Abstract
Purpose
The objective of this trial was to evaluate the efficacy and safety of anti-IgE monoclonal antibody (CMAB007) in Chinese patients with inadequately controlled moderate or severe asthma with increased total IgE level despite medium or high dose inhaled corticosteroids (ICS)/long acting β2-agonist (LABA) treatment.
Methods
This was a multicenter, randomized, placebo controlled, double blinded, phase 3 trial. Eligible patients with moderate or severe asthma with increased total IgE level (60–1,500 IU/mL) receiving optimal ICS-LABA were randomly assigned to receive CMAB007 or placebo treatment at a 2:1 ratio for 24 weeks. The primary efficacy endpoint was asthma exacerbation (AE) rate, the key second endpoints were asthma control test (ACT) score, pulmonary function and safety.
Results
A total of 392 patients were included in the efficacy analysis. AE rate was 0.45 with CMAB007 and 0.66 with placebo (hazard ratio, 0.68; 95% confidence interval, 0.49, 0.96; P = 0.030). The proportions of patients showing an increase of at least 3 points from baseline in ACT scores were greater in the CMAB007 group than in the placebo group at Week 8 (49.8% vs. 36.9%, P = 0.018), Week 16 (59.4% vs. 42.9%, P = 0.003) and Week 24 (60.2% vs. 47.0%, P = 0.019). Greater improvement of pre-bronchodialteor forced expiratory volume in 1 second was achieved in the CMAB007 group at 4 weeks (11.40% vs. 5.03%, P = 0.006), 8 weeks (16.27% vs. 6.57%, P = 0.003), 12 weeks (16.51% vs. 6.60%, P = 0.002) and 16 weeks (20.18% vs. 7.42%, P = 0.002). The incidence of adverse events was similar between the CMAB007 (77.2%) and placebo groups (75.2%).
Conclusions
CMAB007 reduces AE and improves asthma control, lung function and quality of life without additional safety concern in Chinese patients having moderate to severe asthma with increased total IgE level.
Trial Registration
ClinicalTrials.gov Identifier: NCT03468790.
Keywords: Asthma, IgE, antibody, asthma exacerbation, omalizumab, treatment outcome, lung function
INTRODUCTION
Asthma is characterized by chronic airway inflammation. The prevalence of asthma is increasing rapidly worldwide. In China, some epidemiologic surveys showed that the incidence of asthma among adults was 4.2%.1,2 A recent study in China reported that moderate-to-severe asthma was approximately 16% of newly diagnosed cases.3
Asthma is a heterogeneous disease, with different clinical phenotypes. Allergic asthma is the most common phenotype of asthma, of which the proportion is as high as 50%–90% in severe asthma.4 Allergic asthma would be triggered by various allergens, and can be identified by skin prick testing or by measuring the level of total or specific immunoglobulin E (IgE) in serum. Allergic asthma is a typical type I hypersensitivity resulting from the over-expression of IgE in response to environmental allergens. In allergic asthma, exposure to allergen initiates a complex series of events leading to the production of allergen-specific IgE, which binds to high affinity receptors on effector cells such as mast cells and basophils. The cross-linking of these cell-bound IgE molecules by antigen results in the release of pro-inflammatory mediators such as histamine, prostaglandins, leukotrienes, chemokines and cytokines from these cells.5
Asthma medication can be adjusted up or down in a stepwise approach to achieve good symptom control and to minimize future risk of asthma-related mortality, exacerbations, persistent airflow limitation and medication side-effects. According to Global Initiative for Asthma (GINA) 2023,6 maintenance medium (> 400–800 μg for budesonide, or > 250–500 μg for fluticasone propionate) or high (> 800 μg for budesonide, or > 500 μg for fluticasone propionate) dose inhaled corticosteroids (ICS)/long acting β2-agonist (LABA) are provided at step 4. However, a proportion of patients would just be partly controlled or even remain uncontrolled despite treatment at step 4. For these patients, add-on anti-IgE therapy based on phenotype are recommended.
Omalizumab was the first anti-IgE antibody developed for the treatment of allergic moderate to severe asthma and other allergic conditions.7 Omalizumab has been extensively evaluated in allergic severe asthma, which significantly reduced asthma exacerbations (AEs).8,9,10 However, there were few data in regard of efficacy and safety of omalizumab in Chinese patients with moderate to severe asthma. CMAB007 (omalizumab α, developed by Mabpharm Limited, Taizhou, China) is a recombinant Chinese Hamster Ovary cell-derived humanized IgG1κ monoclonal anti-IgE antibody. It is exactly the same as Omalizumab in amino acid sequence and the human pharmacokinetics similarity to Omalizumab has been demonstrated.11 To evaluate the efficacy and safety of CMAB007 add-on therapy in Chinese patients with moderate-severe asthma with increased total IgE level who were inadequately controlled despite GINA step 4 treatment, we conducted this randomized, placebo-controlled, double-blind phase 3 trial.
