Tezepelumab: An Anti-Thymic Stromal Lymphopoietin Monoclonal Antibody for the Treatment of Asthma

Abstract

Asthma is a common chronic respiratory disease in which epithelial cytokines and airway inflammation play critical pathophysiological roles. Thymic stromal lymphopoietin (TSLP), an epithelial cytokine, is central in the initiation and persistence of airway inflammation in asthma. Tezepelumab is a human immunoglobulin G2λ (IgG2λ) monoclonal antibody developed for treating moderate-to-severe asthma by specifically binding to TSLP and preventing its binding to the TSLP receptor on inflammatory cells. In this narrative review, we describe the results of clinical trials that evaluated the pharmacokinetics, pharmacodynamics, efficacy and safety of tezepelumab in patients with moderate-to-severe asthma. We also introduce the ongoing clinical trials in patients with asthma as well as future trials investigating the use of tezepelumab for other indications.

Plain language summary

Asthma is a long-term disease that causes inflammation in the cells of the lung. One of the cytokines (proteins) involved in asthma is called thymic stromal lymphopoietin (TSLP). This cytokine is produced by the airway epithelium, a layer of cells covering the respiratory tract in the lungs, where it activates inflammatory cells. Tezepelumab is a new drug that blocks the activity of TSLP in the lungs and helps reduce asthma symptoms, such as coughing and breathlessness. In this article, we describe the clinical trials that investigated how well tezepelumab works, as well as its safety, in people with moderate or severe asthma. We also describe the trials of tezepelumab that are now underway in people with asthma, allergies or other inflammatory diseases.

Tweetable abstract

This review describes the pharmacokinetics, pharmacodynamics, efficacy, safety and ongoing trials of tezepelumab, a human IgG2λ monoclonal antibody designed to inhibit thymic stromal lymphopoietin produced by the airway epithelium, for treating asthma. #asthma, #lunghealth

Keywords::

• asthma
• clinical trial
• epithelial cytokine
• inflammation
• innate lymphocyte
• lung health
• tezepelumab
• Th2 cell
• thymic stromal lymphopoietin

The incidence of asthma, a common chronic respiratory disease, varies among countries and is thought to affect 1–18% of the general population. It is characterized by wheezing, shortness of breath, chest tightness, coughing and airflow limitation. These symptoms and airflow limitation, as well as their severity, vary over time [1].

The understanding of asthma pathology has advanced in recent years. Factors such as exercise, exposure to allergens and irritants, weather changes and viral or bacterial respiratory infection are common asthma triggers, with airway hyper-responsiveness and chronic airway inflammation due to these stimulants being at the center of this condition. It is now known that the airway epithelium activates various airway inflammation pathways via epithelial cytokines in response to the stimuli mentioned above (Figure 1) [2].

Figure 1. Role of thymic stromal lymphopoietin in driving disease mechanisms in different asthma endotypes.

In allergic eosinophilic inflammation, TSLP initiates pathways involving Th2 lymphocytes, basophils, and mast cells to drive airway eosinophilia. In non-allergic eosinophilic inflammation, TSLP activates innate lymphocytes such as ILC2s that contribute to airway eosinophilia. TSLP also mediates structural mechanisms that contribute to airway remodeling, involving airway smooth muscle cells and fibroblasts.

IgE: Immunoglobulin E; IL: Interleukin; ILC2: Group 2 innate lymphoid cell; T2: Type 2; Th: T helper; TSLP: Thymic stromal lymphopoietin.

Reproduced with permission from [2].

Approximately 5–10% of asthma patients have severe asthma, in which asthma symptoms cannot be controlled with conventional therapies, including inhaled corticosteroids (ICSs) and long-acting β₂-agonists (LABAs) [3]. Such refractory cases are treated with biologics, such as an anti-immunoglobulin E (IgE) antibody, anti-IL-5 antibody, anti-IL-5Rα antibody, or anti-IL-4Rα antibody. However, some patients do not adequately respond to these biologics, which target cytokines downstream of airway inflammation [1].

Tezepelumab was developed as a biologic with a unique mechanism of action that involves inhibiting the action of thymic stromal lymphopoietin (TSLP). This epithelial cytokine activates a wide range of immune cells involved in airway inflammation in asthma (Figure 1) [2]. In this review article, we summarize the characteristics of tezepelumab, including its mechanism of action, pharmacokinetics, pharmacodynamics, efficacy, and safety. We also discuss its potential as a treatment option for patients with severe uncontrolled asthma poorly controlled with other biologics.

