American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Aug 2023
Randomized Controlled Trial Multicenter StudyEnsifentrine, a Novel PDE3 and PDE4 Inhibitor for the Treatment of COPD: 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 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. ⋯ gov identifier NCT04542057, EudraCT identifier 2020-002069-32).
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Am. J. Respir. Crit. Care Med. · Aug 2023
ReviewTargeting Type 2 Inflammation and Epithelial Alarmins in Chronic Obstructive Pulmonary Disease: A Biologics Outlook.
Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous, progressive inflammatory airway disease associated with a significant impact on patients' lives, including morbidity and mortality, and significant healthcare costs. Current pharmacologic strategies, including first- and second-line therapies such as long-acting β2-agonists, long-acting muscarinic antagonists, inhaled corticosteroids, phosphodiesterase-4 inhibitors, and macrolides, provide relief to patients with COPD. However, many patients remain symptomatic, with persistent symptoms and/or acute exacerbations and progressive lung function loss. ⋯ Significant progress is being made, with evolving understanding of the pathobiology of COPD leading to novel therapeutic targets including epithelial alarmins. In this review, we describe the current therapeutic landscape in COPD, discuss unmet treatment needs, review the current knowledge of type 2 inflammation and epithelial alarmins in COPD, explore potential biomarkers of type 2 inflammation in COPD, and finally provide a rationale for incorporating therapies targeting type 2 inflammation and epithelial alarmins in COPD. Video Abstract available online at www.atsjournals.org.
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Am. J. Respir. Crit. Care Med. · Aug 2023
Childhood Cigarette Smoking and Risk of COPD in Older U.S. Adults.
Rationale: It is not certain the extent to which childhood smoking adds chronic obstructive pulmonary disease (COPD) risk independent of lifetime cigarette exposure. Objectives: We examined the association between age started smoking cigarettes regularly, current smoking status, smoking history, and risk of COPD. Methods: Cross-sectional survey of U. ⋯ Conclusions: Among adults aged ⩾40 years, one-fifth of childhood smokers have COPD. Lifetime cigarette smoking explained some but not all of the higher risk. If replicated, this suggests a lung development window of enhanced vulnerability to cigarette smoking.