Abstract
Aim
Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin and is approved for adolescents and adults with severe asthma. This analysis assessed pharmacokinetics (PK), pharmacodynamics and safety of tezepelumab up to 85 days postdose in adolescents and children.
Methods
The adolescent PK study (NCT02512900), in adolescents aged 12–17 years with mild‐to‐moderate asthma, and TRAILHEAD (NCT04673630), in children aged 5–11 years with mild, moderate or severe asthma, were both open‐label, single‐dose, Phase 1 studies.
Results
In the adolescent PK study, 21 adolescents (median age: 14 years) received a single 140‐mg subcutaneous tezepelumab dose. The mean maximum concentration (C max; 24.0 [SD: 6.6] μg/mL) was observed at a median time of 6 (range: 1–20) days postdose, with a mean terminal half‐life of 25.3 (SD: 4.7) days. The mean area under the concentration–time curve (AUC0–infinity) was 952 (SD: 289) μg*day/mL. In TRAILHEAD, 18 children (median age: 8 years) received a single 70‐mg subcutaneous tezepelumab dose. The C max (27.1 μg/mL [SD: 11.9]) was observed at a median time of 3.5 (range: 2–10) days postdose, with a mean terminal half‐life of 25.7 (SD: 5.9) days. The mean AUC0–infinity was 974 (SD: 320) μg*day/mL. Changes from baseline in blood eosinophil count, fractional exhaled nitric oxide and serum immunoglobulin E (IgE) reflected expected pharmacodynamic effects of tezepelumab. No new safety signals were identified.
Conclusions
These results were consistent with previous studies of tezepelumab in other groups, supporting development of tezepelumab for asthma in the paediatric population.
Keywords: adolescents, asthma, paediatric population, pharmacodynamics, pharmacokinetics, tezepelumab
1. What is already known about this subject
Tezepelumab is a monoclonal antibody that inhibits thymic stromal lymphopoietin, a key cytokine in asthma pathogenesis.
Although tezepelumab is approved for adolescents and adults with severe, uncontrolled asthma, its pharmacokinetics (PK), pharmacodynamics and safety profile in younger children remained to be established.
What this study adds
The adolescent PK study (adolescents, [12–17 years old] with mild‐to‐moderate asthma) and TRAILHEAD (children, [5–11 years old] with mild, moderate or severe asthma) showed that tezepelumab has a pharmacokinetic, pharmacodynamic and safety profile in adolescents and children consistent with that observed in other age groups after a single subcutaneous dose.
1. INTRODUCTION
The worldwide prevalence of childhood asthma has been estimated at 10%. 1 Approximately 3%–20% (depending on diagnostic criteria and region) of children with asthma experience severe disease, 2 , 3 exhibiting higher morbidity and an increased risk of mortality compared with those with mild‐to‐moderate asthma. 4 , 5 Uncontrolled paediatric asthma is associated with a reduced health‐related quality of life, persistent bronchial obstruction and a higher rate of asthma exacerbations, which can be severe and life‐threatening. 6 , 7 , 8 Furthermore, children with severe, uncontrolled asthma face considerable personal, familial and economic burdens, including school and parental work absences, hospital stays and medication costs. 8 , 9 Treatment of such patients contributes significantly to the overall healthcare costs related to asthma and presents a considerable clinical challenge to paediatricians.
Biologic treatments that target the Type 2 (T2) inflammatory pathway involved in asthma pathogenesis (specifically omalizumab, mepolizumab, benralizumab and dupilumab) are currently approved by the United States Food and Drug Administration for the treatment of allergic and eosinophilic asthma in children aged 6–11 years. 10 , 11 , 12 However, no biologic treatment that works across asthma phenotypes is currently approved for children younger than 12 years old.
Thymic stromal lymphopoietin (TSLP), an epithelial cytokine at the top of the inflammatory cascade, plays a crucial role in the pathophysiology of asthma. 13 It is primarily expressed by the airway epithelium and is released in response to environmental triggers, activating multiple downstream inflammatory pathways, including T2 and non‐T2 processes, through its interactions with various adaptive and innate immune cells and structural cells. 13 TSLP levels have been shown to positively correlate with disease severity and impaired lung function in patients with asthma. 14 , 15 , 16
Tezepelumab is a human immunoglobulin (Ig)G2λ monoclonal antibody that blocks the activity of TSLP 17 and is approved globally at a dose of 210 mg subcutaneously (SC) every 4 weeks (Q4W) for the treatment of adults and adolescents (aged 12–17 years) with severe asthma. 18 , 19 In the Phase 3 NAVIGATOR study (NCT03347279), treatment with tezepelumab 210 mg SC Q4W vs. placebo led to significant reductions in the annualized asthma exacerbation rate and clinically meaningful improvements in lung function (pre‐bronchodilator [BD] forced expiratory volume in 1 s [FEV1]) and health‐related quality of life in adults and adolescents with severe, uncontrolled asthma. 20 The pharmacokinetics (PK) and dose–response of tezepelumab are well characterized in adults 21 , 22 but have not yet been reported in children.
This analysis reports the results of two Phase 1 studies, the adolescent PK study (NCT02512900) and TRAILHEAD (NCT04673630), which assessed the PK, immunogenicity, pharmacodynamics (PD), safety and tolerability of tezepelumab after a single subcutaneous dose in adolescents (aged 12–17 years) and children (aged 5–11 years), respectively. These studies were performed to support the dose selection of tezepelumab in two Phase 3 studies in patients with severe, uncontrolled asthma: NAVIGATOR, which included adolescents aged 12–18 years, and HORIZON (NCT06023589), which has enrolled children aged 5–11 years.
2. METHODS
2.1. Study design
The adolescent PK study and TRAILHEAD were Phase 1, open‐label, single‐dose studies of tezepelumab conducted in adolescents with mild‐to‐moderate asthma and children with mild, moderate or severe asthma, respectively. The primary objective of both studies was the characterization of PK in adolescents and children with asthma.