Mechanism of action

TSLP is produced by airway epithelial cells following the inhalation of allergens, viruses, fungi or bacteria that irritate the airway epithelium. TSLP activates several inflammatory cells, such as dendritic cells, group 2 innate lymphoid cells (ILC2s) and mast cells, which promotes type 2 inflammation by increasing type 2 cytokine production (Figure 1) [2,4–6]. It was further reported that TSLP induces neutrophilic inflammation under specific in vitro conditions, indicating it is also involved in non-type 2 inflammation [7]. Furthermore, it has been confirmed that TSLP increases collagen production from fibroblasts and induces the growth of airway smooth muscle, indicating that it affects airway remodeling [2]. Thus, we know that TSLP is involved in the induction and perpetuation of airway inflammation and that it widely activates immune cells and inflammatory pathways related to the pathology of type 2 and non-type 2 asthma [2,4].

Reportedly, there is increased expression of TSLP in the airway tissue of asthma patients compared with that of healthy adults. Additionally, the increase in TSLP correlates with symptom severity, respiratory function, airway obstruction, airway hyperresponsiveness, airway remodeling and steroid resistance [2,4].

Tezepelumab is a human immunoglobulin G2λ (IgG2λ) monoclonal antibody designed to specifically bind to TSLP and inhibit it from binding to the TSLP (IL-7Rα heterodimeric) receptor [8]. In vitro studies showed that tezepelumab inhibited TSLP and suppressed the activation of TSLP receptor-bearing cells, thus confirming its mechanism of action. When tezepelumab was added to TSLP receptor-bearing cells, it inhibited TSLP-induced phosphorylation of STAT5 and cell proliferation. Furthermore, tezepelumab suppressed the production of CCL17 from human dendritic cells induced by TSLP [9].

Pharmacokinetics & pharmacodynamics

The pharmacokinetics of tezepelumab were investigated in two phase I ascending-dose trials in healthy adults [10]. After a single subcutaneous dose of tezepelumab 210 mg, the median time to maximum blood concentration (t_max) was 93.65 h, the mean half-life was 25.7 days, and the bioavailability was 81%. In the multiple-dose trial in which tezepelumab 210 mg was subcutaneously administered three times (every 4 weeks), the median t_max after the last dose was 167 h. After administration of tezepelumab 210 mg every 4 weeks, the mean serum trough concentration increased over time, approaching a steady state by Week 12 [11].

In the phase IIb PATHWAY trial, subcutaneous administration of tezepelumab 210 mg once every 4 weeks was predicted to achieve approximately 90% of the peak pharmacologic action for suppressing asthma exacerbations and a decrease in fractional exhaled nitric oxide (FeNO) based on the pharmacokinetic–pharmacodynamic model. Additionally, this was selected as the dosage regimen for a phase III trial [12].

In the phase III NAVIGATOR trial, antidrug antibodies were detected in 4.9% of patients in the tezepelumab group and 8.3% in the placebo group. These values were low and were not considered to affect the efficacy and safety of tezepelumab [13].

The pharmacodynamic effect of tezepelumab in a clinical setting was first investigated in a phase I trial in which adult patients with mild allergic asthma received three intravenous doses of placebo or tezepelumab (700 mg, once every 4 weeks). The decreases in forced expiratory volume in 1 s (FEV₁) during early and late asthmatic responses after allergen inhalation were suppressed in the tezepelumab group compared with the placebo group. In addition, tezepelumab significantly reduced blood and sputum eosinophil counts and suppressed the elevation of FeNO after allergen inhalation [8].

The clinical pharmacodynamics of tezepelumab have been further investigated in global studies (Table 1), including the 52-week phase IIb PATHWAY trial in adults with severe uncontrolled asthma [14], the 28-week Phase II CASCADE trial in adults with uncontrolled moderate-to-severe asthma [15], and the 52-week phase III NAVIGATOR trial of adults and adolescents with severe uncontrolled asthma [13]. Compared with placebo, administration of tezepelumab was associated with reductions in a range of type 2 inflammatory biomarkers and clinical markers, such as airway submucosal and blood eosinophil counts, FeNO, total serum IgE, IL-5, IL-13, periostin and thymus activation regulated chemokine (Figure 2) [15,16]. Furthermore, in the NAVIGATOR trial, the changes in the blood eosinophil counts and FeNO were apparent within 2 weeks of starting tezepelumab, and in the follow-up, long-term DESTINATION extension, the changes were sustained to Week 104, along with a gradual decline in total serum IgE levels until Week 104 [17].

