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FormalPara Tezepelumab (TEZSPIRE™): Key Points

A human IgG2λ monoclonal antibody being developed by Amgen and AstraZeneca for the treatment of asthma, COPD, CRSwNP, chronic spontaneous urticaria and eosinophilic oesophagitis

Received its first approval on 17 December 2021 in the USA

Approved for use as an add-on maintenance treatment for patients aged ≥ 12 years with severe asthma

1 Introduction

Asthma is a heterogeneous disease with distinct mechanistic pathways (endotypes) of inflammation [1,2,3]. The Type 2 (T2) high endotype is found in most patients with severe asthma [2]; interactions between allergens, irritants, pollutants or viruses, and the airway epithelium results in the release of various mediators [e.g. IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)] and ultimately the activation of IL-4, IL-5 and IL-13, and the secretion of IgE by B cells [1]. Biologic therapies targeting IL-4, IL-5, IL-13 and IgE (i.e. downstream inflammatory mediators) have shown promising efficacy in patients with the T2 high endotype [1].

TSLP is a cytokine derived mainly from epithelial cells [4]. It mediates airway structural cell and immune cell interactions and occupies an upstream position in the asthma inflammatory cascade, with its levels in patients with asthma correlating with airway obstruction, disease severity and glucocorticoid resistance [4, 5]. Tezepelumab (tezepelumab-ekko; TEZSPIRE™) is a first-in-class human IgG2λ monoclonal antibody that inhibits the action of TSLP [4, 6].

figure a

Key milestones in the development of tezepelumab, focusing on phase III clinical trials. BLA Biologics License Application, CRSwNP chronic rhinosinusitis with nasal polyps, Est. estimated

It is being developed by Amgen and AstraZeneca for the treatment of asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic spontaneous urticaria and eosinophilic oesophagitis [4, 6]. Tezepelumab received its first approval (in the USA in December 2021) for the add-on maintenance treatment of patients aged ≥ 12 years with severe asthma; it is the only biologic approved for severe asthma with no phenotype (e.g. eosinophilic or allergic) or biomarker limitations. Tezepelumab is not indicated for the relief of acute bronchospasm or status asthmaticus [4, 6]. The recommended dosage of tezepelumab is 210 mg, administered subcutaneously (by a healthcare provider), once every 4 weeks (q4w) [4].

A regulatory assessment of tezepelumab for the treatment of asthma is currently underway in the EU and Japan [7]. Tezepelumab received orphan drug designation for the treatment of eosinophilic oesophagitis in October 2021 in the USA, and is undergoing clinical development for the treatment of COPD, CRSwNP and chronic spontaneous urticaria [8]. The clinical development of tezepelumab for the treatment of atopic dermatitis has been discontinued.

1.1 Company Agreements

In April 2012, Amgen and AstraZeneca entered into an agreement for the development and commercialization of five monoclonal antibodies from Amgen′s clinical inflammation portfolio [AMG 139, AMG 181, AMG 557, AMG 827, and AMG 157 (now known as tezepelumab)] [9]. In 2020, the agreement for tezepelumab was updated [10]. Under the terms of the amended agreement, both companies will continue to share costs and profits equally following a royalty payment by AstraZeneca to Amgen, with AstraZeneca continuing to lead development and Amgen continuing to lead manufacturing. In North America, Amgen and AstraZeneca will jointly commercialize tezepelumab, with Amgen recording US sales and AstraZeneca recording Canadian sales, while in all countries outside the USA and Canada AstraZeneca alone will commercialize tezepelumab [10].

