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Single Technology Appraisal

Tezepelumab for treating severe asthma [ID3910]

Appraisal Committee Meeting – 08 November 2022

First committee meeting

The following documents are made available

The final scope and final stakeholder list are available on the NICE website.

Pre-technical engagement documents

1. Company submission from Astrazeneca

• a. Company evidence submission summary for committee

• b. Company evidence submission

2. Clarification questions and company responses

3. Patient group, professional group and NHS organisation submissions from:

• a. British Thoracic Society

• b. NHS England and Improvement (Specialised Commissioning)

4. External Assessment Report prepared by PenTAG

Post-technical engagement documents

5. Technical engagement response from company

6. Technical engagement responses from stakeholders:

• a. British Society for Allergy & Clinical Immunology (BSACI) b. Asthma + Lung UK (A+LUK)

7. External Assessment Report critique of company response to technical engagement prepared by PenTAG

8. Appraisal Committee Meeting presentation slides – to follow

Please note that the full submission, appendices to the company’s submission, and company model will be available as a separate file on NICE Docs for information only.

Committee papers

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal

Tezepelumab for treating severe asthma (ID3910)

Document A

Company evidence submission summary for committee

AstraZeneca confirm that all information in the submission summary is an accurate summary or replication of evidence in the main submission and accompanying appendices and that wherever possible a cross reference to the original source is provided.

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Contents

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Submission summary

A.1 Health condition – B.1.3 (page 22)

Asthma is a heterogeneous disease, characterised by chronic airway inflammation, and defined by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity together with variable expiratory airflow limitation (1). Severe asthma is defined as asthma that remains uncontrolled despite optimised treatment with high dose inhaled corticosteroid in combination with a long-acting beta-agonist (ICS-LABA), or that requires high dose ICS-LABA to prevent it from becoming uncontrolled (1). Of the 5.4 million patients receiving treatment for asthma in the UK (2), it is estimated that around 4% have severe asthma (3), of which 65.5% (or 141,000 people) have severe, uncontrolled asthma (4).

The burden of severe, uncontrolled asthma is high due to associated exacerbations and hospitalisations (5). The unpredictability and distress associated with severe, uncontrolled asthma symptoms has a substantial negative impact on the lives of patients, including a detriment in the ability to perform usual daily activities (1, 6, 7) and negatively impacts their mental health (8). Patients with asthma have a higher mortality rate compared with patients with non-severe asthma (9). A 2019 analysis of Office for National Statistics (ONS) data by Asthma UK revealed that overall, more than 12,700 people died from asthma in England and Wales over the past decade, with deaths increasing by 33% between 2008 and 2018 (10). Healthcare costs per patient with severe asthma are higher than those for patients with type 2 diabetes, stroke or chronic obstructive pulmonary disease (COPD) (1, 11). In a 2017 UK study using data from a nationally representative primary care database, the Optimum Patient Care Research Database (OPRCD), the average healthcare costs per person per year with severe asthma ranged from £2,603 to £4,533 (12).

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A.2 Clinical pathway of care – B.1.3.6 (page 29)

In England, treatment for severe, uncontrolled asthma generally follows the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidelines (13), presented in Figure 1. According to BTS/SIGN guidelines, adults with asthma not adequately controlled on the recommended initial or additional controller therapies should be considered for specialist therapies, including high dose ICS, leukotriene receptor antagonist (LTRA), tiotropium bromide, or theophylline (13). Add-on biologic therapies may also be considered, with the choice of biologic prescribed depending on the patient’s asthma phenotype and biomarker profile (13).

Figure 2 outlines the proposed positioning of tezepelumab within the biologic therapy pathway of care for severe asthma patients. The company submission positions tezepelumab as a treatment for adults and adolescents 12 years and older with severe uncontrolled asthma patients despite high dose ICS and an additional controller, who have had 3 or more exacerbations in the prior year, or who are on maintenance oral corticosteroid (mOCS), irrespective of biomarker values. Introducing tezepelumab in this setting will provide access to a biologic treatment for some patients who are currently ineligible and provide an additional first line treatment option for patients who are currently eligible for biologic treatment, with a different mode of action that targets higher up in the inflammatory cascade.

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Figure 1: BTS/SIGN – 2019 guideline for the management of asthma in adults/adolescents

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Abbreviations: BTS, British Thoracic Society; ICS, inhaled corticosteroid; LABA, long-acting β2 agonist; LTRA, leukotriene receptor antagonist; MART, maintenance and reliever therapy; SIGN, Scottish Intercollegiate Guidelines Network.

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Figure 2: Proposed positioning of tezepelumab in the treatment of patients with severe uncontrolled asthma

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Abbreviations: EOS, eosinophil; exacs, exacerbations; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IL, interleukin; mOCS, maintenance oral corticosteroid treatment.

• Adults: (400+ EOS AND 3+ exacs) OR 300+ EOS AND (4+ exacs OR mOCS)

• Adults: 400+ EOS AND 3+ exacs

• § (Adults: 25+ FeNO AND 150-299 EOS AND 4+ exacs) OR (Age 12-17: 25+ FeNO AND 150+ EOS AND 4+ exacs)

• Age 6+: Allergic IgE-mediated asthma AND 4+ exacs OR mOCS

• Add-on to high dose ICS + additional controller.

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A.3 Equality considerations – B.1.4 (page 44)

A recommendation for tezepelumab in patients with severe, uncontrolled asthma who have experienced 3 or more exacerbations in the prior year OR who require mOCS, addresses existing inequality in two main ways:

1. Equality for patients who do not meet biomarker criteria for current biologics: There is currently no biologic treatment option for patients with low eosinophilic, low fractional exhaled nitric oxide (FeNO), non-allergic severe asthma. A recommendation in a broader population will address this and provide a therapy option for thousands of severe asthma patients who are currently ineligible to receive a biologic to help manage their condition.

2. Gender equality: Severe asthma is a condition that is known to have a higher prevalence among females compared with males; throughout their lifetime, females have a higher likelihood of developing asthma and developing a more severe form of asthma than their male counterparts (14). This is supported by the demographics in the tezepelumab NAVIGATOR trial, in which 63.5% of subjects were female. Furthermore, patients with non-eosinophilic phenotypes of severe asthma are more likely to be women when compared with the breakdown by gender of patients with an eosinophilic subtype (81.5% versus 62.9%; p=0.047) (15). With women suffering from non-eosinophilic disease more than men, the reimbursement of tezepelumab across a broad severe asthma patient population, regardless of biomarkers, helps to address the current inequality that exists in terms of biologic treatment options for women.

A.4 The technology – B.1.2 (page 21)

Table 1: Technology being appraised

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----- Start of picture text -----
TSLP, an epithelial cell-derived cytokine, occupies an upstream position in the asthma inflammatory cascade and
plays a central role in the initiation and persistence of airway inflammation in asthma. TSLP regulates immunity at
the airway barrier surface, affecting dendritic cells and other innate and adaptive immune cells, and inducing
downstream inflammatory processes and bronchial hyper-responsiveness. TSLP has also been shown to have
indirect effects on airway structural cells (e.g. fibroblasts and airway smooth muscle).
In asthma, both allergic and non-allergic triggers induce TSLP production. Blocking TSLP with tezepelumab
reduces a broad spectrum of biomarkers and cytokines associated with inflammation (e.g. blood EOS, IgE,
FeNO, IL-5, and IL-13).
Marketing authorisation/CE mark status CHMP positive opinion is anticipated in . MHRA MA is expected in
Indications and any restriction(s) as The draft indication covered in the submission is as follows:
described in the summary of product
characteristics (SmPC) .
Method of administration and dosage







*****************************************************************************
Additional tests or investigations None.
List price and average cost of a course of List price: ****** per vial
treatment Average cost of a course of treatment: Lifetime treatment for responders, 1 year of treatment for inadequate
responders
Patient access scheme (if applicable) A simple PAS has been submitted to PASLU with a net price of **** per vial
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Abbreviations: CHMP, Committee for Medicinal Products for Human Use; EOS, eosinophil; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; MA, marketing authorisation; MHRA, Medicines and Healthcare products Regulatory Agency; TSLP, thymic stromal lymphopoietin. † Subject to approval.

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A.5 Decision problem and NICE reference case – B.1.1 (page 17)

The company submission covers a subset of the technology’s (anticipated) marketing authorisation.

• The (draft) tezepelumab indication is:

  • ---

**************************************************************************.

• This submission covers: Adults and adolescents 12 years and older with severe uncontrolled asthma despite high dose ICS and an additional controller, who experienced 3 or more exacerbations in the prior year OR are on mOCS.

Table 2 summarises the decision problem addressed by the submission.

Table 2: The decision problem – B.1.1 (page 18)

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Final scope issued by NICE Decision problem addressed in the Rationale if different from the final NICE
company submission scope
 The dupilumab eligible population:

Age 18+ AND 4+ Exacs AND 150–
299 EOS AND 25+ FeNO AND non-
mOCS, OR

Age 12–17 AND 4+ Exacs AND
150+ EOS AND 25+ FeNO AND
non-mOCS
 The 3+ exacs or mOCS non-bio eligible
population (people for whom currently
available biologics are not indicated or
suitable):

Age 12+ AND 3+ exacs OR mOCS
minus anti-IL-5 eligible minus
omalizumab eligible minus
dupilumab eligible
Special considerations None Equality for lower eosinophilic disease Please see Section A.3.
including issues and gender equality (severe asthma has a
related to equity or higher prevalence in women than men)
equality
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Abbreviations: EOS, eosinophil; exacs, exacerbations; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL-5, interleukin 5; mOCS, maintenance oral corticosteroid treatment; NA, not applicable; NICE, National Institute for Health and Care Excellence; OCS, oral corticosteroid.

A.6 Clinical effectiveness evidence – B.2.2 (page 46), B.2.3 (page 49)

The pivotal evidence for tezepelumab in the treatment of severe asthma comes from three randomised controlled trials (RCTs), summarised in Table 3:

• PATHWAY (NCT02054130), a Phase 2, multicentre, global, dose-ranging, double-blind, randomised, parallel-arm, placebocontrolled study (16, 17)

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• NAVIGATOR (NCT03347279), a Phase 3 multicentre, global, randomised, double-blind, placebo-controlled, parallel group study (18-20)

• SOURCE (NCT03406078), a Phase 3 multicentre, global, randomised, double-blind, placebo-controlled, parallel group study (21)

Table 3: Clinical effectiveness evidence – B.2.3.1 (pages 50–59)

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Study title NCT02054130 (PATHWAY) [† ] NCT03347279 (NAVIGATOR) NCT03406078 (SOURCE)
(16, 17) (18-20) (21)
Use of oral corticosteroids: unscheduled contact with healthcare
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Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AE, adverse event; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; CGI-I, Clinician Global Impression of Change; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; ER, emergency room; FEV1, forced expiratory volume in the first second; FEF25–75%, forced expiratory flow over 25–75% of the vital capacity; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; NMA, network meta-analysis; OCS, oral corticosteroid; PEF, peak expiratory flow; PGI-S, Patient Global Impression of Severity; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SC, subcutaneous; SCS, systemic corticosteroid; SGRQ, St George’s Respiratory Questionnaire; WPAI-CIQ, Work Productivity

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and Activity Impairment Questionnaire and Classroom Impairment Questionnaire. † PATHWAY informs the economic model indirectly via the NMA.

A.7 Key results of the clinical effectiveness evidence

A.7.1 Annualised asthma exacerbation rate (AAER) – B.2.6.1.1 (page 101), B.2.6.2.1 (page 103), B.2.6.3.2 (page 116)

• PATHWAY: Tezepelumab 70 mg Q4W, 210 mg Q4W, and 280 mg Q2W treatment resulted in statistically significant reductions of 62, 71, and 66%, respectively, in the rate of exacerbations over 52 weeks compared with placebo (all p<0.001).

• NAVIGATOR: Tezepelumab 210 mg Q4W treatment resulted in a clinically meaningful and statistically significant 56% reduction in the rate of asthma exacerbations over 52 weeks compared with placebo (p<0.001).

• SOURCE: Treatment with tezepelumab reduced the rate of exacerbations over 48 weeks by a clinically meaningful 31% compared with placebo (p=0.111), despite subjects also reducing their long-term OCS use over this time frame.

• Tezepelumab was also shown to reduce the rate of exacerbations resulting in hospitalisations or ER visits. In PATHWAY, exacerbations resulting in hospitalisations or ER visits were reduced by 85% in the tezepelumab 210 mg arm versus placebo

  • (p=0.017). In NAVIGATOR, the reduction was 79% (nominal p<0.001), and in SOURCE, the reduction was 41% (p=0.361).

A.7.2 Categorised percent reduction in daily OCS dose while not losing asthma control – B.2.6.3.1 (page 113)

• SOURCE did not meet its primary endpoint (categorised percent reduction in daily OCS dose while not losing asthma control), but a numerical improvement in the odds of achieving a categorical reduction in OCS dose was observed with tezepelumab 210 mg Q4W treatment versus placebo, with a cumulative OR of 1.28 (95% CI: 0.69, 2.35, p=0.434). Results are contextualised in Section A.9.

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A.7.3 Asthma control and symptoms – Appendix L, B.2.6.2.3 (page 104), B.2.6.2.5 (page 108), B.2.6.3.3 (page 117)

• In all three pivotal trials, tezepelumab treatment resulted in greater improvements from baseline in Asthma Control Questionnaire 6- item (ACQ-6) than placebo, with 86.25%, 76.9%, and 65.2% of tezepelumab-treated subjects achieving clinically meaningful improvements in ACQ-6 scores in the NAVIGATOR (statistically greater improvement compared with placebo, p<0.001), PATHWAY, and SOURCE trials, respectively. These improvements are indicative of a reduction in activity limitation and interference with daily life caused by severe, uncontrolled asthma.

• In each trial, improvements in ACQ-6 scores were rapid, being observed at the first timepoint in which they were recorded, and sustained, lasting to the end of the treatment period.

• Asthma Symptom Diary (ASD) scores also improved with tezepelumab treatment. In NAVIGATOR, treatment with tezepelumab resulted in a clinically meaningful improvement from baseline in the weekly mean total ASD score that was statistically significant compared with placebo at Week 52 (LS mean change from baseline for tezepelumab –0.70 versus placebo –0.59; LS mean difference –0.11 [95% CI –0.19, –0.04]; p=0.004). Onset of improvement in ASD was seen as early as Week 2 and was maintained to Week 52. Improvements in ASD were also observed in SOURCE, suggesting that tezepelumab treatment is likely to result in improvements in asthma symptoms that are otherwise impediments to day-to-day living, sleeping, and physical activity.

A.7.4 Lung function – Appendix L, B.2.6.2.2 (page 103), Appendix N

• Tezepelumab treatment resulted in statistically significant and clinically meaningful improvements in lung function (pre-BD FEV1) versus placebo in all three RCTs, with improvements observed at the first post-baseline time point assessed (2 weeks for NAVIGATOR and 4 weeks for PATHWAY and SOURCE) and sustained for the treatment duration.

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A.7.5 Quality of life – Appendix L, B.2.6.2.4 (page 106), B.2.6.2.6 (page 110), B.2.6.3.3 (page 117)

• Tezepelumab treatment resulted in clinically meaningful improvements from baseline in quality of life, including the AQLQ[S]+12, ********************************, compared with placebo in the PATHWAY, NAVIGATOR and SOURCE trials.

• In SOURCE, tezepelumab-treated subjects had a greater improvement in ************************************* compared with placebo despite the reduction in OCS dose (**********************************************).

A.7.6 Safety – B.2.10 (page 179)

• Across the NAVIGATOR, PATHWAY, and SOURCE trials, tezepelumab was well tolerated in patients with severe asthma and demonstrated a favourable risk-benefit profile.