Figure 2. Median percentage change from baseline in biomarker levels over 52 weeks.

(A) Blood eosinophil count, (B) FeNO, (C) IgE, (D) IL-5, (E) IL-13, (F) periostin, (G) TARC.

FeNO: Fractional exhaled nitric oxide; IgE: Immunoglobulin E; IL: Interleukin; MAD: Median absolute deviation; Q4W: Every 4 weeks; TARC: Thymus and activation-regulated chemokine.

Reprinted from [16] under an open access license (http://creativecommons.org/licenses/by-nc/4.0/).

Table 1. Overview of key clinical trials for tezepelumab in patients with asthma.

Trial	Patients	Design	Duration	Dosing	Primary endpoint	Other endpoints	Ref.
CASCADE	116 adults (aged 18–75 years) with uncontrolled moderate-to-severe asthma on medium/high-dose ICS for ≥12 months plus ≥1 asthma controller	International, phase II, exploratory, double-blind, randomized, placebo-controlled, parallel-group trial	28 weeks^†	210 mg Q4W vs placebo	The change in airway submucosal eosinophil count was nominally greater in tezepelumab arm (ratio of geometric LSM: 0.15, nominal p < 0.0010). There were no significant differences in the other inflammatory cell types assessed	Tezepelumab significantly reduced airway hyperresponsiveness to mannitol (LSM change in the interpolated or extrapolated provoking dose of mannitol required to induce ≥15% reduction in FEV1: 197.4 mg vs 58.6 mg, nominal p = 0.030)	[15]
PATHWAY	550 adults (aged 18–75 years) with asthma not well controlled despite LABA plus medium/high-dose ICS for ≥6 months, history of asthma exacerbation	International, phase II, randomized, double-blind, placebo-controlled, parallel-group trial	52 weeks	70 mg Q4W (low), 210 mg Q4W (medium), or 280 mg Q2W (high) vs placebo	AAER at Week 52 was significantly lower in the tezepelumab groups vs placebo group (0.27, 0.20, and 0.23 vs 0.72) (all p < 0.001)	The AAER was consistently lower in the three tezepelumab dose groups vs placebo group when patients were divided by baseline blood eosinophil count, FeNO, or Th2 status. The prebronchodilator FEV1 at Week 52 was significantly greater in all tezepelumab groups (difference vs placebo: 0.12, 0.13, and 0.15 L; all nominal p ≤ 0.015)	[14]
NAVIGATOR	1061 patients (aged 12–80 years) with physician-diagnosed asthma on medium/high-dose ICS for ≥12 months and ≥1 additional controller	International, phase III, randomized, double-blind, placebo-controlled, parallel-group trial	52 weeks with 12-week post-treatment follow-up or long-term extension study	210 mg Q4W vs placebo	AAER at Week 52 was significantly lower in the tezepelumab group than in the placebo group in overall population (0.93 vs 2.10, rate ratio 0.44; p < 0.001) and in patients with blood eosinophil count <300 cells/μl (1.02 vs 1.73, rate ratio 0.59; p < 0.001)	At Week 52, tezepelumab was associated with significantly greater improvements in prebronchodilator FEV1 (0.23 vs 0.09 L; p < 0.001), ACQ-6 scores (-1.55 vs -1.22; p < 0.001), AQLQ scores (1.49 vs 1.15; p < 0.001), and ASD scores (-0.71 vs -0.59; p = 0.002)	[13]
SOURCE	150 patients (aged 18–80 years) with physician-diagnosed asthma on medium/high-dose ICS and history of ≥1 exacerbation within 12 months with OCS dependence	International, phase III, randomized, double-blind, placebo-controlled, parallel-group trial	8-week OCS dose optimization phase followed by 48-week randomized treatment phase (4-week induction phase, 36-week OCS reduction phase, 8-week maintenance phase)	210 mg Q4W vs placebo	Cumulative odds of achieving greater categorized percentage reduction from baseline in daily OCS dose at Week 48 was similar in both groups (cumulative OR 1.28, 95% CI: 0.69–2.35; p = 0.43)	Categorized percentage reduction tended to favor tezepelumab in patients with blood eosinophil count ≥300 cells/μl (cumulative OR 3.49, 95% CI: 1.16–10.49) or ≥150 cells/μl (cumulative OR 2.58, 95% CI: 1.16–5.75). The median final daily OCS dose (mg) was lower in the tezepelumab group vs placebo (0.0, range 0.0–25.0 vs 2.5, range 0.0–35.0) The AAER was numerically lower in the tezepelumab group vs placebo group (1.38 vs 2.00, rate ratio 0.69, 95% CI: 0.44–1.09) The LSM change in prebronchodilator FEV1 was 0.21 vs -0.04 L	[25]
NOZOMI	65 Japanese patients (aged 12–80 years) with severe uncontrolled asthma on medium/high-dose ICS plus ≥1 asthma controller ± OCS	Japanese, phase III, exploratory, single-arm trial	52 weeks	210 mg Q4W	Safety/tolerability of tezepelumab: 94 AEs occurred in 39 patients (60.0%), the most common AE being nasopharyngitis. Severe AEs occurred in two patients, serious AEs in four patients, and AEs of special interest in 11 patients	The AAER was 0.11/patient-year; with exacerbations in five patients. Prebronchodilator FEV1 increased numerically from 2.257 to 2.329 L. ACQ-6 scores decreased by ≥0.5 in 71.4%	[21]
DESTINATION	Adults (aged 18–80 years) and adolescents (aged 12–17 years) with severe uncontrolled asthma 528 and 531 patients in the tezepelumab and placebo groups from NAVIGATOR 74 and 76 patients in the tezepelumab and placebo groups from SOURCE	Phase III, multicenter, randomized, double-blind, placebo-controlled, long-term extension study recruited from NAVIGATOR and SOURCE	104 weeks	210 mg Q4W	In NAVIGATOR, the incidence of AEs over 104 weeks was 49.62 and 62.66 per 100 patient-years for tezepelumab and placebo, respectively. For serious AEs, the incidence was 7.85 and 12.45 per 100 patient-years, respectively In SOURCE, the incidence of AEs over 104 weeks was 47.15 and 69.97 per 100 patient-years for tezepelumab and placebo, respectively. For serious AEs, the incidence was 13.14 and 17.99 per 100 patient-years, respectively	Annualized asthma exacerbation rate ratio over 104 weeks was 0.42 in NAVIGATOR and 0.61 in SOURCE Annualized asthma exacerbation rate from Week 0 of the parent studies to Week 104 of DESTINATION was reduced with tezepelumab vs placebo	[17]

