Abstract
Different ages of asthma onset can lead to similar clinical symptoms but have different underlying mechanisms that may influence treatment response. This post-hoc analysis assessed response to omalizumab in relation to the age of asthma onset. Using pooled data from two phase III studies (patients 12–75 years), changes in exacerbation rates, forced expiratory volume in 1 second (FEV1) and inhaled corticosteroids (ICS) were assessed by age of asthma onset (<18 [n = 574], 18–40 [n = 360], >40 years [n = 136]). Exacerbations (week 16) were reduced with omalizumab versus placebo in all subgroups (relative rate reduction [95% confidence interval]: <18, −53.1% [–73.6,–16.6]; 18–40, −68.3% [–85.5,–31.0]; >40, −38.4% [–77.3,67.4]). FEV1 increased with omalizumab in all subgroups; increases were sustained in <18 and 18–40 years subgroups, but not in >40 years subgroup. ICS dose reductions (week 28) were greater with omalizumab versus placebo, regardless of age of asthma onset, as were percentages of patients with ICS doses reduced by at least 50% and 100%. In conclusion, omalizumab-treated patients had lower exacerbation rates and were more frequently able to reduce/discontinue ICS versus placebo, regardless of age of asthma onset, therefore omalizumab may be beneficial to all eligible patients with allergic asthma.
Trial registration
These studies were conducted before clinical trial registration was required; therefore, clinical trial registration numbers are not available.
Keywords: Immunoglobulin E, inhaled corticosteroids, exacerbations, lung function
Introduction
Asthma is typically thought of as a childhood-onset illness because up to 95% of patients experience their first symptoms before age 6 years (early-onset asthma; ages <12 years); however, onset of asthma during adolescence and adulthood (late-onset asthma; ages ≥12 years) is also possible. Early- and late-onset asthma show similar general asthma symptoms, but early-onset asthma is more often associated with atopy, allergic sensitization, and eosinophilic inflammation, whereas late-onset asthma is associated with chronic rhinosinusitis, nasal polyposis, obesity, and various inflammatory patterns, including eosinophilic, mixed granulocytic, and neutrophilic inflammation.1
Omalizumab, an anti-IgE antibody, is approved for the treatment of moderate to severe persistent allergic asthma in patients ages 6 years and older.2 Although the efficacy and safety of omalizumab has been demonstrated in clinical trials in patients ages 6–75 years with moderate to severe allergic asthma,3,4 whether there is a difference between the response of patients with early- or late-onset asthma has not been investigated. To evaluate this important question, we conducted a post hoc analysis using data from two pivotal phase III clinical trials with patients inadequately controlled moderate to severe allergic asthma.3,4
Methods
Study design and patients
The pivotal studies were phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of omalizumab that enrolled patients (12–75 years) with uncontrolled allergic asthma of at least 1 year’s duration despite treatment with inhaled corticosteroids (ICS).3,4 The study design and primary results of the studies have been published previously.3,4 These studies were conducted before clinical trial registration was required; therefore, clinical trial registration numbers are not available. The studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and informed consent was obtained.
Assessments
Patients were assessed for response to omalizumab (asthma exacerbations [requiring 3 or more days of systemic corticosteroids], lung function [forced expiratory volume in 1 second (FEV1)], ICS dose reduction) by age of asthma onset, defined by diagnosis of asthma at age <18 years, 18–40 years, and >40 years.
Statistical analysis
Exacerbation reductions and their relative rate reductions (omalizumab vs placebo) during the 16-week steroid-stable period were determined using a Poisson regression model with study and treatment group as independent variables normalized by subject-time on steroid-stable period at risk. Improvement in FEV1 from baseline through week 16 was analyzed using an analysis of covariance model (covariates: study, baseline FEV1, treatment, and interaction of baseline FEV1 and treatment). ICS dose reduction was summarized descriptively.
Results
Baseline demographics and clinical characteristics
Of 1070 patients included from the primary studies, about half reported an age of asthma onset of <18 years (n = 574), a third reported an asthma age of onset of 18–40 years (n = 360), and a tenth reported an age of asthma onset of >40 years (n = 136) (Table 1). The percentage of patients with hospitalizations in the previous year was slightly higher for placebo versus omalizumab in the age of asthma onset <18 and >40 years subgroups. Compared with patients in the age of asthma onset 18–40 years and >40 years subgroups, patients in the age of asthma onset <18 years subgroup had numerically lower mean age, a smaller proportion of former smokers, higher mean IgE levels, and longer mean disease duration.
Table 1.
