Digital Features for this Adis Drug Q&A can be found at https://doi.org/10.6084/m9.figshare.24480895.

FormalPara Adis evaluation of tezepelumab in the treatment of severe asthma

First-in-class monoclonal antibody that blocks the action of thymic stromal lymphopoietin

Reduces asthma exacerbations and symptoms, and improves lung function and quality of life in patients with severe uncontrolled asthma, including those with type-2 high and type-2 low asthma

Greatest efficacy is in type-2 high asthma patients

Currently the only biologic with efficacy in type-2 low asthma

Generally well tolerated

What is the rationale for developing tezepelumab in severe asthma?

Approximately 3–10% of patients with asthma exhibit severe disease, defined as asthma that is uncontrolled despite adherence with maximal optimized high-dose inhaled corticosteroid (ICS) and long-acting β2-agonist (LABA) treatment with correct inhaler technique and management of contributory factors, or that worsens when the ICS-LABA dose is reduced [1]. Even with the use of new biologics for severe asthma, ≈ 60% of patients still show partially controlled or uncontrolled asthma, underscoring the need for newer therapies for severe asthma targeting novel pathways [2].

Asthma is a heterogeneous condition characterized by diverse mechanistic pathways (endotypes) and clinical presentations (phenotypes), often with significant overlap [3,4,5,6]. The endotypes can be broadly classified as type 2 (T2)-high and T2-low. T2-high disease is characterized by eosinophilic inflammation, which can be either allergic or nonallergic in nature, primarily driven by type 2 cytokines such as interleukin (IL)-4, IL-5 and IL-13. These cytokines contribute to airway eosinophilia, excessive mucus production and the synthesis of immunoglobulin (Ig) E. T2-high biomarkers include blood eosinophil counts (BEC), fractional exhaled nitric oxide (FeNO) and serum total IgE. On the other hand, T2-low disease is characterized by neutrophilic or paucigranulocytic inflammation, typified by the absence of T2-high biomarkers [3,4,5,6].

Monoclonal antibodies that specifically target the downstream effects of IL-4, IL-5, IL-13 or IgE have demonstrated promising efficacy in patients with severe T2-high asthma [1]. However, 30–50% of patients with severe asthma present with T2-low disease, which is unresponsive to these biologics [7]. Hence, strategic targeting of upstream epithelial alarmins, such as thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, holds the potential to improve clinical outcomes in a diverse spectrum of asthma endotypes and phenotypes [8].

TSLP sits at the top of the intricate inflammatory cascade in asthma [3]. Secreted by airway epithelial cells in response to environmental triggers, TSLP activates multiple downstream inflammatory pathways, leading to airway inflammation (both eosinophilic and noneosinophilic) and airway hyperresponsiveness (AHR). Besides airway epithelial cells, TSLP is secreted by various immune and structural cells, contributing to sustained airway inflammation. TSLP also acts on structural cells in the airway milieu, contributing to airway remodelling. TSLP is overexpressed in the airways of patients with asthma and its level has been shown to correlate with airway obstruction and disease severity. Thus, TSLP is a promising therapeutic target in asthma [3].

Tezepelumab (tezepelumab-ekko; TEZSPIRE®) is a first-in-class human IgG2λ monoclonal antibody that inhibits the action of TSLP [9, 10]. Subcutaneous (SC) tezepelumab is approved in several countries worldwide, including the USA [9] and those in the EU [10] for the treatment of severe asthma in patients aged ≥ 12 years. Tezepelumab should not be used to treat acute bronchospasm or status asthmaticus. Table 1 provides a summary of the prescribing information for tezepelumab in the EU and USA. Consult local prescribing information for further details.

Table 1 Summary of the prescribing information of tezepelumab (Tezspire®) in the treatment of severe asthma in the USA [9] and the EU [10]
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What are the pharmacodynamic properties of tezepelumab?

