Ensifentrine improves lung function, exacerbations, quality of life in patients with COPD

Key takeaways:

• Patients with COPD experienced several improvements with 3 mg of twice-daily ensifentrine over 24 weeks.
• Patients receiving ensifentrine reported a similar number of adverse events as patients receiving placebo.

WASHINGTON — Over 12 or 24 weeks, patients with COPD receiving ensifentrine showed improved measures of lung function, quality of life and exacerbation rate, according to an American Thoracic Society International Conference presentation.

“What we know today is that ensifentrine demonstrated evidence to be a bronchodilator and an anti-inflammatory to a different mechanism, nonsteroidal anti-inflammatory efficacy, by improving lung function, improving symptoms and reduction in exacerbations,” Antonio Anzueto, MD, ATSF, professor of medicine and section chief of pulmonary at South Texas Veterans Health Care System, said during the presentation. “Exacerbation reduction was consistent across all the clinically important subgroups, and ensifentrine was generally well tolerated with an adverse [event] profile compared to placebo.”

In two global, multicenter, randomized, double blind, parallel-group, placebo-controlled phase 3 trials (ENHANCE-1 and ENHANCE-2), Anzueto and colleagues analyzed adults with moderate to severe COPD who were symptomatic and smoked a minimum of 10 pack-years to determine if 3 mg of twice-daily nebulized ensifentrine (Verona Pharma) changed baseline FEV₁ area under the curve (AUC) from 0 to 12 hours at week 12 compared with placebo.

In ENHANCE-1, 477 patients received ensifentrine and 283 received placebo, and these numbers were slightly greater in ENHANCE-2, with 498 patients receiving ensifentrine and 291 patients receiving placebo, according to the presentation.

Combining both cohorts, the demographics included 55% aged 65 years or older, 47% women and 56% current smokers. Further, the overall population had a mean predicted FEV₁ of 51.5%, 62% on LABA or LAMA, and 18% on LABA or LAMA plus inhaled corticosteroids.

Further, slightly more than half of the overall population (56%) had moderate COPD, 72% had chronic bronchitis and 23% had an exacerbation within 15 months of screening, according to the presentation.

In both trials, patients receiving ensifentrine showed a significant increase in average FEV₁ AUC over 12 hours compared with placebo (ENHANCE-1, + 87 mL; ENHANCE-2, + 94 mL; P < .001 for both).

Patients receiving ensifentrine also demonstrated statistically significant peak FEV₁ vs. placebo, with a FEV₁ peak of 147 mL in the first trial and 146 mL in the second trial (P < .001 for both). Compared with placebo, morning trough FEV₁ measures were also significantly higher in the ensifentrine group (ENHANCE-1, + 35 mL; P = .041; ENHANCE-2. + 49 mL; P = .002).

Researchers also observed better symptom and quality of life scores in patients receiving ensifentrine compared with placebo in both trials. When looking at both scores in these patients, Anzueto’s presentation slide said that the drug showed “early and sustained improvement.” Compared with placebo, ensifentrine showed improvement in Evaluating Respiratory Symptoms (E-RS) scores at week 6 (P < .05), week 12 (P ≤ .01) and week 24 (P < .05) in ENHANCE-1, and this was also observed in ENHANCE-2 at week 6 (P ≤ .001) and week 12 (P < .05).

Quality of life was measured using the St. George’s Respiratory Questionnaire, and researchers found that patients receiving ensifentrine in ENHANCE-1 had significant score improvements at week 6 (P < .05), week 12 (P ≤ .01) and week 24 (P < .05). No significant improvements were observed in ENHANCE-2, according to the presentation.

Dyspnea, measured using the Transition Dyspnea Index, also improved in patients taking ensifentrine, Anzueto said. Compared with placebo, in both ENHANCE-1 and ENHANCE-2 ensifentrine showed improvement in breathlessness at week 6 (P ≤ .001 for both), week 12 (P ≤ .001; P ≤ .01) and week 24 (P ≤ .001 for both).

When evaluating use of rescue medication, Anzueto’s slide said that there was a “consistent decrease in daily mean rescue medication use” with ensifentrine, and this was seen at week 12 (P ≤ .01) and week 24 (P ≤ .001) in ENHANCE-1 and week 6 (P < .05) and week 12 (P < .05) in ENHANCE-2.

Over 24 weeks, researchers also found significant decreases in moderate/severe COPD exacerbation rates with ensifentrine compared with placebo. Patients receiving this drug had a 36% (P = .0503) reduction in exacerbation rate in ENHANCE-1, with an even greater reduction rate in ENHANCE-2 at 43% (P = .009). Further, this effect was found across several subgroups that broke patients down by their smoking status, background medication, use of inhaled corticosteroid, chronic bronchitis, baseline eosinophils and history of exacerbations. Notably, when dividing patients based on FEV₁ reversibility, this treatment effect was only borderline significant for ensifentrine vs. placebo with a reversible FEV₁ (RR = .09; 95% CI, 0.49-1.88).

In ENHANCE-1, researchers evaluated patients for up to 48 weeks, and over this time they observed that ensifentrine (n = 280) compared with placebo (n = 89) had a 44% exacerbation rate reduction (P = .052) and 52% exacerbation risk reduction (P = .007), according to the presentation.

Additionally, time to first exacerbation was delayed in patients receiving ensifentrine, with a 38% (P = .0382) risk reduction in ENHANCE-1 and a 42% (P = .0089) risk reduction in ENHANCE-2, according to the presentation.

Lastly, Anzueto said that in both trials, ensifentrine had a similar incidence of serious treatment-emergent adverse events — including those that made a patient discontinue the study — to placebo, demonstrating that it was well tolerated. In both trials, there were different adverse events that more than 1% of patients receiving ensifentrine reported. In ENHANCE-1, these patients experienced back pain (2.5%), hypertension (1.3%) and toothache (1.3%), whereas in ENHANCE-2, patients with this treatment reported COPD (2.2%), diarrhea (1.6%), nasopharyngitis (1.8%) and sinusitis (1.2%).

Regarding the 1.6% of patients that experienced diarrhea, Anzueto said this adverse event did not start in the expected 2 to 4 weeks of starting therapy but instead after 3 to 4 months.

"So there doesn't seem to be any association with any of the events that we have seen," Anzueto said.