Omalizumab effectiveness in asthma-COPD overlap: Post hoc analysis of PROSPERO
Authors: Nicola A. Hanania, Bradley E. Chipps, Noelle M. Griffin, Bongin Yoo, Ahmar Iqbal, Thomas B. Casale
Journal: Journal of Allergy and Clinical Immunology (2018)

Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO), defined as the coexistence of clinical features of asthma and COPD, is common.1Vaz Fragoso C.A. Murphy T.E. Agogo G.O. Allore H.G. McAvay G.J. Asthma-COPD overlap syndrome in the US: a prospective population-based analysis of patient-reported outcomes and health care utilization.Int J Chron Obstruct Pulmon Dis. 2017; 12: 517-527Crossref PubMed Scopus (29) Google Scholar, 2Woodruff P.G. van den Berge M. Boucher R.C. Brightling C. Burchard E.G. Christenson S.A. et al.American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report.Am J Respir Crit Care Med. 2017; 196: 375-381Crossref PubMed Scopus (71) Google Scholar Although ACO is heterogeneous, common subphenotypes of ACO include those with asthma who are older than 40 years with a history of smoking and/or those who have persistent, progressive, and partially reversible airflow limitation.2Woodruff P.G. van den Berge M. Boucher R.C. Brightling C. Burchard E.G. Christenson S.A. et al.American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report.Am J Respir Crit Care Med. 2017; 196: 375-381Crossref PubMed Scopus (71) Google Scholar Epidemiologic studies suggest that ACO is associated with higher disease burden, lower quality-of-life scores, and higher health care utilization than COPD or asthma alone.1Vaz Fragoso C.A. Murphy T.E. Agogo G.O. Allore H.G. McAvay G.J. Asthma-COPD overlap syndrome in the US: a prospective population-based analysis of patient-reported outcomes and health care utilization.Int J Chron Obstruct Pulmon Dis. 2017; 12: 517-527Crossref PubMed Scopus (29) Google Scholar, 3Wurst K.E. St Laurent S. Hinds D. Davis K.J. Disease burden of patients with asthma/COPD overlap in a US claims database: impact of ICD-9 coding-based definitions.COPD. 2017; 14: 200-209Crossref PubMed Scopus (24) Google Scholar Unfortunately, patients with ACO are often excluded from asthma or COPD clinical trials, including trials for recently approved targeted asthma therapies (eg, dupilumab).4Wenzel S. Castro M. Corren J. Maspero J. Wang L. Zhang B. et al.Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet. 2016; 388: 31-44Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar Treatment of ACO is directed to treat symptoms and airway inflammation and typically comprises inhaled corticosteroids (ICSs) with add-on bronchodilators (long-acting beta-agonists ± long-acting muscarinic antogonists) although ACO phenotypes may be less responsive to ICSs than are patients with asthma.3Wurst K.E. St Laurent S. Hinds D. Davis K.J. Disease burden of patients with asthma/COPD overlap in a US claims database: impact of ICD-9 coding-based definitions.COPD. 2017; 14: 200-209Crossref PubMed Scopus (24) Google Scholar Omalizumab, a monoclonal anti-IgE antibody approved for patients (≥6 years) with moderate-to-severe allergic asthma inadequately controlled with ICSs, is not approved for patients with COPD or ACO. Efficacy of omalizumab in ACO has been suggested in case reports,5Tat T.S. Cilli A. Omalizumab treatment in asthma-COPD overlap syndrome.J Asthma. 2016; 53: 1048-1050Crossref PubMed Scopus (26) Google Scholar, 6Yalcin A.D. Celik B. Yalcin A.N. Omalizumab (anti-IgE) therapy in the asthma-COPD overlap syndrome (ACOS) and its effects on circulating cytokine levels.Immunopharmacol Immunotoxicol. 2016; 38: 253-256Crossref PubMed Scopus (42) Google Scholar but patients with ACO have also been excluded from omalizumab clinical trials. Therefore, well-conducted, real-life large studies might be good data sources to assess the clinical potential of omalizumab for patients with ACO. To this end, we performed a post hoc, exploratory analysis of clinical outcomes of adult patients with ACO treated with omalizumab in the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (PROSPERO) (clinicaltrials.gov identifier: NCT01922037).7Casale T.B. Luskin A.T. Busse W. Zeiger R.S. Trzaskoma B. Yang M. et al.Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study.J Allergy Clin Immunol Pract. 2018; ([published online ahead of print May 22, 2018])https://doi.org/10.1016/j.jaip.2018.04.043Abstract Full Text Full Text PDF Scopus (132) Google Scholar PROSPERO, a US, multicenter, single-arm, prospective, 48-week observational study of omalizumab, examined patients 12 years or older with asthma in a real-life setting not excluded for having comorbid COPD or a current or past history of smoking cigarettes.7Casale T.B. Luskin A.T. Busse W. Zeiger R.S. Trzaskoma B. Yang M. et al.Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study.J Allergy Clin Immunol Pract. 2018; ([published online ahead of print May 22, 2018])https://doi.org/10.1016/j.jaip.2018.04.043Abstract Full Text Full Text PDF Scopus (132) Google Scholar In PROSPERO, demographic and clinical characteristics, medical history, medication use, and smoking history were documented at baseline. Spirometry was performed at baseline, 6 months, and week 48 according to American Thoracic Society criteria.8Miller M.R. Hankinson J. Brusasco V. Burgos F. Casaburi R. Coates A. et al.Standardisation of spirometry.Eur Respir J. 2005; 26: 319-338Crossref PubMed Scopus (11409) Google Scholar The number of exacerbations was recorded at baseline for the period 12 months before study enrollment and monthly during the study period using the same criteria. Exacerbations were defined as worsening of asthma symptoms requiring oral corticosteroids and/or emergency department visit or hospitalization, and were confirmed by medical records. Asthma Control Test (ACT) scores were also recorded at baseline and during the study. The ACT is a 5-item questionnaire that scores each question from 1 (poor control) to 5 (complete control) to yield an overall ACT score range of 5 to 25. ACT scores of 20 or more reflect well-controlled asthma, scores of 16 to 19 suggest asthma that is not well controlled, and scores of 15 or less indicate asthma that is very poorly controlled. The minimally important difference for the ACT is 3. Statistical analyses were based on all enrolled adult patients (≥18 years) at study enrollment. Descriptive statistics were used to summarize baseline demographic and clinical characteristics at study entry, the number of exacerbations at baseline and at week 48, and the change from baseline to week 48 in FEV1 measurement and ACT score. This post hoc analysis included 737 of 806 adult patients (91.4%) from PROSPERO who initiated omalizumab. To assess the relative effects of omalizumab in patients with and without ACO, 2 separate mutually exclusive subgroup analyses were performed using 2 different ACO definitions (see Fig E1 in this article's Online Repository at www.jacionline.org). Using data from 737 adult PROSPERO patients, descriptive analyses were performed between the ACO A cohort (n = 56), comprising patients with a medical history of asthma and a COPD diagnosis from medical history or self-report, and the non-ACO cohort (n = 681). Similarly, using data from 713 adult PROSPERO patients who have not missing baseline FEV1/forced vital capacity ratio value and known smoking status, descriptive analyses were performed between the ACO B cohort (n = 50), comprising patients with a medical history of asthma, a postbronchodilator ratio of FEV1 over forced vital capacity of less than 0.7, and smoking history of greater than or equal to 10 pack-years, and the non-ACO B cohort (n = 663). Overall, patients in each ACO cohort had a higher mean age compared with their counterparts in the non-ACO cohort (Table