Tezepelumab binds to human TSLP with a dissociation constant of 15.8–29.2 pM and prevents interaction with its heterodimeric TSLP receptor with a half maximal inhibitory concentration of 100–200 pM [11]. Although its mechanism of action is not fully understood, tezepelumab is believed to reduce asthma exacerbations in severe asthma through the following complementary mechanisms of action [12]:

  • Reduces IL-5 production, leading to decreased eosinophilic airway inflammation and exacerbation risk.

  • Decreases IL-4 and IL-13 production, reducing the production of IgE and improving lung function by inhibiting mucus overproduction and goblet cell hyperplasia.

  • Attenuates AHR by reducing TSLP’s effects on mast cells and airway smooth muscle cells.

In a proof-of-concept phase 1 trial in patients with atopic asthma, tezepelumab reduced allergen-induced bronchoconstriction and airway inflammation [11]. Compared to placebo, tezepelumab attenuated early (0–2 h) and late (3–7 h) asthmatic responses following allergen challenge. Additionally, tezepelumab decreased blood and sputum eosinophil counts both before and after the allergen challenge, as well as reduced FeNO levels. Tezepelumab treatment was also associated with reduced AHR to methacholine [11].

In a 28-week phase 2 trial (CASCADE) in patients with moderate-to-severe uncontrolled asthma, tezepelumab significantly (nominal p ≤ 0.030 vs placebo) reduced airway submucosal eosinophil counts (primary endpoint) and AHR to mannitol, but had no statistically significant effect on the airway remodelling [13]. Notably, tezepelumab recipients experienced a reduction in occlusive mucus plugs (assessed by computed tomography imaging), which correlated with improved lung function [14].

In a separate 12-week phase 2 trial (UPSTREAM), the blockade of TSLP with tezepelumab did not result in a significant reduction in AHR to mannitol (p = 0.06 vs placebo), which was the primary endpoint of the study [15]. However, the tezepelumab group had a significantly higher proportion of patients without AHR to mannitol compared to the placebo group (45.0% vs 15.0%; p = 0.04) [15]. Tezepelumab decreased the release of alarmins and T2 cytokines in response to viral stimulation, while the production of antiviral interferon-β remained unaffected [16].

Tezepelumab reduced biomarkers of eosinophilic inflammation and allergic reactions in patients with severe uncontrolled asthma in phase 2 (PATHWAY) [17,18,19] and phase 3 (NAVIGATOR) [20] trials. In NAVIGATOR, compared with patients receiving placebo, those receiving tezepelumab experienced greater reductions from baseline in FeNO levels [least-squares mean difference − 13.8 parts per billion (ppb); 95% CI − 17.1 to − 10.6], BEC (− 130 cells/µL; − 156 to − 104) and serum total IgE levels (– 208.0 IU/mL; − 303.7 to − 112.3) at 52 weeks [20]. The reductions in FeNO levels and BEC were seen as early as week 2 and were sustained throughout the 52-week treatment period; IgE levels decreased gradually over the course of the treatment period [20]. In PATHWAY, tezepelumab normalized the elevated levels of serum IL-5 and IL-13 that were seen at baseline in patients with severe asthma [18].

Pharmacokinetic-pharmacodynamic models based on PATHWAY data predict that SC tezepelumab at 210 mg every 4 weeks achieves ≈ 90% of the maximal drug effect on asthma exacerbation rate and FeNO levels, with no meaningful added benefit from higher doses [21]. Consequently, this regimen was selected for phase 3 studies in patients with severe asthma [21].

The SC administration of tezepelumab via an accessorized prefilled syringe and an autoinjector (also called prefilled pen) by healthcare professionals, patients and caregivers was associated with high rates of successful administration (91.7% and 92.4%, respectively) in a phase 3 trial (PATH-HOME) in patients aged 12–80 years with severe uncontrolled asthma [22]. Both devices showed comparable performance when used both at home and in the clinic during the study [22].

