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).

Article Details

Citation Copy to clipboard

Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, Sciurba F

Am J Respir Crit Care Med. 2023 Aug 15;208(4):406-416. doi: 10.1164/rccm.202306-0944OC.

PubMed ID

37364283 [ View in PubMed

]

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 beta(2)-agonists, respectively. Post-bronchodilator FEV(1) percentage predicted values were 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV(1) 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).

DrugBank Data that Cites this Article

Drugs: Ensifentrine