2 Scientific Summary

2.1 Pharmacodynamics

Tezepelumab binds to human TSLP (dissociation constant of 15.8 pmol/L), blocking its interaction with its receptor, an action that is believed to reduce the biomarkers and cytokines associated with airway inflammation, including airway submucosal eosinophils, blood eosinophils, fractional exhaled nitric oxide (FeNO), IgE, IL-5 and IL-13 [4]. In a multinational phase II mechanistic study (CASCADE; NCT03688074) in adults with uncontrolled, moderate-to-severe asthma, subcutaneous tezepelumab 210 mg q4w significantly (nominal p ≤ 0·030) reduced airway submucosal eosinophil counts (primary endpoint), regardless of baseline blood eosinophil counts, and airway hyperresponsiveness (AHR) to mannitol [11]. In patients aged ≥ 12 years (NAVIGATOR; NCT03347279) [4] or ≥ 18 years (PATHWAY; NCT02054130) [12] with severe asthma, and in those aged ≥ 18 years with oral corticosteroid (OCS)-dependent asthma (SOURCE; NCT03406078) [13], subcutaneous tezepelumab 210 mg q4w reduced blood eosinophil counts and FeNO, IL-5, IL-13 and serum total IgE levels. Where reported, the effect was seen early (week 2 in NAVIGATOR [4] and week 4 in PATHWAY [12]), sustained throughout the treatment period (NAVIGATOR and PATHWAY) and persisted for 12–16 weeks following treatment cessation (PATHWAY [14]). Moreover, at week 52 in PATHWAY, IL-5 and IL-13 levels in tezepelumab, but not placebo, recipients were reduced to levels approaching those seen in a separate cohort of age-matched healthy individuals [15]. In PATHWAY, reductions from baseline in matrix remodeling (MMP-10 and periostin), eosinophil-related (IL5RA and PAPP-A) and thymus and activation-regulated chemokine (TARC) protein levels were significantly (p < 0.05) greater in the tezepelumab group than the placebo group [16].

According to pharmacokinetic/pharmacodynamic modelling, subcutaneous tezepelumab 210 mg q4w is predicted to be associated with ≈ 90% of the maximum tezepelumab effect on FeNO levels and asthma exacerbation rates [17]. Further increases in dose are not expected to result in additional, clinically meaningful treatment benefit [17].

In a phase I proof-of-concept study (NCT01405963) in 31 adults with stable allergic asthma, tezepelumab (700 mg q4w, administered intravenously on days 1, 29 and 57) attenuated most measures of allergen-induced early and late asthmatic responses, and also blood and sputum eosinophil and FeNO levels before and after the allergen challenge compared with placebo [18].

In CASCADE, tezepelumab 210 mg q4w did not appear to affect airway remodeling, with no significant differences seen between the tezepelumab and placebo groups in the ratio changes from baseline to treatment end in reticular basement membrane thickness and epithelial integrity (as assessed by the proportions of denuded, damaged and intact epithelium) [11]. It is, however, worth noting that the baseline mean reticular basement membrane thickness values in the respective groups (3·86 µm and 3·81 µm) were more typical of healthy individuals than patients with moderate to severe asthma [11].

Inhibiting TSLP signalling with tezepelumab (700 mg q4w, administered intravenously) [n = 20] did not significantly reduce AHR to mannitol compared with placebo (n = 20) [mean change from baseline in the provoking dose of mannitol causing a 15% reduction in forced expiratory volume in 1 sec (FEV1) of 1.9 vs 1.0 doubling doses] in adults with uncontrolled asthma and AHR to mannitol participating in a 12-week, randomized, double-blind, phase II study (UPSTREAM; NCT02698501) [19]. However, the proportion of patients without AHR to mannitol at week 12 was significantly higher in tezepelumab versus placebo recipients (45.0% vs 15.0%; p = 0.04) [19]. Tezepelumab did not appear to affect antiviral resistance, with its use in this study not affecting IFNβ expression by human bronchial epithelial cells [20]

The subcutaneous administration of tezepelumab 210 mg via an accessorized pre-filled syringe (n = 111) and an autoinjector (n = 105) was functional and reliable in patients aged ≥ 12 years with uncontrolled asthma participating in a randomized, open-label, multinational, phase III study (PATH-HOME; NCT03968978) [21].

