Ensifentrine Shows Promise as Add-On, Stand-Alone Therapy in COPD: M. Bradley Drummond, MD, MHS

Ensifentrine showed improved lung function, reduced exacerbations, and better patient-reported outcomes of breathing and overall chronic obstructive pulmonary disease (COPD) management, says M. Bradley Drummond, MD, MHS, professor of medicine, University of North Carolina at Chapel Hill. The findings were presented at the American Thoracic Society (ATS) 2025 International Conference.

This transcript was lightly edited; captions were auto-generated.

Transcript

Can you breakdown the dual mechanism of ensifentrine and how it has revolutionized COPD treatment/management?

Historically, we've had 3 basic targets to help treat patients with COPD; these are our long-acting muscarinic antagonists [LAMAs] and our long-acting β agonists [LABAs], which are airway bronchodilators. Then, we have inhaled corticosteroids [ICS]. So those are the 3 main targeted mechanisms that we have to treat our patients. Ensifentrine is novel in that it is a phosphodiesterase 3 and 4 inhibitor delivered through a nebulized system. These medications target the lungs by bronchodilatory mechanisms. They also are anti-inflammatory, and they may have some role in mucus hypersecretion. What's exciting about these medications is that they're a totally different target than what we have with our previously existing LAMAs, LABAs, and ICS. The appeal of this medication is potentially as either an add-on to existing therapies or as a novel therapy on its own for maintenance.

Can you discuss how this drug is helping to address unmet needs among patients with COPD?

The addition of this medicine in our toolbox has been very helpful, because many of our patients with COPD, despite maximal existing inhaled therapies, still don't have sufficient disease control. They're still short of breath, they have frequent breathing flares or exacerbations, and they have reduced lung function. We really as a COPD community have been waiting for new medications to try to help us improve these important outcomes, both physiologically and from the patient's perspective. I think that the uptake of this medication is because it targets these key outcomes: lung function, exacerbations, and symptom improvement, in a totally novel mechanism, and having the ability to use it on its own or as add-on therapy is really what's made it an exciting addition to our toolbox.

Two posters on ensifentrine were presented at ATS. Can you share the findings?

The original ENHANCE program, which was ENHANCE-1 [NCT04535986] and ENHANCE-2 [NCT04542057], which were the studies that ultimately got the drug approved by the FDA, were published last year. These were 2 parallel studies, a large group of COPD patients, and the patients could be on different combinations of medications to be enrolled in the study. They could be on no maintenance medication. They could be on a bronchodilator with or without inhaled corticosteroids. The 2 posters that are relevant to this discussion are both posters that try to answer the question, “What is the benefit of ensifentrine in patients who are not on any background maintenance therapy when they enrolled in the study?” ENHANCE-1 and ENHANCE-2 reported all the data pooled together and showed that there were improvements in lung function, reduction in exacerbations, and improvement in patient-reported outcomes of shortness of breath. But what we don't know is, where does this fit as far as its own initiation of therapy in patients who previously aren't on any baseline medication? That's what these 2 posters are about.

One poster does focus on lung function and also reads out exacerbation data. About 40% of the ENHANCE participants were not on any background medication, so these 2 posters focus on that 40%. When you look at comparing the ensifentrine vs placebo, you do see an improvement in the lung function with ensifentrine compared to placebo, which was statistically significant. This is both at looking at the FEV₁ [forced expiratory volume in 1 second] area under the curve or also looking at the FEV₁ peak value at serial time points. Importantly, there was also a numerical reduction in the exacerbation frequency in these patients who were not on any background maintenance therapy before starting or at time of enrollment. These findings were really aligned with what was seen in a larger study. That's one poster that focused on lung function and also reports out the exacerbation data.

The second poster focuses on the patients’ reported outcomes, so objective measures of shortness of breath and measures of COPD disease control. Similar to the parent studies, this subgroup analysis of the 40% of patients who were not on background maintenance therapy, again, the trends in some of them were significant. [Some] saw improvements in patient-reported outcomes of shortness of breath, as measured by several different standardized questionnaires in the group receiving ensifentrine compared to placebo. This is important because the FDA approval for this medication, the indication is for maintenance therapy for COPD, but it doesn't say that it has to be added on to existing medication, because the study didn't require that the study included patients who are also on background or on no background medication.

These 2 posters, I think, help frame if there's a benefit of ensifentrine in patients who are not on any other therapy but are symptomatic, and the data would support from these 2 posters that there is a benefit of lung function, exacerbation reduction, and symptom improvement. I think this helps clinicians understand that we don't have to use this exclusively as an add-on therapy to people already on inhalers, but if somebody wanted to start this as a first-line therapy for symptomatic COPD, these data would support that there is a clinical benefit.