The adolescent PK study was performed at six investigational sites in Poland. Eligible participants were adolescents aged 12–17 years (inclusive) who had physician‐diagnosed asthma for at least 6 months before screening. Participants must have been receiving low‐, medium‐ or high‐dose inhaled corticosteroids (ICS; total daily dose ≥100‐μg fluticasone propionate dry powder inhaler or equivalent) plus another controller, with a stable dose for at least 3 months before screening. Pre‐BD FEV1 at screening must have been at least 70% of the predicted normal value, with an increase in post‐BD FEV1 of at least 12% or at least 200 mL. Detailed inclusion/exclusion criteria are provided in Table S1.
At least 20 participants were planned to be enrolled in the adolescent PK study, 10 aged 12–14 years (Cohort 1) and 10 aged 15–17 years (Cohort 2). In addition, at least five participants were to weigh between 30 and 50 kg. All participants received a single subcutaneous dose of tezepelumab 140 mg on Day 1, with a 12‐week (84 days) PK and safety follow‐up period (Figure S1a). Treatment was administered via two injections (70 mg/mL, 2 × 1 mL), one in each anterior thigh, in a formulation with excipients including sodium acetate, sucrose and polysorbate 20.
TRAILHEAD was performed at six centres in the United Kingdom, Hungary and South Africa. Eligible participants were children aged 5–11 years (inclusive) who had physician‐diagnosed asthma for at least 6 months before screening. Participants must have been receiving low‐, medium‐ or high‐dose ICS (total daily dose ≥100‐μg fluticasone propionate dry powder inhaler or equivalent) plus another controller for at least 6 months, with a stable dose for at least 3 months before screening. Pre‐BD FEV1 at screening must have been at least 50% of the predicted normal value. Detailed inclusion/exclusion criteria are provided in Table S2.
Approximately 24 participants were planned to be enrolled in TRAILHEAD, with approximately 14 participants receiving tezepelumab. At least four participants were to have a body weight of below 25 kg and at least three participants were to have a body weight of between 25 and 40 kg. All participants received a single subcutaneous dose of tezepelumab 70 mg on Day 1, with a 12‐week (84 day) PK and safety follow‐up period (Figure S1b). Tezepelumab was administered via a single injection (110 mg/mL, 1 × 0.65 mL) in the anterior thigh, in a formulation with excipients including acetate, L‐proline and polysorbate 80.
In both studies, tezepelumab was given as an add‐on to an existing asthma controller medication regimen. Additional controller or rescue medication use during the study was allowed.
2.2. Outcomes and assessments
The primary objective of both studies was to describe the PK profile of tezepelumab in the respective patient populations. In the adolescent PK study, serum samples for PK analysis were collected before tezepelumab administration on Day 1 and on Days 2, 4, 7, 11, 15, 22, 29, 43, 57 and 85/end of study. In TRAILHEAD, serum samples for PK analysis were collected before tezepelumab administration on Day 1 and on Days 3, 7, 11, 15, 29, 57 and 85/end of study. Serum tezepelumab concentrations were measured by enzyme‐linked immunosorbent assay. The limit of quantification for the assay in both the adolescent PK study and TRAILHEAD was 10 ng/mL. PK parameters were derived from tezepelumab serum concentration/time profiles using noncompartmental analyses. The parameters assessed were the area under the concentration–time curve to the last quantifiable time point (AUC0–t ) and to infinite time (AUC0–infinity), maximum mean serum concentration (C max), time to reach C max (t max), terminal elimination half‐life (t 1/2), apparent clearance from the central compartment (CL/F) and apparent steady‐state volume of distribution.
To compare exposures across age groups, the established population PK model of tezepelumab 23 was used to derive individual post hoc (empirical Bayes) estimates of CL/F for participants in the two Phase 1 studies (the adolescent PK study and TRAILHEAD) and the Phase 3 NAVIGATOR study. Individual CL/F estimates were then used to calculate predicted steady‐state area under the concentration–time curve (AUCss), which was compared graphically across studies and age groups.
Immunogenicity assessment was a secondary objective of both studies. In the adolescent PK study, serum samples to measure the presence of anti‐drug antibodies (ADAs) were collected before tezepelumab administration on Day 1 and on Days 29, 57 and 85/end of study. In TRAILHEAD, serum samples for ADA analysis were collected before tezepelumab administration on Days 1, 29 and 85/end of study (Figure S1). Confirmed ADA‐positive samples were tested using a neutralizing antibody (nAb) assay.
PD/efficacy evaluation was an exploratory objective in both studies. In the adolescent PK study, pulmonary function (pre‐BD FEV1) was measured at Days 0, 29 and 85, blood eosinophil counts (BECs) were measured at Days 0, 2, 4, 7, 11, 15, 22, 29, 43, 57 and 85, and serum total IgE levels were measured at Days 0 and 43. In TRAILHEAD, pre‐BD FEV1, BEC, fractional exhaled nitric oxide (FeNO) levels and serum total IgE levels were measured at Days 0, 14, 28 and 84.
Safety was assessed in terms of adverse events (AEs) and serious AEs at enrolment and at every subsequent study visit. AEs were coded by Medical Dictionary for Regulatory Activities (Version 19.0 for the adolescent PK study and Version 25.0 for TRAILHEAD), and the type, incidence, severity and relationship to the study drug were summarized.
2.3. Statistical analyses
No formal statistical hypothesis tests were performed, and no formal sample size calculation was conducted. Descriptive statistics were used to summarize PK and non‐PK results.
2.4. Ethics
The protocols and protocol amendments, informed consent forms and other relevant documents for both studies were reviewed and approved by independent ethics committees and/or institutional review boards before the studies were initiated. The studies were performed in accordance with the Declaration of Helsinki and were consistent with International Council for Harmonisation/Good Clinical Practice guidelines. Central approvals for the adolescent PK study were obtained from independent ethics committees in Poland (RNN/121/15/KE). Central approvals for TRAILHEAD were obtained from independent ethics committees in London, United Kingdom (20/LO/1041), and Cape Town, South Africa (702/2021). See Tables S3 and S4 for further details on the ethics committees that provided approvals for the adolescent PK study and TRAILHEAD, respectively. Written informed consent was obtained from the participants' legal representatives, and written informed assent was obtained from the patient, together with any locally required authorization. The authors confirm that the principal investigators for this paper are Piotr Kuna (the adolescent PK study) and Jonathan Grigg (TRAILHEAD).