What are the pharmacokinetic properties of tezepelumab?

The pharmacokinetics data for SC tezepelumab are derived from a population pharmacokinetic model, which is developed using data from seven clinical trials involving healthy volunteers, adults with atopic dermatitis, atopic asthma or severe uncontrolled asthma, as well as adolescents with mild asthma [21]. Following a single SC administration, tezepelumab exhibits dose-proportional pharmacokinetics over a dose range of 2.1–420 mg (0.01 to 2-fold the recommended dose). Tezepelumab’s pharmacokinetics are best described by a linear two-compartment model with first-order absorption [9].

Tezepelumab reaches peak plasma concentration within 3–10 days after SC administration [9]. The estimated bioavailability of tezepelumab is ≈ 77%, and there are no clinically significant differences in bioavailability when it is injected into the abdomen, thigh or upper arm. With 210 mg once every 4 weeks, steady-state concentrations are reached after 12 weeks, with a 1.86-fold accumulation ratio for trough plasma concentration. Tezepelumab has central and peripheral volumes of distribution of 3.9 and 2.2 L, respectively. Degradation of tezepelumab occurs through ubiquitously distributed proteolytic enzymes. Tezepelumab is eliminated via intracellular catabolism, with no evidence of target-mediated clearance. The estimated clearance for tezepelumab is 0.17 L/d for a 70 kg individual and the elimination half-life is ≈ 26 days [9].

Sex or race has no clinically meaningful effects on the pharmacokinetics of tezepelumab [9]. There have been no formal studies assessing the effect of abnormal liver or kidney function on tezepelumab pharmacokinetics. Tezepelumab clearance was similar in patients with mild or moderate kidney impairment (estimated creatinine clearance 30–89 mL/min) and those with normal kidney function (≥ 90 mL/min). However, the effect of severe kidney impairment (< 30 mL/min) on tezepelumab clearance has not been assessed. Since tezepelumab is not metabolized by hepatic enzymes, hepatic impairment is unlikely to affect tezepelumab pharmacokinetics [9].

There are no formal drug–drug interaction studies involving tezepelumab [9]. Commonly co-administered asthma medications, such as leukotriene receptor antagonists, theophylline/aminophylline, and oral and inhaled corticosteroids, did not have any clinically meaningful impact on tezepelumab clearance [9].

Tezepelumab pharmacokinetics after a single SC 210 mg dose were comparable when administered via a vial-and-syringe, an accessorized prefilled syringe or an autoinjector in a phase 1 trial (PATH-BRIDGE) in healthy volunteers [23].

What is the efficacy of tezepelumab in severe asthma?

Tezepelumab reduces asthma exacerbations in patients with severe uncontrolled asthma, as demonstrated in two randomized, double-blind, placebo-controlled, multicentre trials: the phase 2 PATHWAY trial [17] and the phase 3 NAVIGATOR trial [20]. The key eligibility criteria in these trials were:

  • Age 18–75 years (PATHWAY) or 12–80 years (NAVIGATOR).

  • Physician-diagnosed asthma requiring regular treatment with medium- or high-dose ICS and ≥ 1 additional asthma controller medication, with or without oral corticosteroids (OCS).

  • ≥ 2 asthma exacerbations in the past 12 months.

  • Reduced lung function [prebronchodilator forced expiratory volume in 1 second (pre-FEV1) < 80% of the predicted normal value in adults and < 90% in adolescents].

  • Suboptimal asthma control [Asthma Control Questionnaire 6 (ACQ-6) score ≥ 1.5].

In both trials, eligible patients received tezepelumab 210 mg or placebo every 4 weeks for 52 weeks while continuing their background asthma therapy throughout the duration of the trials [17, 20]. The dose-ranging PATHWAY trial included two additional tezepelumab dosage arms, but these are not approved dosages and will not be discussed further [17]. The primary endpoint in both trials was the annualized asthma exacerbation rate (AAER), reported as events per patient-year, over the randomized treatment period in the overall population [17, 20]. Within each trial, patient demographics and baseline characteristics were generally well balanced between treatment groups [17, 20].

