Current Treatment Options for Asthma and COPD— Are We Satisfied?

There are several differences between the pathophysiologic molecular mechanisms of asthma and COPD. At a symposium held May 18, 2003, a panel of experts discussed these differences and explained the molecular mechanism of both diseases. They also identified new treatment options for asthma and COPD.

This program was supported by an educational grant from ALTANA Pharma AG.

Molecular Mechanisms in the Pathophysiology of Asthma and COPD

Richard Martin, MD, Professor, National Jewish Medical and Research Center, Denver, discussed the pathophysiologic mechanisms of asthma and COPD. “If there is a lot of overlap, then perhaps, in regard to therapy, a single drug or at least a combination of drugs may help both diseases,” said Dr. Martin.

“For all disease entities, we know that there are host factors involved,” he explained. For COPD, the host factor interacts with environmental factors, such as smoking, occupational exposure, and air pollution. Host factors combined with environmental factors lead to airway inflammation, airway hyperreactivity, and mucus hypersecretions. These conditions are in common with asthma. “There are many characteristics in both asthma and COPD that are similar,” he said.

In general, there are distinct differences in the inflammatory component of these two conditions. Usually, the major controller cells are the CD4-positive T lymphocyte in asthma and the CD8-positive T lymphocyte in COPD. “The macrophage may be a controller cell for both asthma and COPD,” he added. Eosinophils often predominate in asthma and neutrophils often predominate in COPD. Regarding cytokines, IL-4, IL-5, and IL-13 are the predominate cytokines in asthma and IL-1, IL-8, and tumor necrosis factor alpha are the predominate ones in COPD.

Dr. Martin summarized two studies on the CD8-positive T lymphocytes in COPD (O’Shaughnessy, et al. Am J Respir Crit Care Med. 1997; 155:852; Saetta, et al. 1998; 157:822). When looking at the large airways, there was a weak, but significant, inverse correlation between lung function and CD8-positive cell counts. This correlation is even more significant in the small airways. “In the small airways, the greater the number of CD8-positive lymphocytes, the lower the lung function in COPD,” he explained. Similarly, a higher sputum neutrophil count is associated with a more rapid decline in lung function.

He reviewed a study that analyzed the differences and similarities of asthma and COPD patients (Fabbri, et al. Am J Respir Crit Care Med. 2003; 167:418). Both groups of patients had relatively nonreversible lung function. Interestingly, the asthmatics had more positive skin tests to allergens. Although there was a wide spread, the mean count of sputum eosinophils was significantly greater in asthmatics than in COPD patients. Likewise, the mean count of sputum neutrophils was significantly greater in COPD patients than in asthmatics. The FEV1 and the FEV1:FEC ratio were virtually the same in both groups. Albuterol provided little FEV1 improvement for either group; however, inhaled steroids led to a 12% improvement in asthmatics, but just a 4% improvement in COPD patients. “Asthmatics appear to respond much better to inhaled steroids,” said Dr. Martin.

There are marked differences between asthmatics and COPD patients in terms of the histopathological characteristics of lung biopsies. Immunohisto-chemical staining demonstrated that asthmatics have higher numbers of eosinophils in lung tissue than COPD patients, as expected. The sub-basement membrane thickness of large airways was minimal for COPD patients but was thickened for asthma patients. “This is a characteristic of remodeling in the asthmatic that we don’t see in the COPD patient,” he explained.

Dr. Martin reviewed findings regarding the location of disease in both asthma and COPD patients. In emphysema patients, the inflammation involves the alveolar spaces. “Is asthma only a larger airway disease that does not extend to the alveolar tissue?” he asked.

To answer this question, he cited a 1990 study that looked at peripheral airway resistance in asthmatics via a bronchoscope (Wagner, et al. Am Rev Respir Dis. 1990; 141:584). In mild asthmatic subjects, peripheral airway resistance was markedly elevated. In another study, eosinophilic staining was evident in the smaller airways, the alveolar tissue area, and even the alveolar septum. “Asthma is an airway disease that can extend all the way to the alveolar tissue,” he said. Therefore, inflammation encompasses both the large and small airways in asthma and COPD.