† Or 52 weeks if the final assessment at 28 weeks was delayed due to COVID-19.

AAER: Annualized asthma exacerbation rate; ACQ-6: Asthma Control Questionnaire-6; AE: Adverse event; AQLQ: Asthma Quality of Life Questionnaire; ASD: Asthma Symptom Diary; CI: Confidence interval; FeNO: Fractional exhaled nitric oxide; FEV₁: Forced expiratory volume in 1 s; ICS: Inhaled corticosteroid; LABA: Long-acting β₂-agonist; LSM: Least-squares mean; OCS: Oral corticosteroid; OR: Odds ratio; Q2W: Every 2 weeks; Q4W: Every 4 weeks; Th2: Type 2 helper T.

The effect of tezepelumab on airway hyperresponsiveness was investigated in the Phase II CASCADE trial. Tezepelumab improved airway hyperresponsiveness induced by mannitol stimulation compared with placebo, measured in terms of the least-squares mean (LSM) change in mannitol PD₁₅ from baseline to end of treatment (197.4 vs 58.6 mg; the difference in LSM change: 138.8 mg, 95% confidence interval [CI] 14.2–263.3; p = 0.030) [15].

Overall, these studies confirmed the pharmacodynamic effects of tezepelumab on inhibiting TSLP and improving the underlying pathological conditions in asthma.

Efficacy

The main clinical studies that were conducted to investigate the efficacy and safety of tezepelumab in patients with asthma are summarized in Table 1.