Baseline demographics and clinical characteristics by age of asthma onset subgroup.
| Characteristic | Age of asthma onset | |||||
|---|---|---|---|---|---|---|
| <18 years | 18–40 years | >40 years | ||||
| Omalizumab (n = 288) | Placebo (n = 286) | Omalizumab (n = 184) | Placebo (n = 176) | Omalizumab (n = 70) | Placebo (n = 66) | |
| Age, y, mean ± SD | 33.6 ± 13.0 | 33.6 ± 13.1 | 42.1 ± 9.1 | 41.0 ± 9.7 | 58.3 ± 7.8 | 57.3 ± 6.6 |
| Male, n (%) | 151 (52.4) | 152 (53.1) | 63 (34.2) | 61 (34.7) | 31 (44.3) | 24 (36.4) |
| Race, n (%) | ||||||
| Black | 15 (5.2) | 17 (5.9) | 10 (5.4) | 6 (3.4) | 7 (10.0) | 4 (6.1) |
| White | 262 (91.0) | 260 (90.9) | 169 (91.8) | 153 (86.9) | 63 (90.0) | 57 (86.4) |
| Other | 11 (3.8) | 9 (3.1) | 5 (2.7) | 17 (9.7) | 0 | 5 (7.6) |
| BMI, kg/m2, mean ± SD | 26.5 ± 5.9 | 26.5 ± 5.6 | 28.2 ± 6.3 | 27.6 ± 6.5 | 28.2 ± 5.8 | 29.2 ± 6.5 |
| Baseline BDP, mean ± SD | 667.7 ± 216.6 | 646.5 ± 211.8 | 664.0 ± 218.6 | 681.9 ± 249.1 | 698.0 ± 253.3 | 763.6 ± 292.9 |
| FEV1, mL, mean ± SD | 2578.5 ± 775.2 | 2543.8 ± 751.8 | 2348.7 ± 625.3 | 2431.7 ± 742.0 | 2000.4 ± 566.8 | 2001.4 ± 583.5 |
| ppFEV1, %, mean ± SD | 68.5 ± 15.1 | 67.9 ± 14.9 | 70.1 ± 13.6 | 70.8 ± 13.2 | 68.0 ± 16.9 | 67.2 ± 15.3 |
| Reversibility, %, mean ± SD | 26.5 ± 14.8 | 25.9 ± 13.4 | 28.1 ± 15.3 | 26.7 ± 14.5 | 23.3 ± 12.8 | 23.5 ± 11.9 |
| IgE, IU/mL, mean ± SD | 210.0 ± 158.0 | 211.7 ± 158.5 | 188.3 ± 159.1 | 191.9 ± 145.1 | 174.4 ± 151.3 | 136.2 ± 123.5 |
| EOS, cells/μL, mean ± SD | 328.1 ± 186.0 | 325.6 ± 180.3 | 268.5 ± 164.1 | 339.1 ± 232.6 | 285.0 ± 243.4 | 303.1 ± 206.7 |
| Asthma duration, y,mean ± SD | 27.3 ± 13.4 | 28.1 ± 13.8 | 13.6 ± 9.1 | 13.7 ± 9.0 | 10.2 ± 7.1 | 8.8 ± 5.9 |
| Hospitalization in last year,n (%) | 6 (2.1) | 18 (6.3) | 8 (4.3) | 8 (4.5) | 3 (4.3) | 5 (7.6) |
| ED visit in last year, n (%) | 33 (11.5) | 33 (11.5) | 21 (11.4) | 23 (13.1) | 7 (10.0) | 8 (12.1) |
| Former smoker, n (%) | 52 (18.1) | 59 (20.6) | 48 (26.1) | 56 (31.8) | 25 (35.7) | 26 (39.4) |
| Dosing Q4W, n (%) | 159 (55.2) | 159 (55.6) | 107 (58.2) | 101 (57.4) | 43 (61.4) | 46 (69.7) |
BDP: beclomethasone dipropionate; BMI: body mass index; ED: emergency department; EOS: eosinophils; FEV1: forced expiratory volume in 1 second; IgE: immunoglobulin E; IU: international units; ppFEV1: percent predicted forced expiratory volume in 1 second; Q4W: every 4 weeks; SD: standard deviation.
Exacerbations
During the 16-week steroid-stable period, exacerbation rates were lower for omalizumab-treated patients versus placebo-treated patients in all age of asthma onset subgroups, and 95% confidence intervals (CIs) overlapped substantially, suggesting that exacerbations rates may be similar between the age of onset groups. However, 95% CIs for placebo-corrected reductions in exacerbations for the >40 years subgroup crossed zero (Figure 1(a)), suggesting that the omalizumab-treated group may not be different from placebo, but this may be due to low patient numbers.
Figure 1.