Because nocturnal worsening of symptoms is a characteristic of asthma, Dr. Martin looked at nighttime transbronchial biopsies of asthma patients. The alveolar tissue area of a nocturnal asthmatic were abnormal at 4 a.m. “There is not one single cell between the alveolar spaces and there’s a tremendous inflammatory influx into the alveolar tissue area,” he said. In comparison, an asthmatic who did not have nocturnal worsening had more normal looking alveolar spaces with much less inflammation.

Dr. Martin concluded by summarizing the similarities and differences of asthma and COPD. “Some aspects are very similar and some are markedly different. “A question remains if a single drug can be developed to treat both asthma and COPD,” he said.

Potential Targets of Pharmaceutical Intervention

“As clinicians, how can we approach therapeutic targets for these kinds of diseases?” began Stephen Rennard, MD, Larson Professor for Research in Respiratory Diseases, University of Nebraska Medical Center, Omaha.

He used an ancient reference on strategy by a Japanese philosopher as an analogy for targeting disease. According to this philosopher, there are only three ways to forestall the enemy. “You can attack first, you can attack at the same time as the enemy, or you can attack after the enemy attacks,” explained Dr. Rennard who added, “I think we can gain some insight from this, in terms of how we can approach the very complex pathophysiology of these diseases.”

Dr. Rennard explained the concept behind the use of retinoids in the treatment of COPD. Retinoids would fit into the “attack after the enemy” strategy. Early in development, the lung buds from the gastrointestinal tract undergo a well-defined series of differentiation stages. The branching airways invade the surrounding mesenchyme and, as the process continues, both the epithelium and mesenchyme between the branches thin. By birth, the opposite layers of epithelium have become very closely opposed and become gas exchange units in the primitive alveolar sac.

“These gas exchange units are not alveoli,” explained Dr. Rennard. Alveolarization is a secondary process that, in humans, occurs just prior to and following birth. “The process of alveolarization is under complex hormonal control,” he said. Retinoids play a key role in this process. Animal studies have shown that retinoids can induce alveolarization after emphysema has developed. Retinoids are currently being tested in humans.

“For the majority of the therapies that we talk about most often, we’re really talking about attacking at the same time,” said Dr. Rennard. This means treating the disease once it’s been diagnosed. “We’re trying to mitigate the progression of disease,” he explained.

“Inhaled glucocorticoids have been tested, both in asthma and COPD, with remarkably unsatisfying effects on disease progression,” said Dr. Rennard. In a large study of children with mild to moderate asthma, inhaled budesonide or nedocromil failed to alter the reduction in lung function growth. Similarly, in a large study of COPD patients, inhaled budesonide did not alter the rate at which lung function is lost.

“There was a small improvement in lung function compared to placebo over the first six months,” he said. After that, the rate of lung function decline was the same for both study groups. In another study, by Jones et al., the effects of steroids on the number of exacerbations of COPD were analyzed (Eur Respir J 2003;21:68). Inhaled fluticasone caused a statistically significant reduction in the number of exacerbations as compared with placebo. “Steroids not only reduced exacerbations, they also had an effect on health status, or quality of life,” explained Dr. Rennard.

Dr. Rennard stressed that FEV1 is not the only parameter that should be evaluated in asthma and COPD. “FEV1 is not a great predictor of health status,” he explained. How far somebody can walk correlates much better with their health status than how well they can breathe. He cited a study that found no association between the 12-minute walking distance and FEV1. COPD patients are weak, and their weakness is a much better correlate of their performance than is their lung function.

“When we think about targets for these diseases, we need to vastly broaden our approach so we can bring to bear the new technologies on things that are meaningful for our patients,” he said. According to Dr. Rennard, any drug that targets neutrophils would be good because it is believed that neutrophils are doing bad things. However, it remains unclear as to whether CD8 lymphocytes should be targeted. “Because we’ve seen biopsy studies from only a few dozen patients, it may be premature to think that CD8 cells are the secret of the disease,” he explained. Although increasing numbers of CD8 lymphocytes is correlated with worsening disease, it isn’t known whether they are causing or mitigating disease.

