Recent findings presented at the American Thoracic Society (ATS) 2025 International Conference highlight the therapeutic potential of ensifentrine, a novel dual phosphodiesterase 3 and 4 inhibitor, for patients with chronic obstructive pulmonary disease (COPD).
Novel Dual Mechanism Offers New Treatment Pathway
Ensifentrine represents the first new mechanistic approach to COPD treatment in years, working through a completely different pathway than traditional therapies. Dr. M. Bradley Drummond, professor of medicine at the University of North Carolina at Chapel Hill and co-medical director of UNC Pulmonary Specialty Clinics, explained the significance of this innovation.
"Historically, we've had three basic targets to help treat patients with COPD: long-acting muscarinic antagonists (LAMAs), long-acting β agonists (LABAs), which are airway bronchodilators, and inhaled corticosteroids (ICS)," said Dr. Drummond. "Ensifentrine is novel in that it is a phosphodiesterase 3 and 4 inhibitor delivered through a nebulized system."
This dual mechanism provides both bronchodilatory and anti-inflammatory effects, potentially addressing multiple aspects of COPD pathophysiology. The medication may also play a role in reducing mucus hypersecretion, a common and troublesome symptom for many COPD patients.
Addressing Unmet Needs in COPD Management
Despite maximal therapy with existing inhaled medications, many COPD patients continue to experience inadequate disease control, persistent shortness of breath, frequent exacerbations, and reduced lung function. The COPD community has long awaited new therapeutic options to address these challenges.
"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," Dr. Drummond noted. "The uptake of this medication is because it targets these key outcomes: lung function, exacerbations, and symptom improvement, in a totally novel mechanism."
The disease burden of COPD remains substantial, with up to 50% of US patients reporting bothersome symptoms that impact their daily lives. Ensifentrine's approval by the FDA in 2024 offers a new option for these patients.
ENHANCE Trial Results Support Efficacy
The FDA approval of ensifentrine was based on data from the phase 3 ENHANCE clinical trial program, which consisted of two randomized, double-blind, placebo-controlled trials (ENHANCE-1 and ENHANCE-2) involving approximately 800 patients with moderate to severe, symptomatic COPD across North America and Europe.
Two posters presented at the ATS conference focused specifically on the approximately 40% of ENHANCE participants who were not on any background maintenance therapy at enrollment. These analyses aimed to determine ensifentrine's efficacy as a stand-alone treatment.
Improved Lung Function and Reduced Exacerbations
The first poster demonstrated that patients receiving ensifentrine monotherapy experienced statistically significant improvements in lung function compared to placebo. This was evident in both the forced expiratory volume in 1 second (FEV1) area under the curve and FEV1 peak values at serial time points.
Importantly, there was also a numerical reduction in exacerbation frequency among patients receiving ensifentrine who were not on any background maintenance therapy before enrollment. These findings aligned with the results observed in the larger study population.
Enhanced Patient-Reported Outcomes
The second poster focused on patient-reported outcomes, revealing that ensifentrine monotherapy significantly improved measures of dyspnea, COPD symptoms, and health-related quality of life compared to placebo.
Specifically, the Transition Dyspnea Index (TDI) was significantly improved at all assessment points with ensifentrine monotherapy versus placebo. At week 24, the ensifentrine group had a least-squares mean of 2.0 (95% CI, 1.6 to 2.3) compared to 1.1 (95% CI, 0.7 to 1.5) in the placebo group (P <.05).
The Evaluating-Respiratory Symptoms (E-RS) Total Score was also reduced with ensifentrine monotherapy versus placebo at weeks 6, 12, and 24. Additionally, the St. George's Respiratory Questionnaire (SGRQ) Total Score showed significant improvements at weeks 6 and 12 (P <.05), with numerical improvements versus placebo at week 24.
Patients treated with ensifentrine monotherapy also demonstrated reduced rescue medication use compared to placebo at all assessment points (P <.05), with a week 24 least-squares mean change from baseline of -0.86 versus -0.36 average daily puffs in the placebo group.
Flexible Treatment Option
One of the key advantages of ensifentrine is its flexibility in treatment positioning. The FDA approval indicates the drug for maintenance therapy for COPD without specifying whether it must be used as an add-on to existing medications.
"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," Dr. Drummond explained. "These two posters 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 that there is a benefit of lung function, exacerbation reduction, and symptom improvement."
This flexibility allows clinicians to consider ensifentrine as either a first-line therapy for symptomatic COPD patients or as an add-on for those already on standard inhaler regimens who require additional symptom control.
Clinical Implications
As the first nebulized non-steroidal therapy with a novel dual mechanism of action, ensifentrine represents an important addition to the COPD treatment arsenal. The data presented at ATS 2025 supports its use across different patient populations and treatment scenarios.
For patients not yet on maintenance therapy, ensifentrine offers a new first-line option with demonstrated benefits in lung function, symptom control, and quality of life. For those already on standard therapies but with persistent symptoms, it provides a mechanistically distinct add-on option that may address previously untreated aspects of the disease.
The availability of ensifentrine expands treatment options for clinicians managing patients with COPD, potentially improving outcomes for this chronic, progressive respiratory condition that continues to pose significant challenges for patients and healthcare systems alike.