MATERIALS AND METHODS
Participants
Eligible patients having with a confirmed diagnosis of moderate or severe asthma and a serum total IgE level of 60–1,500 IU/mL were included. In this trial, moderate asthma was defined as asthma characterized by daily symptoms that influenced activity and sleep, with nocturnal symptoms occurring once a week or more, and forced expiratory volume in 1 second (FEV1) % predicted ≥ 60%–< 80%, and severe asthma was defined as asthma that had frequently daily symptoms, frequent nocturnal symptoms, limited activity, FEV1% predicted < 60%. Allergic asthma was identified by measuring the level of total IgE in serum. Participants should also meet the following additional criteria: duration of asthma ≥ 1 year; aged 15–75 years; weighing 20–150 kg; baseline FEV1% less than 80% of the predicted value; at least one AE requiring systemic glucocorticoid treatment during one year before screening; asthma is partly controlled or still uncontrolled despite treatment with fluticasone propionate > 250 μg/day or budesonide > 400 μg/day for at least 3 months without dose adjustments during 4 weeks before screening. The key exclusion criteria were as the followings: Patients with elevated IgE levels caused by parasitic infections, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome or other conditions; current smokers or prior smokers with a smoking index > 10 pack-years and quitted smoking less than 10 years; a history of current malignancy, lymphatic proliferative disease or splenomegaly; uncontrolled hypertension; concomitant with other lung diseases such as chronic obstructive pulmonary disease, bronchiectasis, or pulmonary interstitial fibrosis; treatment with any anti-IgE monoclonal antibody within 12 months or any other biologic agent within 6 months prior to screening; or use of other investigational drugs within at least 30 days.
This trial was conducted in accordance with the current Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the Institutional Review Board (IRB) of the First Affiliated Hospital of Guangzhou Medical University (IRB number: Ethics[2017]-medicine-026-01) Written informed consent form was obtained from every patient before any procedure of this trial.
Study design
This was a multicenter, randomized, double-blinded, placebo-controlled, phase 3 trial with a 24 weeks treatment period to determine the efficacy and safety of CMAB007 as add-on therapy in patients with moderate or severe asthma with increased total IgE level who were inadequately controlled despite GINA step 4 treatment. This trial was conducted from April 2018 to March 2021 at 42 sites in China. Following 4–8 weeks run-in period, 393 patients were randomly assigned in a 2:1 ratio to receive subcutaneous injections of CMAB007 or placebo normalized for body mass and baseline serum IgE level for 24 weeks. For patients requiring 75–300 mg omalizumab, administration was at 4-week intervals. For patients requiring 450–750 mg omalizumab, the monthly dose was divided into 2 equal portions administered at 2-week intervals (Supplementary Tables S1 and S2). Patients in both the CMAB007 and placebo groups received fixed-dose ICS-LABA daily as background treatment, and only the short-acting β2 agonist (SABA)was permitted as rescue therapy with not more than 8 puffs/day as needed, throughout the screening, run-in and treatment phase. Except for the ICS-LABA background therapy and SABA rescue treatment, any other asthma controller, reliever or immunosuppressant was prohibited during this trial, unless for short-term treatment of acute asthma exacerbations and specific adverse events, such as allergic reactions.
Assessments
Patients made visits every 4 weeks for efficacy and safety evaluation until week 24.
Efficacy assessment
Patients were instructed to record the morning and nocturnal peak expiratory flow (PEF). Spirometry were performed at least 12 hours after suspension of ICS/LABA and 6 hours after inhibition of salbutamol at every visit; asthma control test (ACT) score, asthma quality of life questionnaire (AQLQ) score, and investigator and patient global evaluation of treatment effectiveness (GETE) were assessed every 8 weeks.
The primary efficacy variable was the AE rate (mean AE per patient) during 24-week treatment period which was defined as worsen of asthma symptoms requiring one of the follows: 1) unscheduled visit for medical care; 2) systemic therapy with corticosteroids; 3) hospitalization; 4) emergency visit. The secondary variables were number of patients who experienced at least one exacerbation, time to first exacerbation, asthma symptom score (daytime, nocturnal), ACT score, AQLQ score, GETE assessed by investigators and patients, asthma rescue medication (number of puffs/day), pulmonary function (FEV1, forced vital capacity [FVC], FEV1/FVC) and PEF (daytime, nocturnal).
Safety assessment
Discomforts were recorded in the diary cards and were collected at each visit. Complete blood count, biochemical examination and urinalysis were performed at screening, week 0, week 8, week 16 and week 24. Vital signs were assessed at each visit and physical examinations were conducted at screening and at the end of this trial. Safety was analyzed through adverse events throughout the study, characterized by their type, incidence, severity, duration, seriousness, and relatedness to investigational treatment.
Statistical analyses
Statistical analysis was conducted by using SAS, version 9.4 (SAS Institute, Cary, NC, USA). Based on the results of INNOVATE trial,8 It was assumed that the asthma exacerbations rate in the placebo group throughout 24 weeks was 1, and would be reduced by 30% in the CMAB007 group. Considering 20% withdrawal, the sample size of 400 with a 2:1 ratio in the CMAB007 (n = 267) and placebo (n = 133) groups, would achieve 84% power at 0.05 significant level.
