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). To evaluate the efficacy of ensifentrine compared with placebo for lung function, symptoms, quality of life, and exacerbations in patients with COPD. 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. 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 β-agonists, respectively. Post-bronchodilator FEV percentage predicted values were 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV 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  < 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];  = 0.050; ENHANCE-2, rate ratio, 0.57 [0.38, 0.87];  = 0.009) and increased time to first exacerbation (ENHANCE-1, hazard ratio, 0.62 [0.39, 0.97];  = 0.038; ENHANCE-2, hazard ratio, 0.58 [0.38, 0.87];  = 0.009). Adverse event rates were similar to those for placebo. 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.

gov and EudraCT (ENHANCE-1, www.

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

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