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)

Rationale: Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and anti-inflammatory effects. Replicate Phase 3 trials of nebulized ensifentrine were conducted (ENHANCE-1 and ENHANCE-2) to assess these effects in patients with COPD. Objectives: To evaluate the efficacy of ensifentrine compared to placebo on lung function, symptoms, quality of life and exacerbations in patients with COPD. Methods: Phase 3, multi-center, randomized, double-blind, parallel-group, placebo-controlled trials, conducted between September 2020 and December 2022 at 250 research centers/pulmonology practices in 17 countries. Patients 40-80 years with moderate/severe, symptomatic COPD enrolled. Main Results: 760 (ENHANCE-1) and 789 (ENHANCE-2) patients were randomized and treated, with 69% and 55% taking concomitant LAMA or LABA, respectively. Post-bronchodilator FEV1 was 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV1 AUC0-12h vs placebo (ENHANCE-1: 87mL [95% CI 55,119]; ENHANCE-2: 94mL [65,124]; both p<0.001). Ensifentrine treatment significantly improved symptoms (E-RS) and quality of life (SGRQ) vs placebo at Week 24 in ENHANCE-1, but not ENHANCE-2. Ensifentrine treatment reduced the rate of moderate/severe exacerbations vs placebo over 24 weeks (ENHANCE-1: RR=0.64 [0.40,1.00], p=0.050; ENHANCE-2: RR=0.57 [0.38,0.87], p=0.009) and increased time to first exacerbation (ENHANCE-1: HR=0.62 [0.39,0.97], p=0.038; ENHANCE-2: HR=0.58 [0.38,0.87], p=0.009). Adverse event rates were similar to 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 registrations available at www.clinicaltrials.gov, IDs: NCT04535986, NCT04542057. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).