The primary efficacy analysis population consisted of all randomly assigned patients who received at least one dose of investigational medicine (CMAB007 or placebo). The safety population comprised all patients who received at least one dose of investigational medicine with at least one safety assessment. The Poisson regression via generalized estimating equation was used to analyze the primary variable, with grouping, dosing regimen (dose and frequency), background treatment strata (fluticasone propionate > 250–500 μg daily/budesonide > 400–800 μg daily, fluticasone propionate > 500 μg daily/budesonide > 800 μg daily) and centers as covariates in the model. Considering patients who discontinued early in the placebo group would be more likely to have AEs than those in the CMAB007 group if they had remained in the group, one exacerbation was added to the total for the patient who terminated investigational treatment prematurely, unless the patient had an AE within 7 days before withdrawal, as the INNOVATE trial did.8 Three pre-specified sensitivity analyses were applied to the primary variable. These methods are summarized as follows: 1) Observed exacerbations: used observed exacerbations only. 2) Single exacerbation imputation: assigned one exacerbation to the patients who discontinued (not an additional one). 3) Maximum observed exacerbations imputation: assigned the maximum number of observed exacerbations for both groups. The statistical method for sensitivity analyses was the same as the primary analysis.
Secondary endpoint analyses were descriptive statistics and P values were nominal. As to continuous variables of the secondary endpoints, the analysis of variance F-test was performed in the analysis, and the non-parametric test after rank transformation would be applied in the condition that the data was not a normal distribution. As for the category variables, the Cochran-Mantel-Haenszel statistic was used in the secondary analysis. There was no interim analysis in this trial.
RESULTS
Patient baseline characteristics
Among 656 patients screened, 393 patients across 42 sites in China were randomly assigned to either CMAB007 group (263 patients) or placebo group (130 patients) in a 2:1 ratio. Thirteen (4.9%) and 13 (10.0%) patients discontinued treatment in the CMAB007 and placebo groups, respectively, and 5 patients (1.9%) in the CMAB007 group and 1 patient (0.8%) in the placebo group were due to adverse events (Fig. 1). The CMAB007 and placebo groups were well-balanced for baseline characteristics and demographics (Table 1). There were about 1.3 times as many females as males in this trial. The patients were all 18 years of age or older. The mean duration of asthma were 11.5 years. Allergic rhinitis coexisted in 48.3% and 45.0% of patients in the CMAB007 and placebo groups, respectively. The proportion of patients complicated with chronic rhinosinusitis in the CMAB007 and placebo groups were 6.1% and 2.3%. Of the patients treated with budesonide/fluticasone propionate in the 4 weeks prior to screening, 88.5% were on medium dose (99.1% and 74.2% for budesonide and fluticasone propionate, respectively), and 11.2% were on high dose. At baseline, 69.4% of patients were diagnosed as partly-controlled cases despite medium or high dose ICS-LABA treatment, and 30.6% were uncontrolled. The FEV1 of predicted were less than 59.8% in half patients, with a mean of 57.3%. The baseline median ACT scores were 18, indicating half of patients were poor asthma controlled. During the previous year plus run-in period, patients had experienced an average of 1.8 episodes of asthma exacerbations.
Fig. 1. Patient distribution flow chart.
AE, adverse event.
Table 1. Demographic and baseline characteristics of the patients.
