The efficacy and safety of tezepelumab in the treatment of uncontrolled asthma: A systematic review and meta-analysis of randomized controlled trials

Background:

Tezepelumab is a human thymic stromal lymphopoietin (TSLP) antibody with effects in asthma. Therefore, our study aimed to evaluate the overall efficacy and safety of tezepelumab for the treatment of uncontrolled asthma.

Methods:

The databases Cochrane Library, PubMed, Embase, Web of Science, and Clinical Trials were searched from inception to April 1, 2022. Only randomized controlled trial (RCTs) that evaluated tezepelumab and a comparator for treating uncontrolled asthma were included. Additionally, articles were limited to English. The primary outcome was clinical efficacy, and the secondary outcome was adverse events. The risk of bias and quality were assessed by the Cochrane Collaboration bias assessment tool. The meta-analysis was performed using Review Manager Version 5.3.

Results:

Four RCTs with a total of 1600 patients were included in the study. Pooled analysis indicated that tezepelumab had significantly decreased annualized asthma exacerbations (odds ratio [OR] = 0.67, 95% confidence interval [CI] = [0.57, −0.80], P < .00001) and the asthma control questionnaire score of 6 (ACQ-6) among the patients (standard mean difference [SMD] = −0.29, 95% CI = [−0.39, −0.20], P < .00001) compared to placebo. Furthermore, tezepelumab treatment significantly improved forced expiratory volume in 1 second (FEV1, SMD = 0.28, 95% CI = [0.11, 0.45], P = .001). Regarding safety, the pooled analysis indicated that patients treated with tezepelumab showed no significant difference in adverse events that led to discontinuation of the treatment, but they experienced some other (non-serious) adverse events compared to the placebo group. However, there was a significant decrease in the incidence of serious adverse events and any adverse events in the tezepelumab group. Tezepelumab use was associated with adverse events, including nasopharyngitis, headache, and bronchitis, despite effectively treating asthma.

Conclusion:

Tezepelumab effectively improved FEV1, reduced the disease symptom score, and decreased the risk of exacerbations in uncontrolled asthma patients. Tezepelumab was associated with some adverse events compared to placebo. This suggests that careful management of adverse events is required if tezepelumab is used to treat asthma patients.

1. Introduction

Asthma is a chronic, heterogeneous disease that is highly defined by chronic inflammation of the airways. The inflammatory processes are triggered by various airborne stimuli. According to current estimates, 339 million people worldwide suffer from asthma, with approximately 5% to 10% of these patients having severe asthma.^[1,2] Patients with severe asthma have a high rate of comorbidities, drug side effects, healthcare resource dependence, and medication costs. Severe asthma remains uncontrolled despite the use of standard-of-care therapy, which includes inhaled corticosteroids, long-acting beta2-agonists, short-acting beta 2-agonist, oral corticosteroids, macrolides, leukotriene receptor antagonists, and sublingual immunotherapy.^[3,4] Over the last decade, increased knowledge of the mechanisms underlying the pathogenesis of asthma has facilitated the development of modern biological therapy for the treatment of severe asthma.^[5,6] Modern biological therapy targets the pro-inflammatory cytokines or mediators, including IL-5, IL-4, IL-13/IL4, IgE, and thymic stromal lymphopoietin (TSLP).^[7–9]

TSLP is an epithelial cell-derived cytokine in the airways, belonging to the group of alarmins, that plays a central role in the pathogenesis of asthma by activating and maintaining downstream inflammatory processes in response to multiple triggers, including viruses, bacteria, fungi, allergens, pollutants, smoke, other airborne irritants, and physical injury.^[10,11] TSLP is a distant paralog of the cytokine IL-7. Growing evidence suggests that TSLP plays a role in type-2 inflammation and non-T2 processes in asthma. One study has demonstrated that the expression of TSLP is increased in the airways of asthma patients compared to healthy controls.^[10] Tezepelumab, also known as MEDI9929 or AMG 157, is a first-in-class human monoclonal antibody for severe asthma that selectively blocks TSLP interaction with its heterodimeric receptor. It is also a fully human IgG2λ monoclonal antibody that binds to human TSLP and inhibits several downstream inflammatory pathways.^[12] Tezepelumab is the first and only biologic to consistently and significantly reduce asthma exacerbations in a wide population of patients with severe asthma. The molecule Tezspire (generic name tezepelumab-ekko) is being developed by AstraZeneca in collaboration with Amgen. The drug has a molecular weight of approximately 147 kDa and must be given subcutaneously by a healthcare provider. The Food and Drug Administration (FDA) approved tezepelumab for marketing on December 17, 2021, as a maintenance treatment in addition to other therapies for patients aged 12 years with severe asthma symptoms that were not controlled by ongoing medication.^[13] This is the only biologic that is approved for severe asthma across all phenotypes (such as eosinophilic or allergic) without any biomarker limitations.