In the Phase III NAVIGATOR trial, tezepelumab was associated with a significant reduction in the annual asthma exacerbation rate (AAER) versus placebo at Week 52 (rate ratio [RR] 0.44, 95% CI: 0.37–0.53; p < 0.001), together with improvements in prebronchodilator FEV₁ (difference vs placebo 0.13 L, 95% CI: 0.08–0.18; p < 0.001), Asthma Control Questionnaire-6 (ACQ-6; difference vs placebo -0.33, 95% CI: -0.46 to -0.20; p < 0.001), and Asthma Quality of Life Questionnaire (AQLQ; difference vs placebo 0.34, 95% CI: 0.20–0.47; p < 0.001). Notably, improvements in prebronchodilator FEV₁ were confirmed at 2 weeks post-tezepelumab initiation (Figure 3) [13].

Figure 3. Change from baseline to Week 52 in prebronchodilator FEV₁.

Bars indicate 95% confidence intervals.

FEV₁: Forced expiratory volume in 1 s.

Reprinted with permission from [13].

The efficacy of tezepelumab was also investigated in subgroups of patients divided by baseline blood eosinophil count [13]. In patients with a baseline blood eosinophil count of ≥300 cells/μl, tezepelumab suppressed the AAER by 70% versus placebo (RR 0.30, 95% CI: 0.22–0.40), which was accompanied by improvements in prebronchodilator FEV₁ (difference vs placebo 0.23 L, 95% CI: 0.15–0.31), ACQ-6 (difference vs placebo -0.50, 95% CI: -0.69 to -0.31), and AQLQ (difference vs placebo 0.51, 95% CI: 0.30–0.71). Tezepelumab was also associated with a suppression of AAER by 41% in patients with a baseline blood eosinophil count of <300 cells/μl (RR 0.59, 95% CI: 0.46–0.75) and by 39% in patients with a baseline blood eosinophil count of <150 cells/μl (RR 0.61, 95% CI: 0.42–0.88). Thus, although the suppression in AAER was greater in patients with a high baseline eosinophil count, the results demonstrate the effectiveness of tezepelumab in patients with a low baseline eosinophil count. Moreover, in a pooled analysis of the Phase IIb PATHWAY and phase III NAVIGATOR trials, tezepelumab showed clinically meaningful effects on suppressing AAER, regardless of baseline blood eosinophil count, FeNO level, and perennial antigen positive/negative status (Figure 4) [11]. These efficacy findings, including improved lung function, asthma control, and health-related quality of life, were maintained over 104 weeks in DESTINATION, a long-term extension trial [17].

Figure 4. Annualized asthma exacerbation rate ratios over 52 weeks across different baseline biomarkers in a pooled analysis of the NAVIGATOR and PATHWAY studies.

Time at risk was defined as the total duration of time in which a new exacerbation could occur (i.e., the total follow-up time minus time during exacerbation and 7 days after).

^aAllergic status as defined by a serum immunoglobulin E result specific to any perennial aeroallergen in the fluoroenzyme immunoassay panel.

CI: Confidence interval; FeNO: Fractional exhaled nitric oxide; ppb: Parts per billion; Q4W: Every 4 weeks.

In other subanalyses of the PATHWAY trial, tezepelumab suppressed the AAER versus placebo in each season with RRs of 0.36 (95% CI: 0.17–0.78), 0.20 (95% CI: 0.07–0.59), 0.18 (95% CI: 0.06–0.52), and 0.33 (95% CI: 0.14–0.79) in winter, spring, summer, and autumn, respectively [18]. Moreover, tezepelumab suppressed the AAER in patients with nasal polyps (RR 0.25, 95% CI: 0.07–0.85) and without nasal polyps (RR 0.27, 95% CI: 0.14–0.53) [19].

The efficacy of tezepelumab on asthma exacerbations was also confirmed in Japanese patients with severe asthma enrolled in the NAVIGATOR trial [20], and in the phase III NOZOMI trial performed in Japan [21]. In Japanese patients with severe asthma enrolled in the NAVIGATOR trial, tezepelumab suppressed the AAER by 51% versus placebo (RR 0.49, 95% CI: 0.25–0.99), a similar reduction to that observed in the full analysis population [20]. In the single-arm NOZOMI trial, we found that the AAER decreased from 1.3/patient-year for the year before starting treatment to 0.11/patient-year after 52 weeks of treatment with tezepelumab, a notable reduction considering the trial was conducted during the COVID-19 pandemic (June 2019–June 2021) [21].