| Characteristics | CMAB007 (n = 263) | Placebo (n = 130) | Total (n = 393) | P value | |
|---|---|---|---|---|---|
| Age (yr) | 50.7 ± 12.9 | 50.4 ± 11.7 | 50.6 ± 12.5 | 0.522 | |
| Male | 115 (43.7) | 57 (44.2) | 172 (43.9) | 0.931 | |
| Body weight (kg) | 64.3 ± 10.8 | 64.6 ± 12.3 | 64.4 ± 11.3 | 0.790 | |
| Comorbidities | |||||
| Allergic rhinitis | 127 (48.3) | 58 (45.0) | 185 (47.1) | 0.535 | |
| Chronic rhinosinusitis | 16 (6.1) | 3 (2.3) | 19 (4.8) | 0.104 | |
| Total IgE (IU/mL) | 0.100 | ||||
| Mean ± SD | 385.9 (329.9) | 382.1 (339.2) | 384.7 (332.6) | ||
| Median (Q1, Q3) | 261.0 (132.0, 538.0) | 293.0 (144.0, 424.0) | 272.0 (139.0, 480.0) | ||
| Duration of asthma (yr) | 0.819 | ||||
| Mean ± SD | 11.9 (12.3) | 10.6 (10.0) | 11.5 (11.6) | ||
| Median (Q1, Q3) | 7.4 (3.6, 15.6) | 7.1 (3.8, 14.1) | 7.3 (3.7, 15.1) | ||
| Asthma exacerbation during the previous year and run-in period | 0.209 | ||||
| Mean ± SD | 1.9 (3.1) | 1.6 (1.1) | 1.8 (2.6) | ||
| Median (Q1, Q3) | 1.0 (1.0, 2.0) | 1.0 (1.0, 2.0) | 1.0 (1.0, 2.0) | ||
| Asthma control level | 0.558 | ||||
| Partly controlled | 185 (70.3) | 87 (67.4) | 272 (69.4) | ||
| Uncontrolled | 78 (29.7) | 42 (32.6) | 120 (30.6) | ||
| Rescue medication ([puffs/day] in run-in period) | 0.900 | ||||
| Mean ± SD | 1.0 (2.1) | 0.8 (1.4) | 0.9 (1.9) | ||
| Median (Q1, Q3) | 0.2 (0.0, 1.0) | 0.2 (0.0, 1.0) | 0.2 (0.0, 1.0) | ||
| Daily dose of budesonide during 4 weeks prior to screening | 0.644 | ||||
| 400–800 μg | 149 (99.3) | 78 (98.7) | 227 (99.1) | ||
| > 800 μg | 1 (0.7) | 1 (1.3) | 2 (0.9) | ||
| Daily dose of fluticasone propionate during 4 weeks prior to screening | 0.732 | ||||
| 250–500 μg | 83 (73.5) | 38 (76.0) | 121 (74.2) | ||
| > 500 μg | 30 (26.5) | 12 (24.0) | 42 (25.8) | ||
| FEV1 (L) | 0.339 | ||||
| Mean ± SD | 1.679 (0.6823) | 1.740 (0.7039) | 1.699 (0.6910) | ||
| Median (Q1, Q3) | 1.620 (1.160, 2.100) | 1.660 (1.200, 2.390) | 1.630 (1.175, 2.180) | ||
| FEV1/FVC (%) | 0.260 | ||||
| Mean ± SD | 59.605 (12.6132) | 59.947 (12.0853) | 59.718 (12.4275) | ||
| Median (Q1, Q3) | 60.610 (50.480, 68.530) | 59.620 (51.150, 69.450) | 60.325 (50.880, 68.665) | ||
| FEV1 (% of predicted) | 0.534 | ||||
| Mean ± SD | 56.8 (16.8) | 58.2 (15.9) | 57.3 (16.5) | ||
| Median (Q1, Q3) | 58.9 (44.0, 70.9) | 63.0 (46.4, 71.0) | 59.8 (45.0, 71.0) | ||
| Morning PEF | 0.054 | ||||
| Mean ± SD | 249.4 (100.5) | 273.0 (112.7) | 257.1 (104.8) | ||
| Median (Q1, Q3) | 239.2 (179.2, 303.7) | 265.8 (185.2, 341.9) | 248.3 (180.0, 316.1) | ||
| Nocturnal PEF | 0.051 | ||||
| Mean ± SD | 251.0 (99.7) | 275.0 (113.7) | 258.9 (105.0) | ||
| Median (Q1, Q3) | 243.3 (179.4, 307.2) | 266.1 (195.9, 338.2) | 249.4 (183.6, 318.4) | ||
| Daytime clinical symptom score | 0.047 | ||||
| Mean ± SD | 1.1 (1.0) | 0.9 (1.0) | 1.0 (1.0) | ||
| Median (Q1, Q3) | 0.7 (0.3, 1.8) | 0.5 (0.2, 1.5) | 0.7 (0.2, 1.8) | ||
| Nocturnal clinical symptom score | 0.865 | ||||
| Mean ±SD | 0.5 (0.7) | 0.5 (0.7) | 0.5 (0.7) | ||
| Median (Q1, Q3) | 0.2 (0.0, 0.8) | 0.2 (0.0, 0.7) | 0.2 (0.0, 0.7) | ||
| ACT score | 0.176 | ||||
| Mean ± SD | 17.2 (4.0) | 17.7 (4.1) | 17.4 (4.1) | ||
| Median (Q1, Q3) | 18.0 (15.0, 20.0) | 18.0 (15.0, 21.0) | 18.0 (15.0, 20.0) | ||
| Overall AQLQ score | 0.041 | ||||
| Mean ± SD | 127.5 (21.8) | 132.4 (19.6) | 129.1 (21.2) | ||
| Median (Q1, Q3) | 131.0 (115.0, 143.0) | 136.0 (123.0, 145.0) | 132.0 (118.0, 144.0) | ||
Values are presented as mean ± standard deviation or number (%).
IgE, immunoglobulin E; SD, standard deviation; Q, quartile; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; ACT, asthma control test; AQLQ, asthma quality of life questionnaire.
Efficacy
AEs
Among the 393 randomized patients, except for 1 patient with concomitant pulmonary alveolar diffusion dysfunction in the CMAB007 group, the remaining 392 cases were all included in the full analysis set (FAS). Based on the FAS population, the AE rate was 0.45 per patients with CMAB007 and 0.66 per patient with placebo respectively during the 24-week treatment phase. The analysis demonstrated statistically significant difference between the 2 groups (hazard ratio [HR], 0.68; 95% confidence interval, 0.49, 0.96; P = 0.030).