2.2 Pharmacokinetics

The pharmacokinetics of tezepelumab are best described by a two-compartment model with first order absorption and elimination, and are consistent with those of other IgG2 monoclonal antibodies [17]. They are dose-proportional over a 2.1–420 mg (0.01–2-fold the recommended dose) dose range following a single subcutaneous dose [4]. According to a population pharmacokinetic analysis, the estimated absolute bioavailability of tezepelumab is ≈ 77%, with the subcutaneous administration of tezepelumab at different injection sites (abdomen, thigh or upper arm) not resulting in any clinically relevant differences in bioavailability. The maximum serum concentration of tezepelumab was reached in ≈ 3–10 days following subcutaneous administration, with steady-state achieved after 12 weeks using a q4w dosing regimen [4].

As tezepelumab is a human monoclonal antibody, it is degraded by proteolytic enzymes that are widely distributed in the body (rather than metabolized by hepatic enzymes) and is eliminated by intracellular catabolism: there is no evidence of target-mediated clearance within the studied dose range [4]. The elimination half-life of tezepelumab is ≈ 26 days [4].

No clear differences in the pharmacokinetics of subcutaneous tezepelumab were identified between Japanese and non-Japanese populations in a phase I study (NCT01913028) [22], or when administered via a vial-and-syringe, accessorized prefilled syringe or autoinjector in healthy volunteers in another phase I study (PATH-BRIDGE; NCT03989544) [23].

Features and properties of tezepelumab

Alternative names

AMG 157; MEDI-9929; tezepelumab-ekko; Tezspire

Class

Anti-inflammatories; antiasthmatics; monoclonal antibodies; skin disorder therapies

Mechanism of action

Thymic stromal lymphopoietin inhibitors

Route of administration

Subcutaneous

Pharmacodynamics

Binds to human TSLP (dissociation constant of 15.8 pmol/L), blocking its interaction with its receptor, an action thought to reduce the biomarkers and cytokines associated with airway inflammation

Pharmacokinetics

Dose proportional over a 2.1–420 mg dose range; maximum serum concentration reached in ≈ 3–10 days; elimination half-life of ≈ 26 days

Most frequent adverse events

Pharyngitis, arthralgia and back pain

ATC codes

 WHO ATC code

D11A-X (Other Dermatologicals); R03D-X11 (Tezepelumab)

 EphMRA ATC code

D11A (Other Dermatological Preparations); R3 (Anti-Asthma and COPD Products)

Chemical name

Immunoglobulin G2, anti-(human thymic stromal lymphopoietin) (human monoclonal MEDI9929 heavy chain), disulfide with human monoclonal MEDI9929 lambda-chain, dimer

  1. TSLP thymic stromal lymphopoietin

2.3 Therapeutic Trials

2.3.1 Asthma

Add-on therapy with subcutaneous tezepelumab 210 mg q4w was associated with fewer exacerbations and better lung function, asthma control and health-related quality of life compared with placebo in patients aged ≥ 12 years with severe asthma participating in a 52-week, randomized, double-blind, multinational, phase III study (NAVIGATOR; NCT03347279) [5]. At week 52, the annualized rate of asthma exacerbations (primary endpoint) was significantly lower with add-on tezepelumab (n = 529) than add-on placebo (n = 532) [0.93 vs 2.10; rate ratio (RR) 0.44 (95% CI 0.37–0.53); p < 0.001]. Findings for this endpoint were consistent regardless of allergic status or baseline biomarker category [e.g. baseline eosinophil count of < 300 cells/µL: RR 0.59 (95% CI 0.46–0.75); p < 0.001] in prespecified subgroup analyses, and were seen for exacerbations requiring an emergency room visit/hospitalization [RR 0.21 (95% CI 0.12–0.37)] or hospitalization [RR 0.15 (95% CI 0.07–0.33)]. In terms of key secondary endpoints, statistically significant (p ≤ 0.002) and clinically meaningful improvements in least-squares mean (LSM) changes from baseline in pre-bronchodilator FEV1 [0.23 vs. 0.09 L; LSM between-group difference (BGD) 0.13 L (95% CI 0.08–0.18)], the Asthma Control Questionnaire 6 (ACQ-6) score [− 1.55 vs − 1.22 points; LSM BGD − 0.33 (95% CI − 0.46, − 0.20)], the Asthma Quality of Life Questionnaire (standardized) for patients aged ≥ 12 years [AQLQ(S)+12] overall score [1.49 vs 1.15 points; LSM BGD 0.34 (95% CI 0.20–0.47)], and the weekly mean Asthma Symptom Diary (ASD) overall score [−0.71 vs −0.59 points; LSM BQD − 0.12 (95% CI − 0.19, − 0.04)] were seen at week 52 with add-on tezepelumab (n = 528) compared with add-on placebo (n = 531). Improvements in each of the key secondary endpoints were seen from the first post-baseline assessment and sustained throughout the treatment period [5]. Moreover, the odds of achieving a clinically meaningful improvement in ACQ-6 [86% vs 77% of patients; odds ratio (OR) 1.99 (95% CI 1.43–2.76)] and AQLQ(S)+12 [78% vs 72%; OR 1.36 (95% CI 1.02–1.82)] were significantly higher with add-on tezepelumab than add-on placebo [4].