Phosphodiesterase 4 inhibitors are very appealing targets because they increase cAMP levels in cells. This results in anti-inflammatory actions on CD8 cells, neutrophils, monocytes, macro-phages, and a variety of other cells. “Many of these effects ought to have beneficial effects in asthma and COPD,” Dr. Rennard explained. He described a study conducted by Kohyama and colleagues that looked at the effect of phosphodiesterase 4 inhibitor on fibroblasts (Am J Respir Cell Mol Biol. 2002;26: 694). Fibroblasts were chosen because they are believed to mediate scar formation, such as peribronchiolar fibrosis. Increasing amounts of phosphodiesterase 4 inhibitor results in the inhibition of contraction of fibroblast cells. “It may be possible to mitigate the tissue remodeling effects with therapeutic approaches like this,” said Dr. Rennard.

Patients with these lung conditions can have different things going on. “If we think about targeting the pathophysiologic mechanisms in these patients, some of those targets will be appropriate for some patients and some targets will not be appropriate for some patients,” said Dr. Rennard. He concluded, “I think that the burden is going to be on clinicians to come up with more appropriate ways of segregating these patients and of developing appropriate clinical endpoints for assessing these targets.”

Emerging Role of PDE 4 Inhibitors in The Treatment of Asthma and COPD

The most familiar phosphodiesterase (PDE) inhibitor is theophylline. “I’ve spent half my career trying to debunk theophylline, yet it always comes back and there is some interest there,” said Peter Calverley, MD, Professor of Respiratory Medicine, University of Liverpool, United Kingdom.

Theophylline has a bad reputation because of adverse effects such as cardiac rhythm disturbances and convulsions. “People thought, wouldn’t it be nice if we could split down those components of theophylline that might be helpful?” he said.

“We’ve already seen a variety of phosphodiesterases, which have some beneficial effects,” said Dr. Calverley. “In lung disease, we’re mostly interested in PDE 3 and PDE 4 inhibition,” he added. Use of these drugs is associated with bronchodilation and, perhaps, anti-inflammatory effects. “The PDE 4 inhibitors might hit a lot of cells, innocent bystanders or active participants alike, in the diseases we would like to modify,” he explained. In particular, neutrophils and eosinophils would be affected.

According to Dr. Calverley, many pharmaceutical companies have pursued phosphodiesterase 4 inhibitors. “A very large number of them haven’t worked or have been deemed to have problems that the company thought was not worth pursuing,” he explained. There are two contenders left standing: cilomilast and roflumilast.

These PDE 4 inhibitors have not had serious cardiac or neurological toxicity. Cilomilast is not as highly selective as roflumilast. Using Norwegian brown rats in an asthma model, roflumilast was more effective at inhibiting alveolar eosinophil influx following challenge with inhaled ovalbumin than cilomilast, which in turn was more effective than theophylline.

Roflumilast has good bioavailability following oral administration and has a long half-life of about 10 hours, plus an active metabolite, roflumilast-N-oxide, that has a half-life of 20 hours. “You can give it once a day, which is good,” said Dr. Calverley. Roflumilast doesn’t interfere with other enzymes, reducing the chances for drug-drug interactions. These properties are in common with cilomilast, though cilomilast is dosed twice a day. He believes that these PDE 4 inhibitors are more likely to do something original and different in COPD than in asthma. Cilomilast was relatively ineffective for asthma and the asthma research program was discontinued at a fairly early stage. Roflumilast is still being pursued as both a COPD and an asthma medication.

In a biopsy study of COPD patients, the PDE 4 inhibitor caused a significant reduction in the numbers of CD8-positive T lymphocytes, smaller reductions in the numbers of CD4-positive T lymphocytes and neutrophils, and no changes in the expression of IL-8 or TNF alpha. “This is the first time that anybody has seen a change in these cells with a pharmaceutical intervention in a COPD population,” said Dr. Calverley. He added, “PDE 4 inhibition may be a way to modify disease, or at least test the role of inflammation in COPD.”

