Chronic obstructive pulmonary disease (COPD)

Ensifentrine

The US Food and Drug Administration (FDA) has approved ensifentrine, a first-in-class dual selective phosphodiesterase (PDE)-3 and PDE-4 inhibitor, for the maintenance treatment of COPD in adults. Ensifentrine combines both bronchodilator and nonsteroidal anti-inflammatory effects within a single molecule delivered via a standard jet nebulizer. In phase 3 trials, ensifentrine significantly improved lung function (FEV1) at 12 weeks compared with placebo (mean difference versus placebo: 92.29 mL [pooled estimate]).[228] Meta-analysis found a statistically significant decrease (40%) in the annualized event rate of moderate or severe COPD exacerbations compared with placebo (based on pooled 24 week data).[228] Only one of the two phase 3 trials reported a statistically significant improvement in quality of life in the ensifentrine group.[229] Ensifentrine appeared to be well tolerated; clinical benefits were apparent when used as monotherapy and with other maintenance therapies.[229] Ensifentrine is not approved in Europe as yet.

Statins

Statins (HMG-CoA reductase inhibitors) are emerging medications in COPD that have been shown to improve some outcomes, with some improvement in lung function of patients with moderate to severe COPD.[230] Although retrospective studies showed decreased rate and severity of exacerbations, hospitalization, and mortality in patients using statin therapy, especially in patients with coexisting cardiovascular disease (CVD) or hyperlipidemia, a prospective study failed to prove this benefit.[231] In a meta-analysis of randomized controlled trials of patients with COPD taking statins, clinical outcomes were better in patients with coexisting CVD, elevated baseline C-reactive protein (CRP), or a high cholesterol level.[232] Further evidence in support of better outcomes in patients with CVD includes a meta-analysis of patients with COPD and comorbid pulmonary hypertension, which revealed improvements in both pulmonary artery pressure and distance walked in 6 minutes following statin therapy.[233] Another meta-analysis compared high-intensity statins with placebo in patients with COPD. Use of statins resulted in a reduction in CRP and interleukin-6, but did not lead to significant difference in exercise capacity or quality of life.[234] [ ]

Interventional therapies

Target lobe volume reduction, a novel technique for selective bronchoscopic lung volume resection, has now become available. In this technique, a one-way valve is inserted into the hyperinflated and emphysematous segment, leading to the collapse of the nonfunctional lung segment. Promising reports have been released from case series of patients undergoing this therapy. This approach is an alternative to surgical lung volume reduction in patients with COPD who are likely to require surgery.[235][236] [ ]

Pharmacogenomic therapy

Pharmacogenomic therapy may be important in COPD. It is important to identify the genetic factors that determine why certain heavy smokers develop COPD and others do not. Identification of genes that predispose to the development of COPD may provide novel therapeutic targets.[237][238]

Club cell protein 16 augmentation

Club cell protein 16 (CC16) is mainly produced by the Club cells (formerly known as Clara cells) in the respiratory tract epithelium. CC16 has anti-inflammatory properties in smoke-exposed lungs, and COPD is associated with CC16 deficiency. Experimental augmentation of CC16 levels reduces inflammation and cellular injury, and so CC16 augmentation may be a new disease-modifying treatment for COPD.[239]

Monoclonal antibodies

Monoclonal antibody therapy targeting interleukin (IL)-5 or its receptor may be beneficial in patients with COPD with an eosinophilic phenotype.[240][241] One Cochrane review found that treatment with mepolizumab or benralizumab resulted in a greater reduction in moderate and severe exacerbations than placebo. A subsequent meta-analysis of patient data from the phase 3 COPD mepolizumab clinical trials indicated that patients with higher blood eosinophil counts experienced greater reduction in moderate and severe exacerbations.[242] Phase 3 studies of mepolizumab and benralizumab in COPD are ongoing. Other monoclonal antibodies in trials for COPD mostly target acute exacerbations, and include the IL-4 receptor antagonist dupilumab.[243] Dupilumab is approved in Europe for add-on maintenance treatment in adults with uncontrolled COPD characterized by raised blood eosinophils. However, it is not approved in the US for this indication as yet. One randomized placebo-controlled phase 3 trial of patients with COPD with blood eosinophil count of ≥300 cells/microliter and an elevated exacerbation risk (despite the use of standard triple therapy) found that dupilumab reduced exacerbations and respiratory symptoms, improved FEV₁, and improved quality of life.[244]

Other medical therapies

The increasing awareness of the role of inflammation in COPD has led to consideration of drugs that attack various targets in the inflammatory cascade. Many broad-spectrum anti-inflammatory drugs are now in phase 3 development for COPD and may enter the COPD market within the next decade. Nitric oxide inhibitors, leukotriene modifiers, and tumor necrosis factor antagonists are among these novel therapies.[245] Long-term (≥6 months) treatment with acetylcysteine may decrease exacerbation prevalence but does not appear to affect exacerbation rate, lung volumes, or FEV₁.[246] Antiplatelet therapy is associated with decreased all-cause mortality in patients with COPD, independent of cardiovascular risk.[247] Epidermal growth factor receptor kinase has potential to combat mucus overproduction. Therapy to inhibit fibrosis is being developed. There is also a search for serine protease and matrix metalloprotease inhibitors to prevent lung destruction and the subsequent development of emphysema, as well as drugs such as retinoid that may even reverse this process.[248]

Emerging treatments