Patients eligible for NAVIGATOR had a history of ≥ 2 asthma exacerbations requiring oral or injectable corticosteroid treatment or resulting in hospitalization in the previous 12 months; reduced lung function at baseline (defined as a pre-bronchodilator FEV1 of < 80% and < 90% of the predicted normal values in adults and adolescents); an ACQ-6 score of ≥ 1.5 at screening; and were receiving regular treatment with medium or high-dose inhaled corticosteroids (ICS) and ≥ 1 additional asthma controller, with or without OCS [4, 5]. A minimum baseline level of blood eosinophils or FeNO was not required in, and background asthma therapy continued throughout NAVIGATOR [4, 5]. The primary and key secondary endpoints were evaluated in a hierarchical manner [5]. Asthma exacerbations were defined as a worsening of asthma requiring the use of or a dose increase in oral or injectable corticosteroids for ≥ 3 days, or a single depo-injection of corticosteroids, and/or emergency department visits requiring use of oral or injectable corticosteroids and/or hospitalization [4]. At baseline, patients (n = 1059) had a mean pre-bronchodilator FEV1 of 1.8 L, an ACQ-6 score (scores range from 0 to 6, with lower scores indicating better disease control) of 2.8, a mean AQLQ[S]+12 overall score [scores range from 1 (maximum impairment) to 7 (no impairment)] of 3.9 and a weekly mean ASD score [scores range from 0 (no symptoms) to 4 (worst possible symptoms)] of 1.4 [5]. Minimum clinically important differences are 0.1 L in pre-bronchodilator FEV1, and 0.5 points in the ACQ-6 score, the AQLQ[S]+12 overall score and the ASD score. At treatment end (week 52), patients either entered a 12-week post-treatment follow-up period or a long-term extension study (DESTINATION; NCT03706079) [5].