Cumulative evidence has focused on the safety and tolerability of tezepelumab in asthma patients by evaluating a wide range of data, including clinical trials and posthoc analyses of clinical trials. Tezepelumab had a good efficacy and safety profile in the previous study. However, there remains a significant need for more extensive data to guide future research and clinical use. To address this issue, we performed a comprehensive systematic review and meta-analysis of double-blinded randomized controlled trial (RCTs) covering patients with asthma to evaluate the efficacy and adverse events after treatment with tezepelumab compared to placebo.

2. Methods

2.1. Data sources and search strategy

We scanned the databases PubMed, Embase, Cochrane Central Trials, and Web of Science from inception to April 1, 2022. Unpublished data are available at Clinical trials. The text and medical subject heading terms included: “Tezepelumab” [MeSH term] OR Tezspire OR AMG 157 OR MEDI9929. And articles were limited to English. The Supplementary Table 1, http://links.lww.com/MD/J478 gives the search strategy.

2.2. Study selection

Following the completion of the search, duplicate records were removed using ENDNOTE X8.0. The titles and abstracts of records were independently read by 2 researchers (Yu and Deng) for preliminary screening. The full text of literature that potentially met the inclusion criteria was also reviewed. The inclusion criteria were as follows: studies on patients diagnosed with uncontrolled asthma; RCTs; studies using tezepelumab as the intervention; studies comparing it with a placebo or comparators; and studies reporting clinical efficacy and safety as the outcome (Table 1). Clinical efficacy was considered as the primary outcome, while adverse events were considered as the secondary outcome.

Table 1.

The summary of inclusion and exclusion criteria.

Study characteristics	Inclusion	Exclusion	Report characteristics	Inclusion	Exclusion
Participants	18 yr olde age	Age <18 yr	Language	English	Other language
Setting	Tezepelumab as the intervention, compared with other drugs or placebo	No comparator or only tezepelumab using	Yr	Not restricted	N/A
Target conditions	Uncontrolled asthma	Other pulmonary disease	Publication status	Published or not	N/A
Study design	RCTs, blinding	In vivo, in vitro, animal model, and pharmacokinetic and pharmacodynamic studies

RCT = randomized controlled trial.

2.3. Data extraction

Two independent reviewers (Yu and Deng) extracted information such as the trial name, publication date, interventions, number of patients, trial duration, therapy duration, randomization procedures, study population, age, sex, and study site from the included studies. In case of any disagreement, a third reviewer (Lin) was consulted to resolve it. In this study, the exclusion criteria included in vitro studies, animal model studies, and pharmacokinetic and pharmacodynamic (PK/PD) studies, in that order. Abstracts were also excluded.

2.4. Quality assessment

The overall quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation tool.^[14] The risk of bias in each included study was evaluated using the Cochrane Collaboration bias assessment tool.^[15] The research quality of all included studies was evaluated based on the following criteria: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other biases. Two reviewers independently rated the studies as having a “low risk,” “high risk,” or “unclear risk” of bias.