2.5. Nomenclature
All drug/molecular target nomenclature conforms to the IUPHAR/BPS Guide to Pharmacology nomenclature classification. 24
3. RESULTS
3.1. Participant disposition and baseline clinical characteristics
In the adolescent PK study, between 22 September 2015 and 17 May 2016, 21 participants (15 males and 6 females) received tezepelumab (Figure 1a and Table 1). The median age (range) was 14 years (12–17 years). Six participants weighed between 30 and 50 kg, inclusive, at baseline. The median body weight was 56.5 kg (range: 39–92 kg), and the median body mass index was 21.2 kg/m2 (range: 17–27 kg/m2). No participants had visited the emergency department up to 12 months before study entry owing to their asthma; no participants had been admitted to the hospital in this period. All participants were using at least one ICS at baseline, with most participants receiving budesonide (42.9%) or fluticasone propionate (38.1%).
FIGURE 1.
Patient disposition in (A) the adolescent PK study and (B) TRAILHEAD (children). PK, pharmacokinetics.
TABLE 1.
Baseline demographics and clinical characteristics.
| Demographic or characteristic | Adolescent PK study (12–17 years old) (N = 21) | TRAILHEAD (5–11 years old) (N = 18) |
|---|---|---|
| Age, years | ||
| Mean (SD) | 14.7 (1.4) | 7.9 (1.8) |
| Median (range) | 14 (12–17) | 8 (5–11) |
| Sex, n (%) | ||
| Female | 6 (28.6) | 7 (38.9) |
| Male | 15 (71.4) | 11 (61.1) |
| Weight, kg | ||
| Mean (SD) | 59.7 (14.2) | 30.6 (13.9) |
| Median (range) | 56.5 (39.0–92.0) | 24.7 (17.1–67.0) |
| Race, n (%) | ||
| Asian | 0 | 2 (11.1) |
| Black or African American | 0 | 1 (5.6) |
| White | 21 (100.0) | 6 (33.3) |
| Other | 0 | 9 (50.0) |
| BMI, kg/m2, mean (SD) | 21.2 (3.4) | 17.3 (4.3) |
| Asthma duration, years, mean (SD) | N/A | 4.9 (2.5) |
| Age at asthma onset, years, mean (SD) | 6.5 (3.9) | 3.4 (2.3) |
| BEC, cells/μL | ||
| Mean (SD) | 320 (300) | 438 (389) |
| <150 | N/A | 5 (27.8) |
| 150 to <300 | N/A | 3 (16.7) |
| 300 to <450 | N/A | 3 (16.7) |
| ≥450 | N/A | 7 (38.9) |
| FeNO, ppb, mean (SD) | N/A | 32.6 (26.1) |
| Total serum IgE, IU/mL, mean (SD) | 458.1 (387.5) | 1094.5 (1778.3) |
| ICS use, n (%) | ||
| Budesonide | 9 (42.9) | 7 (38.9) |
| Fluticasone propionate | 8 (38.1) | 9 (50.0) |
| Beclometasone dipropionate | 1 (4.8) | 3 (16.7) |
| Ciclesonide | 3 (14.3) | 0 |
| Exacerbations in the 6 months before study entry a | ||
| 0 | N/A | 10 (55.6) |
| 1 | N/A | 3 (16.7) |
| 2 | N/A | 5 (27.8) |
| Pre‐BD FEV1, L, mean (SD) | 3.2 (0.7) | 1.5 (0.5) |
| Pre‐BD FEV1%‐predicted, mean (SD) | 99.3 (14.5) | 95.3 (11.7) |
Abbreviations: BD, bronchodilator; BEC, blood eosinophil count; BMI, body mass index; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; IgE, immunoglobulin E; N/A, data not available; SD, standard deviation.
Percentages are based on the 18 patients in the safety analysis set. These data were not collected in the adolescent PK study. No patients in the adolescent PK study experienced an exacerbation requiring hospital admission in the 12 months before Visit 1.
In TRAILHEAD, between 23 February 2021 and 27 September 2022, 18 participants (11 males and 7 females) received tezepelumab (Figure 1b and Table 1). The median age (range) was 8 years (5–11 years). Nine participants had a body weight below 25 kg, five participants had a body weight between 25 and 40 kg, and four participants had a body weight above 40 kg. Eight of the 18 participants experienced an exacerbation within the 6 months before screening. All participants were using ICS at baseline, with the most commonly used ICS being budesonide (38.9% of the participants).
3.2. PK
In the adolescent PK study, the mean serum concentrations of tezepelumab peaked at approximately 6 days after administration (t max), with a C max of 24.0 μg/mL. The drug exposures declined with a mono‐exponential phase until 84 h postdose, with a t 1/2 of 25.3 days. Exposure within the study (after administration of 140 mg SC) was slightly higher in the participants with the lowest body weights (30–50 kg) in comparison with the participants above 50 kg. The mean AUC0–t were 1110 and 739 μg*day/mL, and mean C max were 29.8 and 21.7 μg/mL in participants weighing 30–50 kg and >50 kg, respectively. See Table 2 for further PK results and Figure 2a for concentration–time profiles of tezepelumab 140 mg SC in adolescents (12–17 years old).
TABLE 2.
