Dr Nicola Hanania on the Future of COPD Research

Several studies have demonstrated the benefits of triple therapy in patients with chronic obstructive lung disease (COPD) with a history of frequent and/or severe exacerbations.

Although these trials mark a step in the right direction for patients with COPD, more research needs to be done to understand both the phenotypes and endotypes of the disease, explained Nicola Hanania, MD, MS, a pulmonary critical care physician and director at the Airway Clinical Research Center, Baylor College of Medicine in Houston, Texas.

In an interview with The American Journal of Managed Care^® (AJMC^®), Hanania discusses findings of his most recent analysis investigating the effects of triple therapy among older patients and lays out some potential areas of future research into the disease.

Hanania, who has 26 years of clinical experience, is also an interim section chief of the pulmonary critical care section at Ben Taub Hospital in Houston.

The following interview has been edited for length and clarity.

AJMC^®: You recently coauthored an analysis looking into the effects of age on the efficacy and safety of once-daily, single-inhaler triple therapy in patients with COPD. What did you find?

Hanania: This was an analysis of a large study that looked at the effect of triple therapy in COPD. The study is called IMPACT, which showed the efficacy and safety of triple-inhaler therapy, including inhaled corticosteroid (ICS) when added to long-acting β₂-agonist (LABA)/long-acting muscarinic antagonist (LAMA) in COPD. We were interested to see if a subgroup of patients had a better effect than others. Obviously, with aging, one gets worried about side effects and toxicity of giving medications in older patients. In this subanalysis, we looked at whether the main findings in this study—which showed superiority of triple therapy and exacerbation reduction—were still sustained in a population of older individuals.

Basically, we replicated what we've seen in the younger population and in the general study population, in patients who are 65 and older. We did not find a different response in patients who are older to such a therapy, which is reassuring because although not all patients with COPD are older, some of them are, and these patients have other comorbidities, including cardiovascular [problems] and others. One has to make sure that these patients—although this is a clinical trial, it's not a real-life study—that older patients received the same benefit as the younger patients with no increased risk of adverse effects. That was our main finding.

We also have now looked at a large population of studies, the paper is still in press, in the International Journal of COPD, looking at triple therapy, not just in one device, but in separate devices. [This] replicated very similar findings that in general, in older individuals with COPD, use of triple therapy is a safe and effective. Now obviously this has to be underlined with the fact that not every patient with COPD will need triple therapy, I have to emphasize that.

AJMC^®: Studies have indicated triple therapy can result in a reduction in all-cause mortality compared with dual and monotherapies. Do you believe this finding is class effect?

Hanania: I think very interesting data have come from both the IMPACT study as well as the ETHOS study. These are 2 large clinical trials that looked at 2 different triple combinations of inhalers, LABA/LAMA/ICS, different devices, different chemicals, but similar compounds. [Both used] long-acting beta-agonists, long-acting muscarinic antagonists, and an inhaled steroid. While these effects on mortality were not the primary end points of these studies, when [researchers] looked at the analysis of these trials, effect on mortality was significant, especially in those patients with high risk of exacerbation.

I think we're coming to an era in COPD where we don't have any good drugs to decrease mortality (as you know, COPD is the 3rd leading cause of death around the word and 4th in the United States), to finding some hope, at least on reduction in mortality. But I have to underline the fact that mortality outcomes in both these trials were not the primary outcome of the studies. Scientifically, you have to be very careful. The main outcome of the studies was exacerbation reduction. Both of them achieved that, and triple therapy does decrease exacerbation in patients with high exacerbation risk. Mortality was reduced. It wasn't the primary outcome. I think we have to do a large study looking at it as a primary outcome. But I definitely strongly believe these data are not just a fluke, they are very important data, we cannot ignore them.

AJMC^®: What are the next steps for research on triple therapy?

Hanania: We're in the era with COPD of phenotyping, and of course endotyping. And it's always nice to know who would be the most responsive to triple therapy. I have to underline the fact that ICS in COPD have been overused for many years and continue to do so. We know that the GOLD strategy and American Thoracic Society guidelines for COPD emphasize [them] and inhaled steroids should be entertained in patients with a high risk of exacerbation. There are data that show that patients with high blood eosinophils may be good patients to respond or at least where you can treat them with ICS-containing agents. Those are data are emerging.