At respective dosages of 280 mg q4w, 210 mg q4w and 70 mg q4w (n = 137, 137 and 138), subcutaneous tezepelumab as an add-on therapy for the treatment of severe asthma significantly (p < 0.001) lowered annualized rates of asthma exacerbations (primary endpoint) at week 52 by 66%, 71% and 62% compared with placebo (n = 138) [0.23, 0.20 and 0.27 vs 0.72] in adults participating in a 52-week, randomized, double-blind, placebo-controlled, multinational, phase II, dose-ranging study (PATHWAY; NCT02054130) [24]. Findings for this endpoint were consistent for the 210 mg q4w dosage and generally consistent for the 280 mg q4w and 70 mg q4w dosages regardless of baseline blood eosinophil counts, FeNO level or Th2 status in prespecified subgroup analyses [24]. Moreover, over the 52-week treatment period, add-on therapy with subcutaneous tezepelumab 280 mg q4w, 210 mg q4w and 70 mg q4w lowered annualized rates of asthma exacerbations that required hospitalization by 74–84%, all-cause hospitalizations by 48–73% and all-cause emergency department visits by 37–84%, compared with placebo [25]. In terms of secondary endpoints, statistically significant (nominal p < 0.05) and clinically meaningful improvements in LSM changes from baseline in pre-bronchodilator FEV1 were seen at week 52 with add-on tezepelumab 280 mg q4w, 210 mg q4w and 70 mg q4w (n = 116, 121 and 130), respectively, compared with add-on placebo (n = 131) [0.10, 0.08 and 0.07 vs. − 0.06 L; LSM BGD 0.15, 0.13 and 0.12] [24]. Improvements in this endpoint were seen from the first post-baseline assessment (week 4) and sustained throughout the treatment period. At week 52, there were statistically significant (nominal p < 0.05), but not clinically meaningful, improvements in LSM changes from baseline in the ACQ-6 score with add-on tezepelumab 280 mg q4w (n = 49) and 210 mg q4w (n = 44) [− 1.22 and − 1.20 points vs − 0.91 points for placebo (n = 53); LSM BGD − 0.31 and − 0.29], but not 70 mg q4w, and in the AQLQ(S)+12 overall score with add-on tezepelumab 280 mg q4w (n = 48) [1.32 vs 0.97 points for placebo (n = 47); LSM BGD 0.34], but not 210 mg q4w or 70 mg q4w [24].

Patients eligible for PATHWAY had uncontrolled asthma despite the use of long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids; a history of ≥ 2 asthma exacerbations requiring oral or injectable corticosteroid treatment or 1 asthma exacerbation resulting in hospitalization in the previous 12 months; reduced lung function at baseline [defined as a pre-bronchodilator FEV1 of < 80% and < 90% of the predicted normal values in adults and adolescents]; an ACQ-6 score of ≥ 1.5 at screening; and were on regular treatment with medium or high-dose ICS and ≥ 1 additional asthma controller, with or without OCS [4, 24]. A minimum baseline level of blood eosinophils or FeNO was not required in, and background asthma therapy continued throughout PATHWAY [4, 24]. The primary endpoint was evaluated in a hierarchical manner (tezepelumab vs placebo) as follows: tezepelumab 280 mg, then tezepelumab 210 mg and then tezepelumab 70 mg [24]. Asthma exacerbations were defined as a worsening of asthma requiring the use of oral or injectable glucocorticoids or a doubling of the dose of oral glucocorticoids for ≥ 3 days, an emergency department visit requiring the use of oral or injectable glucocorticoids or hospitalization [24].

Add-on therapy with subcutaneous tezepelumab 210 mg q4w (n = 74) did not significantly reduce the (cumulative) odds of achieving a category of greater percentage reduction from baseline in the daily maintenance OCS dose at week 48 (primary endpoint) compared with add-on placebo (n = 76) [OR 1.28 (95% CI 0.69–2.35)] in adults with severe OCS-dependent asthma participating in a 48-week, randomized, double-blind, placebo-controlled, multinational phase III study (SOURCE; NCT03406078) [26, 27]. The (cumulative) odds of achieving this endpoint were 2.58-fold (95% CI 1.16–5.75) and 3.49-fold (95% CI 1.16–10.49) higher with tezepelumab versus placebo in adults with a baseline blood eosinophil count of ≥ 150 and ≥ 300 cells/µL; no effect was seen in the baseline blood eosinophil < 300 and < 150 cells/µL count subgroups [27]. Although the reduction from baseline in the annualized asthma exacerbation rate (key secondary endpoint) at week 48 did not significantly differ between the tezepelumab and placebo groups, pre-bronchodilator FEV1 was improved by 0.26 L (95% CI 0.13–0.39) despite reductions in the maintenance OCS dose. Improvements in FEV1 were seen from the first post-baseline assessment (week 4) and sustained throughout the treatment period [27]. SOURCE comprised a ≤ 8-week OCS optimization period and a 48-week treatment period (which consisted of a 4-week induction period, followed by a 36-week OCS reduction period and then an 8-week maintenance period) [26, 27]. Percentage reductions from baseline in the daily maintenance OCS dose at week 48 were categorized as 90–100, 75 to < 90, 50 to < 75, 0 to < 50, and no change or any increase [26]. Patients enrolled in this study were able to enter a long-term extension study (DESTINATION; NCT03706079) [26].