Indirect comparisons of AAER between tezepelumab and other biologics were made in a systematic review of randomized controlled trials, which included the phase III NAVIGATOR trial and phase IIb PATHWAY trial. The analyses revealed that tezepelumab suppressed the AAER by 63% versus placebo (RR 0.37, 95% CI: 0.23–0.57). The RRs of AAER for each biologic versus tezepelumab were similar among the biologics, with no significant differences. However, the ranking of the AAER showed that the surface under the cumulative ranking curve (SUCRA) was greatest for tezepelumab (84%) among the biologics assessed [22]. Furthermore, in a meta-analysis that compared tezepelumab with other biologics, the SUCRA for AAER in tezepelumab-treated patients was 79.9%, 75.6%, 85.0% and 80.5% in patients with a baseline blood eosinophil count of <150, ≥150, <300 and ≥300 cells/μl, respectively. These values were greater for tezepelumab than those for the other biologics in each subgroup [23]. Additionally, a recent Bayesian network meta-analysis found that tezepelumab and dupilumab were associated with greater improvements in both exacerbation rates and lung function compared with other biologics, further supporting the above results [24]. Based on these analyses, tezepelumab demonstrated the strongest inhibitory effects on asthma exacerbation among the biologics examined in the systematic review.

The oral corticosteroid-sparing effect of tezepelumab was evaluated in the global phase III SOURCE trial in patients with severe asthma who continuously required oral corticosteroid (OCS) in addition to ongoing treatment with an ICS and LABA [25]. The proportion of patients with a baseline blood eosinophil count <300 cells/μl was 65%. A significant difference was not found between the tezepelumab and placebo groups in terms of the percent reduction in the OCS dose at Week 48 relative to baseline (odds ratio [OR] 1.28, 95% CI: 0.69–2.35; p = 0.43). Many patients in both treatment groups achieved a ≥90% reduction in OCS dose (54.1% for tezepelumab vs 46.1% for placebo), demonstrating a large placebo effect. Two important factors that likely contributed to the considerable placebo response include the long duration of the OCS reduction phase and the possibility of multiple down-titration attempts, which were both unique features of the SOURCE trial design. Nevertheless, when patients were divided according to baseline blood eosinophil count, tezepelumab was associated with a greater percent reduction in the OCS dose among patients with an eosinophil count of ≥150 cells/μl (OR 2.58, 95% CI: 1.16–5.75). Additionally, 54% of patients in the tezepelumab group were able to discontinue OCS administration by 48 weeks versus 46% in the placebo group. The OCS discontinuation rate for tezepelumab was similar to the values reported for other biologics (dupilumab: 48% [26]; benralizumab: 52% [27]; mepolizumab: 14% [28]).

The efficacy of tezepelumab in other diseases has also been evaluated. One trial examined whether tezepelumab induced resistance against allergen stimulation when administered in combination with allergen immunotherapy in patients with rhinitis symptoms caused by cat allergy [29]. Administration of subcutaneous allergen immunotherapy (SCIT) plus intravenous tezepelumab for 52 weeks significantly improved the peak nasal symptoms, with effects that persisted to Week 104, compared with SCIT alone. In addition, the transcriptomic analysis of the nasal epithelium at Week 104 revealed a persistent reduction in the expression of genes related to type 2 inflammation in patients treated with SCIT and tezepelumab.

Safety

The safety and tolerability of tezepelumab have been investigated both in animal models and in clinical trials of patients with moderate-to-severe asthma.

Multiple studies of cynomolgus monkeys treated with tezepelumab (intravenous and/or subcutaneous) for up to 6 months [30] revealed no evidence of proliferative or preneoplastic lesions, no harmful reproductive or developmental toxicities, and no harmful effects on the mother, fetus, or offspring in pregnant monkeys. Furthermore, there were no harmful effects of tezepelumab over 6.5 months in any of the offspring.

In the phase III NAVIGATOR trial [13], adverse events (AEs) occurred in 77.1% of patients in the tezepelumab group and 80.8% in the placebo group; serious AEs occurred in 9.8 and 13.7% of patients, respectively. Thus, the overall frequencies of AEs and serious AEs were comparable in both groups. The most common AEs were nasopharyngitis (tezepelumab vs placebo: 21.4 vs 21.5%), upper respiratory tract infection (11.2 vs 16.4%), headache (8.1 vs 8.5%), and asthma (5.1 vs 11.1%). Similar outcomes were reported in other international clinical trials [10,15,25].