• The safety profile of tezepelumab was similar to that of optimised standard of care, with commonly reported AEs such as nasopharyngitis and headache occurring at comparable rates in both treatment arms.

• Across the clinical trial programme there were no anaphylactic or serious allergic reactions considered causally related to tezepelumab by the investigator.

• Tezepelumab was associated with low discontinuation rates in patients with severe, uncontrolled asthma across phenotypes and irrespective of biomarkers.

A.8 Evidence synthesis – B.2.9 (page 151)

Because the economic model enrolled a stratified patient population, NMA outcomes, where possible, were also assessed in the following subgroups of patients: High blood EOS level (≥150 cells/µL, ≥300 cells/µL), low blood EOS level (<150 cells/µL, <300 cells/µL), ≥3 exacerbations in the prior 12 months, high FeNO level (≥25 ppb, ≥50 ppb), allergic asthma. The following specific NMAs were used to inform the model:

 Reduction in AAER:

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• High blood EOS level (≥300 cells/µL) subgroup (anti-IL-5 eligible population [benralizumab, mepolizumab]) – Section B.2.9.2.1.2 (page 158)

• Low blood EOS level (<300 cells/µL) subgroup (dupilumab eligible population) – Section B.2.9.2.1.4 (page 160)

• Allergic asthma subgroup (omalizumab eligible population) – Section B.2.9.2.1.8 (page 164)

• Reduction in AAERs leading to hospitalisations ITT population: – Section B.2.9.2.2 (page 165)

• mOCS reduction – High blood EOS level (≥300 cells/µL) subgroup (anti-IL-5 eligible population [benralizumab, mepolizumab]) – Section B.2.9.2.3.1 (page 168)

Overall, in each NMA listed above, with the exception of the reduction in AAER high blood EOS level (≥300 cells/µL) subgroup (in which dupilumab 300 mg – which is not a NICE-recommended dose – was the highest ranked treatment), tezepelumab was the numerically favoured treatment.

A.9 Key clinical issues – B.2.13.2 (page 193)

• Results from the SOURCE trial favoured tezepelumab over placebo, but the primary endpoint (categorised percent reduction in the daily OCS dose without loss of asthma control at Week 48) did not reach statistical significance and hence was not met. The reasons for this are believed to be:

  • The strong placebo response rate seen in SOURCE, which could have played a role in the observed OCS dose reduction results.

  • The proportion of patients in the placebo arm with successful categorised percent reduction in OCS dose – which was substantially higher than was anticipated based on previous OCS-reduction studies with biologics (22).

  • SOURCE had a longer OCS dose reduction period (36 weeks versus 16-20 weeks in other studies) giving all patients, including -

  • those receiving placebo, a greater opportunity to down titrate their daily OCS dose to 0 mg compared with other studies, in turn contributing to the higher observed placebo response rate in SOURCE.

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• Protocol guidance in SOURCE strongly encouraged investigators to continue OCS down-titration despite periodic worsening of asthma. This was investigated further via a post hoc analysis in which the duration of the OCS reduction phase was reduced from 36 weeks to 20 weeks and further OCS reduction was not permitted in subjects who experienced one or two exacerbations (or in patients who did not meet the asthma control criteria after randomisation). This analysis resulted in a nominally statistically –

• significantly higher odds of subjects achieving a 90 100% reduction in OCS compared with placebo (cumulative OR: 2.16; 95% CI: 1.20, 3.89; nominal p=0.010)

• The above assumptions as to why SOURCE did not meet statistical significance on the primary endpoint have been validated with UK clinicians. In addition to the trial design, clinicians also believe that patient recruitment/selection may have had a part to play. Clinicians highlighted that there are no UK centres included in the trial and that the majority were from the South American region where clinical practice allows quicker dose escalation and treatment switching leading to a greater placebo response (23). Despite these limitations, clinicians still perceive there to be value in the data that SOURCE produced as there were subgroups with significant responses despite seeing a larger placebo effect than hoped. As a result, in clinical practice, clinicians would expect to see OCS sparing as result of tezepelumab treatment based off experience with current biologics and tezepelumab’s mode of action targeting higher up in the inflammatory cascade and their understanding of severe asthma immunology in relation to the mode of action of tezepelumab (23).

• In the NMA for the reduction in AAER leading to hospitalisations outcome, data were only available for the ITT population, whereas it would have been preferrable to have been able to mirror the subgroup approach as used for the reduction in AAER outcome.

• No data were available from the NMA to inform the relative effects of omalizumab in reducing mOCS. An assumption of equivalence between tezepelumab and omalizumab was therefore required in the economic model

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A.10 Overview of the economic analysis – B.3.2.2.1 (page 218)

The economic evaluation assessed the cost-effectiveness of tezepelumab as an add-on to SoC and (in totality) considered patients with severe uncontrolled asthma despite high dose ICS and an additional controller, who experienced 3 or more exacerbations in the prior

year, or who are on mOCS. The modelled patient population was stratified into subgroups so as to take account of NICE's

recommendations in appraisals conducted for biologic treatments in this disease area (see Table 97 in Form B).

The base case model was a 5-state Markov cohort model with 4-week cycles considered over a lifetime (60 year) horizon. Definitions of health states were as follows:

• Controlled asthma: ACQ-6 <1.5 without exacerbation

• Uncontrolled asthma: ACQ-6 ≥1.5 without exacerbation

• Exacerbation: Worsening of asthma symptoms which causes one of three composite events:

  • Burst of OCS for at least three consecutive days

  • An emergency room or A&E visit

  • Hospitalisation

• Exacerbations in the model were defined as either controlled or uncontrolled based on asthma status prior to the exacerbation

• Dead: Includes asthma-related mortality and all-cause (non-asthma-related) mortality

A schematic of the model structure is presented in Figure 3.

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Figure 3: Model structure – B.3.2 (page 219)

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Abbreviations: A&E, Accident and Emergency; OCS, oral corticosteroid.

A.11 Incorporating clinical evidence into the model

A.11.1 Treatment efficacy – B.3.3.2 (page 226)

Treatment efficacy was captured in the model through cost offsets and QALY gains. The main treatment benefits associated with tezepelumab versus SoC included: reduction in the rate of exacerbations, reduction in the proportion of exacerbations leading to hospitalisation, reduction in ACQ-6 score, and OCS sparing.

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A.11.2 Consequences of OCS use – B.3.3.3 (page 248)

OCS-related adverse events were modelled in terms of their impact on both costs and QoL. In order to quantify the impact of OCS use, AstraZeneca commissioned a matched historical cohort study using the OPCRD, and the Clinical Practice Research Datalink (CPRD) database (AstraZeneca data on file 2017). Modelled adverse events associated with OCS use and their annual probabilities are summarised in Table 121 (page 248) of Form B. Annual probabilities were converted to 4-week probabilities in the model.

A.11.3 Mortality – B.3.3.4 (page 250)

Mortality was captured in the model as asthma-specific mortality and all-cause mortality. Asthma-specific mortality occurred as a result of exacerbation, with the risk varying according to the type of exacerbation and the age of the patient. Asthma-specific mortality was sourced using ONS data for ICD-10 codes J45-J46, stratified by age and gender. All-cause mortality formed the baseline mortality rate in the model and was taken from the latest UK life tables, stratified by age and gender (24). Exacerbation-specific mortality used input values from three UK studies: Watson 2007 (25), Roberts 2013 (26), and the 2014 National Review of Asthma Deaths (NRAD) report (27).

The methods used in the model for calculating mortality aligned with those described in the NICE submission for benralizumab (28) but with exacerbation data derived from NAVIGATOR and SOURCE. The approach assumed that asthma-related mortality could only occur following an exacerbation.

A.12 Key model assumptions and inputs – B.3.6.2 (page 267)

The derivation of model inputs is described in full at sections B.3.3 to B.3.5. A list of all model parameters can be found at Appendix P. Key assumptions are presented in Table 4.

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Table 4: Key model assumptions

Abbreviations: ACQ, Asthma Control Questionnaire; ACQ-6, Asthma Control Questionnaire 6-item; ITT, intent-to-treat; mOCS, maintenance oral corticosteroid treatment; NMA, network meta-analysis.

A.13 Base case ICER (deterministic) – B.3.7.1 (page 267)

The base case considered tezepelumab as an add-on to SoC treatment and (in totality) in patients with severe asthma despite high dose ICS and an additional controller, who either experienced three or more exacerbations in the prior year, or who were receiving mOCS. The modelled patient populations were stratified into subgroups to take account of NICE’s previous recommendations in appraisals conducted for biologic treatments in this disease area. By demonstrating cost-effectiveness across all subgroups, tezepelumab can be considered cost-effective in all patients with severe uncontrolled asthma despite high dose ICS and an additional controller, who have 3 or more exacerbations in the prior year or who are on mOCS, and irrespective of biomarker values.

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Note that the model considered tezepelumab at its confidential PAS price whereas the comparator biologics were included using their respective list prices.

Table 5: Base case results (anti-IL-5 eligible)

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Technologies Total costs Total QALYs Total LYG Incremental Incremental Incremental ICER ICER versus
(£) costs (£) QALYs LYG incremental baseline
(£/QALY) (£/QALY)
Tezepelumab (PAS price) + SoC ******* ****** ****** - - - - -
Mepolizumab + SoC ******** ****** ****** ******* ****** ****** Dominated Dominated
Benralizumab + SoC ******** ****** ****** ******* ***** ****** £1,039,106 Dominated
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Abbreviations: ICER, incremental cost-effectiveness ratio; IL, interleukin; LYG, life years gained; PAS, Patient Access Scheme; QALY, quality-adjusted life year; SoC, standard of care.

Table 6: Base case results (dupilumab eligible)

Abbreviations: ICER, incremental cost-effectiveness ratio; LYG, life years gained; PAS, Patient Access Scheme; QALY, quality-adjusted life year; SoC, standard of care.

Table 7: Base case results (omalizumab eligible)

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Abbreviations: ICER, incremental cost-effectiveness ratio; LYG, life years gained; PAS, Patient Access Scheme; QALY, quality-adjusted life year; SoC, standard of care.

Table 8: Base case results (non-bio eligible [3+ exacerbations OR mOCS])

Abbreviations: ICER, incremental cost-effectiveness ratio; LYG, life years gained; mOCS, maintenance oral corticosteroid treatment; PAS, Patient Access Scheme; QALY, qualityadjusted life year; SoC, standard of care.

A.14 Probabilistic sensitivity analysis – B.3.8.1 (page 277)

The results of PSA were found to be highly congruent with the deterministic base case results and showed that, in the anti-IL-5 eligible, dupilumab eligible, and omalizumab eligible cohorts, tezepelumab remained the dominant treatment choice. In the non-bio eligible cohort, the ICER decreased slightly from £29,968 to £29,962. At a cost-effectiveness threshold of £20,000 per QALY, tezepelumab was costeffective in ***** of simulations, increasing to ****** at a cost-effectiveness threshold of £30,000 per QALY.

Table 9: Probabilistic results (anti-IL-5 eligible)

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----- Start of picture text -----
Technologies Total costs Total Total LYG Incremental costs Incremental Incremental LYG ICER ICER versus
(£) QALYs (£) QALYs incremental baseline (£/QALY)
(£/QALY)
Tezepelumab (PAS
price) + SoC ******* ****** ****** - - -
Mepolizumab + SoC ******** ****** ****** ******* ****** ****** Dominated Dominated
Benralizumab + SoC ******** ****** ****** ******* ***** ***** £519,074 Dominated
----- End of picture text -----

Abbreviations: ICER, incremental cost-effectiveness ratio; IL, interleukin; LYG, life years gained; PAS, Patient Access Scheme; QALY, quality-adjusted life year; SoC, standard of care.

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Table 10: Probabilistic results (dupilumab eligible)

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----- Start of picture text -----
Technologies Total costs Total Total LYG Incremental costs Incremental Incremental LYG ICER ICER versus
(£) QALYs (£) QALYs incremental baseline (£/QALY)
(£/QALY)
Tezepelumab (PAS
price) + SoC ******* ****** ****** - - -
Dupilumab + SoC ******** ****** ****** ******* ****** ****** Dominated Dominated
----- End of picture text -----

Abbreviations: ICER, incremental cost-effectiveness ratio; LYG, life years gained; PAS, Patient Access Scheme; QALY, quality-adjusted life year; SoC, standard of care.

Table 11: Probabilistic results (omalizumab eligible)

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----- Start of picture text -----
Technologies Total costs Total Total LYG Incremental costs Incremental Incremental LYG ICER ICER versus
(£) QALYs (£) QALYs incremental baseline (£/QALY)
(£/QALY)
Tezepelumab (PAS
price) + SoC ******* ****** ****** - - -
Omalizumab + SoC ******** ****** ****** ******** ****** ****** Dominated Dominated
----- End of picture text -----

Abbreviations: ICER, incremental cost-effectiveness ratio; LYG, life years gained; PAS, Patient Access Scheme; QALY, quality-adjusted life year; SoC, standard of care.

Table 12: Probabilistic results (non-bio eligible [3+ exacs OR mOCS])

Abbreviations: exacs, exacerbations; ICER, incremental cost-effectiveness ratio; LYG, life years gained; mOCS, maintenance oral corticosteroid treatment; PAS, Patient Access Scheme; QALY, quality-adjusted life year; SoC, standard of care.

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A.15 Key sensitivity and scenario analyses – B.3.8.2 (page 281) and B.3.8.4 (page 292)

Figure 4: Tornado diagrams

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Table 13: Key scenario analyses

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----- Start of picture text -----
Scenario and cross Brief rationale Impact on base-case ICER
reference
 Incremental cost *******
----- End of picture text -----

 Incremental QALY: ******  ICER versus baseline (£/QALY): Dominated Dupilumab eligible (scenario 3) Dupilumab (vs tezepelumab):  Incremental cost *******  Incremental QALY: ******  ICER versus baseline (£/QALY): Dominated

Abbreviations: EOS, eosinophil; FeNO, fractional exhaled nitric oxide; ICER, incremental cost-effectiveness ratio; IL, interleukin; NMA, network meta-analysis; ppb, parts per billion; QALY, quality-adjusted life year; SoC, standard of care.

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A.16 Innovation – B.2.12 (page 190)

Tezepelumab is a first-in-class human monoclonal antibody that blocks the activity of TSLP. By blocking the activity of TSLP at the top of the airway inflammatory pathway, tezepelumab reduces the initiation and persistence of multiple downstream inflammatory responses (17, 30, 31). Thus, the effects of tezepelumab are potentially broader than those of current biologic therapies for severe asthma, which are targeted to single or downstream inflammatory pathways (32). This novel mechanism of action allows tezepelumab to deliver efficacy for severe asthma patients regardless of biomarkers or phenotype.

Tezepelumab is the only biologic proven to consistently reduce the rate of asthma exacerbations in severe asthma patients across phenotypes and irrespective of baseline levels of blood EOS, FeNO, or specific IgE (17, 19) . Furthermore, tezepelumab has also been shown to reduce the levels of FeNO, IL-4, IL-5, IL-13 and IgE. In clinical trials, tezepelumab significantly reduced the rate of asthma exacerbations by up to 71% versus SoC across all severe, uncontrolled asthma patients regardless of phenotype and irrespective of biomarker levels (17, 19). The NMA conveyed a numerical advantage for tezepelumab versus NICE recommended biologics for exacerbations and hospitalised exacerbations. Tezepelumab is the first and only biologic that has demonstrated statistically significant reductions in annual exacerbation rates among patients with low EOS counts (<300 cells/µL and <150 cells/µL).

