Global projections estimate that the incidence of chronic obstructive pulmonary disease (COPD) is likely to rise in the coming decade and become the third most common cause of death, worldwide, by 2030.1 Current COPD treatment focuses on symptom management, predominantly with the use of bronchodilators. However, despite these treatments many patients continue to experience exacerbations, which contribute significantly to both patient and healthcare disease burden.2,3 Consequently, recent COPD research has concentrated on optimizing existing treatments, in addition to the continued development of novel compounds. These topics continued to be a focal point of presentations and discussions at the 103rd American Thoracic Society (ATS) International Congress, held in San Diego, CA, US, on May 18–23, 2018.
In their late breaking oral presentation, Mereo showed data from the phase II randomized controlled AETHER clinical trial evaluating BCT-197 (acumapimod), a P38 Inhibitor for the treatment of acute severe exacerbations of COPD. The study enrolled 282 patients with ongoing severe exacerbations requiring hospitalizations and treated them with one of two doses of BCT-197 or placebo, in addition to standard of care for 5 days. After 7 days of treatment, patients demonstrated a significant improvement from baseline in forced expiratory volume in 1 second (FEV1) with both high and low doses of BCT-197 compared with placebo (p<0.012 and p≤0.001). Additionally, high dose BCT-197 reduced the number of COPD exacerbations requiring re-hospitalization in the 3–5 months after the original exacerbation event by ≥50% compared with placebo. The safety profile of BCT-197 was expected for the trials patient population.4
Also focusing on COPD exacerbations, Cirassia presented data from the phase IV ASCENT study, assessing the long-term effect of the long-acting muscarinic antagonist (LAMA) aclidinium (400 µg twice-daily) on exacerbations, and its cardiovascular safety in patients with moderate to very severe COPD. In contrast to most COPD trials, which exclude patients with cardiovascular morbidities, of the 3,589 patients enrolled in ASCENT, nearly half had a history of a cardiovascular event and nearly all had at least two atherothrombotic risk factors. During the first of year treatment, aclidinium reduced the rate of moderate to severe COPD exacerbations by 22% (p<0.001), and exacerbations requiring hospitalization by 35% compared with placebo (p=0.006). Given that cardiovascular disease is the most common COPD comorbidity, Cirassia’s application to include the ASCENT data in Aclidinium’s US prescribing information will likely be an important step in advancing treatment options for this patient group.5,6
Cirassia also presented data from the AMPLIFY trial, evaluating the efficacy of the bronchodilator combination, aclidinium/formoterol (400 µg/12 µg twice-daily) compared with the individual components. Aclidinium/formoterol improved FEV1 by 84 mL (p<0.0001) from baseline compared with aclidinium monotherapy and trough FEV1 by 55 mL from baseline compared with formoterol monotherapy (p<0.001).6,7 These results continue to build the evidence base for aclidinium/formoterol in COPD.
Sunovion presented results of several post hoc pooled analyses of randomized controlled trials, focusing on the effect of patient airway reversibility to bronchodilators and smoking status as factors in treatment responses. An analysis of the LAMA glycopyrrolate, given as monotherapy, demonstrated treatment benefits over placebo including improvements in lung function and patient quality of life regardless of airway reversibility.8 In two separate analyses of over 2,000 patients, glycopyrrolate combined with the long-acting-β2 agonist (LABA) indacaterol improved lung function, patient quality of life, and shortness of breath regardless of patient smoking status and airway reversibility.9,10
In news from a compound currently in clinical development, Verona Pharma presented data on their first-in-class dual phosphodiesterase 3 and 4 inhibitor, RPL554, designed to have both anti-inflammatory and bronchodilator properties. In a phase IIa, double-blind, cross-over trial, 30 patients received either RPL554 (1.5 or 6 mg) or placebo twice-daily for 3 days in addition to the LAMA, tiotropium (once daily). The trial demonstrated that both doses of RPL554 produced statistically significant (1.5 mg, p=0.002; 6 mg, p<0.001) and clinically meaningful (>100 mL) additional improvements in lung function (peak FEV1) compared with placebo, when administered with tiotropium. Additionally, both doses of RPL554 produced a faster onset of bronchodilation than placebo (~4 versus ~38 minutes; p<0.001) and reduced air trapping in the lungs (p<0.05), an effect which could contribute to reduced dyspnea. RPL554 was found to be well tolerated with a safety profile consistent with previous studies of RPL554 and tiotropium.11 Verona also presented data from a pharmacokinetic study of RPL554 in 12 healthy participants. It was demonstrated that only 10% of nebulized RPL554 is absorbed into the blood via the gastrointestinal tract, an important effect for ensuring that treatment targeted at the airways.12 Together, these two studies demonstrate the promise of inhaled RPL554 to augment existing bronchodilator treatment strategies.