Asthma exacerbations

In PATHWAY [17] and NAVIGATOR [20], tezepelumab treatment was associated with a significant 71% [17] and 56% [20] reduction in AAER over 52 weeks compared to placebo in patients with asthma that remained uncontrolled despite treatment with LABA and medium-to-high doses of ICS (Table 2). Asthma exacerbations requiring emergency department (ED) visit and/or hospitalization were reduced by 79–86% in the tezepelumab group versus placebo [17, 20, 24]. Among the patients hospitalized for asthma exacerbations in NAVIGATOR, 38% of 13 tezepelumab recipients had an event rated as severe, compared with 82% of 39 placebo recipients [25]. In both PATHWAY and NAVIGATOR, the time to first asthma exacerbation was longer in the tezepelumab than in the placebo group [17, 20], with a hazard ratio of 0.45 (95% CI 0.26 to 0.75; p = 0.002) in PATHWAY [17]. In NAVIGATOR, tezepelumab reduced asthma exacerbations across all seasons in patients with severe uncontrolled asthma, including those with seasonal and perennial allergies [26].

Table 2 Efficacy of tezepelumab in patients with severe uncontrolled asthma
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Findings from PATHWAY and NAVIGATOR are supported by a post hoc pooled analysis of these trials (n = 665 for tezepelumab and 669 for placebo) [24]. Clinically meaningful reductions in AAER were seen in a broad population of patients with severe asthma, including those with or without perennial allergy [as assessed by fluorescence enzyme immunoassay (FEIA)] and those with T2-low asthma; the efficacy improved with increasing levels of T2 biomarkers. Percent reduction in AAER versus placebo (rate ratio; 95% CI) in the pooled analysis were:

  • In the overall population: 60% (0.40; 0.34, 0.48).

  • In biomarker subgroups excluding patients who received maintenance OCS:

T2-high asthma

  • BEC ≥ 300 cells/µL: 73% (0.27; 0.20–0.35).

  • FeNO ≥ 25 ppb: 71% (0.29; 0.22–0.37).

T2-low asthma

  • BEC < 150 cells/µL: 50% (0.50; 0.34–0.73).

  • FeNO < 25 ppb: 46% (0.54; 0.41–0.72).

  • BEC < 150 cells/µL and FeNO < 25 ppb: 35% (0.65; 0.40–1.06).

  • BEC < 150 cells/µL, FeNO < 25 ppb and FEIA negative: 45% (0.55; 0.27–1.12).

Allergy status

  • FEIA negative: 61% (0.39; 0.28–0.54).

  • FEIA positive: 62% (0.38; 0.29–0.48).

Consistent reduction in AAER in the tezepelumab group versus placebo was also seen in other clinically relevant subgroups based on number of exacerbations in the past 12 months (≤ 2 or >2), ICS use at baseline (high or medium), maintenance OCS use (yes or no), history of nasal polyps (yes or no) and body mass index (< 25.0, 25.0 to < 30.0 or ≥ 30.0) [24]. Tezepelumab was also effective in reducing AAER in Japanese patients with severe uncontrolled asthma [27, 28].

Lung function and other benefits

Tezepelumab improves lung function in patients with severe uncontrolled asthma [17, 20, 24]. In the PATHWAY [17] and NAVIGATOR [20] trials, changes from baseline in pre-FEV1 at 52 weeks were significantly greater in tezepelumab than in placebo recipients (Table 2). This benefit was seen at the first time point assessed (week 2 or 4) and was sustained throughout the treatment period [17, 20]. The greatest improvements in pre-FEV1 were seen in patients with baseline eosinophil count ≥ 300 cells/µL [20].