Tezepelumab is currently the only biologic to demonstrate a reduction in airway hyperresponsiveness which is a clinically important and relevant outcome. The CASCADE study demonstrated the effect of tezepelumab on airway tissue inflammatory cells, and the broader mechanisms by which tezepelumab improves clinical asthma outcomes. Tezepelumab is the only biologic currently to show a reduction in airway hyperresponsiveness to mannitol, indicating that the TSLP blockade may have additional benefits in asthma beyond reducing T2 airway inflammation (33). Feedback from UK clinicians (n=7) highlighted how data on airway hyperresponsiveness is an area of clinical differentiation for tezepelumab (23).

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Tezepelumab potentially simplifies the treatment of severe, uncontrolled asthma patients and will provide an additional treatment option for patients who are currently eligible for biologic treatment and provide access to a biologic treatment for some patients who are currently ineligible.

A.17 Budget impact

Table 14: Expected five-year budget impact summary (Tezepelumab list price) – Budget Impact Submission

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----- Start of picture text -----
Year 1 Year 2 Year 3 Year 4 Year 5
Eligible population 92,392 94,055 95,748 97,471 99,226
Eligible population using a biologic 11,449 12,250 13,108 14,026 15,007
(world without tezepelumab)
Eligible population using a biologic ****** ****** ****** ****** ******
(world with tezepelumab)
Population expected to receive ***** ***** ***** ***** *****
tezepelumab
Cost of biologics world without ************ ************ ************ ************ ************
tezepelumab*
Health care resource use cost world ************ ************ ************ ************ ************
without tezepelumab
Total cost of biologic treatments ************ ************ ************ ************ ************
world without tezepelumab
Cost of biologics world with *********** *********** *********** *********** ***********
tezepelumab*
Health care resource use cost world ********* *********** *********** *********** ***********
with tezepelumab
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*Cost of biologics includes SoC cost for all therapies, and administration and monitoring cost (applicable to Reslizumab). Abbreviations: SoC, standard of care.

Table 15: Expected five-year budget impact summary (Tezepelumab net price) – Budget Impact Submission

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----- Start of picture text -----
Year 1 Year 2 Year 3 Year 4 Year 5
Eligible population 92,392 94,055 95,748 97,471 99,226
Eligible population using a biologic 11,449 12,250 13,108 14,026 15,007
(world without tezepelumab)
Eligible population using a biologic ****** ****** ****** ****** ******
(world with tezepelumab)
Population expected to receive ***** ***** ***** ***** *****
tezepelumab
Cost of biologics world without ************ ************ ************ ************ ************
tezepelumab*
Health care resource use cost world ************ ************ ************ ************ ************
without tezepelumab
Total cost of biologic treatments ************ ************ ************ ************ ************
world without tezepelumab
Cost of biologics world with ************ ************ ************ ************ ************
tezepelumab*
Health care resource use cost world ************ ************ ************ ************ ************
with tezepelumab
Total cost of biologic treatment world ************ ************ ************ ************ ************
with tezepelumab
----- End of picture text -----

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*Cost of biologics includes SoC cost for all therapies, and administration and monitoring cost (applicable to Reslizumab). Abbreviations: SoC, standard of care.

A.18 Interpretation and conclusions of the evidence

This appraisal positions tezepelumab as a treatment for adults and adolescents 12 years and older with severe uncontrolled asthma patients despite high dose ICS and an additional controller, who have had 3 or more exacerbations in the prior year, or who are on maintenance OCS, irrespective of biomarker values. Introducing tezepelumab in this setting will provide access to a biologic treatment for some patients who are currently ineligible and provide an additional treatment option for patients who are currently eligible for biologic treatment.

This submission presents the compelling evidence base for tezepelumab and demonstrates that the use of tezepelumab in this indication represents a clinically relevant and cost-effective use of National Health Service (NHS) resources with a base case incremental costeffectiveness ratio (ICER) below that of NICE’s standard willingness to pay threshold regardless of comparator. Having access to tezepelumab in the 3 or more exacerbations or mOCS population will enable more patients to have access to biologic therapy and importantly help to simplify the treatment landscape.

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References

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2. Asthma + Lung UK. Asthma data visualisations. Available at: https://www.asthma.org.uk/support-us/campaigns/datavisualisations/#Prevalence (last accessed: 16 May 22).

3. Asthma UK. What is severe asthma? Last updated: March 2020. Available at: https://www.asthma.org.uk/advice/severeasthma/what-is-severe-asthma (last accessed: 16 Dec 2021).

4. Ryan D, Heatley H, Heaney LG, Jackson DJ, Pfeffer PE, Busby J, et al. Potential Severe Asthma Hidden in UK Primary Care. The Journal of Allergy and Clinical Immunology: In Practice. 2021;9(4):1612-23.e9.

5. Zeiger RS, Schatz M, Dalal AA, Qian L, Chen W, Ngor EW, et al. Utilization and Costs of Severe Uncontrolled Asthma in a Managed-Care Setting. J Allergy Clin Immunol Pract. 2016;4(1):120-9.e3.

6. Song W-J, Won H-K, Lee SY, Park H-K, Cho YS, Chung KF, et al. Patients' experiences of asthma exacerbation and management: a qualitative study of severe asthma. ERJ Open Research. 2021;7(2):00528-2020.

7. Gruffydd-Jones K, Thomas M, Roman-Rodríguez M, Infantino A, FitzGerald JM, Pavord I, et al. Asthma impacts on workplace productivity in employed patients who are symptomatic despite background therapy: a multinational survey. Journal of asthma and allergy. 2019;12:183-94.

8. Vieira AA, Santoro IL, Dracoulakis S, Caetano LB, Fernandes AL. Anxiety and depression in asthma patients: impact on asthma control. Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia. 2011;37(1):13-8.

9. Engelkes M, de Ridder MA, Svensson E, Berencsi K, Prieto-Alhambra D, Lapi F, et al. Multinational cohort study of mortality in patients with asthma and severe asthma. Respir Med. 2020;165:105919.

10. Asthma UK. Asthma death toll in England and Wales is the highest this decade. Published 9 August 2019. Available at: https://www.asthma.org.uk/about/media/news/press-release-asthma-death-toll-in-england-and-wales-is-the-highest-thisdecade/#:~:text=More%20than%201%2C400%20people%20died,in%20the%20last%20year4 (last accessed: 28 Apr 2022).

11. O'Neill S, Sweeney J, Patterson CC, Menzies-Gow A, Niven R, Mansur AH, et al. The cost of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma Registry. Thorax. 2015;70(4):376-8.

12. Barry LE, Sweeney J, O'Neill C, Price D, Heaney LG. The cost of systemic corticosteroid-induced morbidity in severe asthma: a health economic analysis. Respir Res. 2017;18(1):129.

13. Scottish Intercollegiate Guidelines Network (SIGN). SIGN 158 British guideline on the management of asthma. July 2019. Available at: https://www.brit-thoracic.org.uk/document-library/guidelines/asthma/btssign-guideline-for-the-management-ofasthma-2019/ (last accessed: 17 Dec 2021).

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14. Wang E, Wechsler ME, Tran TN, Heaney LG, Jones RC, Menzies-Gow AN, et al. Characterization of Severe Asthma Worldwide: Data From the International Severe Asthma Registry. CHEST. 2020;157(4):790-804.

15. Heaney LG, Perez de Llano L, Al-Ahmad M, Backer V, Busby J, Canonica GW, et al. Eosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort. Chest. 2021;160(3):814-30.

16. AstraZeneca. Clinical Study Report CD-RI-MEDI9929-1146. A Phase 2 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of MEDI9929 in Adult Subjects with Inadequately Controlled, Severe Asthma.

17. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in Adults with Uncontrolled Asthma. New England Journal of Medicine. 2017;377(10):936-46.

18. AstraZeneca. A Multicentre, Randomised, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults and Adolescents with Severe Uncontrolled Asthma (NAVIGATOR). Clinical Study Report. Tezepelumab-D5180C00007.

19. Menzies-Gow A, Colice G, Griffiths JM, Almqvist G, Ponnarambil S, Kaur P, et al. NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020;21(1):266.

20. Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, et al. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. New England Journal of Medicine. 2021;384(19):1800-9.

21. AstraZeneca, Amgen. Clinical Study Report: A Multicentre, Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults with Oral Corticosteroid Dependent Asthma (SOURCE).

22. AstraZeneca. Update on SOURCE Phase III trial for tezepelumab in patients with severe, oral corticosteroid-dependent asthma. Available from: https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-source-phase-iii-trial-for-tezepelumabin-patients-with-severe-oral-corticosteroid-dependent-asthma.html. Last accessed: 17th March 2021. Available. Accessed

23. AstraZeneca. Data on file. KEE input on severe asthma. UK Questionnaire (tezepelumab). 2022.

24. Office for National Statistics. National life tables: UK. Available at: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/lifeexpectancies/datasets/nationallifetablesunit edkingdomreferencetables (last accessed: 31 Mar 2022).

25. Watson L, Turk F, James P, Holgate ST. Factors associated with mortality after an asthma admission: a national United Kingdom database analysis. Respir Med. 2007;101(8):1659-64.

26. Roberts NJ, Lewsey JD, Gillies M, Briggs AH, Belozeroff V, Globe DR, et al. Time trends in 30 day case-fatality following hospitalisation for asthma in adults in Scotland: a retrospective cohort study from 1981 to 2009. Respir Med. 2013;107(8):1172-7.

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27. Healthcare Quality Improvement Partnership (HQIP). Why asthma still kills. The National Review of Asthma Deaths (NRAD). Confidential Enquiry Report. May 2014. Available at: https://www.asthma.org.uk/293597ee/globalassets/campaigns/nrad-fullreport.pdf (last accessed: 1 Apr 2022).

28. National Institute for Health and Care Excellence (NICE). TA565: Benralizumab for treating severe eosinophilic asthma. Published: 6 March 2019. Available at: https://www.nice.org.uk/guidance/ta565 (last accessed: 7 Dec 2021).

29. Jackson DJ, Busby J, Pfeffer PE, Menzies-Gow A, Brown T, Gore R, et al. Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era. Thorax. 2021;76(3):220-7.

30. AstraZeneca. Data on File. Clinical Overview. 2020.

31. AstraZeneca, Amgen. Tezepelumab Mechanism of Action in Asthma. 2020.

32. Menzies-Gow A, Wechsler ME, Brightling CE. Unmet need in severe, uncontrolled asthma: can anti-TSLP therapy with tezepelumab provide a valuable new treatment option? Respir Res. 2020;21(1):268.

33. Diver S, Khalfaoui L, Emson C, Wenzel SE, Menzies-Gow A, Wechsler ME, et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a doubleblind, randomised, placebo-controlled, phase 2 trial. The Lancet Respiratory medicine. 2021;9(11):1299-312.

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal

Tezepelumab for treating severe asthma (ID3910) Document B

Company evidence submission

May 2022

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Contents

Tables and figures

Table 1: Glossary endpoints assessed in the NAVIGATOR, PATHWAY, and SOURCE trials and terms used in dossier .................................................................................................................... 12 Table 2: The decision problem ...................................................................................................... 18 Table 3: Technology being appraised ........................................................................................... 21 Table 4: Summary of NICE technology appraisal guidance on biologics for the treatment of severe asthma .......................................................................................................................................... 33 Table 5: Relative rates of prescribing of biologic therapies currently reimbursed in the UK for the treatment of severe asthma – Data from the UKSAR .................................................................... 36 Table 6: Clinical effectiveness evidence – PATHWAY .................................................................. 46 Table 7: Clinical effectiveness evidence – NAVIGATOR ............................................................... 47 Table 8: Clinical effectiveness evidence – SOURCE ..................................................................... 48

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Table 9: Comparative summary of PATHWAY and NAVIGATOR methodology ............................ 50 Table 10: Summary of SOURCE methodology ............................................................................. 56 Table 11: PATHWAY baseline demographic characteristics (ITT) ................................................. 62 Table 12: PATHWAY baseline disease characteristics (ITT) ......................................................... 63 Table 13: PATHWAY baseline asthma history (ITT) ...................................................................... 65 Table 14: NAVIGATOR baseline demographic characteristics (FAS) ............................................ 69 Table 15: NAVIGATOR baseline clinical characteristics (FAS) ...................................................... 70 Table 16: SOURCE baseline demographic characteristics (FAS) ................................................. 74 Table 17: SOURCE baseline clinical characteristics (FAS) ........................................................... 74 Table 18: Summary of statistical analysis approach in PATHWAY ................................................ 79 Table 19: Summary of statistical analysis approach in NAVIGATOR ............................................ 80 Table 20: Summary of statistical analysis approach in SOURCE .................................................. 85 Table 21: Definitions of analysis sets (PATHWAY) ....................................................................... 88 Table 22: Definitions of analysis sets (NAVIGATOR) .................................................................... 88 Table 23: Definitions of analysis sets (SOURCE) .......................................................................... 88 Table 24: Numbers of subjects in each analysis set in PATHWAY ................................................ 89 Table 25: Completions/withdrawals in PATHWAY ......................................................................... 90 Table 26: Numbers of subjects in each analysis set in NAVIGATOR ............................................ 91 Table 27: Completions/withdrawals in NAVIGATOR ..................................................................... 91 Table 28: Numbers of subjects in each analysis set in SOURCE .................................................. 94 Table 29: Completions/withdrawals in SOURCE ........................................................................... 94 Table 30: Quality assessment results for PATHWAY, NAVIGATOR, and SOURCE ..................... 99 Table 31: AAER over 52 weeks (ITT) .......................................................................................... 101 Table 32: AAER over 52 weeks (FAS) ........................................................................................ 103 Table 33: pre-BD FEV1 change from baseline at 52 weeks (FAS) ............................................... 103 Table 34: ACQ-6 score change from baseline at 52 weeks (FAS) ............................................... 104 Table 35: GEE analysis of ACQ-6 responders (FAS) .................................................................. 105 Table 36: AQLQ(S)+12 score change from baseline at 52 weeks (FAS) ..................................... 106 Table 37: GEE analysis of AQLQ(S)+12 responders (FAS) ........................................................ 107 Table 38: ASD[†] score change from baseline at 52 weeks (FAS) ................................................. 108 Table 39: ASD score responders by time point (FAS) ................................................................. 109 Table 40: Annual exacerbations associated with an ER visit or hospitalisation over 52 weeks (FAS) ................................................................................................................................................... 111 Table 41: EQ-5D-5L score change from baseline at 52 weeks (FAS) .......................................... 112 Table 42: Percent reduction from baseline in final daily OCS dose at Week 48 (FAS) ................ 114 Table 43: Percent reduction from baseline in final daily OCS dose at Week 48; van Elteren Test (FAS) .......................................................................................................................................... 115 Table 44: AAER over 48 weeks (FAS) ........................................................................................ 116 Table 45: Annual exacerbations associated with an ER visit or hospitalisation over 48 weeks (FAS) ................................................................................................................................................... 118 Table 46: Proportion of subjects with reduction from baseline in final daily OCS dose at Week 48 (FAS) .......................................................................................................................................... 119 Table 47: EQ-5D-5L score change from baseline at 48 weeks (FAS) .......................................... 121 Table 48: Demographic characteristics: Sum of all post hoc subgroups (FAS)[†] .......................... 127 Table 49: AAER ratio over 52 weeks: Sum of all post hoc subgroups (negative binomial model; FAS) ........................................................................................................................................... 129 Table 50: CFB to Week 52 in pre-BD FEV1: Sum of all post hoc subgroups (MMRM; FAS) ........ 129 Table 51: CFB to Week 52 in ACQ-6: Sum of all post hoc subgroups (MMRM; FAS) ................. 129 Table 52: Demographic characteristics: Anti-IL-5 eligible subgroup (FAS) .................................. 130 Table 53: AAER ratio over 52 weeks: Anti-IL-5 eligible subgroup (negative binomial model; FAS) ................................................................................................................................................... 131 Table 54: CFB to Week 52 in pre-BD FEV1: Anti-IL-5 eligible subgroup (MMRM; FAS) .............. 131 Table 55: CFB to Week 52 in ACQ-6: Anti-IL-5 eligible subgroup (MMRM; FAS) ........................ 132 Table 56: Demographic characteristics: Dupilumab eligible subgroup (FAS) ............................... 132 Table 57: AAER ratio over 52 weeks: Dupilumab eligible subgroup (negative binomial model; FAS) ................................................................................................................................................... 134