Summary statistics of PK parameters.
| Parameter | Adolescent PK study (12–17 years old) | TRAILHEAD (5–11 years old) | NAVIGATOR population PK modela23 | |||||
|---|---|---|---|---|---|---|---|---|
| 30–50 kg (n = 6) | >50 kg (n = 15) | Total (N = 21) | <25 kg (n = 9) | ≥25 kg (n = 9) | Total (N = 18) | Adolescents 12 to <18 years (n = 40) | Adults 18 to <65 years (n = 391) | |
| Dose, mg b | 140 | 140 | 140 | 70 | 70 | 70 | 210 | 210 |
| AUC0–t , μg*day/mL | 1110 (201) | 739 (159) | 846 (240) | 1020 (292) | 728 (201) | 872 (285) | 1180 (380) | 863 (313) |
| AUC0–infinity, μg*day/mL | 1260 (286) | 828 (180) | 952 (289) | 1110 (353) | 842 (233) | 974 (320) | N/A | N/A |
| C max, μg/mL | 29.8 (3.1) | 21.7 (6.2) | 24.0 (6.6) | 34.7 (11.5) | 19.4 (6.0) | 27.1 (11.9) | 55.2 (16.5) | 39.2 (13.1) |
| t max, days |
5.97 (0.99, 9.97) |
5.91 (1.40, 19.9) |
5.95 (0.99, 19.9) |
1.99 (1.93, 9.96) |
6.95 (1.92, 9.95) |
3.5 (1.9, 10.0) |
N/A | N/A |
| t 1/2, days | 25.3 (4.8) | 25.4 (4.8) | 25.3 (4.7) | 22.8 (5.8) | 28.6 (4.8) | 25.7 (5.9) | N/A | N/A |
| CL/F, L/day | 0.115 (0.024) | 0.177 (0.038) | 0.159 (0.044) | 0.071 (0.032) | 0.089 (0.025) | 0.080 (0.030) | N/A | N/A |
| V/F, L | 4.44 (0.57) | 6.73 (1.87) | 6.07 (1.91) | 2.35 (1.22) | 3.80 (1.03) | 3.08 (1.32) | N/A | N/A |
Note: Parameters are shown as mean (SD) except for t max, which is shown as median (min, max); parameter values are rounded to three significant figures.
Predicted steady‐state exposures in a typical adolescent or adult.
Dose was fixed in each study.
Abbreviations: AUC0–infinity, area under the curve to infinite time; AUC0–t , area under the curve to the last quantifiable time point; CL/F, apparent clearance from the central compartment; C max, maximum concentration; N/A, data not available; PK, pharmacokinetics; SD, standard deviation; t 1/2, terminal elimination half‐life; t max, time to reach C max; V/F, apparent steady‐state volume of distribution.
FIGURE 2.
Geometric mean serum concentration of tezepelumab from baseline to Day 84 in the (a) adolescent PK study and (b) TRAILHEAD (children). gSD, geometric standard deviation.
In TRAILHEAD, the median t max was 3.5 days, which was followed by an exponential decline in serum tezepelumab concentration with time. The mean t 1/2 was 25.7 days, and the mean C max was 27.1 μg/mL, with a CL/F of 0.0802 L/day. Exposure within the study (after administration of 70 mg SC) was slightly higher in the participants with the lowest body weights (<25 kg) in comparison with the participants weighing ≥25 kg. The mean AUC0–t was 1020 and 728 μg*day/mL, and the mean C max was 34.7 and 19.4 μg/mL in participants weighing <25 kg and ≥25 kg, respectively. See Table 2 for further PK results and Figure 2b for concentration–time profiles of tezepelumab 70 mg SC in children (5–11 years old).
A population PK model was previously developed using PK data for tezepelumab pooled from 8 clinical studies, and steady‐state exposures were predicted for adolescent and adult patient subgroups from the Phase 3 NAVIGATOR study. 23 When considered alongside the adolescent PK study and TRAILHEAD data, overall exposure in children and adolescents was within the range observed in the Phase 3 study and as described by the population PK model (Table 2 and Figure 3).
FIGURE 3.
Comparison of tezepelumab exposures across studies and age groups. Model‐predicted tezepelumab AUCss (over 4 weeks) in participants from the Phase 1 TRAILHEAD (70 mg) and the adolescent PK study (140 mg) studies, and the Phase 3 NAVIGATOR study (210 mg SC Q4W) split by adolescents and adults. The horizontal dotted reference lines represent the mean of the simulated exposure in the Phase 2b PATHWAY study for doses of 280 mg SC Q2W and 70 mg SC Q4W in adults. AUC0–4w , ss area under the curve to Week 4, steady state; Q2W, every 2 weeks; Q4W, every 4 weeks; SC, subcutaneously.
3.3. Immunogenicity
In the adolescent PK study, there was one participant (4.8%) who was ADA‐positive at baseline and persistently ADA‐positive post baseline (ADA‐positive on Days 29, 57 and 85) (Table S3); however, the PK profile of this participant was not altered, suggesting no impact due to the presence of ADA. Because the ADA was present at baseline, it is unlikely to be treatment‐emergent. No other participants were ADA‐positive at baseline or at any post‐baseline time point, and no participants developed nAbs following administration of tezepelumab.
In TRAILHEAD, there were three ADA‐positive participants (16.7%); none of them was classified as treatment‐emergent ADA positive (Table S5). No participants were nAb‐positive.
3.4. Pharmacodynamics
In the adolescent PK study, following administration of tezepelumab 140 mg SC on Day 1, an initial reduction in BEC was observed from baseline to Day 4 in both 12‐ to 14‐year‐olds (Cohort 1; from a mean [SD] of 371 cells/μL [337 cells/μL; n = 11] to 238 cells/μL [238 cells/μL; n = 10]; mean [SD] change from baseline: 158 cells/μL [140 cells/μL; n = 10]) and 15‐ to 17‐year‐olds (Cohort 2; from a mean [SD] of 269 cells/μL [266 cells/μL; n = 10] to 156 cells/μL [72 cells/μL; n = 10]; mean [SD] change from baseline: 113 cells/μL [216 cells/μL; n = 10]), which continued to Day 15 (Figure 4a). By Day 85, mean BEC was gradually returning to baseline in Cohort 2 but remained decreased relative to baseline in Cohort 1. FeNO levels were not measured in the adolescent PK study.