Tezepelumab also improves patient-reported outcomes (PROs) in patients with severe uncontrolled asthma, as assessed by ACQ-6, Asthma Quality of Life Questionnaire (standardized) for patients 12 years of age or older, and Asthma Symptom Diary scores [17, 20, 24, 29]. In the NAVIGATOR trial, both tezepelumab and placebo recipients achieved the minimum clinically important difference in these outcomes, but tezepelumab showed significant advantages over placebo (Table 2) [20]. However, the PATHWAY trial did not consistently show significant differences between the groups for PROs (Table 2) [17]. Additionally, the improvements observed in PROs with tezepelumab were relatively less robust in patients with T2-low asthma [24].

In NAVIGATOR, the proportion of patients achieving an on-treatment complete response (a combined measure of exacerbation reduction, asthma control, lung function and clinician assessment) at 52 weeks was significantly higher in the tezepelumab than in the placebo group (48.2% vs 25.3%; odds ratio [OR] 2.78; 95% CI 2.05–3.77) [30].

Tezepelumab treatment substantially reduces healthcare use in patients with severe uncontrolled asthma [25]. In NAVIGATOR, healthcare use outcomes in the tezepelumab versus placebo groups were: asthma-related unscheduled specialist visits (285 vs 406 events); telephone calls with a healthcare provider (234 vs 599); ambulance transports (5 vs 22); ED visits without subsequent hospitalization (16 vs 37); hospitalizations (14 vs 78); and intensive care days (0 vs 31) [25].

Does tezepelumab have an OCS-sparing effect?

Tezepelumab did not have a statistically significant OCS-sparing effect in patients with OCS-dependent asthma, as demonstrated in a randomized, double-blind, placebo-controlled, phase 3 trial (SOURCE) [31]. Eligible patients in this trial were 18–80 years old who had been receiving OCS for asthma for ≥ 6 months and had been taking a stable dose of prednisone or prednisolone 7.5–30 mg daily or equivalent for ≥ 1 month before screening. Other eligibility criteria were broadly similar to those in the PATHWAY and NAVIGATOR trials. After an OCS optimisation phase of ≤ 8 weeks, patients received tezepelumab 210 mg (n = 74) or placebo (n = 76) every 4 weeks for 48 weeks, consisting of a 4-week OCS stable phase, a 36-week OCS reduction phase and an 8-week OCS maintenance phase. In the overall population, there was no significant difference between tezepelumab and placebo groups in the categorised percentage reduction from baseline in maintenance daily OCS dose at week 48 (cumulative OR 1.28; 95% CI 0.69–2.35; primary endpoint). The cumulative OR was significantly higher with tezepelumab than with placebo in patients with baseline BEC of ≥150 cells/μL (2.58; 95% CI 1.16–5.75), but not in those with < 150 cells/μL (0.40; 95% CI 0.14–1.13). Although a significant OCS-sparing effect was not seen, consistent with the PATHWAY and NAVIGATOR trials, tezepelumab treatment was associated with a clinically meaningful reduction in AAER and other benefits in the SOURCE trial [31].

Are the benefits of tezepelumab sustained longer term?

Patients who demonstrated sufficient treatment compliance, attended the end-of-treatment visit and did not meet any of the discontinuation criteria outlined in the NAVIGATOR and SOURCE trials could be subsequently enrolled in a long-term safety study (DESTINATION) [32]. In DESTINATION, patients previously randomized to tezepelumab continued treatment, while those who were previously randomized to placebo were re-randomized to receive either tezepelumab or placebo for a total of 104 weeks, including the duration of the parent studies [32].

The clinical benefits of tezepelumab are sustained in the longer term [32]. In the NAVIGATOR cohort of the DESTINATION trial, the AAER over 104 weeks was 0.82 in the randomized tezepelumab group (n = 528) and 1.93 in the randomized placebo group (n = 531) [rate ratio of 0.42; 95% CI 0.35–0.51], corresponding to a 58% reduction. The randomized tezepelumab group also showed sustained improvements in pre-FEV1, ACQ-6 score, and St George’s Respiratory Questionnaire score throughout the 104-week treatment period compared with the randomized placebo group. These findings were further supported by those from the re-randomized long-term extension analysis set. Similar results were seen for the SOURCE cohort [32].