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Table 58: CFB to Week 52 in pre-BD FEV1: Dupilumab eligible subgroup (MMRM; FAS) ........... 134 Table 59: CFB to Week 52 in ACQ-6: Dupilumab eligible subgroup (MMRM; FAS) .................... 134 Table 60: Demographic characteristics: Omalizumab eligible subgroup (FAS) ............................ 135 Table 61: AAER ratio over 52 weeks: Omalizumab eligible subgroup (negative binomial model; FAS) ........................................................................................................................................... 136 Table 62: CFB to Week 52 in pre-BD FEV1: Omalizumab eligible subgroup (MMRM; FAS) ........ 137 Table 63: CFB to Week 52 in ACQ-6: Omalizumab eligible subgroup (MMRM; FAS) ................. 137 Table 64: Demographic characteristics: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (FAS) .......................................................................................................................................... 138 Table 65: AAER ratio over 52 weeks: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (negative binomial model; FAS) .................................................................................................. 139 Table 66: CFB to Week 52 in pre-BD FEV1: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (MMRM; FAS) ............................................................................................................. 139 Table 67: CFB to Week 52 in ACQ-6: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (MMRM; FAS) ............................................................................................................................. 140 Table 68: Demographic characteristics: Sum of all post hoc subgroups (FAS)[†] .......................... 140 Table 69: AAER ratio over 48 weeks: Sum of all post hoc subgroups (negative binomial model; FAS) ........................................................................................................................................... 142 Table 70: CFB to Week 48 in pre-BD FEV1: Sum of all post hoc subgroups (MMRM; FAS) ........ 142 Table 71: CFB to Week 40 in ACQ-6: Sum of all post hoc subgroups (MMRM; FAS) ................. 142 Table 72: Demographic characteristics: Anti-IL-5 eligible subgroup (FAS) .................................. 143 Table 73: AAER ratio over 48 weeks: Anti-IL-5 eligible subgroup (negative binomial model; FAS) ................................................................................................................................................... 144 Table 74: CFB to Week 48 in pre-BD FEV1: Anti-IL-5 eligible subgroup (MMRM; FAS) .............. 145 Table 75: CFB to Week 48 in ACQ-6: Anti-IL-5 eligible subgroup (MMRM; FAS) ........................ 145 Table 76: Demographic characteristics: Omalizumab eligible subgroup (FAS) ............................ 145 Table 77: AAER ratio over 48 weeks: Omalizumab eligible subgroup (negative binomial model; FAS) ........................................................................................................................................... 147 Table 78: CFB to Week 48 in pre-BD FEV1: Omalizumab eligible subgroup (MMRM; FAS) ........ 147 Table 79: CFB to Week 48 in ACQ-6: Omalizumab eligible subgroup (MMRM; FAS) ................. 147 Table 80: Demographic characteristics: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (FAS) .......................................................................................................................................... 148 Table 81: AAER ratio over 48 weeks: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (negative binomial model; FAS) .................................................................................................. 149 Table 82: CFB to Week 48 in pre-BD FEV1: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (MMRM; FAS) ............................................................................................................. 150 Table 83: CFB to Week 48 in ACQ-6: Non-bio eligible (3+ exacerbations OR mOCS) subgroup (MMRM; FAS) ............................................................................................................................. 150 Table 84: List of RCTs included in the feasibility assessment ..................................................... 152 Table 85: Summary of SUCRA values from random effects (vague priors) NMA for reduction in AAER .......................................................................................................................................... 156 Table 86: Summary of SUCRA values from random effects (vague priors) NMA for reduction in AAER leading to hospitalisations ................................................................................................ 168 Table 87: Summary of SUCRA value from fixed effects NMA for change from baseline in OCS dose by ≥50, ≥75, or ≥90% ......................................................................................................... 170 Table 88: Summary of SUCRA values from fixed effects NMA for change from baseline in OCS dose by ≥50% ............................................................................................................................. 174 Table 89: Overall summary of AEs reported during PATHWAY (as-treated population) .............. 181 Table 90: AEs reported in ≥5% of subjects in the total tezepelumab group of PATHWAY (astreated population) ...................................................................................................................... 181 Table 91: Overall summary of AEs reported in NAVIGATOR (safety analysis set) ...................... 182 Table 92: AEs reported in >3% of subjects in either trial arm of NAVIGATOR (safety analysis set) ................................................................................................................................................... 183 Table 93: Overall summary of AEs reported in SOURCE (safety analysis set) ............................ 184 Table 94: AEs reported in >3% of subjects in either trial arm of SOURCE (safety analysis set) .. 184 Table 95: CASCADE trial summary ............................................................................................ 190

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Table 96: Overview of the three cost-effectiveness evaluations identified in the SLR .................. 212 Table 97: Indicated and modelled patient populations for comparators included in the model ..... 217 Table 98: Features of the current economic analysis compared with previous appraisals ........... 223 Table 99: Patient populations and treatments included in the model ........................................... 226 Table 100: Baseline patient characteristics ................................................................................. 226 Table 101: Transition probabilities (Anti-IL-5 eligible) .................................................................. 230 Table 102: Transition probabilities (Dupilumab eligible) .............................................................. 231 Table 103: Transition probabilities (Omalizumab eligible) ........................................................... 233 Table 104: Transition probabilities (Non-bio eligible [3+ exacerbations OR mOCS]) ................... 234 Table 105: Exacerbation distributions (Anti-IL-5 eligible) ............................................................. 237 Table 106: Exacerbation distributions (dupilumab eligible) .......................................................... 238 Table 107: Exacerbation distributions (omalizumab eligible) ....................................................... 239 Table 108: Exacerbation distributions (non-bio eligible [3+ exacs OR mOCS]) ........................... 239 Table 109: mOCS dose reduction magnitudes (all populations) .................................................. 241 Table 110: mOCS dose reduction magnitudes (Anti-IL-5 eligible) ............................................... 241 Table 111: mOCS dose reduction magnitudes (omalizumab eligible).......................................... 242 Table 112: mOCS dose reduction magnitudes (non-bio eligible [3+ exacs OR mOCS]) .............. 242 Table 113: Tezepelumab discontinuation probability: Natural discontinuation (4-weekly rate) ..... 244 Table 114: Tezepelumab discontinuation probability: 52-week response assessment (4-weekly rate) ............................................................................................................................................ 244 Table 115: Relative annual exacerbation rate (anti-IL-5 eligible) ................................................. 246 Table 116: Relative annual exacerbation rate (dupilumab eligible) .............................................. 246 Table 117: Relative annual exacerbation rate (omalizumab eligible) ........................................... 246 Table 118: Relative annual hospitalised exacerbation rates (all populations) .............................. 247 Table 119: OR for mOCS reduction (anti-IL-5 eligible) ................................................................ 248 Table 120: OR for mOCS reduction (omalizumab eligible) .......................................................... 248 Table 121: mOCS adverse event frequency by dose (annual probabilities)................................. 249 Table 122: Probability of death following asthma-related hospital admission as reported in Watson 2007............................................................................................................................................ 252 Table 123: Locations of asthma-related deaths reported in the NRAD report .............................. 252 Table 124: Proportions of exacerbation types observed in NAVIGATOR and SOURCE ............. 254 Table 125: Probabilities of asthma-related death following an mOCS burst and A&E visit .......... 254 Table 126: Probability of death following hospital admission ....................................................... 255 Table 127: Adjusted probabilities of death following hospitalisation ............................................ 255 Table 128: Summary of mortality probabilities ............................................................................. 255 Table 129: Mixed regression model for utility .............................................................................. 257 Table 130: EQ-5D disutility decrement by OCS-related AE ......................................................... 258 Table 131: Overview of the ten UK studies identified in the HRQoL SLR .................................... 259 Table 132: Market share analysis for SoC acquisition cost calculation ........................................ 262 Table 133: Annual drug acquisition costs .................................................................................... 263 Table 134: Number of annual doses per intervention .................................................................. 263 Table 135: Weekly healthcare resource use frequencies ............................................................ 264 Table 136: Healthcare resource use unit costs ........................................................................... 265 Table 137: mOCS-related adverse event cost by mOCS dose (cyclical cost) .............................. 267 Table 138: Model assumptions ................................................................................................... 268 Table 139: Base case results (anti-IL-5 eligible) .......................................................................... 270 Table 140: Base case results (dupilumab eligible) ...................................................................... 271 Table 141: Base case results (omalizumab eligible) .................................................................... 272 Table 142: Base case results (non-bio eligible [3+ exacerbations OR mOCS]) ........................... 273 Table 143: Probabilistic results (anti-IL-5 eligible) ....................................................................... 274 Table 144: Probabilistic results (dupilumab eligible) .................................................................... 276 Table 145: Probabilistic results (omalizumab eligible) ................................................................. 278 Table 146: Probabilistic results (non-bio eligible [3+ exacs OR mOCS]) ..................................... 280 Table 147: Results of one-way deterministic sensitivity analysis (anti-IL-5 eligible vs benralizumab) ................................................................................................................................................... 282

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Table 148: Results of one-way deterministic sensitivity analysis (anti-IL-5 eligible vs mepolizumab) ................................................................................................................................................... 283 Table 149: Results of one-way deterministic sensitivity analysis (dupilumab eligible) ................. 285 Table 150: Results of one-way deterministic sensitivity analysis (omalizumab eligible) ............... 286 Table 151: Results of one-way deterministic sensitivity analysis (Non-bio eligible [3+ Exacs OR mOCS]) ....................................................................................................................................... 287 Table 152: Results of threshold analysis (anti-IL-5 eligible vs benralizumab) .............................. 290 Table 153: Results of threshold analysis (anti-IL-5 eligible vs mepolizumab) .............................. 290 Table 154: Results of threshold analysis (dupilumab eligible) ..................................................... 291 Table 155: Results of threshold analysis (omalizumab eligible)................................................... 292 Table 156: Results of threshold analysis (Non-bio eligible [3+ Exacs OR mOCS]) ...................... 292 Table 157: Exacerbation-related mortality inputs used in the scenarios and resultant mortality... 295 Table 158: Scenario – mortality calibration to Bourdin et al. (non-bio eligible [3+ exacerbations OR mOCS]) ....................................................................................................................................... 296 Table 159: Scenario – mortality calibration to Bourdin et al. + 50% (non-bio eligible [3+ exacerbations OR mOCS]) ......................................................................................................... 296 Table 160: 3-year mortality in the model for a cohort with starting age 61, with 34.3% males ..... 296 Table 161: Alternative patient baseline characteristics (from NAVIGATOR and SOURCE) ......... 297 Table 162: Scenario – alternative patient characteristics (anti-IL-5 eligible) ................................ 298 Table 163: Scenario – alternative patient characteristics (dupilumab eligible) ............................. 298 Table 164: Scenario – alternative patient characteristics (omalizumab eligible) .......................... 298 Table 165: Scenario – alternative patient characteristics (non-bio eligible [3+ exacerbations OR mOCS]) ....................................................................................................................................... 299 Table 166: Scenario – alternative discount rate (anti-IL-5 eligible) .............................................. 299 Table 167: Scenario – alternative discount rate (dupilumab eligible) ........................................... 300 Table 168: Scenario – alternative discount rate (omalizumab eligible) ........................................ 300 Table 169: Scenario – alternative discount rate (non-bio eligible [3+ exacerbations OR mOCS]) 300 Table 170: Alternative relative annual exacerbation rate (anti-IL-5 eligible) ................................. 301 Table 171: Scenario – Alternative annual exacerbation rate (anti-IL-5 eligible) ........................... 301 Table 172: Alternative relative annual exacerbation rate (dupilumab eligible) ............................. 302 Table 173: Scenario – Alternative (1) relative annual exacerbation rate (dupilumab eligible) ...... 302 Table 174: Scenario – Alternative (2) relative annual exacerbation rate (dupilumab eligible) ...... 302 Table 175: Scenario – Alternative (3) relative annual exacerbation rate (dupilumab eligible) ...... 302

Figure 1: The role of TSLP in driving asthma inflammation ........................................................... 29 Figure 2: BTS/SIGN – 2019 guideline for the management of asthma in adults/adolescents ........ 31 Figure 3: Current treatment pathway for the target population....................................................... 37 Figure 4: Tezepelumab mechanism of action ................................................................................ 41 Figure 5: Proposed positioning of tezepelumab in the treatment pathway of severe uncontrolled asthma .......................................................................................................................................... 43 Figure 6: Schematic of PATHWAY trial design .............................................................................. 59 Figure 7: Schematic of NAVIGATOR trial design .......................................................................... 60 Figure 8: Schematic of SOURCE trial design ................................................................................ 60 Figure 9: Multiple testing procedure used in NAVIGATOR ............................................................ 84 Figure 10: Testing procedure used in SOURCE ............................................................................ 87 Figure 11: CONSORT diagram for NAVIGATOR .......................................................................... 93 Figure 12: CONSORT diagram for SOURCE ................................................................................ 96 Figure 13: Adjusted mean (95% CI) change from baseline in pre-BD FEV1 (FAS) ...................... 104 Figure 14: Adjusted mean (95% CI) change from baseline in ACQ-6 score (FAS) ...................... 106 Figure 15: Adjusted mean (95% CI) change from baseline in AQLQ(S)+12 total score (FAS) ..... 108 Figure 16: Adjusted mean (95% CI) change from baseline in ASD score (FAS) .......................... 109 Figure 17: Time to first asthma exacerbation (Kaplan–Meier plot; FAS) ...................................... 110 Figure 18: Proportion of subjects in different categories of reduction from baseline in final daily OCS dose at Week 48 (FAS) ...................................................................................................... 114