Results of the 3 pre-specified sensitivity analyses all favored CMAB007, showing a statistically significant difference over placebo (Table 2).
Table 2. Rates of asthma exacerbations.
| Outcome measures | CMAB007 (n = 262) | Placebo (n = 130) | ||
|---|---|---|---|---|
| Primary analysis | ||||
| Rates of asthma exacerbations | 0.45 | 0.66 | ||
| HR (95% CI) | 0.68 (0.49, 0.96) | |||
| P value | 0.030 | |||
| Sensitivity analysis | ||||
| Observed exacerbations (no imputation) | ||||
| Rates of asthma exacerbations | 0.40 | 0.59 | ||
| HR (95% CI) | 0.68 (0.48, 0.98) | |||
| P value | 0.038 | |||
| Single exacerbation imputation | ||||
| Rates of asthma exacerbations | 0.43 | 0.60 | ||
| HR (95% CI) | 0.70 (0.50, 0.99) | |||
| P value | 0.043 | |||
| Maximum observed exacerbations imputation | ||||
| Rates of asthma exacerbations | 0.68 | 1.07 | ||
| HR (95% CI) | 0.65 (0.46, 0.91) | |||
| P value | 0.014 | |||
HR, hazard ratio; CI, confidential interval.
GETEs
After 8 weeks of treatment, 59.4% of patients in the CMAB007 group were evaluated by investigators as good or excellent efficacy, and the proportion further improved over time, which were significantly higher than those in the placebo group (Fig. 2A). Results of GETE evaluated by patients were similar with those assessed by investigators (Fig. 2B).
Fig. 2. Effect of CMAB007 or placebo treatment on the GETE.
A, GETE measured by Investigators; B, GETE measured by patients; a, GETE at Week 8, b, GETE at Week 16; c, GETE at Week 24.
GETE, global evaluation of treatment effectiveness.
ACT
The average ACT scores in the CMAB007 and placebo groups were 19.97 and 19.26 (P = 0.110) at Week 8, 20.71 and 19.87 (P = 0.013) at Week 16, 21.08 and 20.50 (P = 0.048) at Week 24, respectively (Supplementary Table S3).
Proportions of patients with an increase of at least 3 points from baseline in ACT scores were greater in the CMAB007 group than those in the placebo group at Week 8 (49.8% vs. 36.9%, P = 0.018), Week 16 (59.4% vs. 42.9%, P = 0.003) and Week 24 (60.2% vs. 47.0%, P = 0.019) (Fig. 3, Supplementary Table S3).
Fig. 3. Proportion of patients with asthma control test increased by ≥ 3 in the CMAB007 and placebo groups.
AQLQ scores
Improvement rates of AQLQ overall score from baseline were significantly greater in the CMAB007 group than those in the placebo group at Week 8 (11.41% vs. 5.62%, P = 0.005), Week 16 (14.26% vs. 7.25%, P = 0.002) and Week 24 (14.73% vs. 8.71%, P = 0.039) (Supplementary Table S3). The improvement in quality of life is mainly reflected in limited activities domain and asthma symptoms domain. There were statistically significant improvements in the average changes of activities scores from baseline between the CMAB007 and placebo groups at Week 8 (11.52% vs. 5.68%, P = 0.040), Week 16 (15.01% vs. 6.64%, P < 0.001), and Week 24 (16.89% vs. 8.88%, P = 0.002) (Supplementary Table S3). As far as the symptoms scores is concerned, the statistically significant differences between the CMAB007 and placebo groups were observed at Week 8 (12.21% vs. 7.45%, P = 0.012) and Week 24 (14.12% vs. 9.79%, P = 0.014) (Supplementary Table S3).
Morning and nocturnal PEF
The CMAB007 group showed statistically greater improvement of morning PEF from week 8 to week 24, with the maximum improvement rates of 20.43% compared toe and the placebo group (10.81%), and with the greatest rate difference of 10.88% at Week 16 (Supplementary Table S3). The results for nocturnal PEF were consistent with those for morning PEF. The maximum improvement rates of nocturnal PEF were 20.35% for the CMAB007 group and 10.28% for the placebo group, respectively, with the greatest rate difference of 11.18% at Week 16 (Supplementary Table S3).
FEV1 and FEV1/FVC
The improvement rates of FEV1% from baseline were statistically greater in the CMAB007 group compared to the placebo group at 4 weeks (11.40% vs. 5.03%, P = 0.006), 8 weeks (16.27% vs. 6.57%, P = 0.003), 12 weeks (16.51% vs. 6.60%, P = 0.002) and 16 weeks (20.18% vs. 7.42%, P = 0.002) (Supplementary Table S3, Supplementary Fig. S1). There were statistically greater proportion of patients with FEV1% increased by ≥ 200 mL from baseline in the CMAB007 group than in the placebo group at each visit, with the greatest rate difference of 17.5% (P = 0.001) at Week 16 (Supplementary Table S3). The statistical differences of improvement rate in FEV1/FVC between the CMAB007 and placebo groups appeared at 4 weeks (4.17% vs. 1.17%, P = 0.042), 8 weeks (6.95% vs. 1.24%, P = 0.002), 12 weeks (6.97% vs. 1.69%, P = 0.002) and 16 weeks (6.76% vs. 2.29%, P = 0.020) (Supplementary Table S3).