2.3.2 Cat Allergy

At week 104 of a randomized, double-blind, placebo-controlled, multicentre, phase I/II study (CATNIP; NCT02237196) [28, 29], the addition of subcutaneous tezepelumab to subcutaneous cat allergen-specific immunotherapy (SCIT) did not significantly reduce the total nasal symptom score (TNSS) area under the curve value at 0–1 h of a nasal challenge (primary endpoint) compared with placebo plus SCIT in 121 adults with a ≥ 2-year history of moderate to severe allergic rhinitis caused by cat exposure. A significant-between-group difference favouring tezepelumab plus SCIT was seen at weeks 25 and 52 (i.e. during treatment) [28].

CATNIP comprised 52 weeks of treatment followed by 52 weeks of observation off therapy and had four treatment arms: tezepelumab plus SCIT, placebo plus SCIT, tezepelumab plus placebo and placebo plus placebo [28]. The TNSS overall score (which ranges from 0 to 12) is the sum of four subscale scores (each ranging from 0 to 3, with higher scores indicating more severe nasal symptoms) measuring nasal congestion and blockade, rhinorrhoea, itching and sneezing [29].

Key clinical trials of tezepelumab

Drug(s)

Indication

Phase

Status

Location

Identifier

Sponsor (Collaborator)

Tezepelumab

Asthma

IV

Completed

Japan

  

Tezepelumab, PL

CRSwNP

III

Recruiting

Multinational

NCT04851964 (WAYPOINT)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

III

Completed

Multinational

NCT03347279 (NAVIGATOR)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

III

Recruiting

Multinational

NCT03927157 (DIRECTION)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

III

Active, no longer recruiting

USA

NCT05062759 (VECTOR)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

III

Active, no longer recruiting

Multinational

NCT03706079 (DESTINATION)

AstraZeneca (Amgen)

Tezepelumab

Asthma

III

Completed

Multinational

NCT03968978 (PATH-HOME)

AstraZeneca (Amgen)

Tezepelumab

Asthma

III

Completed

Japan

NCT04048343 (NOZOMI)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

III

Completed

Multinational

NCT03406078 (SOURCE)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

II

Completed

Multinational

NCT02054130 (PATHWAY)

MedImmune (Amgen)

Tezepelumab, PL

COPD

II

Recruiting

Multinational

NCT04039113 (COURSE)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

II

Completed

Multinational

NCT03688074 (CASCADE)

AstraZeneca (Amgen)

Tezepelumab, PL

Asthma

II

Completed

Denmark

NCT02698501 (UPSTREAM)

Celeste Porsbjerg (Lund University, University of Newcastle, Australia, University of Copenhagen)

Tezepelumab, omalizumab, PL

Chronic spontaneous urticaria

II

Recruiting

Multinational

NCT04833855 (INCEPTION)

Amgen

Tezepelumab, PL

Cat allergy

I/II

Completed

USA

NCT02237196 (CATNIP)

NIAID (Immune Tolerance Network)

  1. COPD chronic obstructive pulmonary disease, CRSwNP chronic rhinosinusitis with nasal polyps, NIAD National Institute of Allergy and Infectious Diseases, PL placebo

2.4 Adverse Events

Add-on therapy with subcutaneous tezepelumab appears to be generally well tolerated in patients aged ≥ 12 years with severe asthma [4, 5, 24] and those aged ≥ 18 years with cat allergy [28].