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Figure 19: Mean (± 1 SE) percentage change from baseline in daily OCS dose over time (FAS) 115 Figure 20: Median (95% CI) percentage change from baseline in daily OCS dose over time (FAS) ................................................................................................................................................... 116 Figure 21: Time to first asthma exacerbation (Kaplan–Meier plot; FAS) ...................................... 117 Figure 22: Time to first asthma exacerbation associated with ER visit or hospitalisation (Kaplan– Meier plot; FAS) .......................................................................................................................... 118 Figure 23: AERR over 52 weeks by pre-planned subgroups (ITT): Tezepelumab 210 mg Q4W . 123 Figure 24: AAER ratio over 52 weeks by baseline biomarker subgroup (FAS) ............................ 124 Figure 25: AAER ratio over 52 weeks by baseline characteristic subgroup (FAS) ....................... 125 Figure 26: Categorised percent reduction in daily OCS dose at Week 48 by baseline characteristic subgroup (FAS) .......................................................................................................................... 126 Figure 27: Evidence network for reduction in AAER (ITT) ........................................................... 155 Figure 28: Pairwise comparisons from the random effects (vague priors) NMA for reduction in AAER (ITT) ................................................................................................................................. 156 Figure 29: Evidence network for reduction in AAER: High blood EOS level subgroup (≥150 cells/µL) ...................................................................................................................................... 157 Figure 30: Pairwise comparisons from the fixed effects NMA for reduction in AAER: High blood EOS level subgroup (≥150 cells/µL) ............................................................................................ 157 Figure 31: Evidence network for reduction in AAER: High blood EOS level subgroup (≥300 cells/µL) ...................................................................................................................................... 158 Figure 32: Pairwise comparisons from the fixed effects NMA for reduction in AAER: High blood EOS level subgroup (≥300 cells/µL) ............................................................................................ 158 Figure 33: Evidence network for reduction in AAER: Low blood EOS level subgroup (<150 cells/µL) ................................................................................................................................................... 159 Figure 34: Pairwise comparisons from the fixed effects NMA for reduction in AAER: Low blood EOS level subgroup (<150 cells/µL) ............................................................................................ 160 Figure 35: Evidence network for reduction in AAER: Low blood EOS level subgroup (<300 cells/µL) ................................................................................................................................................... 161 Figure 36: Pairwise comparisons from the fixed effects NMA for reduction in AAER: Low blood EOS level subgroup (<300 cells/µL) ............................................................................................ 161 Figure 37: Evidence network for reduction in AAER: ≥3 exacerbations in the prior 12 months .... 162 Figure 38: Pairwise comparisons from the fixed effects NMA for reduction in AAER: ≥3 exacerbations in the prior 12 months .......................................................................................... 162 Figure 39: Evidence network for reduction in AAER: High FeNO level (≥25 ppb) ........................ 163 Figure 40: Pairwise comparisons from the fixed effects NMA for reduction in AAER: High FeNO level (≥25 ppb) ............................................................................................................................ 163 Figure 41: Evidence network for reduction in AAER: High FeNO level (≥50 ppb) ........................ 164 Figure 42: Pairwise comparisons from the fixed effects NMA for reduction in AAER: High FeNO level (≥50 ppb) ............................................................................................................................ 164 Figure 43: Evidence network for reduction in AAER: Allergic asthma .......................................... 165 Figure 44: Pairwise comparisons from the fixed effects NMA for reduction in AAER: Allergic asthma ........................................................................................................................................ 166 Figure 45: Evidence network for reduction in AAER leading to hospitalisations (ITT) .................. 167 Figure 46: Pairwise comparisons from random effects (vague priors) NMA for reduction AAER leading to hospitalisations (ITT) .................................................................................................. 167 Figure 47: Evidence network for change from baseline in OCS dose according to predefined reduction categories (ITT) ........................................................................................................... 169 Figure 48: Pairwise comparisons from the fixed effects NMA for change from baseline in OCS dose by ≥50%, ≥75% or ≥90% (ITT) .................................................................................................... 170 Figure 49: Evidence network for change from baseline in OCS dose: High blood EOS level subgroup (≥150 cells/µL)............................................................................................................. 171 Figure 50: Pairwise comparisons from fixed effects NMA for change from baseline in OCS dose: High blood EOS level subgroup (≥150 cells/µL) .......................................................................... 171 Figure 51: Evidence network for change from baseline in OCS dose: High blood EOS level subgroup (≥300 cells/µL)............................................................................................................. 172

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Figure 52: Pairwise comparisons from fixed effects NMA for change from baseline in OCS dose: High blood EOS level subgroup (≥300 cells/µL) .......................................................................... 172 Figure 53: Pairwise comparisons from fixed effects NMA for change from baseline in OCS dose: High blood EOS level subgroup (≥300 cells/µL) including ZONDA .............................................. 173 Figure 54: Pairwise comparisons from fixed effects NMA for change from baseline in OCS dose: High blood EOS level subgroup (≥300 cells/µL) including ZONDA .............................................. 173 Figure 55: Pairwise comparisons from the fixed effects NMA for change from baseline in OCS dose by ≥50% (ITT) ............................................................................................................................. 174 Figure 56: Evidence network for change from baseline in OCS dose by ≥50%: High blood EOS level subgroup (≥150 cells/µL) .................................................................................................... 175 Figure 57: Pairwise comparisons from fixed effects NMA for change from baseline in OCS dose by ≥50%: High blood EOS level subgroup (≥150 cells/µL) ............................................................... 175 Figure 58: Evidence network for change from baseline in OCS dose by ≥50%: High blood EOS level subgroup (≥300 cells/µL) .................................................................................................... 176 Figure 59: Pairwise comparisons from fixed effects NMA for change from baseline in OCS dose by ≥50%: High blood EOS level subgroup (≥300 cells/µL) ............................................................... 176 Figure 60: Evidence network for change from baseline in OCS dose by ≥50%: High blood EOS level subgroup (≥300 cells/µL) including ZONDA ........................................................................ 177 Figure 61: Pairwise comparisons from fixed effects NMA for change from baseline in OCS dose by ≥50%: High blood EOS level subgroup (≥300 cells/µL) including ZONDA ................................... 177 Figure 62: Model structure .......................................................................................................... 220 Figure 63: Patient flow through the model ................................................................................... 220 Figure 64: Cost-effectiveness plane (anti-IL-5 eligible) ................................................................ 270 Figure 65: Cost-effectiveness plane (dupilumab eligible) ............................................................ 271 Figure 66: Cost-effectiveness plane (omalizumab eligible) .......................................................... 272 Figure 67: Cost-effectiveness plane (non-bio eligible [3+ exacerbations OR mOCS]) ................. 273 Figure 68: Incremental cost-effectiveness scatter plot (anti-IL-5 eligible) .................................... 275 Figure 69: Cost-effectiveness frontier (anti-IL-5 eligible) ............................................................. 275 Figure 70: Incremental cost-effectiveness scatter plot (dupilumab eligible) ................................. 277 Figure 71: Cost-effectiveness frontier (dupilumab eligible) .......................................................... 277 Figure 72: Incremental cost-effectiveness scatter plot (omalizumab eligible) .............................. 279 Figure 73: Cost-effectiveness frontier (omalizumab eligible) ....................................................... 279 Figure 74: Incremental cost-effectiveness scatter plot (non-bio eligible [3+ exacs OR mOCS]) ... 281 Figure 75: Cost-effectiveness frontier (non-bio eligible [3+ exacs OR mOCS]) ............................ 281 Figure 76: Results of one-way deterministic sensitivity analysis (anti-IL-5 eligible vs benralizumab) ................................................................................................................................................... 283 Figure 77: Results of one-way deterministic sensitivity analysis (anti-IL-5 eligible vs mepolizumab) ................................................................................................................................................... 284 Figure 78: Results of one-way deterministic sensitivity analysis (dupilumab eligible) .................. 286 Figure 79: Results of one-way deterministic sensitivity analysis (omalizumab eligible) ............... 287 Figure 80: Results of one-way deterministic sensitivity analysis (Non-bio eligible [3+ Exacs OR mOCS]) ....................................................................................................................................... 288 Figure 81: Results of one-way deterministic sensitivity analysis showing ICER (Non-bio eligible [3+ Exacs OR mOCS]) ...................................................................................................................... 289

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Abbreviations

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A&E Accident and Emergency
AAER Annualised asthma exacerbation rate
ACQ-6 Asthma Control Questionnaire 6-item
AE Adverse event
AER Asthma exacerbation rate
AERR Asthma exacerbation rate reduction
AQLQ Asthma Quality of Life Questionnaire
AQLQ(S)+12 Asthma Quality of Life Questionnaire (Standardised) for 12 years and older
ASD Asthma Symptom Diary
BD Bronchodilator
BMI Body mass index
CEAC Cost-effectiveness acceptability curve
CEAF Cost-effectiveness acceptability frontier
CFB Change from baseline
CI Confidence interval
COPD Chronic obstructive pulmonary disease
CrI Credible interval
DIC Deviance Information Criteria
ECG Electrocardiogram
EOS Eosinophil
EQ-5D European Quality of Life-5 Dimensions
EQ-5D-3L/5L European Quality of Life-5 Dimensions-3 Levels/5 Levels
ER Emergency room
Exacs Exacerbations
FAS Full analysis set
FDA US Food and Drug Administration
FEIA Fluorescent enzyme immunoassay
FeNO Fractional exhaled nitric oxide
FEF25–75% Forced expiratory flow over 25–75% of the vital capacity
FEV1 Forced expiratory volume in the first second
FVC Forced vital capacity
GINA Global Initiative for Asthma
HRQoL Health-related quality of life
HTA Health technology assessment
ICER Incremental cost-effectiveness ratio
ICS Inhaled corticosteroid
IgE Immunoglobulin E
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IL Interleukin
ITT Intent-to-treat
IU International Unit
IWRS Interactive Web Response System
LABA Long-acting beta agonist
LAMA Long-acting muscarinic antagonist
LS Least squares
LTRA Leukotriene receptor antagonist
LY Life years
LYG Life years gained
mOCS Maintenance oral corticosteroid treatment
MMRM Mixed-effects model for repeated measures
NA Not applicable
NHS National Health Service
NICE National Institute for Health and Care Excellence
NMA Network meta-analysis
NMB Net monetary benefit
NR Not reported
OCS Oral corticosteroid
OR Odds ratio
PAS Patient Access Scheme
PBO Placebo
PEF Peak expiratory flow
PGI-C Patient Global Impression of Change
PGI-I Patient Global Impression of Improvement
PGI-S Patient Global Impression of Severity
PN Predicted normal
ppb Parts per billion
PRO Patient-reported outcome
PSA Probabilistic sensitivity analysis
PSSRU Personal Social Services Research Unit
QALY Quality-adjusted life year
Q2W Once every 2 weeks
Q4W Once every 4 weeks
Q8W Once every 8 weeks
RCT Randomised controlled trial
SABA Short-acting beta agonist
SC Subcutaneous
SCS Systemic corticosteroid
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SE Standard error
SF-12/36 12-Item/36-Item Short Form Health Survey
SGRQ St George’s Respiratory Questionnaire
SLR Systematic literature review
SoC Standard of care
SUCRA Surface under the cumulative ranking
teze Tezepelumab
TSLP Thymic stromal lymphopoietin
WPAI+CIQ Work Productivity and Activity Impairment Questionnaire and Classroom Impairment
Questionnaire
WTP Willingness to pay
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Glossary

Table 1: Glossary endpoints assessed in the NAVIGATOR, PATHWAY, and SOURCE trials and terms used in dossier

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Endpoint Explanation
AAER The AAER is a measure of the number of asthma exacerbations per patient-year. Asthma
exacerbations are episodic flare-ups of asthma, characterised by a progressive increase
in symptoms of shortness of breath, cough, wheezing or chest tightness, and progressive
decrease in lung function. Exacerbations carry a significant morbidity burden for patients
and may be life-threatening (1).
In the PATHWAY and NAVIGATOR trials, an asthma exacerbation was defined as a
worsening of asthma that led to any of the following:
 A temporary bolus/burst of SCS (or a temporary increase in stable OCS background
dose) for at least 3 consecutive days to treat symptoms of asthma worsening
 An ER or urgent care visit (defined as evaluation and treatment for <24 hours in an
emergency department or urgent care centre) due to asthma that required SCS
 An inpatient hospitalisation (defined as admission to an inpatient facility and/or
evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma
ACQ-6 The ACQ-6 is a validated instrument that measures asthma control. It features six
questions on asthma symptoms (night-time waking, symptoms on waking, activity
limitation, shortness of breath, wheezing) and beta-agonist use. Each question is scored
from 0–6 with the total score being the average of the questions. The ACQ score ranges
between 0 (well controlled) and 6 (extremely poorly controlled) (2). Mean ACQ-6 scores of
≤0.75 indicate well-controlled asthma, scores >0.75 and <1.5 indicate partly controlled
asthma, and a score ≥1.5 indicates uncontrolled asthma (3). Individual changes of at least
0.5 are considered clinically meaningful (4).
AQLQ(S)+12 The AQLQ(S)+12 is an asthma-specific measure of HRQoL valid for use in patients aged
12–70 years. The questionnaire comprises four separate domains: symptoms (11 items),
activity limitations (12 items), emotional function (5 items), and environmental stimuli (4
items). Subjects are asked to recall their experiences during the previous 2 weeks and to
score each of the questions on a 7-point scale ranging from 7 (not impaired at all) to 1
(severely impaired). The overall score is calculated as the mean response to all questions.
The minimally important difference for the AQLQ(s)+12 is a change in score of 0.5 for
overall quality of life and for each of the domains (5).
ASD The ASD was used in the NAVIGATOR and SOURCE trials, and was completed by
subjects twice daily. The ASD consists of 10 items. Five morning items assess night-time
symptom severity in relation to: wheezing, shortness of breath, cough, chest tightness,
and the frequency of night-time awakening. Five evening items assess daytime symptom
severity in relation to: wheezing, shortness of breath, cough, chest tightness, and activity
limitation since waking. Items are scored from 0 (no symptoms, no night-time awakening,
or no activity limitation) to 4 (very severe symptoms, unable to sleep, or extreme activity
limitation). Scores for wheezing, shortness of breath, cough, and chest tightness range
from ‘none’ to ‘very severe’. Responses for all 10 items are required to calculate the daily
ASD score. A 7-day average asthma symptom score can be calculated based on the
mean of at least four of the seven daily ASD scores. The 7-day average ASD score
ranges from 0–4. Individual changes of at least 0.5 are considered clinically meaningful,
and subjects experiencing a change of at least 0.5 are considered responders (6).
CGI-C/PGI-C CGI-C and PGI-C (also known as CGI-I and PGI-I) evaluate change from the initiation of
treatment from the clinician and patient perspective, respectively, on a 7-point categorical
response scale ranging from 1 (very much improved) to 7 (very much worse) (7, 8).
EQ-5D-5L The EQ-5D-5L is a standardised instrument used as a measure of health outcome,
primarily designed for self-completion by respondents. The EQ-5D-5L questionnaire
assesses five dimensions: mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression. Each dimension has five response options (no problems, slight
problems, moderate problems, severe problems, and extreme problems) that reflect
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Endpoint Explanation
increasing levels of difficulty. The questionnaire also includes a VAS, where the subject is
asked to rate current health status on a scale of 0–100, with 0 being the worst imaginable
health state (9).
FEF25–75% The FEF25–75% is the mean forced expiratory flow from the point at which 25% of the FVC
has been exhaled to the point at which 75% of the FVC has been exhaled. FEF25–75% is a
measure of pulmonary function, and impairment of FEF25–75% is considered to be an early
marker of airway obstruction (10).
PEF The PEF (also known as peak flow or peak flow rate) is the maximal rate at which a
patient can exhale following maximal inhalation and is a measure of pulmonary function
that correlates with FEV1. Short-term PEF monitoring may be used to assess response to
treatment, evaluate triggers for worsening symptoms, or to establish a baseline. Excessive
variation in PEF suggests suboptimal asthma control and increases the risk of
exacerbations (1).
Pre-BD FEV1 Pre-BD FEV1 is the volume of air a patient can exhale in 1 second following maximal
inhalation, prior to the administration of a bronchodilator. Pre-BD FEV1 can be used to
assess the severity of obstructive lung diseases, such as asthma, by comparing with
predicted FEV1 value. Pre-BD FEV1 can also be used to assess the patient’s response to
bronchodilators by comparing with post-BD FEV1, known as the reversibility test or
bronchodilator test (11).
Severe Severe asthma is defined as asthma that requires high dose ICS in combination with a
asthma long acting beta-agonist (ICS-LABA) to prevent it from becoming uncontrolled, or that
remains uncontrolled despite optimised treatment with high dose ICS-LABA (1).
SGRQ The SGRQ is a 50-item questionnaire developed to measure health status (quality of life)
in patients with diseases of airways obstruction (12). Scores are calculated for three
domains: symptoms (frequency and severity), activities (that cause or are limited by
breathlessness), impacts (social functioning and psychological disturbances resulting from
airways disease). A total score is calculated from the three domain scores. Scores range
from 0–100, with higher scores indicating more limitations. A minimum change in score of
4 units is considered clinically relevant (13).
Uncontrolled Uncontrolled asthma is defined as one or both of the following (1):
asthma  Poor symptom control (frequent symptoms or reliver use, activity limited by asthma,
might waking due to asthma)
 Frequent exacerbations (≥2/year) requiring OCS, or serious exacerbations (≥1/year)
requiring hospitalisation
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Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; BD, bronchodilator; CGI-C, Clinician Global Impression of Change; CGI-I, Clinician Global Impression of Improvement; ER, emergency room; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; FEF25–75%, forced expiratory flow over 25–75% of the vital capacity; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; HRQoL, health-related quality of life; OCS, oral corticosteroid; PEF, peak expiratory flow; PGI-C, Patient Global Impression of Change; PGI-I, Patient Global Impression of Improvement; SCS, systemic corticosteroid; SGRQ, St George's Respiratory Questionnaire; VAS, Visual Analogue Scale.