Exacerbations and lung function by age of asthma onset. (a) Exacerbation rate at week 16. Values above columns reflect relative rate reductions (95% confidence intervals [CIs]) for omalizumab versus placebo. (b) Least squares mean (LSM) difference in forced expiratory volume in 1 second (FEV1) for omalizumab versus placebo during the 16-week steroid-stable period.
Changes in lung function
Improvements in FEV1 for omalizumab over placebo were sustained or increased throughout the 16-week steroid-stable treatment period for patients with age of asthma onset <18 and 18–40 years (Figure 1(b)). In patients with age of asthma onset >40 years, FEV1 improvement was not sustained, although 95% CIs highly overlapped with the other groups, suggesting the responses may be similar.
ICS dose reductions
There was a greater mean percentage reduction in ICS dose at week 28 in patients receiving omalizumab versus placebo (Figure 2(a)). In addition, the percentage of patients who were able to reduce their ICS dose by 50% or more, or to completely eliminate the use of ICS, was also greater for omalizumab- versus placebo-treated patients (Figure 2(b) and (c)). However, 95% CIs overlapped between the three groups of asthma onset, suggesting that all groups responded similarly to omalizumab. Note that this information should be interpreted only as an efficacy evaluation – ICS dose reduction is not recommended in clinical practice and the omalizumab prescribing information states “do not discontinue systemic or inhaled corticosteroids abruptly upon initiation.”
Figure 2.
Inhaled corticosteroid (ICS) dose reductions by age of asthma onset. (a) Mean percentage reduction in ICS dose. (b) Percentage of patients with at least 50% dose reduction. (c) Percentage of patients with complete elimination (100% of ICS). CI: confidence interval; SD: standard deviation.
Discussion
In this post hoc analysis of two phase III clinical trials in patients aged 12–75 years with moderate-severe allergic asthma, reductions in exacerbation rates were greater, initial increases in lung function were sustained (except in patients with asthma age of onset >40 years), and ICS dose was reduced/discontinued with omalizumab versus placebo in all age of asthma onset subgroups. Overall, the efficacy findings by asthma age of onset broadly matched the previously reported findings across all age ranges.3,4 The previously published safety findings showed that omalizumab was well tolerated, with an adverse event profile similar to that of placebo3,4; the present analysis did not evaluate the safety outcomes of these studies according to age of asthma onset.
We are unaware of any other published studies that have directly evaluated the efficacy of omalizumab by asthma age of onset. But, one retrospective study by Sposato et al. evaluated long-term omalizumab treatment in different age groups: 18–39 years (mean age of asthma onset, 14 years), 40–64 years (mean age of asthma onset, 34 years), and ≥65 years (mean age of asthma onset, 43 years).5 Although the age groups (and some endpoints) are different than in our study, Sposato et al. also showed that omalizumab effectively reduced exacerbations, asthma medication use (ICS and short-acting β2-agonist use), increased lung function, and improved Asthma Control Test scores in all three of the age groups.5
This was a post hoc and not a pre-specified analysis; therefore, no definitive conclusions can be drawn, and sample sizes were small. Moreover, the study population in this analysis may not directly reflect patients considered for add-on biological therapy for asthma in clinical practice.
In conclusion, we found that omalizumab has similar clinical efficacy in patients with allergic asthma across a broad age range of asthma onset.
Acknowledgements
Medical writing assistance was provided by Nicole Tom, PhD, of Envision Pharma Group, and was funded by Genentech, Inc., a member of the Roche Group.
Footnotes
Author contributions: All authors contributed to the conception, study design, and interpretation of the post hoc analysis. CTJH and JK designed and completed the post hoc analysis. All authors drafted, substantially revised, or critically reviewed the article. All authors agreed on the journal selection and approved the final draft accepted for publication.
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LR has received research funding from Sanofi; is a clinical investigator for AstraZeneca and Sanofi; and is a member of the advisory board at AstraZeneca, Novartis, and Sanofi. HP and JK are employees of Genentech, Inc., and shareholders of Roche. CTJH is a former employee of Genentech, Inc. SL is a member of the speakers bureau and is a consultant for AstraZeneca, Genentech, Inc., GlaxoSmithKline, Novartis, and Sanofi-Genzyme.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This analysis was funded by Genentech, Inc., a member of the Roche Group. The primary studies were funded by Genentech, Inc., a member of the Roche Group, and Novartis Pharma AG.
Ethical approval: The primary studies were approved by the relevant institutional review boards and written informed consent was obtained from each participant. The informed consent form allows Genentech, Inc. use of the study data, including this post hoc evaluation of subgroups, to provide further information on the efficacy of omalizumab. All data used for this analysis have been anonymized, and additional institutional review board approval for the analysis reported here was not required.
Data availability: Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche’s criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
ORCID iD
Hooman Pazwash https://orcid.org/0000-0002-6351-9403
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