FIGURE 4.
Changes from baseline in biomarkers of inflammation in the adolescent PK study and TRAILHEAD: (a, b) blood eosinophil count, (c) FeNO level and (d, e) serum total immunoglobulin E level. FeNO levels were not measured in the adolescent PK study. FeNO, fractional exhaled nitric oxide.
A modest decrease in serum total IgE level from baseline (mean [SD]: 477.5 KU/L [341.6 KU/L; n = 10]) to Day 43 (mean [SD]: 410.2 KU/L [342.9 KU/L; n = 11]) was seen in Cohort 1, representing a mean (SD) change from baseline of −33.8 KU/L (57.5 KU/L; n = 10) (Figure 4d). There was no notable change in serum total IgE level in Cohort 2, with the discrepancy between age groups likely attributable to sample size effects. Although a modest increase in pre‐BD FEV1 was observed from Days 29 to 85 (Figure S2a), overall, there was no substantial change in pulmonary function parameters following a single dose of tezepelumab.
In TRAILHEAD, following administration of tezepelumab 70 mg SC on Day 1, there was an initial mean (SD) reduction in BEC of 248 cells/μL (352 cells/μL; n = 16), from a mean (SD) of 438 cells/μL (389 cells/μL; n = 18) at baseline to 188 cells/μL (112 cells/μL; n = 16) on Day 28, followed by a gradual return to baseline by Day 84 (Figure 4b). FeNO levels decreased by a mean (SD) of 17.4 ppb (20.6 ppb; n = 12), from a mean (SD) of 32.6 ppb (26.1 ppb; n = 13) at baseline to 13.7 ppb (10.6 ppb; n = 15) on Day 14, followed by a return to baseline by Day 84 (Figure 4c). No notable changes in serum total IgE levels (Figure 4e) or pulmonary function parameters (Figure S2b) were observed following a single dose of tezepelumab.
3.5. Safety
Overall, clinical laboratory and other safety assessments were consistent with the reported safety profile of tezepelumab. No new safety or tolerability concerns were raised in these studies.
In the adolescent PK study, tezepelumab was well tolerated in 12‐ to 17‐year‐old participants with mild‐to‐moderate asthma. In total, 8/21 (38%) participants receiving tezepelumab reported AEs (Table 3). One participant (9.1%) in Cohort 1 (age 12–14 years) experienced a mild AE of pyrexia that was considered by the investigator to be related to tezepelumab but which resolved without further issues. Five participants reported AEs of moderate intensity; all other AEs were of mild intensity. The AEs reported as moderate intensity were acute sinusitis, bronchitis, nasopharyngitis, pharyngitis and a ligament sprain, each reported as a single event in a single participant. No AEs with the outcome of death were reported, and no serious AEs were reported during the study. No participants reported AEs leading to discontinuation of the study.
TABLE 3.
Summary of on‐study AEs.
| AE, n (%) | Adolescent PK study (N = 21) | TRAILHEAD (N = 18) |
|---|---|---|
| Any AE | 8 (38.1) | 7 (38.9) |
| Any AE leading to death | 0 | 0 |
| Any serious AE | 0 | 0 |
| Any AE leading to withdrawal from the study | 0 | 0 |
| AEs by system organ class | ||
| Preferred term | ||
| Infections and infestations | 6 (28.6) | 5 (27.8) |
| Acute sinusitis | 1 (4.8) | 0 |
| Bronchitis | 2 (9.5) | 0 |
| COVID‐19 | 0 | 2 (11.1) |
| Nasopharyngitis | 3 (14.3) | 2 (11.1) |
| Pharyngitis | 1 (4.8) | 0 |
| Viral upper respiratory tract infection | 0 | 1 (5.6) |
| Injury, poisoning and procedural complications | 2 (9.5) | 1 (5.6) |
| Contusion | 1 (4.8) | 1 (5.6) |
| Fall | 0 | 1 (5.6) |
| Ligament sprain | 1 (4.8) | 0 |
| Gastrointestinal disorders | 1 (4.8) | 1 (5.6) |
| Gastritis | 1 (4.8) | 0 |
| Vomiting | 0 | 1 (5.6) |
| General disorders and administration site conditions | 1 (4.8) | 1 (5.6) |
| Pyrexia | 1 (4.8) | 1 (5.6) |
| Nervous system disorders | 0 | 2 (11.1) |
| Headache | 0 | 2 (11.1) |
| Respiratory, thoracic and mediastinal disorders | 0 | 2 (11.1) |
| Asthma | 0 | 1 (5.6) |
| Cough | 0 | 1 (5.6) |
| Immune system disorders | 0 | 1 (5.6) |
| Seasonal allergy | 0 | 1 (5.6) |
| Musculoskeletal and connective tissue disorders | 0 | 1 (5.6) |
| Pain in extremity | 0 | 1 (5.6) |
Note: Participants with multiple events in the same preferred term are counted only once in that preferred term. Participants with events in more than one preferred term are counted once in each of those preferred terms. Includes AEs that occurred during the on‐study period. The on‐study period is any day between the date of treatment administration and study completion or withdrawal date.
Abbreviations: AE, adverse event; COVID‐19, coronavirus disease 2019.
In TRAILHEAD, tezepelumab was well tolerated in 5‐ to 11‐year‐old participants with mild, moderate or severe asthma; there were no safety findings of concern. In total, 7/18 (39%) participants reported AEs (Table 3). None of the AEs reported was considered causally related to tezepelumab by the investigator. Two participants reported AEs of moderate intensity; all other AEs were of mild intensity. The AEs reported as moderate intensity were asthma and cough, each reported as a single event in a single participant. No AEs with the outcome of death were reported, and no serious AEs were reported during the study. No participants reported AEs leading to discontinuation of the study.