Company evidence submission template for tezepelumab for treating severe asthma (ID3910) © AstraZeneca (2022). All rights reserved

Executive summary

Asthma is a heterogeneous disease, usually characterised by chronic airway inflammation, with a subset of patients suffering from severe asthma which remains uncontrolled despite high dose inhaler therapies

Asthma is defined by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity together with variable expiratory airflow limitation (1).

Inhaled corticosteroids (ICS) are first-line therapy for all patients with persistent asthma, controlling asthma symptoms and preventing exacerbations (14). The majority of patients can achieve the goal of well-controlled asthma with ICS treatments. Severe asthma is defined as asthma that requires high dose ICS in combination with a long acting beta-agonist (ICS-LABA) to prevent it from becoming uncontrolled, or that remains uncontrolled despite optimised treatment with high dose ICS-LABA (1). Of the 5.4 million patients receiving treatment for asthma in the UK (15), it is estimated that around 4% have severe asthma (16), of which 65.5% (or 141,000 people) have severe, uncontrolled asthma (17).

The burden of severe uncontrolled asthma remains high due to associated exacerbations, hospitalisations and excess mortality (18)(24)

Severe uncontrolled asthma places substantial burden on patients and healthcare systems. The unpredictability and distress associated with severe, uncontrolled asthma symptoms has a substantial negative impact on the lives of patients, including a detriment in the ability to perform usual daily activities (1, 19, 20) and negatively impacts their mental health (21).

In a 2015 UK study using asthma registry data from 2012, the healthcare costs per patient with severe asthma were higher than that for type 2 diabetes, stroke, or chronic obstructive pulmonary disease (COPD) (1, 22). The cost burden is mainly driven by the number of exacerbations and hospitalisations, which is three-fold higher in severe uncontrolled asthma compared with non-severe, uncontrolled asthma (18). In a 2017 UK study using data from a nationally representative primary care database (OPRCD), the average healthcare costs per person per year with severe asthma ranged from £2,603 to £4,533 (23).

Patients with severe asthma have a higher mortality rate compared with patients with asthma (24). A 2019 analysis of ONS data by Asthma UK revealed that overall, more than 12,700 people died from asthma in England and Wales over the past decade, with deaths increasing by 33% between 2008 and 2018 (25).

Despite the availability of biologics for severe asthma, a significant unmet need exists for a first-line biologic treatment with efficacy across phenotypes and biomarker profiles, to enable more patients with severe, uncontrolled asthma to achieve disease control and reduce the frequency of exacerbations, hospitalisations, and oral corticosteroid (OCS) use

The inflammatory cascade of severe uncontrolled asthma is complex and heterogeneous. Current biologic agents mostly act on a single specific downstream inflammatory target like eosinophils (EOS), immunoglobulin E (IgE), or cytokines (IL-4, -5 or -13) (37, 38) and have demonstrated effectiveness in specific phenotypes of severe asthma defined by biomarker criteria (EOS ≥300: benralizumab, mepolizumab and reslizumab; IgE: omalizumab; fractional exhaled nitric oxide (FeNO) ≥25 and EOS

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≥150: dupilumab). Therefore the full set of biological mechanisms driving a patient’s asthma are unlikely to be addressed by currently recommended biologics (39) and patients who regularly exacerbate but do not exhibit the above biomarker criteria, do not have access to biologic therapy.

The full set of biological mechanisms driving a patient’s asthma are unlikely to be addressed by currently recommended biologics (39). Furthermore, patients who regularly exacerbate but do not exhibit the above biomarker criteria, do not have access to biologic therapy.

Treatment with biologic therapies is currently recommended in England and Wales to reduce exacerbations, dependency on OCS, and improve asthma control. NICE’s recommendations relate to subsets of the patient population with 3 or more exacerbations in the prior year OR who are on mOCS, and reflect the fact that existing biologics are only effective in subpopulations defined by biomarkers as indicated above.

Whilst existing biologic agents can be life-changing for some patients, others continue to experience uncontrolled disease, resulting in a high exacerbation frequency, limitations on daily life, and poor healthrelated quality of life (HRQoL), as well as substantial healthcare costs for healthcare systems (40, 41).

OCS, either as short courses or as maintenance treatment (mOCS), are widely used in patients who are ineligible for biologic treatment or in whom biologic therapy provides inadequate disease control (1, 2628) however they are associated with short and long term adverse events leading to increased mortality (29, 30).

Short courses of OCS used for treatment of exacerbations are associated with adverse effects, including sleep disturbance, increased infection risk, and thromboembolism (1, 31). Cumulative overexposure to OCS can result in serious systemic adverse effects in both the short- and long-term, including osteoporosis, adrenal suppression, cardiovascular events, and diabetes (26, 28, 32-34), which increases the burden of uncontrolled asthma for patients and healthcare systems (1, 35, 36).

Therefore, there is a need for a biologic treatment option for those who are currently ineligible for existing biologics and an additional first line treatment option for those who are currently eligible for existing biologic therapies.

Tezepelumab is a first-in-class biologic which acts at the top of the asthma inflammatory cascade, blocking the activity of multiple downstream pathways therefore demonstrating efficacy in severe asthma patients across multiple phenotypes and irrespective of baseline levels of currently established biomarkers, EOS, FeNO, or specific IgE (42, 43). Furthermore, tezepelumab has also been shown to reduce the levels of FeNO, IL-4, IL-5, IL-13 and IgE

Tezepelumab is a first-in-class human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP) which sits at the top of the asthma inflammatory cascade (39). Tezepelumab significantly reduces the rate of asthma exacerbations by up to 71% across all severe, uncontrolled asthma patients regardless of phenotype and irrespective of biomarker levels (42, 43). In addition, tezepelumab is currently the only biologic to demonstrate a reduction in airway hyperresponsiveness which is a clinically important and relevant outcome (44).

The pivotal evidence for tezepelumab for the treatment of severe asthma comes from two Phase 3 randomised controlled trials (RCTs), NAVIGATOR and SOURCE, and one Phase 2 RCT, PATHWAY. The NAVIGATOR trial showed that at Week 52, tezepelumab reduced annualised asthma exacerbation rate (AAER) by 56% (rate ratio [RR]: 0.44; 95% confidence interval [CI]: 0.37, 0.53; p<0.001). The

Company evidence submission template for tezepelumab for treating severe asthma (ID3910) © AstraZeneca (2022). All rights reserved

PATHWAY trial showed that, at Week 52, tezepelumab reduced AAER by 71% (RR: 0.29; 95% CI: 0.16,0.51; p<0.001). The SOURCE trial demonstrated that the cumulative odds of achieving a category of greater percentage reduction in OCS dose for daily maintenance at Week 48 with tezepelumab versus placebo were odds ratio (OR) of 1.28 (95% CI: 0.69, 2.35; p=0.43) (Results are contextualised in Section B.2.13.2.1).

This appraisal positions tezepelumab as a clinical and cost-effective treatment for adults and adolescents 12 years and older with severe uncontrolled asthma despite high dose ICS and an additional controller, who have had 3 or more exacerbations in the prior year, or who are on maintenance OCS, irrespective of biomarker values

Introducing tezepelumab in this setting will provide access to a biologic treatment for some patients who are currently ineligible and provide an additional first line treatment option for patients who are currently eligible for biologic treatment, with a different mode of action that targets higher up in the inflammatory cascade.

This submission presents the compelling evidence base for tezepelumab and demonstrates that the use of tezepelumab in this indication represents a clinically relevant and cost-effective use of National Health Service (NHS) resources with a base case incremental cost-effectiveness ratio (ICER) below that of NICE’s standard willingness to pay threshold regardless of comparator. Having access to tezepelumab in the 3 or more exacerbations or mOCS population will enable more patients to have access to biologic therapy and importantly help to simplify the treatment landscape.

Company evidence submission template for tezepelumab for treating severe asthma (ID3910) © AstraZeneca (2022). All rights reserved

B.1 Decision problem, description of the technology and clinical care pathway

B.1.1 Decision problem

This submission covers a subset of the technology’s (anticipated) marketing authorisation.

• The (draft) tezepelumab indication is:

• This submission covers: Adults and adolescents 12 years and older with severe uncontrolled asthma despite high dose ICS and an additional controller, who experienced 3 or more exacerbations in the prior year OR are on mOCS.

Table 2 summarises the decision problem addressed by the company submission.

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Table 2: The decision problem

Company evidence submission template for tezepelumab for treating severe asthma (ID3910) © AstraZeneca (2022). All rights reserved

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Final scope issued by NICE Decision problem addressed in the Rationale if different from the final NICE
company submission scope
 Patient and clinician evaluation of
response
 Lung function
 Mortality
 Time to discontinuation
 Adverse effects of treatment
 Health-related quality of life
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Abbreviations: EOS, eosinophil; Exacs, exacerbations; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL-5, interleukin 5; mOCS, maintenance oral corticosteroid treatment; NA, not applicable; NICE, National Institute for Health and Care Excellence.

Company evidence submission template for tezepelumab for treating severe asthma (ID3910)

© AstraZeneca (2022). All rights reserved

B.1.2 Description of the technology being appraised

Table 3: Technology being appraised

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----- Start of picture text -----
UK approved name and UK approved name: Tezepelumab
brand name Brand name:
Mechanism of action Tezepelumab is an anti-TSLP, human monoclonal antibody (IgG2λ) that
binds to human TSLP with high affinity and prevents its interaction with
the heterodimeric TSLP receptor.
TSLP, an epithelial cell-derived cytokine, occupies an upstream position in
the asthma inflammatory cascade and plays a central role in the initiation
and persistence of airway inflammation in asthma. TSLP regulates
immunity at the airway barrier surface, affecting dendritic cells and other
innate and adaptive immune cells, and inducing downstream inflammatory
processes and bronchial hyper-responsiveness. TSLP has also been
shown to have indirect effects on airway structural cells (e.g. fibroblasts
and airway smooth muscle).
In asthma, both allergic and non-allergic triggers induce TSLP production.
Blocking TSLP with tezepelumab reduces a broad spectrum of biomarkers
and cytokines associated with inflammation (e.g. blood EOS, IgE, FeNO,
IL-5, and IL-13).
Marketing authorisation/CE CHMP positive opinion is anticipated in . MHRA marketing
mark status authorisation is expected in
Indications and any The draft indication covered in the submission is as follows:
restriction(s) as described
in the summary of product
characteristics (SmPC)

Method of administration
and dosage











*******
Additional tests or None.
investigations
List price and average cost List price: ***************
of a course of treatment Average cost of a course of treatment: Lifetime treatment for responders,
1 year of treatment for inadequate responders
Patient access scheme (if A simple PAS has been submitted to PASLU with a net price of **** per
applicable) vial
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Abbreviations: CHMP, Committee for Medicinal Products for Human Use; EOS, eosinophil; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; PAS, Patient Access Scheme; PASLU, Patient Access Scheme Liaison Unit; TSLP, thymic stromal lymphopoietin. † Subject to approval.

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B.1.3 Health condition and position of the technology in the treatment pathway

SUMMARY

• Asthma is a heterogenous disease, usually characterised by chronic airway inflammation. It is defined by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity, together with variable expiratory airflow limitation (1)

• Whereas most asthma patients achieve disease control with standard of care, a small subset of patients have severe asthma defined as asthma that requires high dose ICS-LABA to prevent it from becoming uncontrolled, or that remains uncontrolled despite optimised treatment with high dose ICS-LABA (1)

• Patients with severe, uncontrolled asthma have a high risk of exacerbations, defined as a progressive worsening of asthma symptoms and lung function impairment (1). Asthma exacerbations can be life-threatening and may require emergency care and hospitalisation (45, 46)

• Treatment with biologics, including omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab, is recommended in patients with severe, uncontrolled asthma despite optimised care, with the choice of biologic prescribed depending on asthma phenotype and biomarker profile (1, 47)

• Current biologic therapies for severe, uncontrolled asthma are targeted to single or downstream eosinophilic and allergic inflammatory pathways (see Figure 1); however:

  • A high number of patients are ineligible for biologic therapy as they do not meet biomarker eligibility criteria

  - Over half of patients with severe asthma have uncontrolled or sub-optimally controlled asthma with their current biologic (40, 41) 
  

  • If biologic therapy is not appropriate or ineffective, the main treatment option is OCS, either as short courses or as mOCS, which adds to the clinical burden due to the association of mOCS with adverse events (1, 26, 35, 36)

• Despite the availability of biologics for severe asthma, a significant unmet need exists for a first-line biologic treatment with efficacy across phenotypes and biomarker profiles, to enable more patients with severe, uncontrolled asthma to achieve disease control and reduce the frequency of exacerbations, hospitalisations, and OCS use

• Tezepelumab is a first-in-class anti-TSLP monoclonal antibody (48)

Company evidence submission template for tezepelumab for treating severe asthma (ID3910) © AstraZeneca (2022). All rights reserved

• TSLP is an upstream epithelial-derived cytokine that is released at the top of the inflammatory cascade in response to insults. TSLP activates multiple downstream pathways that are involved in airway inflammation and bronchial hyperresponsiveness in asthma (39, 48, 49)

• By blocking TSLP, tezepelumab thus exerts its therapeutic effect at the top of the inflammatory cascade delivering efficacy across asthma phenotypes and irrespective of biomarkers, including allergic, non-allergic, EOS-high, and EOS-low populations (42) as per the anticipated licensed indication

• This appraisal positions tezepelumab as a treatment for adults and adolescents 12 years and older with severe uncontrolled asthma despite high dose ICS and an additional controller, who experienced 3 or more exacerbations in the prior year, or who are on mOCS, irrespective of biomarker values

B.1.3.1 Asthma overview

Asthma is a heterogenous disease, usually characterised by chronic airway inflammation. It is defined by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity, together with variable expiratory airflow limitation (1). Progressive pathologic airway remodelling may occur, resulting in partially reversible or irreversible airway obstruction (50, 51).

B.1.3.2 Severe, uncontrolled asthma

Asthma presents in varying degrees of severity, ranging from mild, intermittent disease to severe asthma with debilitating, even life-threatening, symptoms (1). The majority of asthma patients are adequately controlled on standard of care but a subset continue to have uncontrolled asthma (1). According to the Global Initiative for Asthma (GINA) 2022 guidelines (1) and the ERS/ATS 2014 guidelines (52), severe asthma is defined as asthma that requires high dose ICS in combination with a long acting beta-agonist (ICS-LABA) to prevent it from becoming uncontrolled, or that remains uncontrolled despite optimised treatment with high dose ICS-LABA.

Asthma control is assessed on the basis of symptom control and future risk of adverse outcomes (1, 52). Evidence for any one of the following criteria for uncontrolled asthma in combination with receipt of a high-dose therapy (i.e. high-dose ICS plus a LABA as specified in the GINA guidelines) thus defines a patient with severe, uncontrolled asthma:

• Poor symptom control:

  • ACQ consistently ≥1.5 or Asthma Control Test (ACT) <20

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• Frequent symptoms, activity limited by asthma, night waking

• Frequent rescue reliever use

• Frequent severe exacerbations (≥2/year) requiring a short course (≥3 days each) of mOCS

• Serious exacerbations requiring hospitalisation (≥1/year; see also Section B.1.3.4.1).