2.5. Outcome measures

The clinical efficacy outcomes of this study included a severe asthma exacerbation rate, forced expiratory volume in 1 second (FEV1), and an asthma control questionnaire score of 6 (ACQ-6). Regarding the safety outcome of this study, any adverse events, adverse events leading to discontinuation of treatment, serious adverse events, and other adverse (not serious) events were evaluated. Moreover, the most common adverse events were listed and included in the analyses. Adverse events were defined according to the FDA and previous studies, including PATHWAY,^[16] CASCADE,^[17] NAVIGATOR,^[18] and SOURCE.^[19] The odds ratio (OR) and 95% confidence interval (CI) were used as the measures of association between adverse events and the use of tezepelumab. A serious adverse event was defined as an event that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, or resulted in persistent or clinically significant disability or incapacity. The adverse events leading to discontinuation were defined as events that occur within the following administration of therapy that are listed as potential adverse effects in the product monograph and lead to discontinuation of therapy.

2.6. Statistical analysis

The statistical software Review Manager version 5.3 was used for the statistical analyses. A 2-sided P < .05 indicated a significant difference. The meta-analysis of OR and standardized mean difference (SMD) was calculated using a random-effects model or a fixed-effects model. The chi-square test-based Cochran Q statistic and I² statistic were used to determine the study heterogeneity, and P < .10 or I² > 50% indicated that the study was heterogeneous.^[20] The fixed-effect model was used when I² was <50% and P was >.10; otherwise, the random-effect model was used.

3. Results

3.1. Literature search and evaluation for study inclusion

A total of 1033 articles were identified from the searches of PubMed (n = 148), EMBASE (n = 537), Cochrane Central (n = 116), Clinical Trials (n = 25), and Web of Science (n = 207). After removing duplicate records (n = 383) and ineligible articles (based on a review of their title and abstract) (n = 643), 7 studies remained. Three articles were excluded after a full-text review. Therefore, 4 studies were included in the meta-analysis (Fig. 1).

Figure 1.

The flowchart of study selection process.

3.2. Study characteristics

A total of 1600 patients were included in the meta-analysis (with 798 in the tezepelumab group and 802 in the placebo group, Table 2). The PATHWAY study^[16] reported 3 different dosages of tezepelumab (70 mg, 210 mg, and 280 mg), only the 210 mg group was included. The CASCADE,^[17] NAVIGATOR,^[18] and SOURCE^[19] studies include only 1 dosage of tezepelumab (210 mg). The NAVIGATOR^[18] study enrolled patients aged 12 to 80 years old. In 3 trials, a follow-up duration of 52 weeks was reported (Table 2).

Table 2.

Characteristics of 4 studies.

Study, yr published	Intervention	No. of patient	Study duration	Therapy duration	Study population	Study design	Study site	Male (%)	Mean ± SD (yr)
Corren et al, 2017 (PATHWAY)	210 mg	137	Between December 2013 and March 2017	52 wk	18–75 yr	phase 2	108 sites in 12 countries	50 (36.5)	52.7 ± 12.7
	placebo	138						44 (31.9)	52.3 ± 11.7
Diver et al, 2021 (CASCADE)	210 mg	59	Between November 2018 and November 2020	52 wk	18–75 yr	phase 2	27 centers in 5 countries	20 (34.0)	50.4 ± 12.7
	placebo	57						31 (54.0)	50.4 ± 13.9
Menzies-Gow et al, 2021 (NAVIGATOR)	210 mg	528	Between November 2017 and September 2020	52 wk	12–80 yr	phase 3	297 sites in 18 countries	193 (36.6)	49.9 ± 16.3
	placebo	531						194 (36.5)	49.0 ± 15.9
Wechsler et al, 2021 (SOURCE)	210 mg	74	Between March 2018 and September 2019	48 wk	18–80 yr	phase 3	60 sites in 7 countries	25 (34.0)	53.5 ± 12.1
	placebo	76						31 (41.0)	53.4 ± 11.9

3.3. Quality assessment

Figures 2 and 3 summarize the overall quality of the studies included in the meta-analysis and their risk of bias. All studies were double-blind and had a low risk of attrition and reporting bias. Additionally, tezepelumab is produced by AstraZeneca and Amgen who funded all the 4 studies. Thus, the results should be interpreted with caution. The assessment of quality using grading of recommendations, assessment, development, and evaluation criteria found high-quality evidence in all analyses performed due to the large number of participants, blinding in all studies, and randomization completed through an interactive response system (Supplementary Table 2, http://links.lww.com/MD/J479).