4. DISCUSSION
The adolescent PK study and TRAILHEAD were open‐label, Phase 1 studies and provided initial insights into the PK, PD and safety profiles of tezepelumab in adolescents and children with asthma. This analysis is the first reported PK/PD evaluation of tezepelumab administration in children aged 5–11 years. The doses investigated in the adolescent PK study and TRAILHEAD were selected to achieve systemic exposures comparable to those associated with an acceptable safety profile and clinical benefit in adults. This was achieved using population PK modelling and simulations with allometric scaling to account for lower body weight, and exposure–response analyses. 23 As asthma pathophysiology and the upstream T2‐inflammatory mechanism targeted by tezepelumab are shared between children and adults, with no evidence of age‐specific differences in target biology, 25 , 26 , 27 , 28 the exposure–response relationship is expected to be similar in paediatric patients and adults. This exposure‐matching approach was therefore used to support dose selection in children and adolescents. Although body weight is the primary determinant of tezepelumab exposure, an age‐based dosing scheme was employed to align with existing regulatory age definitions and with the approved adult dosing framework.
Given the linear PK of tezepelumab and extensive data from single‐ and multiple‐ascending‐dose studies in adults, multiple‐dose exposure can be reliably extrapolated from single‐dose PK. 23 An open‐label, single‐dose design was therefore selected to support dose selection for subsequent Phase 3 studies while minimizing unnecessary paediatric exposure. A limitation of these studies is that it is not possible to evaluate or extrapolate efficacy without repeated dosing, and any potential benefit to the patients is limited. However, efficacy will be assessed comprehensively in the ongoing HORIZON Phase 3 paediatric study (NCT06023589).
Notably, no serious AEs were reported, and none of the participants developed nAbs. These results are consistent with the low immunogenicity rate of tezepelumab observed across adult and adolescent populations. 20 , 29 , 30
Tezepelumab has been evaluated in several Phase 1 clinical studies in adult participants, with initial single and multiple ascending dose studies (Studies 20070620 and 20080390, respectively), 29 one allergen challenge study (Study 20101183) 17 and studies conducted in healthy Japanese and Chinese participants (Studies D5180C00003 31 and D5180C00020 [unpublished], respectively). Multiple intravenous doses of tezepelumab 700 mg demonstrated an acceptable safety profile in healthy participants and those with mild atopic asthma (Studies 20080390 and 20101183, respectively). 17 , 29 Tezepelumab exhibited linear PK with highly consistent and reliable PK profiles across doses, populations and studies; this provided the basis for dose selection in the clinical development programme for different populations and age groups. 17 , 29 , 31
The adolescent PK study was performed in parallel to the Phase 2b PATHWAY study in adults with severe, uncontrolled asthma, which evaluated three subcutaneous dose levels (70 mg Q4W, 210 mg Q4W and 280 mg every 2 weeks [Q2W]). The evaluated dose was selected to comprehensively characterize PK and result in exposures that would be within the safe and efficacious range in the adult Phase 2b PATHWAY study 21 to properly guide dose selection for the Phase 3 study. 20 The results from the adolescent PK study and PATHWAY were evaluated to select the Phase 3 NAVIGATOR dose. The same dose (210 mg Q4W) was evaluated in adult and adolescent patients with asthma in NAVIGATOR, which demonstrated the efficacy and safety of tezepelumab in these populations. 20 Data collected during the adolescent PK study, together with pooled data from the studies in healthy adults and in patients with asthma (a total of eight studies, Phases 1–3), subsequently contributed to population PK modelling that supported the exposure–efficacy and body weight–response analyses of tezepelumab in patients with asthma. 22 , 23 Notably, when adolescents (12–18 years of age) were given the same tezepelumab dose as adults, they had 33.2%–40.7% higher mean exposures than adults (aged 18–65 years), which is mainly attributed to their lower average body weight (see Figure 3). However, these differences were small compared with the overall variability of exposure in the NAVIGATOR population. The mean exposures across all body weight quartiles and age groups in NAVIGATOR were well below the exposures at the highest dose evaluated in PATHWAY (280 mg Q2W), which demonstrated acceptable safety, and above the exposure at 70 mg Q4W, which demonstrated efficacy in PATHWAY. The 210 mg SC Q4W dose is now the approved dose for adolescents (>12 years old), and the results from the adolescent PK study were important for the characterization of PK in this age group. 18 , 19 , 23
The TRAILHEAD study results were used to guide dose selection for the ongoing, Phase 3 HORIZON study of tezepelumab in children aged 5 to <12 years with severe, uncontrolled asthma. PK simulations scaled for the lower body weight of children identified a single subcutaneous dose of 70 mg of tezepelumab to match the PK exposure of 210 mg in adults. The evaluated dose was selected to comprehensively characterize PK and was predicted to result in exposures within the safe and efficacious range as defined in the adult Phase 2b and Phase 3 studies. 20 , 21 Indeed, the 70‐mg dose of tezepelumab used in this study demonstrated a generally similar PK profile in this age group (mean AUC0–inf: 974 μg*day/mL; mean C max: 27.1 μg/mL) to that of tezepelumab 210 mg in adolescents and adults in the population PK model (mean simulated steady‐state AUC: 901 μg*day/mL; mean simulated steady‐state C max: 40.9 μg/mL) (see Figure 3 and Table 2). 23
5. CONCLUSIONS
Tezepelumab was well tolerated by adolescents (aged 12–17 years) with mild‐to‐moderate asthma after a single 140‐mg subcutaneous dose in the adolescent PK study and by children (aged 5–11 years) with mild, moderate or severe asthma after a single 70‐mg subcutaneous dose in the TRAILHEAD study. The PK, PD and safety profiles of tezepelumab in children were as expected from previous studies in other age groups and suggest that tezepelumab can be administered to children. Data from these Phase 1 PK studies were used to inform dose selection in Phase 3 studies of tezepelumab by matching concentration range with adults at an efficacious dose and within the tested exposure range of tezepelumab considered safe. Tezepelumab is currently approved in over 60 countries for adolescents (aged 12–17 years) and adults with severe, uncontrolled asthma. These findings support the inclusion of children and adolescents into Phase 3 studies and the further development of tezepelumab for the treatment of asthma in children.