Other noteworthy findings from DESTINATION include:

  • Patients who received 100 weeks of tezepelumab treatment experienced sustained reductions in serum total IgE levels for 40 weeks after treatment cessation [33]. However, tezepelumab’s effect on other biomarkers (BEC, FeNO) and clinical outcomes (pre-FEV1, ACQ-6) gradually diminished during this period, indicating the need for continued treatment to maintain benefits [34].

  • The proportion of patients achieving on-treatment clinical remission in the tezepelumab versus placebo group was 28.5% versus 21.9% (OR 1.44; 95% CI 0.95–2.19) during weeks 0 to 52, and 33.5% versus 26.7% (OR 1.44; 95% CI 0.94–2.14) during > 52 to 104 weeks. On-treatment clinical remission was defined as ACQ-6 score ≤ 1.5, no asthma exacerbation, stable lung function (pre-FEV1 >95% of baseline) and no OCS use [35].

  • Among patients with severe OCS-dependent asthma (n = 134), the proportion of patients discontinuing OCS over 104 weeks was numerically higher in the tezepelumab than in the placebo groups (37.9% vs 7.7% in the NAVIGATOR cohort; 66.7% vs 46.9% in the SOURCE cohort) [36].

  • In adolescents (age 12–17 years) with severe uncontrolled asthma, tezepelumab reduced AAER by 28% (95% CI – 45 to 64) over 104 weeks compared with placebo, although the sample size was small (n = 82). An open-label, phase 4 study (PASSAGE; NCT05329194) is assessing the efficacy and safety of tezepelumab in this patient population alongside other underrepresented patient populations [37].

What is the tolerability and safety profile of tezepelumab?

Tezepelumab is generally well tolerated and has an acceptable safety profile in patients with severe uncontrolled asthma in clinical trials [17, 20, 24, 31, 32]. In the pooled analysis of the NAVIGATOR and PATHWAY trials, on-treatment adverse events (AEs) occurred in 74.6% of 665 tezepelumab recipients and 76.5% of 669 placebo recipients over 52 weeks [24]. However, the incidence of on-treatment serious AEs (SAEs; 9% vs 13%) and treatment-related AEs (9% vs 8%) was low. Overall, 13 (2%) tezepelumab and 20 (3%) placebo recipients discontinued treatment due to AEs, including 6 (1%) and 12 (2%), respectively, due to SAEs. There were no on-treatment deaths [24]. Adverse reactions that occurred in ≥ 3% of tezepelumab recipients and more commonly than in placebo recipients were pharyngitis (4% vs 3%), arthralgia (4% vs 3%) and back pain (4% vs 3%) [9]. The severity of arthralgia and back pain was generally mild to moderate [24].

In the 104-week DESTINATION study, exposure-adjusted incidence of AEs and SAEs were assessed as the primary endpoint [32]. In this trial, the incidences of on-treatment AEs, including any AEs, any SAEs, and any AEs leading to treatment discontinuation, were lower with tezepelumab than with placebo in both the NAVIGATOR and SOURCE cohorts over 104 weeks (Table 3). The most common AEs (incidence ≥ 10% in any treatment group), regardless of causality, were nasopharyngitis, upper respiratory tract infection, headache, asthma and bacterial bronchitis [32].