Rescue medication use
Statistically significant reduction in rescue medication frequency was observed in the CMAB007 group over the placebo group at Week 4 (−8.10% vs. 19.98%, P = 0.023), Week 8 (−13.18% vs. 30.01%, P = 0.003) and Week 16 (−49.49% vs. −1.78, P = 0.042) (Supplementary Table S3).
Subset analyses of the primary endpoint
Pre-specified subgroup analyses for the primary endpoint were performed by gender (male, female), age (aged ≤ 25, > 25–45, > 45–65, > 65), baseline blood eosinophil level (< 0.15 × 109/L, 0.15–0.3 × 109/L, > 0.3 × 109/L), baseline IgE level (60–100 KU/L, > 100–700 KU/L, > 700–1,200 KU/L, > 1,200–1,500 KU/L), daily dose of background medication (medium dose ICS-LABA, high dose ICS-LABA), baseline asthma control status (partly controlled, uncontrolled), percentage of baseline FEV1 to predicted value (≤ 40%, > 40%–60%, > 60%–< 80%), and number of AEs in the past year plus run-in period (1 time, 2 times, 3 times, 4 times, > 4 times). By gender, baseline IgE level and background medication, the treatment benefits were in the same direction among all subgroups, favoring CMAB007 treatment. By age, the therapeutic effects were consistent across subgroups of aged > 25–45 and > 45–65 years, favoring CMAB007 treatment, and were unfavorable in the subgroups of aged ≤ 25 and > 65 years. By baseline asthma control status, the treatment benefit was in favor of the CMAB007 therapy in the partly-controlled asthma subgroup, but was neutral for uncontrolled asthma subgroup. Likewise, the treatment effects were in the same direction favoring CMAB007 treatments in subgroups of blood eosinophil level < 0.15 × 109/L and > 0.3 × 109/L, and was neutral in subgroup of 0.15–0.3 × 109/L. By percentage of baseline FEV1 to predicted value, the treatment effects were in the same direction favoring CMAB007 treatments in subgroups of > 40%–60% and > 60%–< 80%, while was neutral in subgroup of ≤ 40%. By number of AEs in the past year plus run-in period, the treatment effects were in favor of the CMAB007 treatment in the subgroups of one time and 2 times AE episodes, and were neutral or unfavorable in subgroups of 3 times, 4 times and > 4 times episodes (Fig. 4).
Fig. 4. Subgroup analyses of the primary endpoint (rate of asthma exacerbations).
CI, confidential interval; IgE, immunoglobulin E; F, fluticasone propionate; B, budesonide; FEV1, forced expiratory volume in 1 second.
Safety
Seven hundred and seventy and 291 cases of treatment emergent adverse events (TEAEs) occurred in 203 patients (77.2%) in the CMAB007 group and in 97 patients (75.2%) in the placebo group, respectively. TEAEs with incidence differences that were ≥ 5% between the CMAB007 and placebo groups were not observed. Incidences of the most common TEAEs (≥ 3% in either group) are generally similar between the 2 groups (Table 3). The majority of TEAEs in the CMAB007 and placebo groups were mild (33.8% vs. 33.3%) or moderate (39.5% vs. 35.7%) in severity. Injection site reactions were observed in 7 CMAB007-treated patients (2.7%), all of which were mild or moderate in severity. Dermatitis was observed in 4 CMAB007-treated patients (1.5%), all of which were mild or moderate in severity. Five patients (1.9%) experienced anaphylaxis related to CMAB007, manifested as mild or moderate itching, urticaria, dermatitis, injection site reaction, dizzy, palpitation and nausea. The incidence of serious adverse events in the CMAB007 group (8.4%) was comparable with that in the placebo group (8.5%). No deaths were reported in both groups during this trial.