Figure 2.

Risk of bias summary.

Figure 3.

Risk of bias graph.

3.4. Efficacy

To determine the efficacy of the drug, we assessed measures of severity, including the asthma exacerbation rate, lung function, and ACQ-6 score. Overall, the included studies demonstrated a significant improvement in the efficacy of asthma treatment with the use of tezepelumab, as indicated by all clinical indices. Overall, the pooled analysis of 4 studies showed a significant decrease in the annualized asthma exacerbation rate of tezepelumab (OR = 0.67, 95% CI = [0.57, 0.80]), albeit with high heterogeneity (I² = 76%, P = .006, Fig. 4). In the sensitivity analysis, removing the PATHWAY study decreased the heterogeneity to 0% (P = .49). Furthermore, our analysis showed that treatment with tezepelumab significantly decreased the ACQ-6 scores (SMD = −0.29, 95% CI = [−0.39, −0.20], P < .00001), with low heterogeneity (I² = 0%, P = .69, Fig. 5). The pooled analyses indicated that treatment with tezepelumab significantly improved the FEV1 (SMD = 0.28, 95% CI = [0.11, 0.45]), with low heterogeneity (I² = 46%, P = .13, Fig. 6).

Figure 4.

The effect of tezepelumab treatment on asthma severe exacerbations versus placebo.

Figure 5.

The effect of tezepelumab versus placebo on ACQ-6 score. ACQ-6 = 6-item asthma control questionnaire, Std. mean difference = standardized mean difference.

Figure 6.

The effect of tezepelumab versus placebo on FEV1. FEV1 = forced expiratory volume in 1 s.

3.5. The adverse events risk of tezepelumab

Figure 7 presents the forest plots of the meta-analysis of the 4 included studies. Pooling estimates indicated that patients treated with tezepelumab did not have significantly difference in adverse events leading to discontinuation of treatment (OR = 0.66, 95% CI = [0.34, 1.26], I² = 0%) or other (not serious) adverse events (OR = 0.89, 95% CI = [0.73, 1.09], I² = 58%) compared to placebo. However, the pooling analysis indicated that patients treated with tezepelumab had a significantly lower rate of serious adverse events (OR = 0.66, 95% CI = [0.49, 0.90], I² = 0%) or any adverse events (OR = 0.78, 95% CI = [0.62, 0.99], I² = 0%) compared to placebo. The use of tezepelumab was associated with a lower risk of asthma (OR = 0.47, 95% CI = [0.34, 0.65], I² = 0%) and upper respiratory tract infection (OR = 0.66, 95% CI = [0.48, 0.92], I² = 0%) than placebo (Fig. 8). In addition, there was no statistically significant difference in the risk of nasopharyngitis between tezepelumab (OR = 0.97, 95% CI = [0.76, 1.24], I² = 0%) and placebo. Similar trends were observed for headache (OR = 0.94, 95% CI = [0.66, 1.34], I² = 26%) and bronchitis (OR = 0.99, 95% CI = [0.70, 1.42], I² = 0%, Table 3).

Figure 7.

Risk of adverse events between tezepelumab and placebo in the treatment of asthma.

Figure 8.

Risk of most frequent adverse events between tezepelumab and placebo in the treatment of asthma.

Table 3.

The results of safety in meta-analysis.

Outcomes	Participants		I2	Effect Estimate	P value
	Tezepelumab arm	Comparator arm
Any AEs	599/798	636/802	0%	0.78 [0.62, 0.99]	.04
SAEs	79/798	114/802	0%	0.66 [0.49, 0.90]	.009
AEs leading to treatment discontinuation	15/798	23/802	0%	0.66 [0.34, 1.26]	.2
Other (not including serious) AEs	451/798	474/802	58%	0.89 [0.73, 1.09]	.27
Asthma	65/798	123/802	0%	0.47 [0.34, 0.65]	<.00001
Upper respiratory tract infection	71/661	102/664	0%	0.66 [0.48, 0.92]	.01
Bronchitis	66/798	67/802	0%	0.99 [0.70, 1.42]	.97
Nasopharyngitis	166/798	170/802	0%	0.97 [0.76, 1.24]	.83
Headache	63/798	67/802	26%	0.94 [0.66, 1.34]	.73