I). Median fractional exhaled nitric oxide and blood eosinophil counts were similar in ACO and non-ACO cohorts, whereas total IgE levels at baseline were higher in the ACO B cohort than in the non-ACO B cohort (Table I). As expected, greater numbers of patients were former/current smokers in the each ACO cohort compared with their counterpart non-ACO cohorts (Table I). The mean pack-years in former/current smokers was approximately 2 times greater in the ACO A (22.5 ± 20.5) cohort than in the non-ACO A (11.3 ± 17.2) cohort and approximately 3 times greater in the ACO B (27.7 ± 16.7) cohort than in the non-ACO B (9.5 ± 16.8) cohort. Furthermore, patients in both ACO cohorts who were current/former smokers had done so for longer than patients in their counterpart non-ACO cohort (Table I). Interestingly, mean reversibility was lower in the non-ACO cohorts (7.6% ± 14.5% to 7.8% ± 14.5%) compared with the ACO cohorts (11.4% ± 13.0% to 11.6% ± 12.6%; Table I).Table IBaseline demographic and clinical characteristicsDemographic/clinical characteristicACO A (n = 56)Non-ACO A (n = 681)ACO B (n = 50)Non-ACO B (n = 663)Age (y) Mean ± SD57.6 ± 10.949.8 ± 14.956.8 ± 12.650.0 ± 14.6 Median (min, max)59.5 (24, 78)50.0 (18, 100)56.0 (23, 86)50.0 (18, 100)Sex: female, n (%)40 (71.4)447 (65.6)30 (60.0)440 (66.4)Race, n (%) White42 (75.0)485 (71.2)43 (86.0)468 (70.5) Black/African American6 (10.7)103 (15.1)5 (10.0)98 (14.8) Asian0 (0.0)33 (4.8)0 (0.0)32 (4.8) American Indian or Alaska Native0 (0.0)7 (1.0)0 (0.0)7 (1.1) Native Hawaiian or other Pacific Islander0 (0.0)4 (0.6)0 (0.0)4 (0.6) Multiple2 (3.6)9 (1.3)0 (0.0)11 (1.7) Other6 (10.7)40 (5.9)2 (4.0)43 (6.5)BMI (kg/m2), median (min, max)31.4 (17.6, 49.0)30.2 (17.3, 76.9)28.9 (19.4, 42.6)30.4 (17.3, 76.9)Feno (ppb), median (min, max)19.0 (5, 151.5)23.0 (5, 266)17.0 (5, 142)23.0 (5, 266)Blood EOS (cells/μL), median (min, max)200 (40, 800)220 (0, 2340)200 (0, 570)220.0 (0, 2310)Total IgE (IU/mL), median (min, max)168.3 (11.2, 7693.0)176.1 (1.1, 8659.2)207.8 (5.7, 4846.5)170.4 (1.1, 8659.2)Prebronch FEV1 (L), mean ± SD1.7 ± 0.72.3 ± 0.81.6 ± 0.62.3 ± 0.8Prebronch FEV1 (%pred), mean ± SD62.6 ± 18.175.2 ± 20.553.9 ± 16.675.7 ± 20.0Postbronch FEV1 (%pred), mean ± SD68.5 ± 19.279.8 ± 19.359.0 ± 16.580.4 ± 18.9Postbronch FEV1/FVC (%), mean ± SD66.7 ± 11.874.9 ± 11.457.7 ± 9.875.5 ± 10.8Reversibility (%), mean ± SD11.6 ± 12.67.7 ± 14.511.4 ± 13.07.8 ± 14.5Exacerbations,∗During 12-month period before enrollment. mean ± SD3.6 ± 3.73.0 ± 3.33.5 ± 3.43.0 ± 3.3ACT baseline, mean ± SD12.8 ± 4.813.8 ± 4.911.6 ± 4.613.9 ± 4.9Smoking history, n (%) Current12 (21.4)30 (4.4)10 (20.0)31 (4.7) Former25 (44.6)213 (31.3)40 (80.0)195 (29.4) Never smoker19 (33.9)436 (64.0)0 (0.0)437 (65.9)Number of packs per year, mean ± SD†Former or current smokers.22.5 ± 20.511.3 ± 17.227.7 ± 16.79.5 ± 16.8Years of smoking, mean ± SD†Former or current smokers.28.8 ± 10.714.4 ± 11.828.9 ± 10.213.5 ± 11.5BMI, Body mass index; bronch, bronchodilator; EOS, eosinophils; Feno, fractional exhaled nitric oxide; FVC, forced vital capacity; %pred, percent predicted.∗ During 12-month period before enrollment.† Former or current smokers. Open table in a new tab BMI, Body mass index; bronch, bronchodilator; EOS, eosinophils; Feno, fractional exhaled nitric oxide; FVC, forced vital capacity; %pred, percent predicted. In terms of clinical improvement, decreases in mean asthma exacerbation rate compared with their own baseline mean exacerbation rate and clinically significant improvements in ACT scores were similar in ACO A cohort versus the non-ACO A cohort and in the ACO B cohort versus the non-ACO B cohort (Fig 1). The mean percentage (95% CI) of patients achieving or exceeding minimally important difference for ACT during the study was 57.1% (44.2-70.1%) in the ACO A cohort versus 63.5% (59.8-67.2%) in the non-ACO A cohort, and 62.5% (48.8-76.2%) in the ACO