B.1.3.3 Epidemiology of severe, uncontrolled asthma

Asthma affects children and adults of all ages and is one of the most common chronic diseases with an estimated 262–339 million people affected worldwide (1, 53, 54). Estimates of the proportion of people with asthma who have severe, uncontrolled asthma vary considerably, ranging from 1.8 to 49.2% according to a 2018 systematic literature review, depending on geographic location and diagnostic criteria used (55).

In the UK, there are an estimated 5.4 million people receiving treatment for asthma (15). Of these, it is estimated that around 4% have severe asthma (16), of which 65.5% (or 141,000 people) have severe, uncontrolled asthma (17).

B.1.3.4 The burden of severe, uncontrolled asthma

Severe, uncontrolled asthma is associated with greater clinical, humanistic, and economic burden than non-severe asthma, or asthma that responds to treatment (1, 18, 19, 21, 23, 25, 40, 41, 45, 46, 55-71).

B.1.3.4.1 Clinical burden

Patients with severe, uncontrolled asthma are at high risk of exacerbations, which are potentially life-threatening with a possible need for emergency care (45, 56). An asthma exacerbation is defined as progressive worsening of asthma symptoms, such as shortness of breath, wheezing, cough, and chest tightness. During an exacerbation, lung function is impaired, manifesting as reduced peak expiratory flow (PEF) rate and forced expiratory volume in the first second (FEV1) (1). An exacerbation can be triggered by a wide range of risk factors, including respiratory viral infections, bacteria, environmental allergens (e.g. mould), and other factors such as tobacco smoke and exhaust fumes (57).

Severe, uncontrolled asthma is associated with a high frequency of exacerbations. CPRD data from the UK have shown that the exacerbation rate in severe, uncontrolled asthma is 11 times higher than that of patients without severe, uncontrolled asthma (mean annual exacerbation rate per patient year: 1.088 [95% CI: 1.002, 1.181] versus 0.098 [95% CI:

Company evidence submission template for tezepelumab for treating severe asthma (ID3910) © AstraZeneca (2022). All rights reserved

0.096, 0.100], respectively) (58). AstraZeneca is presently sponsoring the NOVELTY study, an observational study of patients with asthma that aims to describe patient characteristics, treatment patterns, and disease burden over time. In NOVELTY, over the 12-month baseline period, ***** of patients defined as having severe, controlled asthma had no exacerbations compared with ********** of patients with severe, uncontrolled asthma. Furthermore, ***** of patients with severe, uncontrolled asthma had ≥3 exacerbations (59).

Asthma exacerbations are associated with a high mortality rate therefore patients with asthma have a higher mortality rate compared with patients with asthma (24). A 2007 database study in the UK (N=250,043 asthma admissions) reported a mortality rate of 858 (95% CI: 750, 977) per 100,000 hospital admissions for acute severe asthma between 2000 and 2005 (not including emergency room [ER] visits); critical care unit admissions had a higher mortality rate of 3,591 per 100,000 (95% CI: 2,207, 5,491) (45). Similarly, a database study in Scotland collecting data on hospitalisations for asthma (N=116,457) between 1981 and 2009 reported that 0.9% (n=1,000) of hospitalisations resulted in death within 30 days of admission (46). It is well documented that patients who have severe asthma as result of frequent exacerbations have a higher mortality rate compared with patients with asthma (24, 45, 46). In England and Wales, deaths resulting from asthma are increasing. A 2019 analysis of ONS data by Asthma UK revealed that more than 1,400 adults and children died from asthma attacks in 2018, an 8% increase since 2017 (25). Overall, more than 12,700 people died from asthma in England and Wales over the past decade, with deaths increasing by 33% between 2008 and 2018 (25).

In addition to the burden of exacerbations, a broad range of non-respiratory and respiratory comorbidities are commonly reported in the severe, uncontrolled asthma population; these include hypertension, allergy, type 2 diabetes, COPD, and chronic sinusitis (60-64).

The burden of OCS use in severe uncontrolled asthma

In patients for whom biologic therapy provides inadequate disease control, or in patients who are ineligible for biologic treatment, OCS, either as short courses or as mOCS, are the main treatment option (1, 26-28). Patients with severe, uncontrolled asthma and frequent exacerbations are more likely to require frequent mOCS compared with those with moderate disease (27). Short- or long-term mOCS use is associated with the risk of

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becoming mOCS-dependent, i.e. unable to achieve asthma control without mOCS (72). According to a recent (2021) study of UK patients with severe asthma in the UK Severe Asthma Registry, 59.9% of patients on biologics were receiving mOCS (73).

Short courses of OCS used to treatment of acute exacerbations are also associated with adverse effects, including sleep disturbance, increased infection risk, and thromboembolism (1, 31). A study investigating adverse outcomes from OCS use in asthma over a 2-year follow up period found that only 2–4 short courses of OCS at standard doses for treating an asthma exacerbation over a patient’s lifetime was associated with an increased risk of adverse events (such as heart failure, type 2 diabetes, cataract, osteoporosis, and depression/anxiety). The study found that the onset of some adverse outcomes was associated with cumulative exposure of 0.5 to < 1 g of systemic corticosteroids, equivalent to only 4 lifetime courses (31). The current (2022) GINA guidelines recommend a short course (approximately 5–7 days) of OCS only for patients with an acute asthma exacerbation and do not recommend OCS as a long-term treatment due to the risk of adverse events (1). Cumulative overexposure to OCS can result in serious systemic adverse effects in both the short- and long-term, including osteoporosis, adrenal suppression, cardiovascular events, and diabetes (26, 28, 32-34), which increases the burden of uncontrolled asthma for patients and healthcare systems (1, 35, 36). Furthermore, long-term OCS use increases mortality risk in asthma patients (29, 30).

It follows that a treatment that prevents asthma exacerbations in patients with severe, uncontrolled asthma will therefore prevent patients from requiring OCS treatment (either short bursts or chronic use), along with the risks of OCS-dependency and OCS-related AEs it entails.

B.1.3.4.2 Humanistic and quality of life burden

The unpredictability and distress associated with severe, uncontrolled asthma symptoms has a substantial negative impact on the lives of patients, including a detriment in the ability to perform usual daily activities (1, 19). Several studies have shown lower HRQoL scores among patients with severe, uncontrolled asthma versus those with better disease control (55, 61, 65, 66); for example, European Quality of Life-5 Dimensions (EQ-5D) values of 0.728 versus 0.937 have been reported for patients with severe uncontrolled versus controlled asthma, respectively (67). Patients with severe, uncontrolled asthma experience more symptoms, night awakenings, rescue medication use, and activity

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impairment than those with non-severe or controlled asthma (65). Furthermore, the vast majority of patients with uncontrolled asthma experience symptoms that affect at least 1 day per week, which is not seen in patients with controlled asthma (68).

Patients also often experience a negative impact on their mental health, with one study finding that 65.3% of patients with moderate-to-severe, uncontrolled asthma had anxiety and/or depression, as determined by the hospital anxiety and depression scale (HADS) (21). The humanistic burden is compounded by suboptimal disease control that can occur with currently approved biologics (40, 41), meaning that patients continue to experience limitations on daily life and exacerbations that impair their HRQoL.

Symptomatic asthma impacts on workplace productivity. In a global online survey completed by 1,598 working adults with symptomatic asthma (of which 300 were in the UK), respondents indicated that, on average, 9.3% of their working week was missed due to asthma (3.5% among UK subjects), and work productivity loss due to asthma was 36% (21% among UK subjects) (20).

Caring for people with severe asthma has also been shown to impair carer QoL – to a similar degree to that seen in carers of people with COPD and other debilitating diseases such as cancer (74).

B.1.3.4.3 Economic burden

Management of severe, uncontrolled asthma places a substantial economic burden on healthcare systems. Despite affecting the minority of the total asthma population (≤5%), severe, uncontrolled asthma accounts for 40% of all direct costs in asthma (69). The cost burden is mainly driven by the number of exacerbations and hospitalisations, which is three-fold higher than in non-severe, uncontrolled asthma, as well as the number of unplanned ER visits, which is twice that of non-severe, uncontrolled asthma (18). In a 2017 UK study using data from the OPCRD (a nationally representative primary care database), the average annual healthcare costs per person with severe asthma ranged from £2,603 to £4,533 (23). Asthma medication was the major driver of costs, with mOCS use and hospital inpatient visits identified as important additional cost drivers (23). In a 2018 UK cohort study enrolling 363,558 patients with active asthma, total mean per-patient healthcare resource use and associated costs were four times greater in patients with severe uncontrolled eosinophilic asthma versus that for all patients in the cohort (resource use and cost ratio: 3.9; 95% CI: 3.7, 4.1) (70). In a 2020 analysis of the US CHRONICLE

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study, among 1,856 patients with severe asthma, 19% of patients required an ER visit and 12% of patients were hospitalised at least once due to asthma (at any point from 12 months prior to enrolment to each patient’s latest data collection) with a mean hospital stay of 5 days (71). ICU admission was required in 14% of asthma hospitalisations, with a mean ICU stay of 4 days.

B.1.3.5 Asthma phenotypes and the role of TSLP in the pathophysiology of asthma

Asthma is a heterogenous disease, and patients with similar clinical presentations are described as having the same ‘phenotype’. Clinical phenotypes are typically based on asthma history and well-defined clinical characteristics, such as age of onset and allergic or non-allergic status (75, 76).

The variable clinical presentations observed in asthma are driven by different biological mechanisms, and with the advent of current biologic treatments, inflammatory phenotypes have more recently been used to describe asthma populations grouped together by either biomarker expression or perceived underlying inflammatory biology. Key biomarkers include serum specific IgE, blood (and sputum) EOS, and FeNO (1, 75, 77). Key inflammatory phenotypes include allergic (atopic), eosinophilic, and non-eosinophilic asthma (e.g. neutrophilic or paucigranulocytic asthma) (75). Allergic asthma is confirmed by positive allergy skin tests and/or increased levels of the biomarker serum specific IgE, whilst eosinophilic asthma is characterised by an increase in blood (and sputum) EOS (75).

The IgE, EOS, and FeNO biomarkers are currently used to define different subtypes of asthma, as they are indicative of distinct inflammatory pathways; these are central to the management of severe, uncontrolled asthma, as biologic treatments are prescribed on the basis of individual inflammatory pathways in current clinical practice (39, 48, 75). However, most severe, uncontrolled asthma patients are positive for one or two of these key biomarkers, but relatively few patients are either positive or negative for all three of these biomarkers (38, 78-80). This can indicate either the upregulation of multiple key inflammatory pathways or a lack of upregulation of these pathways. As a result, it is often unclear if a patient has an allergic phenotype, an eosinophilic phenotype, or neither phenotype (48).

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Biomarkers (e.g. IgE, FeNO, sputum or blood eosinophils), when available, can help inform biologic selection but may not be specific enough to clearly identify an asthma phenotype and the biologic best suited to a patient (81). Therefore there is a need for a treatment option that works earlier on in the inflammatory cascade than existing biologics to provide optimal treatment regardless of inflammatory pathway.

TSLP is an upstream proinflammatory epithelial-derived cytokine that plays a central role in the initiation of airway inflammation in asthma, and initiates downstream inflammatory cascades in response to environmental insults as illustrated in Figure 1 (42, 48). The role of TSLP across phenotypes and biomarkers makes it an attractive therapeutic target for severe, uncontrolled asthma, since, by targeting TSLP, multiple downstream inflammatory pathways can be influenced (39, 77). Accordingly, the latest (2022) GINA guidelines were updated to include anti-TSLP as a new class of biologic therapy for severe asthma (1). TSLP as a therapeutic target in the treatment of severe, uncontrolled asthma is discussed further in Section B.1.3.9.1.

Figure 1: The role of TSLP in driving asthma inflammation

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Abbreviations: IgE, immunoglobulin E; IL, interleukin; T2, Type 2; TSLP, thymic stromal lymphopoietin. Source: Adapted from Gauvreau 2020 (48), Porsbjerg 2020 (82).

B.1.3.6 Treatment options for severe, uncontrolled asthma

Treatment with biologic therapies is currently recommended in England and Wales to reduce exacerbations, dependency on OCS and improve asthma control. NICE’s

recommendations relate to subsets of the patient population with 3 or more exacerbations in the prior year or who are on mOCS, and reflect the fact that existing biologics are only effective in subpopulations defined by biomarkers. In England and Wales, treatment for

Company evidence submission template for tezepelumab for treating severe asthma (ID3910) © AstraZeneca (2022). All rights reserved

severe, uncontrolled asthma generally follows the BTS/SIGN guidelines, which are summarised below alongside the relevant NICE technology appraisal guidance. GINA guidelines for difficult-to-treat and severe asthma are summarised in Section B.1.3.6.2.

B.1.3.6.1 UK guidelines

The aim of asthma treatment according to the BTS/SIGN guidelines (47) is to achieve disease control, with complete asthma control defined as:

• No daytime symptoms

• No night-time awakening due to asthma

• No need for rescue medication

• No asthma attacks

• No limitations on activity, including exercise

• Normal lung function (FEV1 and/or PEF >80% predicted or best)

• Minimal side effects from medication

The guidelines define difficult asthma as persistent symptoms and/or frequent asthma attacks despite treatment with high-dose inhaled corticosteroid (ICS) plus a long-acting beta agonist (LABA) or leukotriene receptor antagonist (LTRA); or medium-dose ICS plus a LABA or LTRA and an appropriate additional therapy (see below); or continuous or frequent use of oral steroids. It is recommended that patients with difficult asthma are systematically evaluated, including confirmation of an asthma diagnosis, identification of persisting symptoms, and assessment of therapy adherence.

Guidelines on the pharmacological management of asthma in adults and adolescents are summarised in Figure 2.

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Figure 2: BTS/SIGN – 2019 guideline for the management of asthma in adults/adolescents

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Abbreviations: BTS, British Thoracic Society; ICS, inhaled corticosteroid; LABA, long-acting β2 agonist; LTRA, leukotriene receptor antagonist; MART, maintenance and reliever therapy; SIGN, Scottish Intercollegiate Guidelines Network.

For adults and adolescents aged >12 years with an asthma diagnosis, short-acting bronchodilators (e.g. short-acting beta agonists [SABA], inhaled ipratropium bromide, and theophyllines) should be prescribed to relieve symptoms. ICSs are the first choice of preventer therapy, with the starting dose determined according to disease severity (usually a low dose for adults/adolescents). LTRAs, sodium cromoglicate, nedocromil sodium, and theophyllines may also be considered.

Add-on therapies may be required if asthma is not adequately controlled with low-dose ICS alone. Inhaled LABA is the first choice of add-on therapy in adults/adolescents. If there is an improvement when LABA is added but control remains suboptimal, the LABA can be continued and the dose of ICS increased to medium. If there is no improvement when a LABA is added, consideration should be given to stopping the LABA before increasing the dose of ICS. An alternative to increasing the ICS dose is adding a LTRA.

In adults with asthma that is not adequately controlled on the recommended initial or additional controller therapies (medium-dose ICS plus LABA or LTRA), specialist therapies should be considered:

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• Increase ICS to high dose

• Add LTRA if not already tried, or

• Add tiotropium bromide, or

• Add a theophylline

For patients with a high mOCS burden, the following treatments may be considered:

• Omalizumab

• Mepolizumab, reslizumab, or benralizumab

Bronchial thermoplasty may be considered in cases of severe asthma that is poorly controlled despite optimal medical therapy.

For the management of acute asthma, the BTS/SIGN guidelines recommend using highdose inhaled β2 agonists as first-line treatment in patients with acute asthma and intravenous β2 agonists if inhaled therapy cannot be used reliably. Steroids should also be administered in adequate doses to all patients with an acute asthma attack as early as possible.

