Therapeutic Strategies in the Management of COPD - Episode 10
Fernando J. Martinez, MD: Is there something for a primary care clinician, who has 14 chronic diseases to manage in a 7-minute period of time, because he’s got 35 patients that he has got to see, that can help us in terms of predicting when there’s going to be benefit with a particular therapy?
There’s large, controversial, evolving literature regarding the role that circulating eosinophils have. There have been 5 papers in the last week-and-a-half published on this, with contradictory results. I don’t know the exact answer to this, whether eosinophils identify a person that has more of Frank’s allergic asthmatic component, whether that’s the biological process, or whether it’s the patient’s host response to deal with viral infections with eosinophils that are supposed to be aiding us. Exactly why that’s occurring is unclear to me. There is a hint, amongst multiple studies, that eosinophils are likely going to be predictive. But in whom, and at what threshold, I still think remains unclear. What do you guys think?
Frank C. Sciurba, MD, FCCP: Fernando, for the first time in this discussion, mentioned an important term, “personalized.” The other words for that are “precision medicine” and “targeting.” Jim talks about the WISDOM study, which was a non-inferiority study. When you withdrew steroids, it didn’t meet the non-inferiority criteria. Therefore, we say steroids didn’t benefit. But the reality is, about 5% more exacerbations, not statistically significant or not inferior, occurred. In that 5% of people who suffered, the point is finding biomarkers to identify the subgroups of patients, whether they’re clinical biomarkers or blood eosinophils. If we use the old-fashioned style, where we have 1000 patients in a trial, and the average goes up here, but you look at the individuals and some of them are dropping while a bunch of them are going up, and a bunch of them are staying the same, and you start looking more precisely at that group, you’re going to dissect patients who benefitted and didn’t benefit. Can we predict those up front? That is the key question. Eosinophils are currently the bullseye in determining whether it is going to work or not, and we need to dissect it a little further.
Byron Thomashow, MD: The COPD Foundation, working with the FDA, set up a biomarkers consortium. The concept was that biomarkers, as most people know, serve as endpoints for clinical trials. So, they’re really important. If you do a drug study and you aim for a biomarker that the FDA doesn’t recognize, the study may be fine, but you may not get your drug approved. So, the COPD Foundation has run this. Frank is now the medical director, and eosinophil counts are one of the ones we hope to look at.
Fernando J. Martinez, MD: We’ve already submitted a letter to the FDA that eosinophils are going to be coming their way.
James F. Donohue, MD: One of the things with eosinophils, in the studies we lose our power when we start looking at 500, 600 cells. There’s just never enough numbers in the study. However, if you do have enough, the risk of an exacerbation, when you start getting up to 400 and 500 cells, becomes 50%. So, you can do a quantitative analysis around that concept to come up with a quantitative estimate of what the risks of these various drugs are. That’s coming out in the Chest Journal. It’s online now, but I think we all should look forward to that.
Peter L. Salgo, MD: I seem to hear that we can go without the inhaled corticosteroids but, in a subset where eosinophils may be higher than we would like, then steroids might make sense?
Byron Thomashow, MD: I think you come back to the question that you asked Jim. So many people are on triple therapy, already. I can’t tell you that’s wrong. For some people, it’s probably right. I will tell you that I do what Frank does. If they’ve had a history of pneumonia, if they’ve got osteoporosis, if they’ve got other concerns, I’d be more likely to try to downgrade them off of the inhaled steroid to a LAMA/LABA. On the other hand, if someone comes in to me and they’re doing fine, and they don’t have those issues, I’m probably going to leave them alone. But perhaps, more importantly, as a starting point, if they’re very mild, maybe you could use a LAMA alone? But beyond that, I’m with Frank. I start with a LAMA/LABA combination, unless this eosinophil thing or the asthma concept would change it.
Frank C. Sciurba, MD, FCCP: As an example of a complexity, if they have a little osteoporosis and 7% eosinophils, are you less likely to taper them?
Byron Thomashow, MD: I am probably less likely to, and more likely to treat their osteoporosis.
Frank C. Sciurba, MD, FCCP: So, there’s not absolutes here. We’re beginning to take these into account. If they had 0%, but they’ve had a bunch of flare-ups and they’ve previously been tapered, are you going to taper that steroid? No, because it’s not an absolute.
Byron Thomashow, MD: That’s correct.
Peter L. Salgo, MD: What are the eosinophils doing? Are they reacting to some etiologic agent, or are they actually the primary cause of the symptoms and the disease?
James F. Donohue, MD: We can say that in an exacerbation, it’s usually primarily neutrophils and macrophages. And then, the eosinophils come in later. That’s why we use oral corticosteroids or systemic corticosteroids in the treatment of an acute exacerbation. But clearly, some patients have asthma/COPD overlap and they express this Th2 inflammation. We can measure it by looking at eosinophils, and things like that. So, I think it’s a little bit of everything. The inflammatory cascade has a lot of different components.
Byron Thomashow, MD: The one thing I think we can all agree on is that systemic steroids have only 1 role in this disease, 5 to 7, maybe 10, but 5 to 10 days during an acute exacerbation. For all of these people who come in to us on 5 mg, 10 mg, 20 mg of prednisone, for years, that has no role in this disease.
Peter L. Salgo, MD: What about if exacerbations are continuing despite an inhaled regimen? What else can you add to decrease the exacerbation?
James F. Donohue, MD: Two drugs that have been used widely, they have some evidence behind them and they’re part of a PCORI (Patient-Centered Outcomes Research Institute) study, would be Daliresp, a phosphodiesterase-4 inhibitor, and azithromycin, a common antibiotic used daily, macrolides. They’re actually being compared in a study, but most physicians use either. The side effect profile of the phosphodiesterase-4 inhibitor is a little bit more pronounced with gastrointestinal side effects, but they’re both approved drugs. Not approved for that indication with the macrolide, but widely used. And, in development now with these asthmatic phenotypes, a lot of people are looking at biologics that have been used in asthma for COPD. But I don’t find that as terribly attractive to me.
Byron Thomashow, MD: There are a couple of nebulized versions of phosphodiesterase-4 inhibitors that may be coming fairly soon that don’t have the gastrointestinal side effects. They might be worthwhile.
Frank C. Sciurba, MD, FCCP: I have a comment that relates to this question, the future of this question, and the last question. There was a biological experiment which was just presented at the European Respiratory meetings. It was put online by the New England Journal of Medicine 2 years ago. The experiment tested a drug, mepolizumab, which is an IL-5 modulator that specifically decreases eosinophil count. This drug only worked in patients with an elevated eosinophil count. It abrogated eosinophil levels within 4 weeks to almost 0%. The higher the eosinophil count, up front, the more likely we are to reduce exacerbations with this drug. So, that answers a biological question of, is the eosinophil the bear, or the bear track? It suggests that, at least in part, the eosinophil is the bear. And the second thing is, that could be Jim’s fifth drug, after it goes to the FDA and he does his usual presentations to convince them that it’s a worthwhile drug.
Transcript edited for clarity.