AUTHOR CONTRIBUTIONS
Anna Lundahl, Jonathan Grigg, Lubna Abuqayyas, Piotr Kuna, Gillian Hunter, Beata Pawlikowska, Jacob Leander, Michael Levin, Atul Gupta, James Paton, Katharine C. Pike, Jane R. Parnes, Gun Almqvist and Stephanie L. Roseti wrote the manuscript. Anna Lundahl, Lubna Abuqayyas, Gillian Hunter, Beata Pawlikowska, Jane R. Parnes, Gun Almqvist and Stephanie L. Roseti designed the research. Jonathan Grigg, Michael Levin, Atul Gupta, James Paton, Katharine C. Pike and Piotr Kuna performed the research. Anna Lundahl, Gillian Hunter, Beata Pawlikowska, Gun Almqvist, Jacob Leander and Stephanie L. Roseti analysed the data.
CONFLICT OF INTEREST STATEMENT
A.L., G.H., B.P., J.L., G.A. and S.L.R. are employees of AstraZeneca and may own stock or stock options in AstraZeneca. J.G. has received speaker/advisory board fees from AstraZeneca, OM Pharma, Omron and Sanofi and has received grants from Mariomed and OM Pharma. L.A. and J.R.P. are employees of Amgen and own stock in Amgen. P.K. has received personal fees for lectures from Adamed, Alvogen, AstraZeneca, Berlin‐Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, LEK‐AM, Menarini Group, Mylan, Novartis, Polpharma, Sanofi and Teva Pharmaceuticals. M.L. has received speaker/advisory board fees from AbbVie, Bayer, Cipla, ECN, Glenmark Pharmaceuticals, Organon, Pharmadynamics and Sanofi and has received grants from AstraZeneca, Novartis and Sanofi. A.G. has received consultancy fees for Aerogen, AstraZeneca, Boehringer Ingelheim, GSK and Novartis. J.P. has no disclosures. K.C.P. has received speaker/advisory board fees from Adherium, Novartis and Sanofi and has received grants from AstraZeneca.
Supporting information
Table S1. Inclusion and exclusion criteria for the adolescent PK study.
Table S2. Inclusion and exclusion criteria for the TRAILHEAD study.
Table S3. List of institutional review boards/ethics committees for the adolescent PK study.
Table S4. List of institutional review boards/ethics committees for the TRAILHEAD.
Table S5. Summary of on‐study ADA responses.
Figure S1. Study design for (a) the adolescent PK study and (b) TRAILHEAD.
Figure S2. Change over time in mean pre‐BD FEV1 from baseline to Day 85 in (a) adolescents (adolescent PK study) and (b) children (TRAILHEAD).
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the patients and their families for their participation, as well as the study teams, site staff and investigators who made these studies possible. The authors would like to thank Cecil Chen for his contribution to this study. Medical writing support was provided by Freyja McClenahan, PhD, of PharmaGenesis London, with funding from AstraZeneca and Amgen Inc.
Lundahl A, Grigg J, Abuqayyas L, et al. Pharmacokinetics and safety of tezepelumab in children with mild, moderate or severe asthma and adolescents with mild‐to‐moderate asthma. Br J Clin Pharmacol. 2026;92(11):3819‐3830. doi: 10.1002/bcp.70666
Jonathan Grigg, principal investigator for TRAILHEAD.
Piotr Kuna, principal investigator for the adolescent PK study.
Funding information The adolescent PK and TRAILHEAD studies were funded by AstraZeneca and Amgen Inc.
DATA AVAILABILITY STATEMENT
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.
REFERENCES
- 1. Zhou W, Tang J. Prevalence and risk factors for childhood asthma: a systematic review and meta‐analysis. BMC Pediatr. 2025;25(1):50. doi: 10.1186/s12887-025-05409-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Manti S, Magri P, De Silvestri A, et al. Epidemiology of severe asthma in children: a systematic review and meta‐analysis. Eur Respir Rev. 2024;33(174):240095. doi: 10.1183/16000617.0095-2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Lai CKW, Beasley R, Crane J, et al. Global variation in the prevalence and severity of asthma symptoms: phase three of the international study of asthma and allergies in childhood (ISAAC). Thorax. 2009;64(6):476‐483. doi: 10.1136/thx.2008.106609 [DOI] [PubMed] [Google Scholar]
- 4. Scichilone N, Barnes PJ, Battaglia S, et al. The hidden burden of severe asthma: from patient perspective to new opportunities for clinicians. J Clin Med. 2020;9(8):9. doi: 10.3390/jcm9082397 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Nagakumar P, Thomas H. Management of problematic severe asthma in children. Paediatr Child Health. 2017;27(7):318‐323. doi: 10.1016/j.paed.2017.03.002 [DOI] [Google Scholar]
- 6. Fleming L, Wilson N, Bush A. Difficult to control asthma in children. Curr Opin Allergy Clin Immunol. 2007;7(2):190‐195. doi: 10.1097/ACI.0b013e3280895d0c [DOI] [PubMed] [Google Scholar]
- 7. Fitzpatrick AM, Teague WG. Progressive airflow limitation is a feature of children with severe asthma. J Allergy Clin Immunol. 2011;127:282‐284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Papadopoulos NG, Čustović A, Cabana MD, et al. Pediatric asthma: an unmet need for more effective, focused treatments. Pediatr Allergy Immunol. 2019;30(1):7‐16. doi: 10.1111/pai.12990 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Serebrisky D, Wiznia A. Pediatric asthma: a global epidemic. Ann Glob Health. 2019;85:6. doi: 10.5334/aogh.2416 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Gupta A, Pouliquen I, Austin D, et al. Subcutaneous mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma. Pediatr Pulmonol. 2019;54(12):1957‐1967. doi: 10.1002/ppul.24508 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Wedner HJ, Fujisawa T, Guilbert TW, et al. Benralizumab in children with severe eosinophilic asthma: pharmacokinetics and long‐term safety (TATE study). Pediatr Allergy Immunol. 2024;35:e14092. [DOI] [PubMed] [Google Scholar]