Philips presented the results of an economic analysis of a 5-year study investigating the use of home oxygen therapy (HOT) in combination with home non-invasive ventilation (HMV), compared with HOT alone. The economic analysis, which assessed the accumulated healthcare costs for patients, found that the HOT-HMV provided savings of approximately $3,900 per patient in the US, in addition to improved quality of life compared with HOT alone.13 There were no savings in the UK model; however, HOT-HMV was still well within the range of cost effectiveness.14 David White, from Philips further describes these findings:
One final highlight was the Proaxsis’ presentation of a novel and simple point of care test (NEATstik®) for monitoring active neutrophil elastase. Neutrophil elastase is associated with bacterial infections and is a therapeutic target in several chronic respiratory diseases. The test, which can produce qualitative results in 10 minutes from sputum samples, was demonstrated to correctly identify the presence of elevated neutrophil elastase in approximately 90% of samples.15 Additionally, data validating a new high-sensitivity version of the Proaxsis neutrophil elastase assay were also presented. The assay was found to detect neutrophil elastase at concentrations present in samples such as exhaled breath and nasal fluid. As not all patients are able to produce sputum samples, this new high-sensitivity assay may be useful in assessing neutrophil elastase concentrations in non-sputum tissue compartments.16
Although there are currently no disease modifying treatments available for COPD, the results presented at the ATS meeting highlighted the progress that has been made in optimizing existing treatments to reduce the incidence of detrimental disease events such as exacerbations. They also provided new insights into novel classes of treatments and assays currently undergoing clinical development.
1. World Health Organization (WHO). Burden of COPD. Available at: //www.who.int/respiratory/copd/burden/en/ (accessed May 30, 2018).
2. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev. 2010;19:113–8.
3. Global Initiative for Chronic Obstructive Lung Disease. Global stratergy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2018. Available at: //goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf (accessed May 30, 2018).
4. Wedzicha JA, MacKinnon A, Parkin JM. Effectiveness of acumapimod oral P38 inhibitor in the treatment of acute severe exacerbations of COPD: results of the AETHER phase II trial. Am J Respir Crit Care Med. 2018;197:A7710.
5. Wise RA, Scirica BM, Schoenfeld DA, et al. Effects of aclidinium bromide on major adverse cardiovascular events and COPD exacerbations in patients with COPD and cardiovascular risk factors. Am J Respir Crit Care Med. 2018;197:A7711.
6. Circassia. Circassia announces positive data presented at 2018 American Thoracic Society conference from Tudorza® phase IV and Duaklir® phase III studies, 2018. Available at: https://www.circassia.com/media/press-releases/circassia-announces-positive-data-presented-at-2018-american-thoracic-society-conference-from-tudorza-phase-iv-and-duaklir-phase-iii-studies/ (accessed May 30, 2018).
7. Sethi S, Kerwin EM, Watz H, et al. AMPLIFY: a randomized, phase III study evaluating the efficacy and safety of aclidinium/formoterol versus monotherapy in patients with COPD. Am J Respir Crit Care Med. 2018;197:A4241.
8. Bowling A, Goodin T, Price B, et al. Lung function and patient-reported outcomes response to glycopyrrolate (SEEBRI™ Neohaler®) in chronic obstructive pulmonary disease (COPD) patients by reversibility: pooled analysis of the GEM1 and GEM2 studies. Am J Respir Crit Care Med. 2018;197:A2391.
9. Sanjar S, Goodin T, Bowling A, et al. Lung function and patient-reported outcomes response to indacaterol/glycopyrrolate (UTIBRON™ Neohaler®) in chronic obstructive pulmonary disease (COPD) patients by smoking status: pooled analysis of the FLIGHT1 and FLIGHT2 studies. Am J Respir Crit Care Med. 2018;197:A2389.
10. Sharma S, Goodin T, Bowling A, et al. Lung function and patient-reported outcomes response to indacaterol/glycopyrrolate (UTIBRON™ Neohaler®) in chronic obstructive pulmonary disease (COPD) patients by reversibility: pooled analysis of the FLIGHT1 and FLIGHT2 studies. Am J Respir Crit Care Med. 2018;197:A2386.
11. Newman KB, Singh D. RPL554, a first-in-class dual PDE3/4 inhibitor, causes rapid additional bronchodilation when dosed with tiotropium in COPD patients. Am J Respir Crit Care Med. 2018;197:A4227.
12. Newman KB, Armstrong M, Maurer BT, et al. Low oral bioavailability of RPL554, a first-in-class dual PDE3/4 inhibitor, demonstrates that its nebulized, inhaled formulation is appropriate for delivering optimal pulmonary dose. Am J Respir Crit Care Med. 2018;197:A3022.
13. Criner GJ, Gu Q, Murphy PB, et al. Cost-effectiveness of home oxygen therapy-home mechanical ventilation (HOT-HMV) for treatment of chronic obstructive pulmonary disease (COPD) with chronic hypercapnic respiratory failure following an acute exacerbation of COPD in the United States (US). Am J Respir Crit Care Med. 2018;197:A2518.
14. Murphy PB, Brueggenjuergen B, Reinhold T, et al. Cost-effectiveness of home oxygen therapy-home mechanical ventilation (HOT-HMV) for treatment of chronic obstructive pulmonary disease (COPD) with chronic hypercapnic respiratory failure following an acute exacerbation of COPD in the United Kingdom (UK). Am J Respir Crit Care Med. 2018;197:A2517.
15. Thulborn S, Cane JL, Connolly C, et al. Evaluating the sensitivity and specificity of Neatstik® technology compared to an activity-based immunoassay in sputum samples. Am J Respir Crit Care Med. 2018;197:A4776.
16. McCafferty D, Moffitt KL, Robb C, et al. Augmentation of ProteaseTag® active neutrophil elastase immunoassay sensitivity. Am J Respir Crit Care Med. 2018;197:A3676.