Table 3 Exposure-adjusted incidence of on-treatment adverse events in the phase 3 DESTINATION trial [32]
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In DESTINATION, the incidences of on-treatment cardiac SAEs and death were numerically higher in the randomized tezepelumab group than in the randomized placebo group (Table 3) [32]. Pooled on-study incidences of these events for the all-tezepelumab group, compared to the randomized placebo group, showed a similar trend. However, no specific pattern was observed regarding the cause or timing of study drug administration in relation to these events, and an independent adjudication committee determined that none of these events were treatment-related. Furthermore, in a prespecified analysis, adjudicated pooled on-study incidence of major adverse cardiovascular events per 100 patient-years did not differ significantly between the all-tezepelumab group (n = 840) and the randomised placebo group (n = 607) [0.65 vs 0.46; difference 0.19, 95% CI – 0.58 to 0.85] [32]. The risk of cardiac SAEs with tezepelumab is due to be assessed further, including in a post-authorization safety study [38].

The overall risk of SAEs related to infections and infestations (Table 3), including on-treatment pneumonia, was similar between tezepelumab and placebo groups in the DESTINATION trial [32]. In a post hoc analysis, tezepelumab did not increase the incidence of COVID-19-related AEs, SAEs, and fatal AEs compared to placebo. SAEs of respiratory, thoracic and mediastinal disorder were less frequent with tezepelumab than with placebo (Table 3), mainly due to fewer asthma exacerbations resulting in hospitalisation or an ED visit in the tezepelumab group [32].

Tezepelumab SC injections are associated with a low incidence of injection-site reactions (ISRs), such as erythema, swelling and pain [9]. In the pooled analysis of the NAVIGATOR and PATHWAY trials, in which tezepelumab and placebo were administered by a healthcare provider using a vial-and-syringe, ISR incidences were 4% and 3%, respectively [24]. In the NAVIGATOR cohort of DESTINATION trial, on-treatment ISR incidences were 2.40 and 2.15 per 100-patient years in the randomized tezepelumab and placebo groups [32]. In the PATH-HOME trial, tezepelumab administered via an accessorized prefilled syringe had an ISR incidence of 5.7%, while the incidence was 0% when administered via an autoinjector [22].

Hypersensitivity-related SAEs with tezepelumab were rare and were observed only in the NAVIGATOR cohort of the DESTINATION trial, with on-treatment incidences of 0.33 and 0.29 per 100 patient-years in the randomized tezepelumab and placebo groups, respectively [32]. The incidences of on-treatment malignancies in the respective treatment groups were: 0.65 and 0.72 per 100 patient-years in the NAVIGATOR cohort and 0.77 and 0 per 100 patient-years in the SOURCE cohort [32].

In a single-arm, 52-week, phase 3 study, the safety and tolerability profile of tezepelumab in Japanese patients with severe uncontrolled asthma was found to be generally similar to that of the global population with this condition [27].

What is the current clinical position of tezepelumab in severe asthma?

Tezepelumab is a novel, effective and generally well tolerated treatment option for patients with severe asthma across a wide range of phenotypes. Administered subcutaneously once every 4 weeks, tezepelumab offers a clinically meaningful reduction in AAER across a wide range of patients with different phenotypes and endotypes. Tezepelumab also improves lung function and patient-reported asthma outcomes. The efficacy of tezepelumab is sustained over up to 104 weeks. Tezepelumab is generally well tolerated and has an acceptable safety profile, despite a numerical imbalance in cardiac SAEs between the tezepelumab and placebo arms.

A key differentiating feature of tezepelumab is its broad immunological effects and effectiveness compared to previously available biologics (Table 4). Unlike its predecessors, which target specific downstream T2 inflammatory pathways and were limited in their efficacy to subsets of patients with allergic or eosinophilic asthma, tezepelumab is effective in both eosinophilic and noneosinophilic asthma, as well as allergic and nonallergic asthma. Tezepelumab is effective in patients with low BEC (< 150 cells/µL), a characteristic not shared by other biologics approved for eosinophilic asthma [39]. Furthermore, tezepelumab is currently the only biologic with efficacy in T2-low asthma. Notably, sensitization or biomarker tests are not required before starting tezepelumab therapy. However, one limitation of tezepelumab is its lack of demonstrated efficacy in reducing OCS use in patients with OCS-dependent asthma [31], while biologics targeting IL-4Rα and IL-5/IL-5Rα have shown an OCS-sparing effect in these patients (Table 4).