- 12. Bacharier LB, Jackson DJ. Biologics in the treatment of asthma in children and adolescents. J Allergy Clin Immunol. 2023;151(3):581‐589. doi: 10.1016/j.jaci.2023.01.002 [DOI] [PubMed] [Google Scholar]
- 13. Gauvreau GM, Sehmi R, Ambrose CS, Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets. 2020;24(8):777‐792. doi: 10.1080/14728222.2020.1783242 [DOI] [PubMed] [Google Scholar]
- 14. Li Y, Wang W, Lv Z, et al. Elevated expression of IL‐33 and TSLP in the airways of human asthmatics in vivo: a potential biomarker of severe refractory disease. J Immunol. 2018;200(7):2253‐2262. doi: 10.4049/jimmunol.1701455 [DOI] [PubMed] [Google Scholar]
- 15. Shikotra A, Choy DF, Ohri CM, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol. 2012;129:104‐11.e1‐9. [DOI] [PubMed] [Google Scholar]
- 16. Ying S, O'Connor B, Ratoff J, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2‐attracting chemokines and disease severity. J Immunol. 2005;174:8183‐8190. [DOI] [PubMed] [Google Scholar]
- 17. Gauvreau GM, O'Byrne PM, Boulet LP, et al. Effects of an anti‐TSLP antibody on allergen‐induced asthmatic responses. N Engl J Med. 2014;370(22):2102‐2110. doi: 10.1056/NEJMoa1402895 [DOI] [PubMed] [Google Scholar]
- 18. Tezspire (tezepelumab) prescribing information. AstraZeneca. Accessed July 28, 2024; 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761224s001lbl.pdf [Google Scholar]
- 19. Tezspire (tezepelumab) summary of product characteristics 2022. AstraZeneca. Accessed July 28, 2024. Available at https://www.ema.europa.eu/en/medicines/human/EPAR/tezspire [Google Scholar]
- 20. Menzies‐Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. 2021;384(19):1800‐1809. doi: 10.1056/NEJMoa2034975 [DOI] [PubMed] [Google Scholar]
- 21. Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377(10):936‐946. doi: 10.1056/NEJMoa1704064 [DOI] [PubMed] [Google Scholar]
- 22. Neang L, Zheng Y, Griffiths JM, et al. Pharmacokinetic and pharmacodynamic modeling of tezepelumab to guide phase 3 dose selection for patients with severe asthma. J Clin Pharmacol. 2021;61:901‐912. doi: 10.1002/jcph.1803 [DOI] [PubMed] [Google Scholar]
- 23. Zheng Y, Abuqayyas L, Quartino A, et al. Population pharmacokinetic modeling and exposure‐efficacy and body weight‐response analyses for tezepelumab in patients with severe, uncontrolled asthma. J Clin Pharmacol. 2024;64(8):908‐921. doi: 10.1002/jcph.2433 [DOI] [PubMed] [Google Scholar]
- 24. Alexander SP, Kelly E, Marrion NV, et al. The concise guide to pharmacology 2017/18: overview. Br J Pharmacol. 2017;174:S1‐S16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Papadopoulos NG, Bacharier LB, Jackson DJ, et al. Type 2 inflammation and asthma in children: a narrative review. J Allergy Clin Immunol Pract. 2024;12(9):2310‐2324. doi: 10.1016/j.jaip.2024.06.010 [DOI] [PubMed] [Google Scholar]
- 26. Lin SC, Huang JJ, Wang JY, Chuang HC, Chiang BL, Ye YL. Upregulated thymic stromal lymphopoietin receptor expression in children with asthma. Eur J Clin Invest. 2016;46(6):511‐519. doi: 10.1111/eci.12623 [DOI] [PubMed] [Google Scholar]
- 27. Berraïes A, Hamdi B, Ammar J, Hamzaoui K, Hamzaoui A. Increased expression of thymic stromal lymphopoietin in induced sputum from asthmatic children. Immunol Lett. 2016;178:85‐91. doi: 10.1016/j.imlet.2016.08.004 [DOI] [PubMed] [Google Scholar]
- 28. Chorvinsky E, Nino G, Salka K, Gaviria S, Gutierrez MJ, Pillai DK. TSLP bronchoalveolar lavage levels at baseline are linked to clinical disease severity and reduced lung function in children with asthma. Front Pediatr. 2022;10:971073. doi: 10.3389/fped.2022.971073 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Parnes JR, Sullivan JT, Chen L, Dias C. Pharmacokinetics, safety, and tolerability of tezepelumab (AMG 157) in healthy and atopic dermatitis adult subjects. Clin Pharmacol Ther. 2019;106(2):441‐449. doi: 10.1002/cpt.1401 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Cole J, Cąpała‐Szczurko I, Roseti S, et al. Effect of tezepelumab on the humoral immune response to seasonal quadrivalent influenza vaccination in patients with moderate to severe asthma: the phase 3b VECTOR study. Pulm Ther. 2024;10(1):53‐67. doi: 10.1007/s41030-023-00245-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Sakamoto K, Matsuki S, Irie S, et al. A phase 1, randomized, placebo‐controlled study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Clin Pharmacol Drug Dev. 2020;9(7):833‐840. doi: 10.1002/cpdd.775 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma; 2014. https://ginasthma.org/wp-content/uploads/2019/01/2014-GINA.pdf [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Inclusion and exclusion criteria for the adolescent PK study.
Table S2. Inclusion and exclusion criteria for the TRAILHEAD study.
Table S3. List of institutional review boards/ethics committees for the adolescent PK study.
Table S4. List of institutional review boards/ethics committees for the TRAILHEAD.
Table S5. Summary of on‐study ADA responses.
Figure S1. Study design for (a) the adolescent PK study and (b) TRAILHEAD.
Figure S2. Change over time in mean pre‐BD FEV1 from baseline to Day 85 in (a) adolescents (adolescent PK study) and (b) children (TRAILHEAD).
Data Availability Statement
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.