In patients with severe asthma, the frequency and type of adverse events (AEs) did not differ to a meaningful extent between the tezepelumab and placebo groups in NAVIGATOR [5], with the overall incidence of AEs similar between the tezepelumab and placebo groups in PATHWAY [24]. Moreover, the safety profile of subcutaneous tezepelumab in SOURCE was similar to that seen in NAVIGATOR and PATHWAY [4]. In NAVIGATOR, AEs occurred in 77.1% of 528 tezepelumab 210 mg q4w recipients and 80.8% of 531 placebo recipients, AEs leading to treatment discontinuation in 2.1% and 3.6% of patients and serious AEs (SAEs) in 9.8% and 13.7% of patients [5]. Severe infections were reported in 8.7% of patients in each treatment group; there were no reports of treatment-related anaphylactic reactions nor cases of Guillain–Barré syndrome. Two patients (from the placebo group) died during NAVIGATOR [5]. In PATHWAY, ≥ 1 AE occurred in 65.0% of 137 tezepelumab 280 mg q4w recipients, 65.7% of 137 tezepelumab 210 mg q4w recipients, 67.4% of 138 tezepelumab 70 mg q4w recipients and 65.9% of 138 placebo recipients, ≥ 1 AE leading to treatment discontinuation in 2.2%, 1.5%, 0% and 0.7% of patients, respectively, and ≥ 1 SAE in 13.1%, 9.5%, 12.3% and 13.0% of patients, respectively [24]. Upon removal of asthma-related AEs, the overall AE incidence was similar across the groups. One tezepelumab 70 mg q4w recipient (pneumonia and stroke) and one tezepelumab 210 mg q4w recipient (Guillain–Barré syndrome) experienced SAEs considered by the investigator to be treatment related; the tezepelumab 70 mg q4w recipient who experienced pneumonia and stroke died 8 weeks after the cessation of treatment, with the death (from stroke) considered to be treatment related [24].

In a pooled analysis [4] of patients (aged ≥ 12 years) who had received ≥ 1 dose of subcutaneous tezepelumab 210 mg q4w in NAVIGATOR [5] and PATHWAY [24], the most frequently reported adverse reactions (occurring in ≥ 3% of patients and with a higher incidence in the tezepelumab group than the placebo group) were pharyngitis (4% of 665 tezepelumab recipients and 3% of 669 placebo recipients), arthralgia (4% vs 3%) and back pain (4% vs 3%). Injection-site reactions (e.g. erythema, swelling or pain at the injection site) were reported in 3.3% of tezepelumab recipients and 2.7% of placebo recipients [4].

As with all therapeutic proteins, there is potential for immunogenicity with tezepelumab [4]. In NAVIGATOR and an additional study, anti-drug antibodies (ADAs) were detected in 5% of 601 tezepelumab 210 mg q4w recipients. Eleven and one of these 29 patients developed treatment-emergent and neutralizing antibodies, respectively. Moreover, ADA titers were generally low and often transient. There was no evidence of ADAs impacting the pharmacodynamics, pharmacokinetics, efficacy or safety of tezepelumab [4].

In patients with a history of moderate to severe allergic rhinitis caused by cat exposure (CATNIP), there were a few hypersensitivity events reported in the SCIT-containing treatments arms; these were not seen in the tezepelumab plus placebo or placebo plus placebo arms [28].

2.5 Ongoing Clinical Trials

There are various ongoing studies of tezepelumab in patients with asthma. Three multicentre, phase III studies are recruiting patients [NCT03927157 (DIRECTION)] or are active [NCT05062759 (VECTOR) and NCT03706079 (DESTINATION)]. Tezepelumab is also being investigated in multinational studies in adults with severe CRSwNP [phase III; NCT04851964 (WAYPOINT)], moderate to very severe COPD [phase II; NCT04039113 (COURSE)] and chronic spontaneous urticaria [phase II; NCT04833855 (INCEPTION)].

3 Current Status

Tezepelumab received its first approval on 17 December 2021 as an add-on maintenance treatment for patients aged ≥ 12 years with severe asthma in the USA [4, 6].