4. Discussion

We selected 4 randomized, placebo-controlled clinical trials that investigated the efficacy of tezepelumab. All trials were industry-sponsored, and all of the studies were double-blind, placebo-controlled, RCTs, but the smaller study populations could result in possible bias. The rate of exacerbation, change in FEV1, and the scores of various symptoms were the primary endpoints for all trials. This meta-analysis compares data from all RCTs investigating the use of tezepelumab in the treatment of severe asthma. The pooled analysis of efficacy revealed that treatment with tezepelumab could significantly improve FEV1, reduce the disease symptom score, and reduce the risk of exacerbations in patients with uncontrolled asthma. In this study, tezepelumab was demonstrated to have beneficial effects on clinical parameters, including FEV1, ACQ-6, and exacerbation rate. These observations should be considered alongside data from previous studies. Like in previous RCT studies, the data from this meta-analysis suggests that tezepelumab can reduce the number of exacerbations and the disease symptom score, as well as improve FEV1 in patients with uncontrolled asthma.

Asthma is a chronic, heterogeneous disease. Results of several studies have demonstrated that TSLP plays a role in T2 inflammation and the non-T2 process of asthma. TSLP is a cytokine that is involved in the first immune defense response, which mediates respiratory allergic reactions and activates dendritic cells to release Th2-related cytokines, leading to the promotion of airway remodeling. Tezepelumab is the first anti-TSLP drug to improve lung function by blocking TSLP. Results of the pooled analysis demonstrate that tezepelumab could significantly improve FEV1 in patients with uncontrolled asthma. The clinical relevance of this finding suggests the possible effect of tezepelumab on airway remodeling. Besides, a previous study^[21] reported a significant effect of tezepelumab on lung function compared to placebo in the study participants. However, that study only included 1 study on treatment with tezepelumab. In contrast, our meta-analysis included 4 studies with a larger total sample of 1600 patients.

The ACQ-6 is a simple questionnaire that is used to measure the adequacy of asthma control and the change in asthma control, which occurs either spontaneously or as a result of treatment. Four trials^{[16,18,19,22]} reported that tezepelumab could significantly reduce the ACQ-6 scores and asthma symptom scores, which was consistent with our findings. In this study, it was observed that treatment with tezepelumab significantly decreased the ACQ-6 scores.

The rate of exacerbation in asthma is related to the mortality of asthma patients. Thus, reducing the rate of asthma exacerbation is vital for managing asthma. Tezepelumab has been demonstrated to reduce rates of exacerbation in patients diagnosed with moderate to severe asthma.^{[16,18,19,22]} In this study, the pooled analysis of efficacy revealed that treatment with 210 mg tezepelumab reduced the risk of exacerbations by approximately 67% in patients diagnosed with uncontrolled asthma. These results confirm the control of symptoms mediated by tezepelumab through the blocking of the TLSP pathway in patients with moderate to severe asthma. Tezepelumab also improved health-related quality of life. In the PATHWAY study, rates of exacerbation decreased by approximately 62% to 71%.^[16]

The pooled analysis of safety data from 4 clinical trials involving asthma patients revealed that patients treated with Tezepelumab experienced lower rates of adverse events compared to placebo. The likelihood of experiencing any adverse events, adverse events leading to treatment discontinuation, other (non-serious) adverse events, serious adverse events, and the most frequent adverse events was lower. Notably, our results indicated that asthma patients treated with tezepelumab had significantly different rates of occurrence for any adverse events or serious adverse events. However, a network meta-analysis study reported that there were no significant differences in the incidence of any adverse events among patients treated with tezepelumab and placebo.^[21] Additionally, the frequency of adverse events ranged from 5.0% to 93.8% in our meta-analysis. Our meta-analysis indicated that 49.5% of the 216 patients in the PATHHOME study (phase 3, open-label) reported experiencing all adverse events, with similar frequencies observed in the 2 device groups.^[23] The pooled results of 1 study indicated that the incidence of any adverse events among the overall participants treated with either tezepelumab, dupilumab, benralizumab, mepolizumab, or placebo was similar.^[21]

