fourth intervention being investigated?
The fourth area is nonpharmacologic interventions, such as bronchoscopic avenues for patients with emphysema. One trial involved putting valves in the upper lobes of patients with emphysema. Lung volume reduction surgery is also being performed for patients with end-stage disease (severe emphysema in the upper lobes).
What do you envision 3 or 4 years from now?
This is a very slow-moving field, which is a bit frustrating. New drugs are expensive to research, and the US Food and Drug Administration has put in many safety issues, which is important but slows approval.
A few years from now, we will likely have 1 or 2 of the LABAs available. The PDE 4 inhibitor roflumilast will probably come on board in 2011, but I do not think we will move far forward. Five years down the road we will likely see more of the novel agents on the market.
The key question is, how will longacting bronchodilators compete with the drugs we have now? Many of the current agents will go off patent and will be cheap. They may have to be given twice daily, but if they are cheaper, they may still be preferred, because patients may not be able to afford the long-acting medications. That is a concern now. This is a competitive field, and the long-acting bronchodilators will have to differentiate themselves. People will also have to look at an easier way of delivery.
Nebulized delivery is emerging— in the United States at least—so there may be more combination therapies in a nebulized platform.
- Centers for Disease Control and Prevention. Stroke drops to fourth leading cause of death in 2008. Press Release. December 9, 2010. www.cdc.gov/media/pressrel/2010/r101209.html. Accessed January 4, 2011.
- Centers for Disease Control and Prevention. National Center for Health Statistics, 1960-2010. www.cdc.gov/nchs/data/about/nchs_50th_brochure.pdf. Accessed January 4, 2011.