What I see in the future is we need more biomarkers to help us subdivide these patients to better personalize the approach for this disease. We are there partly but not completely. I think it would be nice to know which of the phenotypes responds best to triple therapy. If the effect of mortality is correct, should that be taken seriously for patients with moderate COPD? We don't know that. The patients enrolled in these studies all had severe COPD with history of exacerbation. But is there an effect on modifying the disease by giving these patients triple therapy early in the disease? We have no idea whether that's true. Until we do, we shouldn't be rushing into using it as first-line therapy. Disease modification is a big unmet need in COPD, as it is in asthma and other airway diseases. Can we modify the disease? We know smoking cessation does. We have not seen any drugs so far, other than oxygen therapy, that can reduce mortality. Now the triple therapy can in the subpopulation of severe disease. Can they do so in patients with early COPD? We don't know yet. That's a big unmet need. But that requires huge studies, commitment, and long-term follow up. I think that is an unmet need and it answers an important question. Another unmet need is developing more biomarkers in COPD. Now we are looking at not only biomarkers biologically, but also radiologic biomarkers that may help [providers]. If I see a computed tomography (CT) scan, I will decide, well, this patient may respond best to this treatment versus that. Radiologic biomarkers are emerging, I think it's a great tool. It's not ready for primetime use in clinic yet. That's another unmet need, is developing new biomarkers for this disease.

AJMC^®: In your opinion, what does the future of COPD research look like, taking into account the COVID-19 pandemic, and rises in risk factors like vaping and air pollution? What are other priorities in this field?

Hanania: I think you can look at this at different levels. I think for many years, we sort of thought about COPD as the “blue bloaters” and the “pink puffers” and it was a simple disease, one size fits all. But that is not true. In the year 2021 now, we know that this disease has multiple faces, multiple phenotypes and also endotypes. We're still working on those. Endotypes reflect the mechanism of the disease. On a genetic part, there's quite a bit of data accumulating about the potential gene, or susceptible genes for COPD that need to be elaborated upon and continued. On an environmental part, we know that not all COPD patients are smokers. There are other exposures that need to be looked at. But what about the nonsmokers with COPD? We don't know too much about those, but they do exist, [and account for] maybe 20% of patients with COPD. The contribution of other exposures like vaping [should be explored]. Secondhand smoke is something that needs to be looked at.

On a biologic level, we need to look at more the mechanisms, biomarkers, and mediators so that we can target biologics. Right now, there are several studies ongoing to look at biologics in COPD, these are using monoclonal antibodies or small molecule inhibitors. It'd be nice if we shut down the cascade of inflammation in COPD. Can we prevent the disease from progressing? We don't know yet. There are also other targeted therapies to look at mucociliary dysfunction, mucus hypersecretion. We need some drugs to look at remodeling and restructuring of the airway and destruction of the lung. That's another area that needs to be looked at.

On a clinical level, I think we've done quite a bit on phenotyping of this disease. We know some of the clinical tools to divide the patients on exacerbators, or those with chronic bronchitis and those with emphysema. I think more tools to help us as clinicians divide these [cohorts are needed].

You can see that the needs are multilevel and starting from the genetic part, the biologic part, the environmental part, and the clinical part, which is good in a way. It keeps us busy as COPD researchers. But there's a need for investment in these studies, not only from pharma, but also from other entities and foundations and of course, the NIH, to help us. You mentioned COVID-19 and I think that's another area that is of interest. COVID-19 is here to stay. It did affect our patients with COPD. Unfortunately, they are at higher risk of worsening. There are some data to show that some medication like ICS may be helpful in these patients. How does it fit in the equation? We don't know yet. I think that's something that maybe needs to be also added as one of the unmet needs: is to study more the effect of COVID-19 on this population and post COVID-19, what happens to these patients, which we still don't know.

AJMC^®: Is there anything we did not touch on you would like to include, or do you have any final thoughts you'd like to share?

Hanania: People may be interested in nonpharmacological approaches. There are emerging nonpharmacologic approaches for COPD, such as bronchoscopic lung volume reduction. It's something that we're getting more and more acquainted with. FDA approved a couple of valves that can be implanted in patients with emphysema, which may help their dyspnea and shortness of breath. I think we're seeing an expansion of pharmacologic therapies. I'm very pleased that biologic therapies are being looked at. There is a light at the end of the tunnel for these patients. But we're not there yet. We still need to continue to work on how to improve outcomes.