The safety and tolerability of tezepelumab were also assessed in Japanese patients enrolled in the NAVIGATOR [20] and NOZOMI trials [21]. Among Japanese patients enrolled in the NAVIGATOR trial, AEs occurred in 86.2% of patients in the tezepelumab group and 87.2% in the placebo group, consistent with the overall population. No new safety signals were identified in the Japanese subgroup [20]. In the NOZOMI trial, in which safety was the primary endpoint, AEs and serious AEs were observed in 60.0% and 6.2% of patients, respectively [21]. Overall, the results of these trials provide evidence for the safety and tolerability of tezepelumab in Japanese patients. The safety profile of tezepelumab found in these studies was consistent with that observed over 104 weeks in the DESTINATION trial [17].

Regarding AEs of special interest, one case of Guillain–Barré syndrome related to tezepelumab was reported in a patient who experienced a viral infection in the PATHWAY trial [14]. However, similar events were not reported in subsequent trials.

In the NAVIGATOR trial, infection was reported as a serious AE in 2.5% of patients in the tezepelumab group and 2.4% of patients in the placebo group, and malignant tumor was reported in 0.9% of patients in both groups [17]. These results suggest that tezepelumab does not increase the risk of infection or malignant tumors.

In the DESTINATION trial [17], a higher number of serious cardiac disorders was reported in the tezepelumab group than in the placebo group. However, there were no consistent patterns regarding the cause or timing of these cardiac-related AEs. All patients who experienced such events had at least one baseline cardiovascular risk factor, heart disease, or other confounding factors that presumably influenced these events. The incidence of adjudicated major adverse cardiac events was 0.65 and 0.46 per 100 patient-years in the tezepelumab and placebo groups, respectively (difference 0.19/100 patient-years, 95% CI: -0.58–0.85) [17]. The incidence rate of cardiac AEs in patients treated with tezepelumab in the DESTINATION trial was similar to other biologics for the treatment of severe asthma [31–34]. Regarding infection risk, the DESTINATION trial also revealed that the incidence rates of any severe infection or infestation were 2.39/100 patient-years in patients who received tezepelumab versus 2.38/100 patient-years in those who received placebo [17]. Finally, the VECTOR trial (NCT05062759) is expected to provide information regarding the effects of tezepelumab on influenza vaccine antibody production.

Approval status

Tezepelumab was first approved in the USA on 17 December 2021 as an add-on maintenance treatment for severe asthma in patients aged ≥12 years [35]. By the end of 2022, tezepelumab had been approved in Japan, the EU, Canada, and Switzerland, while the United Arab Emirates, Mexico, Iceland, Norway, Israel and Brazil approved the use of tezepelumab by the end of January 2023 [30,36].

Conclusion

The efficacy and safety of tezepelumab for severe uncontrolled asthma were confirmed in multiple clinical trials conducted internationally and in Japan. Tezepelumab suppresses asthma exacerbations in patients with a variety of asthma phenotypes by inhibiting TSLP, an epithelial cytokine that acts as a source of airway inflammation, and by suppressing the activation of a wide range of immune cells.

The results of several ongoing clinical trials will provide further evidence regarding the clinical efficacy and safety of tezepelumab in patients with asthma. In particular, the SUNRISE (NCT05398263) and WAYFINDER (NCT05274815) trials will further investigate the OCS-sparing effect of tezepelumab. Beyond these trials, it will be important to accumulate data on the efficacy and safety of tezepelumab in real-world clinical practice; that is, from post-marketing surveillance.

The present review is limited by the fact that it is based solely on published information, and any as-yet unpublished findings cannot be reflected. Furthermore, a systematic review methodology was not applied to the literature search.

Considering that tezepelumab improves airway hyperresponsiveness as well as a wide range of biomarkers, we may look to achieve asthma remission, the ultimate goal of treatment advocated by Menzies-Gow A, et al. [37]. To help realize this goal, early intervention trials are needed to establish a treatment strategy that identifies ideal timing for treatment initiation according to each therapeutic agent as well as effective dosages.