The overall safety profile of tezepelumab was comparable to that of placebo in all RCTs, with the most common adverse events being asthma, nasopharyngitis, headache, upper respiratory tract infection, and bronchitis. In the PATHHOME study, the most common adverse event associated with the use of tezepelumab was nasopharyngitis, reported in 9.3% of participants.^[23] While the PATH-BRIDGE study reported the occurrence of nasopharyngitis in 24.5% of participants.^[24] However, all trials reported similar incidence rates of nasopharyngitis in the tezepelumab and placebo groups.^[16–19] A study by Shih-Lung Cheng reported that nasopharyngitis, upper respiratory tract infection, headache, and asthma were the most common adverse events observed more frequently in the placebo group than in the tezepelumab group.^[8]

Although injection-site reactions are generally considered adverse events related to drug use, the PATHWAY study^[16] did not report such reactions in any group, while the SOURCE study^[19] did not report any injection-site reactions in the tezepelumab-treatment group, with just 1 case in the placebo group. In contrast, the CASCADE study^[17] reported injection-site reactions in 12% of patients in the tezepelumab group and 4% of patients in the placebo group, while the NAVIGATOR study^[18] reported such reactions in 3.6% of patients in the tezepelumab group and 2.6% in the placebo group. In the pooled safety population, injection-site reactions were observed in 3.3% of patients treated with tezepelumab, compared to 2.7% of patients treated with placebo.^[25] The occurrence of injection-site reactions was relatively low in this and other studies on tezepelumab, compared to studies on other biologics, in which the reported occurrence ranged from 2% to 45%.^[24]

Although a placebo is a dummy medication without any pharmacological effects, approximately 79.3% of patients in the placebo group experienced some adverse event in all 4 included trials. One possible explanation for this is the “placebo effect,” a phenomenon in which negative effects are attributed to the placebo.^[26–28] On the other hand, the higher prevalence of adverse events in the placebo groups can also be explained by the clinical characteristics of the disease. In heterogeneous and chronic inflammation (such as asthma), respiratory tract involvement is common. Furthermore, according to our pooled results, the most common adverse events, including oropharyngeal pain, asthma, nasopharyngitis, upper respiratory tract infections, and bronchitis, were more frequent in the placebo group and were primarily respiratory-related. These adverse events may be attributed to the high prevalence of respiratory symptoms in asthma patients.

This meta-analysis has some limitations, which are related to the intrinsic characteristics of the included studies. First, the number of studies included in the meta-analysis is small and involves selected populations of asthmatic patients. Second, the comparator was only a placebo. Finally, since all the RCTs were funded by the pharmaceutical industry companies AstraZeneca and Amgen, which produced tezepelumab, the positive outcomes should be interpreted cautiously. Our study also had some strengths. For instance, our patient selection was highly consistent, and all trials were of high quality, which increased the internal validity of our meta-analysis.

5. Conclusion

In this study, we compared the clinical efficacy and safety of the recommended usage of tezepelumab according to the instruction manual (210 mg administered subcutaneously every 4 weeks). According to the pooled analysis, tezepelumab could significantly reduce the disease symptom score and risk of severe exacerbations, as well as improve FEV1 in patients with uncontrolled asthma. Regarding safety, tezepelumab was associated with a lower risk of adverse events, especially nasopharyngitis, headaches, and bronchitis, compared to placebo. The use of tezepelumab in the treatment of asthma patients had a higher prevalence of asthma and upper tract infection, which suggested that careful management of these adverse events is required.

Author contributions

Data curation: Fei Lin, Bin Yu, Bowen Deng.

Formal analysis: Fei Lin, Rong He.

Investigation: Bin Yu, Bowen Deng.

Methodology: Rong He.

Writing – original draft: Fei Lin.

Writing – review & editing: Rong He.