B cohort versus 62.9% (59.2-66.5%) in the non-ACO B cohort. Modest mean (95% CI) improvements in postbronchodilator FEV1 after 48 weeks of treatment, compared with their own baseline values, were observed in both the ACO A and the non-ACO A cohorts. In contrast, a small decrease in postbronchodilator FEV1 was observed in the ACO B cohort compared with an improvement in the non-ACO B cohort (see Fig E2 in this article's Online Repository at www.jacionline.org). One possible reason for this is the higher proportion of current or former smokers in the ACO B cohort who were also the heaviest smokers in terms of pack-years. Both former and, in particular, current smokers have been observed to have greater declines in FEV1 than never smokers.9Anthonisen N.R. Connett J.E. Murray R.P. Smoking and lung function of Lung Health Study participants after 11 years.Am J Respir Crit Care Med. 2002; 166: 675-679Crossref PubMed Scopus (569) Google Scholar Adverse events and safety results from PROSPERO involved in this analysis have been published previously.7Casale T.B. Luskin A.T. Busse W. Zeiger R.S. Trzaskoma B. Yang M. et al.Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study.J Allergy Clin Immunol Pract. 2018; ([published online ahead of print May 22, 2018])https://doi.org/10.1016/j.jaip.2018.04.043Abstract Full Text Full Text PDF Scopus (132) Google Scholar Our analysis of a large-scale, real-world study suggests that patients with ACO treated with omalizumab over 48 weeks experienced improvements in asthma outcomes similar to those in patients without ACO. These findings were present regardless of how patients with ACO were identified and are consistent with results of previously published case series. In 1 case series, 3 patients with ACO treated with omalizumab for more than 1 year showed improvements in ACT scores (from <10 to >20) along with decreases in hospitalizations and exacerbations.5Tat T.S. Cilli A. Omalizumab treatment in asthma-COPD overlap syndrome.J Asthma. 2016; 53: 1048-1050Crossref PubMed Scopus (26) Google Scholar Another case series of 10 patients with ACO similarly found that omalizumab was associated with improvements in ACT score.6Yalcin A.D. Celik B. Yalcin A.N. Omalizumab (anti-IgE) therapy in the asthma-COPD overlap syndrome (ACOS) and its effects on circulating cytokine levels.Immunopharmacol Immunotoxicol. 2016; 38: 253-256Crossref PubMed Scopus (42) Google Scholar Furthermore, patients with COPD typically experience an annual decline in lung function, whereas throughout the 48 weeks of this study, lung function was preserved in the ACO A cohort, suggesting some protection, compared with COPD studies that show a historical decline in lung function. However, further data are required to confirm if these effects are maintained long-term (>48 weeks). This analysis of PROSPERO is limited by its post hoc nature, as well as the potential for recall bias especially in relation to smoking history, COPD diagnosis, and exacerbations before study entry. The fact that this analysis is based on a study with no placebo control is another limitation. Despite these limitations, this analysis represents one of the largest cohorts to date of patients with ACO treated in a real-world setting. Our analysis suggests that patients with ACO treated with omalizumab had similar clinical outcomes to patients with asthma without ACO in terms of improvements in exacerbation frequency and ACT scores irrespective of how patients with ACO were identified. Furthermore, lung function was preserved throughout the 48 weeks of this study in the ACO cohort identified by a medical history of asthma and a medical history or self-reported diagnosis of COPD. Fig E2Mean (95% CI) change from baseline in postbronchodilator FEV1 after 12 months of omalizumab in the ACO and non-ACO cohorts.View Large Image Figure ViewerDownload Hi-res image Download (PPT)