Dr. Calverley summarized a placebo-controlled study of cilomilast in COPD (Lancet. 2001;358:265-70). Over the course of the 6-week study, there was a FEV1 difference of approximately 160 mls between both arms of the study. Even when a bronchodilator is used at the beginning and the end, the increase with the bronchodilator is similar. “Cilomilast is not just acting as a bronchodilator, it’s probably modifying something else on top of that,” explained Dr. Calverley. Patients who received placebo felt about the same as they did when they started the study. Those who received the PDE 4 inhibitor had a significant improvement in well being and an improvement in symptoms.

A 6-month dose ranging study of roflumilast in COPD patients was conducted. Patients receiving placebo exhibited a small improvement but those receiving roflumilast exhibited a significant, although modest, improvement in FEV1. Patients in the roflumilast group had a 48% reduction in the number of exacerbations, as compared with an 8% reduction in the placebo group. “The total number of exacerbations, over six months in each of the study arms, was around 12 to 18,” commented Dr. Calverley. This tiny number of exacerbations reflects the problems of defining exacerbations in the COPD population. Safety data was encouraging and suggests that roflumilast is better tolerated than cilomilast.

He summarized another large 6-month study of roflumilast in COPD patients. Patients who received roflumilast had a 75 ml improvement in FEV1, which was higher than placebo. There was evidence that roflumilast has a biological effect, but there were no significant changes in health status in this study. “We’re not seeing changes that are large enough in this one study to shift health status or exacerbation numbers largely because these people were not sick enough,” explained Dr. Calverley. According to Dr. Calverley, this problem has occurred before with the inhaled steroids. “At the moment for COPD, we can say that at least one of the PDE 4 inhibitors, roflumilast, is relatively well tolerated and does have a small effect,” he concluded.

Dr. Calverley reviewed studies of roflumilast in asthmatics. In a large dose ranging study, the higher dose of roflumilast resulted in a mean increase in FEV1 of about 400 mls. Other studies on asthmatics include an open label extension study, a comparator study using a standardized dose of beclomethasone, and allergen challenge studies. In one asthma allergen challenge study, the inflammatory response was attenuated by two different doses of roflumilast, most effectively by the higher dose.

“I find it comforting to suggest that all these cells, all of these networks, all of these things that ought to be blocked by PDE 4 inhibitors, can be translated in a model system which is clinically relevant,” explained Dr. Calverley.

“Ultimately, I think we need to apply the same sort of rigor in conducting clinical trials that we do in conducting bench top experiments. I think that if we do that, then we’ll get a clearer idea of where these potentially very important drugs are going to fit in with our future use of them,” Dr. Calverley concluded.

Faculty Disclosures

Peter Calverley, MD
Off Label Use

Richard Martin, MD
Consultant: GlaxoSmithKline, Schering, 3M, Aventis, Forest, Merck, AstraZeneca, ALTANA
Research Funding: GlaxoSmithKline, Schering, 3M, Aventis, Forest, Merck, AstraZeneca, ALTANA
Speaker’s Bureau: GlaxoSmithKline, Schering, 3M, Aventis, Forest, Merck, AstraZeneca, ALTANA

Stephen Rennard, MD
Consultant: Amersham, AstraZeneca, Aventis, Bayer, Byk Gulden-Altana, Genaera, GlaxoSmithKline, Globomax, Novartis, Ono Pharma, Otsuka, RJ Reynolds, Roche, Sanofi-Synthelabo, Schering-Plough
Speaker: AstraZeneca, Boehringer Ingelheim, Byk Gulden-Altana, GlaxoSmithKline, Novartis
Laboratory and Clinical Research: Centocor, Elan, GlaxoSmithKline, Novartis, Pfizer, Philip Morris, RJ Reynolds, Sanofi-Synthelabo, Schering-Plough