Table 3. Number of patients (%) with most frequently occurring treatment emergent adverse events by preferred term (≥ 3% in either group).
| Adverse events | CMAB007 (n = 263) | Placebo (n = 129) | P value |
|---|---|---|---|
| Upper respiratory tract infection | 88 (33.5) | 46 (35.7) | 0.666 |
| Urinary tract infection | 18 (6.8) | 7 (5.4) | 0.589 |
| Bronchitis | 12 (4.6) | 5 (3.9) | 0.754 |
| Pharyngitis | 10 (3.8) | 4 (3.1) | 0.951 |
| Respiratory tract infection | 6 (2.3) | 5 (3.9) | 0.567 |
| Infectious pneumonia | 6 (2.3) | 6 (4.7) | 0.333 |
| Nasopharyngitis | 6 (2.3) | 5 (3.9) | 0.567 |
| Allergic rhinitis | 17 (6.5) | 4 (3.1) | 0.165 |
| Cough | 14 (5.3) | 3 (2.3) | 0.171 |
| Asthma exacerbation* | 8 (3.0) | 3 (2.3) | 0.938 |
| Alanine aminotransferase increased | 8 (3.0) | 3 (2.3) | 0.938 |
| Hyperglycemia | 2 (0.8) | 4 (3.1) | 0.182 |
| Hyperlipidemia | 3 (1.1) | 4 (3.1) | 0.331 |
| Hypertension | 8 (3.0) | 7 (5.4) | 0.381 |
Values are presented as number (%).
*Defined as asthma exacerbations that met the criteria for serious adverse events.
Immunogenicity
Among subjects in the CMAB007 group, 18 patients (6.8%) were positive for anti-drug antibody (ADA) before medication, while 17 patients (6.6%) and 25 patients (9.7%) were positive at the 4th and 24th weeks after study medication, respectively. During the overall treatment period, a total of 35 patients (13.5%) showed at least one ADA positive reaction. There were no neutralizing antibody (Nab) detected before medication, and 2 patients (8.0%) appeared positive at Week 24. ADA or Nab positivity had no effect on AEs.
DISCUSSION
Although several trials evaluating the efficacy of omalizumab in Chinese population with moderate and severe asthma have been published,12,13,14,15,16,17 there are some limitations. First, AE rate was not used as the primary endpoint in these trials, which is the gold standard for asthma evaluation. Second, most of these trials are retrospective or post-hoc analysis. The pivotal phase 3 trial of omalizumab by Li et al. 17 in the Chinese population was prospectively designed with lung function as the primary endpoint. The other prospective trial was an observational real-world study.14 Current trial is a well-designed trial that prospectively confirmed the efficacy and safety of anti-IgE monoclonal antibody with the AE rate as the primary endpoint in Chinese patients with moderate-to-severe asthma with increased total IgE level. In this trial, CMAB007 significantly reduced the risk of AE by 32% in targeted patients compared to placebo, which is comparable with that of omalizumab INNOVATE trial, a pivotal trial conducted in Europe.8
In this trial, the improvement of lung function were observed in the CMAB007-treated patients. The proportion of patients with FEV1 increased by ≥ 200 mL from baseline, and the improvement rates of FEV1 from baseline were all greater in the CMAB007 group than those in the placebo group at 4-week, 8-week 12-week and 16-week, which is recognized as clinically meaningful. The CMAB007 group also showed greater improvement rates from baseline in morning and nocturnal PEF when compared to the placebo group, with the greatest rate differences in 10.88% and 11.18%, respectively. Previously reported trials have also shown improvement of lung function in omalizumab-treated patients with moderate to severe asthma with increased total IgE level. In INNOVATE trial,8 the FEV1 were increased by 190 mL and 96 mL in the omalizumab and placebo groups at the study end, respectively. In the pivotal trial of omalizumab conducted in China by Li et al.,17 the average change from baseline in morning PEF at week 24 was the primary endpoint but was not met, and the significant improvements occurred at weeks 4–20. The FEV1% predicted from week 8–24 were significantly improved with omalizumab compared to the placebo, with the least squares mean treatment difference of 4.12% at Week 24.
Improvement in asthma symptom control in the CMAB007 group was observed in this trial. Given that a change of 3 points in ACT scores is clinically detectable,18 the CMAB007 group showed greater clinically relevant improvement in ACT than the placebo group at each visit, and the greatest difference of proportion of patients with ACT increased by ≥ 3 from baseline was 18%. Furthermore, the proportion of patients in the CMAB007 group rating the effect of treatment as excellent/good efficacy were approximately 20% and 16% higher than those in the placebo group for investigators’ and patients’ GETE, respectively. These results are also consistent with those in INNOVATE trial8 and trial by Li et al. 17 In the INNOVATE trial, the proportion of patients who were classified as excellent/good efficacy were 17.7% and 21.0% higher in the omalizumab group than those in the placebo group for investigators’ and patients’ GETE, respectively. In the trial by Li et al.,17 the differences in the proportion of patients who were classified as excellent/good efficacy between the omalizumab and placebo groups were 19.6% and 10.3% for investigators’ and patients’ GETE, respectively.
