Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials)

Abstract

Rationale: Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and antiinflammatory effects. Replicate phase III trials of nebulized ensifentrine were conducted (ENHANCE-1 and ENHANCE-2) to assess these effects in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of ensifentrine compared with placebo for lung function, symptoms, quality of life, and exacerbations in patients with COPD. Methods: These phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trials were conducted between September 2020 and December 2022 at 250 research centers and pulmonology practices in 17 countries. Patients aged 40-80 years with moderate to severe symptomatic COPD were enrolled. Measurements and Main Results: Totals of 760 (ENHANCE-1) and 789 (ENHANCE-2) patients were randomized and treated, with 69% and 55% receiving concomitant long-acting muscarinic antagonists or long-acting β₂-agonists, respectively. Post-bronchodilator FEV₁ percentage predicted values were 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV₁ area under the curve at 0-12 hours versus placebo (ENHANCE-1, 87 ml [95% confidence interval, 55, 119]; ENHANCE-2, 94 ml [65, 124]; both P < 0.001). Ensifentrine treatment significantly improved symptoms (Evaluating Respiratory Symptoms) and quality of life (St. George's Respiratory Questionnaire) versus placebo at Week 24 in ENHANCE-1 but not in ENHANCE-2. Ensifentrine treatment reduced the rate of moderate or severe exacerbations versus placebo over 24 weeks (ENHANCE-1, rate ratio, 0.64 [0.40, 1.00]; P = 0.050; ENHANCE-2, rate ratio, 0.57 [0.38, 0.87]; P = 0.009) and increased time to first exacerbation (ENHANCE-1, hazard ratio, 0.62 [0.39, 0.97]; P = 0.038; ENHANCE-2, hazard ratio, 0.58 [0.38, 0.87]; P = 0.009). Adverse event rates were similar to those for placebo. Conclusions: Ensifentrine significantly improved lung function in both trials, with results supporting exacerbation rate and risk reduction in a broad COPD population and in addition to other classes of maintenance therapies. Clinical trial registered with www.

Clinicaltrials: gov and EudraCT (ENHANCE-1, www.

Clinicaltrials: gov identifier NCT04535986, EudraCT identifier 2020-002086-34; ENHANCE-2, www.

Clinicaltrials: gov identifier NCT04542057, EudraCT identifier 2020-002069-32).

Keywords: COPD; dual PDE3 and PDE4 inhibitor; ensifentrine; nebulized therapy.

Figure 1.

(A) Patient flow in the ENHANCE-1 trial. Proportions are based on the modified intention-to-treat population (mITT). Randomized patients excluded subjects from two trial sites because of significant noncompliance with Good Clinical Practice. *The 48-week subset in ENHANCE-1 was randomized 3:1. ^†n = 281 allocated to ensifentrine (n = 280 treated; mITT). ^‡n = 89 allocated to placebo (n = 89 treated; mITT). ^§Patients were allowed to remain in the trial after discontinuing treatment. There were 18 (3.8%) ensifentrine-treated and 11 (3.9%) placebo-treated patients who discontinued treatment because of an adverse event. (B) Patient flow in the ENHANCE-2 trial. Proportions are based on the mITT. Randomized patients excluded subjects from one trial site because of significant noncompliance with Good Clinical Practice. *Patients were allowed to remain in the trial after discontinuing treatment. There were 24 (4.8%) ensifentrine-treated and 14 (4.8%) placebo-treated patients who discontinued treatment because of an adverse event. BID = twice daily; COPD = chronic obstructive pulmonary disease.

Figure 2.

(A) Kaplan-Meier plot of time to first moderate or severe chronic obstructive pulmonary disease (COPD) exacerbation over 24 weeks in the ENHANCE-1 trial (modified intention-to-treat population [mITT]). Hazard ratio versus placebo (95% confidence interval [CI]), 0.62 (0.39, 0.97); P = 0.038. (B) Kaplan-Meier plot of time to first moderate or severe COPD exacerbation over 24 weeks in the ENHANCE-2 trial (mITT). Hazard ratio versus placebo (95% CI), 0.58 (0.38, 0.87); P = 0.009.