The search for novel treatments for chronic obstructive pulmonary disease (COPD) continues. Recent years have seen much interest in investigating phenotype-directed strategies, namely eosinophil-guided treatments, following the success of anti-interleukin-5
(anti-IL-5) biologics in asthma.1 There has also been continued interest in vaccination strategies to reduce the risk of pneumonia, in addition to further assessment on the impact of pulmonary rehabilitation on patient outcomes. Highlights of the 104th American Thoracic Society international congress, held in Dallas, Texas, United States on 17–22 May, 2019, reflected these themes.
AstraZeneca presented data from the GALATHEA and TERRANOVA trials, investigating the impact of benralizumab in patients with moderate-to-very severe COPD, eosinophilic inflammation and a history of exacerbations despite receiving double or triple therapy.2 Both Phase III trials had a randomised, double-blind, placebo-controlled design and included 1,120 (GALATHEA) and 1,545 (TERRANOVA) patients with baseline eosinophil counts of at least 220 cells/µL. In GALATHEA, benralizumab 30 mg and 100 mg reduced the annual rate of exacerbations compared with placebo, the primary study endpoint, by 4% and 17%, respectively, although these differences failed to reach statistical significance (p=0.65 and p=0.05). Changes from baseline in forced expiratory volume in 1 second (FEV1) and St. George’s Respiratory Questionnaire total score with benralizumab were small and did not reach significance compared with placebo. The results of TERRANOVA, which included a 10 mg dose of benralizumab, were broadly similar to GALATHEA and also failed to reach statistical significance. The incidence of adverse events were low in both trials and similar to placebo.2 These results follow on from several recent trials investigating eosinophil-targeted treatments, which similarly demonstrated less than clear-cut benefits in patients with eosinophilic COPD.3
The role of eosinophils in directing the use of oral corticosteroid therapy in patients with acute exacerbations of COPD requiring hospitalisation was also investigated in the randomised, open-label, non-inferiority CORTICO-COP trial.4 All patients (n=159) received 80 mg of intravenous methylprednisolone on Day 1. From Day 2 onwards, patients received oral prednisolone at 37.5 mg/day every day for four days (control group) or 37.5 mg/day on days when blood eosinophil counts were ≥300 cells/µL (eosinophil-guided group). The primary outcome of the number of days alive and out of hospital within the 14 days of enrolment was not significantly different between eosinophil-guided and control groups (8.9 versus 9.3 days; p=0.34). Additionally, there were no between-group differences in the number of treatment failures (defined as the recurrence of acute exacerbations requiring emergency department visits, hospitalisation or intensification of pharmacological treatment) and the incidence of acute exacerbations and death. Importantly, eosinophil-guided therapy permitted a significant reduction in the median duration of corticosteroid therapy from five days in the control group to two days (p<0.0001).4
Verona Pharma presented their latest results on RPL554, a first-in-class, inhaled dual phosphodiesterase (PDE) 3/4 inhibitor for COPD maintenance therapy.5 In a post hoc analysis of a previous Phase II study, patient response to RPL554 (n=403) over 4 weeks was assessed according to baseline reversibility to albuterol. Patients with reversible disease, defined as a pre- to post-albuterol change in FEV1 of 200 mL and ≥12%, demonstrated 216–293 mL improvements from baseline over placebo in peak FEV1 from 0–3 hours, compared with only 85–128 mL improvements in the non-reversible subgroup. In contrast, reductions in patient symptom scores were similar in both reversible and non-reversible patients.5
The results of a large-scale study of 21,748 patients with COPD investigated the effectiveness of the seasonal influenza vaccination, as recommended by all major COPD management guidelines, despite currently limited evidence.6 By comparing the current seasonal influenza vaccination status of influenza test-positive cases with test-negative controls, it was demonstrated that the seasonal influenza vaccine reduced the incidence of laboratory-confirmed influenza-associated hospitalisations by at least 22%. Vaccine efficacy did not change based on patient-, COPD- and specimen collection-related factors. The study highlighted the need for more effective influenza vaccines and additional preventive strategies.6
The effect of physical activity and pulmonary rehabilitation on mortality in patients with COPD was also another topic of interest, building on the results of previous small-scale observational studies. A pragmatic randomised controlled trial assessed the impact of the physical activity coaching intervention, Walk On! (WO) in 2,707 patients with a history of COPD exacerbations in the previous 12 months requiring hospital care.7 No difference was found in the primary composite outcome of all-cause acute care utilisation and death but the per-protocol propensity score adjusted model demonstrated a 48% lower risk of death in WO patients compared to standard care.7 A separate, retrospective cohort study of 124,065 patients hospitalised for a COPD exacerbation in 2012, assessed the impact of pulmonary rehabilitation (PR) on patient survival.8 Using a propensity score methodology to match those initiating PR within three months of hospital discharge with those not initiating PR, the study demonstrated that patients initiating PR had a 65% lower risk of death within 1 year versus those not initiating PR. However, the authors also advise caution when interpreting the study results as it was also noted that initiation of PR within 6 weeks of discharge versus > 6 weeks was associated with a 68% higher risk of mortality.8
In summary, results for the eosinophil-directed treatment of COPD have been mixed, with two big clinical trials failing to demonstrate statistically significant reductions in exacerbation rates with benralizumab but the use eosinophil-directed OCS treatment for COPD exacerbations allowed for a reduced duration of OCS exposure. Also, new results of the PDE 3/4 inhibitor, RPL554, suggest a promising new option in the armamentarium against COPD. Finally, large-scale studies of influenza vaccination and PR for COPD confirm their ability to reduce patient mortality but also highlight that more needs to be done to improve patient outcomes.
1. GAA-INTERASMA Global Asthma Association, GINA: 2019 updates to the pocket guide for asthma management and prevention, 2019. Available at: https://interasma.org/2019/04/25/gina-2019-updates-to-the-pocket-guide-for-asthma-management-and-prevention/ (accessed 12 June 2019).
2. Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the prevention of COPD exacerbations. N Engl J Med. 2019; doi: 10.1056/NEJMoa1905248 [Epub ahead of print]
3. Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017;377:1613–29.
4. Sivapalan P, Lapperre TS, Janner J, et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial. Lancet Respir Med. 2019; doi: 10.1016/S2213-2600(19)30176-6 [Epub ahead of print]
5. Singh D, Maurer BT, Martinez FJ, et al. A3846/P596 RPL554 (Dual PDE3/4 enzyme inhibitor): baseline airway reversibility impacts immediate bronchodilation, in contrast to progressive symptom improvement. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
6. Gershon AS, Chung H, Porter J, et al. A2377 Influenza vaccine effectiveness in older patients with chronic obstructive pulmonary disease (COPD). Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
7. Nguyen HQ, Liu I, Moy M, et al. A2645 Effect of physical activity coaching on acute care utilization and survival in COPD: a pragmatic controlled trial (Walk On!) Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
8. Lindenauer PK, Stefan MS, Priya A, et al. A4269 Association Between pulmonary rehabilitation following hospitalization for COPD and 1-year mortality. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.