It is well established that asthma exerts a profound effect on quality of life, particularly in term of the emotional aspect and ability to perform activities.19 The AQLQ adopted in this trial was modified by Cai et al. 20 on the basis of Juniper AQLQ. In this trial, CMAB007 add-on treatment showed improvement over placebo in respect to the overall AQLQ scores as well as activities and symptoms domains scores in some extent, starting at week 8 after treatment. We also calculated the number of puffs of SABA taken daily during 4-week intervals between visits. Statistical advantage of reduction in rescue medication frequency from baseline were seen in CMAB007 over placebo groups at Week 4, Week 8 and Week 16. The greater reduction in the use of SABA use supports the finding of a reduction in AE. We defined subgroups by demographic characteristics and variables that were prognostic of clinical outcomes. A favorable treatment effects of CMAB007 were observed across subgroups by gender, baseline IgE level and daily dose of background ICS-LABA medication. Particularly, the rationale of dosing regimens of CMAB007 was supported by the consistency in efficacy across subgroups by IgE level at baseline. By age, baseline blood eosinophil level, baseline asthma control status, baseline FEV1%, and asthma episodes in the past year plus run-in period, the treatment benefits were in favor of the CMAB007 therapy in subgroups with larger sample sizes and were unfavorable or neutral in the ones with smaller sample sizes. AEs are small probability events and follow Poisson distribution, so the sample size should be large enough to observe such events and make statistical inferences. Thus, we considered this heterogeneity of CMAB007 treatment effects was due to the limited sample sizes.
CMAB007 was well tolerated, without adding unduly to the side-effects. The overall incidence of TEAEs in the CMAB007 group (77.2%) was comparable with that in the placebo group (75.2%). Most adverse events were mild or moderate in severity and were manageable. Incidences of injection site reactions (2.7%) and dermatitis (1.5%) were low. The incidence of anaphylaxis in CMAB007 group was 1.9%, all of which were mild or moderate. No deaths were reported in this trial.
ADA and Nab formations were detected in 35 (13.5%) and 2 (5.7%) patients, respectively. None of the 2 Nab-positive patients experienced AEs and unsuspected adverse events during this trial, indicating that ADA formations may have no deleterious effect on CMAB007 treatments. The ADA incidence should be interpreted in light of the fact that pre-exist ADAs were detected at baseline in 18 patients among these 35 ADA-positive ones, and therefore, the incidence of ADA induction was overestimated. Indirect comparison of ADA incidences between CMAB007 and omalizumab would also be misleading, since detection of ADA formation is highly dependent on the specificity and sensitivity of the assay, and is influenced by timing of sample collections, sample handling, concomitant medications, etc.
Since the development program of CMAB007 was initiated when omalizumab was not marketed in China, it was not allowed to compare CMAB007 with omalizumab directly, which was the limitation of this trial. For historical comparisons with omalizumab, this trial was designed with reference to 2 pivotal phase 3 trials of omalizumab. The INNOVATE trial8 was conducted in Europe, of which the target population, background treatment, primary endpoint and other details were nearly the same as ours. The design of the trial by Li et al. 17 was also the same as ours except its primary efficacy variable was the change from baseline in morning PEF at 24-week. In the INNOVATE trial, the AE rate during the 28-week treatment phase was 0.68 with omalizumab and 0.91 with placebo, respectively, and reach statistical significance in post-hoc analysis after adjusting for imbalance in baseline AEs, meaning 26% reduction in AE risk. As regards asthma symptom control and lung function, similar improvements were also observed in this trial as in the INNOVATE trial and the trial by Li et al. 17 The other limitation of this trial was that the duration of observation was not long enough to assess long-term safety. We have been collecting safety information of CMAB007 in clinical practice and to date, no new safety signals were reported.
In conclusion, CMAB007 reduces the risk of AEs and improves asthma control, lung function and quality of life without additional safety concern in Chinese patients with moderate or severe asthma with increased total IgE level. CMAB007 could be recommended as add-on therapy to patients with moderate-severe asthma with increased total IgE level who were inadequately controlled despite ICS-LABA treatment.
ACKNOWLEDGMENTS
We acknowledge all investigators not listed as authors for their commitment to this trial: Chang Cai, Zhenshun Cheng, Jiaxi Feng, Xiying Feng, Yadong Gao, Zhongliang Guo, Zhenhong Hu, Yong Huang, Yi Jiang, Manxiang Li, Wei Li, Guifen Pang, Li Peng, Lei Rong, Baohua Sun, Daoxin Wang, Yixin Wan, Jianming Xu, Ping Zhang, Wei Zhang, Hong Zhu, Xiaoli Zhu. We would also like to thank all patients who contributed to this trial.
Funding for this trial was supported by Mabpharm Limited, Taizhou, China. We also appreciate the sponsor for involving in the design, data collection and analysis of this study.
Footnotes
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Subcutaneous CMAB007 doses (mg) every 4 weeks for study subjects
Subcutaneous CMAB007 doses (mg) every 2 weeks for study subjects
Comparison of secondary endpoints between the 2 groups
Improvement rate of FEV1 from baseline in the CMAB007 and placebo groups. FEV1, forced expiratory volume in 1 second.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Subcutaneous CMAB007 doses (mg) every 4 weeks for study subjects
Subcutaneous CMAB007 doses (mg) every 2 weeks for study subjects
Comparison of secondary endpoints between the 2 groups
Improvement rate of FEV1 from baseline in the CMAB007 and placebo groups. FEV1, forced expiratory volume in 1 second.