Table 4 Differential features of biologics used in the treatment of severe asthm
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There are no head-to-head studies comparing tezepelumab with other biologics. However, meta-analyses reveal that the efficacy of tezepelumab is broadly similar to or numerically better than that of other biologics in patients with severe asthma, including various biomarker subgroups [39,40,41,42,43]. This holds especially true in the context of reductions in ED and hospitalization visits due to asthma exacerbations [39, 42].

The Global Initiative for Asthma (GINA) guidelines recommend, if available and affordable, an add-on T2-targeted biologic (including tezepelumab) for severe asthma in patients with exacerbations and/or poor symptom control despite taking at least high-dose ICS-LABA, and who have eosinophilic biomarkers or need maintenance OCS [1]. The choice of biologic should be based on local payer eligibility criteria, T2 comorbidities (e.g. atopic dermatitis, nasal polyps), predictors of asthma response, cost, administration frequency, route of administration (IV, SC, possibility for self-administration) and patient preference. Some of these features for the available biologics are summarized in Table 4. Tezepelumab and dupilumab are options in patients with no evidence of T2 inflammation. Tezepelumab has evidence of efficacy in this population, although GINA has noted that the evidence is insufficient in those taking maintenance OCS. In contrast, dupilumab only has evidence of efficacy in patients with no evidence of T2 inflammation who are taking maintenance OCS [1].

The National Institute for Health and Care Excellence (NICE) [44] and the Scottish Medicines Consortium (SMC) [45] recommend tezepelumab as an additional maintenance treatment option for individuals aged ≥ 12 years with severe asthma, who are inadequately controlled despite using high-dose ICS and another maintenance medication. NICE restricts tezepelumab use to those with ≥ 3 exacerbations in the previous year or those currently on maintenance OCS [44]. Whereas SMC's restrictions are ≥ 3 exacerbations in the previous year without maintenance OCS treatment, or BEC of ≥ 150 cells/µL and maintenance OCS use [45]. Both recommendations are contingent upon the manufacturer supplying tezepelumab at the commercially agreed patient access scheme prices. NICE finds tezepelumab cost-effective compared to other biologicals (mepolizumab, benralizumab, resilizumab, dupilumab, omalizumab) and when other biological treatments aren't suitable [44]. The base case shows an increased cost-effectiveness ratio (ICER) below £20,000 per quality-adjusted life-year (QALY) gained [44]. SMC estimates tezepelumab is cost-effective compared to standard of care (SoC), with an ICER of £14,800 per QALY gained in the base case [45]. Both NICE and SMA analyses are based on the patient access scheme prices of tezepelumab [44, 45].

Cost-effectiveness analyses comparing tezepelumab plus SoC with SoC alone for severe asthma based on the list prices of tezepelumab are available for the USA [46] and Canada [47]. From a US healthcare system perspective, the base case ICER was US$430,000 per QALY gained, at a 3% annual discount rate over a lifetime horizon [46]. Similarly, from a Canadian public payer perspective, the corresponding ICER was CA$192,357 at a 1.5% annual discount rate over a 50-year horizon [47]. However, in a key scenario analysis, tezepelumab was found to be dominant (i.e. more effective and less costly) compared to currently reimbursed biologics in Canada [47].

A prospective, observational study (ASCENT) in Europe and Canada is evaluating the real-world effectiveness of tezepelumab in patients with severe asthma [48]. Results from this study are awaited with interest. Additional investigations in the following areas would be valuable in further delineating the clinical position of tezepelumab in the management of severe asthma:

  • Longer-term safety, particularly cardiac safety.

  • Efficacy in OCS-dependent asthma.

  • Efficacy when treatable traits are comprehensively managed before starting therapy.