Because of the pathophysiological role of TSLP, it is an important signaling molecule not only in asthma but also in a range of inflammatory disorders [2,4]. Therefore, tezepelumab is expected to be useful for treatment of various diseases. Several trials are ongoing in patients with inflammatory disorders, including the WAYPOINT trial (NCT04851964) in patients with chronic sinusitis with nasal polyps, the COURSE trial (NCT04039113) in patients with moderate-to-severe chronic obstructive pulmonary disease, and the INCEPTION trial (NCT04833855) in patients with spontaneous urticaria. The results of these trials will guide appropriate use of tezepelumab for a variety of indications.

Executive summary

Introduction

• Asthma is a common chronic respiratory disease that affects up to 18% of the general population and is characterized by wheezing, shortness of breath, chest tightness, coughing and airflow limitation.

• The pathophysiology of asthma includes airway inflammation, mediated by epithelial cytokines, one of which is thymic stromal lymphopoietin (TSLP).

Mechanism of action

• Tezepelumab is a human immunoglobulin G2λ (IgG2λ) monoclonal antibody that binds to TSLP and inhibits its binding to the TSLP receptor, suppressing the inflammatory activities mediated by TSLP.

Pharmacokinetics & pharmacodynamics

• Pharmacokinetic studies showed that administering tezepelumab at a dose of 210 mg every 4 weeks was predicted to achieve approximately 90% of the peak pharmacologic action.

• Clinical trials, such as PATHWAY, CASCADE, and NAVIGATOR, have confirmed that tezepelumab improves type 2 inflammatory biomarkers, airway submucosal and blood eosinophil count, cytokine levels, fractional exhaled nitric oxide, and forced expiratory volume in 1 second in asthma patients, confirming its pharmacodynamic effects.

Efficacy

• The NAVIGATOR and PATHWAY trials demonstrated that tezepelumab suppressed the annualized asthma exacerbation rate (AAER) compared with placebo. This effect was also observed regardless of the baseline biomarker level.

• Tezepelumab also demonstrated effectiveness in reducing the AAER in a subset of Japanese patients enrolled in the NAVIGATOR trial, as well as the NOZOMI trial conducted in Japan.

• In the SOURCE trial, tezepelumab was associated with a reduction in the oral corticosteroid dose among patients with a baseline blood eosinophil count of ≥150 cells/μL.

Safety

• Regarding safety, no harmful effects of tezepelumab were observed in a range of toxicity studies in cynomolgus monkeys.

• Results of clinical trials, including in Japanese patients, indicate that tezepelumab is well tolerated and has a low risk of serious adverse events.

Approval status

• Based on the clinical trials, tezepelumab has thus far been approved in the USA, the EU, Japan, Canada, Switzerland, the United Arab Emirates, Mexico, Iceland, Norway, Israel and Brazil.

Conclusion

• Several ongoing trials will provide more insight into the use of tezepelumab in asthma and in other potential indications, including chronic obstructive pulmonary disease, chronic sinusitis with nasal polyps and spontaneous urticaria.

Author contributions

M Shinkai and T Yabuta developed the concept for the review article and conducted the literature search and analysis. Both authors participated in the visualization of the article, writing of the original draft, and revisions and editing of the final version of the manuscript.

Financial & competing interests disclosure

M Shinkai received honoraria for lectures and funding for medical writing from AstraZeneca and has participated as the primary investigator of the NOZOMI and NAVIGATOR studies. T Yabuta is an employee of AstraZeneca. Funding was provided by AstraZeneca K.K. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors thank Keyra Martinez Dunn of Edanz, Japan, and Nicholas D. Smith (EMC K.K.) for providing medical writing support, which was funded by AstraZeneca, Japan, through EMC K.K., Japan, in accordance with Good Publication Practice guidelines (www.ismpp.org/gpp-2022).

Additional information

Funding

M Shinkai received honoraria for lectures and funding for medical writing from AstraZeneca and has participated as the primary investigator of the NOZOMI and NAVIGATOR studies. T Yabuta is an employee of AstraZeneca. Funding was provided by AstraZeneca K.K. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors thank Keyra Martinez Dunn of Edanz, Japan, and Nicholas D. Smith (EMC K.K.) for providing medical writing support, which was funded by AstraZeneca, Japan, through EMC K.K., Japan, in accordance with Good Publication Practice guidelines (www.ismpp.org/gpp-2022).