Nebulised ipratropium bromide can be added to β2 agonist treatment for patients with acute severe or life-threatening asthma or those with a poor initial response to β2 agonist treatment. A single dose of intravenous magnesium sulphate should be considered for patients with acute severe asthma (PEF <50% best or predicted) who have not had a good initial response to inhaled bronchodilator therapy.

The NICE guidelines for the treatment of asthma (NG80) do not cover the management of severe asthma or acute asthma attacks (83), but the NICE pathway for managing asthma includes (under the category of ‘difficult and severe asthma’) guidance on the use of the currently reimbursed biologics: omalizumab, mepolizumab, benralizumab, reslizumab, and dupilumab. This guidance is summarised in Table 4. NICE’s recommendations relate to subsets of the patient population with 3 or more exacerbations in the prior year OR who are on mOCS, and reflect the fact that existing biologics are only effective in subpopulations defined by biomarkers.

Note that NICE has also recently published a COVID-19 rapid guideline for severe asthma (NG166), which recommends that patients receiving biologic therapy should continue to do so, as these therapies do not suppress immunity (84).

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Table 4: Summary of NICE technology appraisal guidance on biologics for the treatment of severe asthma

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Abbreviations: EOS, eosinophil; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; LABA, long-acting beta agonist; NICE, National Institute for Health and Care Excellence; OCS, oral corticosteroid; ppb, parts per billion; SCS, systemic corticosteroid; SmPC, Summary of Product Characteristics.

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B.1.3.6.2 GINA 2022 guidelines

GINA recently (2022) updated its guidance for the management of difficult-to-treat and severe asthma (1). In patients with elevated Type 2 biomarkers despite high-dose ICS, non-biologics should be considered first given the high cost of biologic therapy. If available and affordable, use of an add-on Type 2-targeted biologic should be considered in “patients with exacerbations or poor symptom control despite taking at least high dose ICS-LABA, and who have allergic or eosinophilic biomarkers or need maintenance OCS”. Recommended biologics include omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab.

Specific to tezepelumab, the GINA 2022 guidelines recommend tezepelumab treatment for severe asthma irrespective of biomarkers (1).

Response to biologic add-on therapy should be reviewed after the first 3–4 months and then every 3–6 months thereafter. In patients with a good response to Type 2-targeted biologic therapy, the guidelines recommend re-evaluating the need for asthma medication every 3–6 months. Consider first a gradual decrease or cessation of OCS due to their significant adverse effects, and then a reduction in ICS dose after 3–6 months; however, inhaled therapy should not be stopped completely.

B.1.3.7 Current treatment patterns in the UK

The UK Severe Asthma Registry (UKSAR) is the world’s largest national severe asthma registry collecting standardised data on referrals to UK specialist services. A study of UKSAR data assessed biologic treatment patterns for 2,225 patients with severe asthma over the period November 2016 to February 2020 (73). In total, 68.9% of patients were prescribed biologic therapy and the proportion of patients receiving each biologic is presented in Table 5. The most commonly prescribed biologic was mepolizumab, which represented more than half (50.3%) of all prescriptions. Benralizumab (26.1%) and omalizumab (22.6%) were also frequently used, while reslizumab (0.6%) and dupilumab (0.3%) combined made up <1% of all prescribed biologics. It should be noted that the relative proportions likely reflect the duration of availability of the specific therapy at the time of the analysis, the eligible population size, and individual physician preferences.

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Table 5: Relative rates of prescribing of biologic therapies currently reimbursed in the UK for the treatment of severe asthma – Data from the UKSAR

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Biologic therapy n (%)
Mepolizumab 731 (50.3)
Benralizumab 380 (26.1)
Omalizumab 329 (22.6)
Reslizumab 9 (0.6)
Dupilumab 5 (0.3)
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Abbreviations: UKSAR, UK Severe Asthma Registry. Source: Jackson 2021 (73).

In the UK currently, all available biologic therapies for severe asthma are biomarkerspecific, meaning that patients must meet biomarker criteria in order to be eligible for treatment with a particular biologic. An overview of available biologics and their respective eligible patient population (by biomarker profile) is presented in Figure 3. (See also Table 4, which summarises the licensed indications and NICE recommendation for each biologic).

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Figure 3: Current treatment pathway for the target population

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Abbreviations: EOS, eosinophil; exacs, exacerbations; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IL, interleukin; mOCS, maintenance oral corticosteroid treatment.

† Adults: (400+ EOS AND 3+ exacs) OR 300+ EOS AND (4+ exacs OR mOCS)

¶ Adults: 400+ EOS AND 3+ exacs

§ (Adults: 25+ FeNO AND 150-299 EOS AND 4+ exacs) OR (Age 12-17: 25+ FeNO AND 150+ EOS AND 4+ exacs)

‡ Age 6+: Allergic IgE-mediated asthma AND 4+ exacs OR mOCS

• Add-on to high dose ICS + additional controller.

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B.1.3.8 Unmet needs in the treatment of severe asthma

Asthma is a heterogeneous disease driven by multiple inflammatory pathways, yet current biologic therapies for severe asthma are targeted to single pathways (37, 38). Therefore, the full set of biological mechanisms driving an individual patient’s asthma are unlikely to be addressed by currently recommended biologics (39) leaving the following areas of unmet need:

 There is a need for additional treatment options for those who are currently ineligible for existing biologic therapies: A significant number of patients are ineligible for current biologic treatments, in part due to not having any clear driver of inflammation. As shown in Figure 3, patients without an allergic or eosinophilic asthma phenotype have no biologic therapy options, and thus a substantial proportion of patients with severe, uncontrolled asthma have a gap in their disease management options (39, 95). There remains a particular unmet need among the subgroup of severe, uncontrolled asthma patients with low eosinophils (<150 cells/µL) for whom there are no biologics available (96). AstraZeneca is currently conducting a real-world evidence study to demonstrate the burden of disease and unmet need in this patient subgroup compared with patients with high eosinophil counts/those who are eligible for biologic treatment. ******************** ***********************. UK clinicians have also highlighted the need for effective treatment options specifically for patients who are on the cusp of the biologic eligibility criteria including those patients who fit the dupilumab biomarker eligibility criteria but are not on mOCS (96). There are more limited treatment options for adolescent patients compared with adult patients as benralizumab, mepolizumab and reslizumab are recommended only for adults. Having a treatment option that works well in the adolescent population will be valuable as currently only a small proportion are eligible for biologic therapy (96).

• There is a need for additional first line treatment options for those who are currently eligible for existing biologic therapies: An estimated 57% of patients with severe asthma who are treated with currently approved biologics remain suboptimally controlled due to underlying inflammation that is left unaddressed by their current biologic treatment (40). These patients continue to experience uncontrolled disease, resulting in a high exacerbation frequency, limitations on daily life and poor HRQoL, as well as substantial healthcare costs for healthcare systems (40, 41). Due to persistent asthma symptoms and inability to taper or discontinue mOCS use, many

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patients will be forced to switch biologic therapy; 34% of anti-IL-5 biologic-treated patients will switch to another biologic therapy (97). Clinicians highlighted that there are some patients, more so in adolescents, that have both allergic and eosinophilic asthma. More often than not they would be treated for the eosinophilic part of their asthma however these patients are often sub-optimally controlled as only part of the inflammatory pathway is being targeted. Therefore having a treatment that can target and treat both parts of the inflammatory cascade would be beneficial (96). Clinicians also mentioned that some patients on current biologic therapy develop antidrug antibodies and so there is a need for more treatment options (96).

For patients experiencing insufficient control of their exacerbations with existing biologics, or who are ineligible for existing biologics, their primary treatment option is OCS, either through frequent short courses or mOCS. Evidence suggests that mOCS overuse remains a frequent issue among the severe, uncontrolled asthma population (98, 99), leading to a further clinical burden to patients and increased healthcare use from the treatment of adverse effects such as osteoporosis, adrenal suppression, cardiovascular events, and diabetes (27, 32, 34-36). Asthma control is therefore very important to minimise risk of exacerbations and consequent requirement for either acute or chronic OCS use, which may progress to dependence with time. In line with this, the GINA 2022 guideline encourages careful day-to-day adjustment of controller therapy in order to reduce the risk of exacerbations requiring OCS (1).

A conclusion from the committee in the recent NICE TAG for dupilumab (TA751) states that “there is a need for new treatments with a different mode of action for people with severe asthma with Type 2 inflammation whose asthma does not respond with current standard care, and for people not eligible for current NICE recommended biologicals” (94). Expediting treatment initiation with a first-line biologic that is effective regardless of phenotype and irrespective of biomarkers would increase the number of patients eligible for a biologic therapy and remove the need to bridge the treatment gap with OCS use.

B.1.3.9 Tezepelumab in the clinical pathway of care

Tezepelumab is expected to meet unmet clinical needs in the treatment of severe asthma through its unique mechanism of action and efficacy across phenotypes, irrespective of biomarker levels (39, 42) as per the anticipated licensed indication. If recommended by NICE, tezepelumab will become the only biologic reimbursed in England and Wales that is

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recommended for severe uncontrolled asthma patients with 3 or more exacerbations in the prior year or who require mOCS, irrespective of biomarkers or phenotypes.

B.1.3.9.1 Mechanism of action

Tezepelumab is a first-in-class anti-TSLP monoclonal antibody (48). The airway epithelium is the first point of contact for inhaled viruses, bacteria, allergens, smoke extract, and other environmental insults that can trigger asthma (42, 48, 100). TSLP is an upstream epithelial-derived cytokine that is released at the top of the inflammatory cascade in response to insults. TSLP activates multiple downstream pathways that are involved in airway inflammation and bronchi hyperresponsiveness in asthma (39, 48, 49).

Tezepelumab specifically binds to human TSLP with high affinity and prevents its interaction with the TSLP receptor complex on cells involved in the inflammatory response (39, 42, 48). This inhibits the inflammatory cascade and reduces initiation and persistence of downstream inflammatory responses (42, 48, 100). Tezepelumab inhibits the release of a broad range of cytokines (e.g., IL-5, IL-13) and biomarkers (e.g., EOS, IgE, and FeNO), showing that it inhibits multiple downstream inflammatory pathways via its blockage of TSLP. Tezepelumab’s mode of action is a key differentiator from currently available biologic therapies for severe asthma which target single or downstream inflammatory pathways (39). Based on this, clinicians expect tezepelumab to have a similar degree of efficacy to current biologics but to be effective in a broader population as TLSP is at the top of the inflammatory cascade (96).

Clinicians also believe that by acting earlier on in the inflammatory cascade, it is likely that tezepelumab will enable dual treatment of those patients that have both allergic and eosinophilic asthma. Currently, these patients can only be treated with a biologic that only targets one component (normally eosinophilic part) and so sometimes are sub optimally controlled or have to switch treatment (96).

In addition, some clinicians acknowledge that as tezepelumab acts directly on the airway epithelia, they would expect its treatment failure rate to be lower than that of biologics as result of impact on airway hyperresponsiveness and other mechanistic effects of working higher in the inflammatory cascade. Current biologics either don’t have data or have very poor data on airway hyperresponsiveness which is a very important endpoint in clinical practice, and a hallmark of asthma used to characterise disease diagnosis (96).

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As a result of its novel mechanism of action, tezepelumab delivers efficacy across all severe, uncontrolled asthma patients regardless of their biomarker profile or phenotype (39, 42), addressing the needs of patients ineligible for existing biologic therapies and providing another treatment option for patients currently eligible for biologics.

The mechanism of action of tezepelumab is illustrated in Figure 4.

Figure 4: Tezepelumab mechanism of action

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Abbreviations: IgE, immunoglobulin E; IL, interleukin; T2, Type 2; TSLP, thymic stromal lymphopoietin. Source: Adapted from Gauvreau 2020 (48), Porsbjerg 2020 (82).

B.1.3.10 Tezepelumab positioning

The inflammatory cascade of severe uncontrolled asthma is complex and heterogeneous. Current biologic agents mostly act on a single specific downstream inflammatory target like eosinophils (EOS), IgE, or cytokines (IL-4, -5 or -13) (37, 38) and have demonstrated effectiveness in specific phenotypes of severe asthma defined by biomarker criteria. Inflammation in severe asthma is complex, dynamic and heterogeneous. Patients with severe uncontrolled asthma often exhibit overlapping or changing phenotypes (37, 38, 101-104) and almost 15% of patients present with no defined inflammatory pathway (78). By exerting its effect at the top of the TSLP inflammatory cascade, tezepelumab delivers efficacy across asthma phenotypes and irrespective of biomarker levels as per the anticipated licensed indication (105). Providing access to tezepelumab in the 3 or more exacerbations or mOCS population will help simplify the treatment landscape and enable more patients to have access to biologic therapy. Insights leveraged from clinicians in the UK show that they unanimously agree in the value of having a biologic with a simpler and broader recommendation (96) (105). Introducing tezepelumab in this setting will provide

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access to biologic therapy for some patients who are currently ineligible and will provide an alternative treatment option for patients who are currently eligible.

The pivotal evidence for tezepelumab for the treatment of severe asthma comes from two Phase 3 RCTs, NAVIGATOR and SOURCE, and one Phase 2 RCT, PATHWAY. The NAVIGATOR trial showed that at Week 52, tezepelumab reduced AAER by 56% (rate ratio [RR]: 0.44; 95% CI: 0.37, 0.53; p<0.001). The PATHWAY trial showed that, at Week 52, tezepelumab reduced AAER by 71% (RR: 0.29; 95% CI: 0.16,0.51; p<0.001). The SOURCE trial demonstrated that the cumulative odds of achieving a category of greater percentage reduction in OCS dose for daily maintenance at Week 48 with tezepelumab versus placebo were odds ratio [OR] of 1.28 (95% CI: 0.69, 2.3; p=0·43). (Results are contextualised in Section B.2.13.2.1).

This appraisal positions tezepelumab as a treatment for adults and adolescents 12 years and older with severe uncontrolled asthma patients despite high dose ICS and an additional controller, who experienced 3 or more exacerbations in the prior year, or who are on mOCS, irrespective of biomarker values, as outlined in Figure 5.

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Figure 5: Proposed positioning of tezepelumab in the treatment pathway of severe uncontrolled asthma

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Abbreviations: EOS, eosinophil; exacs, exacerbations; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IL, interleukin; mOCS, maintenance oral corticosteroid treatment.

† Adults: (400+ EOS AND 3+ exacs) OR 300+ EOS AND (4+ exacs OR mOCS)

¶ Adults: 400+ EOS AND 3+ exacs

• § (Adults: 25+ FeNO AND 150-299 EOS AND 4+ exacs) OR (Age 12-17: 25+ FeNO AND 150+ EOS AND 4+ exacs)

• Age 6+: Allergic IgE-mediated asthma AND 4+ exacs OR mOCS

• Add-on to high dose ICS + additional controller.

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B.1.4 Equality considerations

• A recommendation for tezepelumab in patients with severe, uncontrolled asthma who have 3 or more exacerbations in the prior year OR who are on mOCS, as outlined in Section B.1.3.10, addresses existing inequality issues in two main ways:

  1. Equality for patients who do not meet biomarker criteria for current biologics: There is currently no biologic treatment option for patients with low eosinophilic, low FeNO, non-allergic severe asthma. A recommendation in a broader population will address this and provide a therapy option for thousands of severe asthma patients who are currently ineligible to receive a biologic to help manage their condition.

  2. Gender equality: Severe asthma is a condition that is known to have a higher prevalence among females compared with males; throughout their lifetime, females have a higher likelihood of developing asthma and developing a more severe form of asthma than their male counterparts (60). This is supported by the demographics in the tezepelumab NAVIGATOR trial (see Section B.2.3.3.2), in which 63.5% of subjects were female. Furthermore, patients with non-eosinophilic phenotypes of severe asthma are more likely to be women when compared with the breakdown by gender of patients with an eosinophilic subtype (81.5% versus 62.9%; p=0.047) (106). With women suffering from non-eosinophilic disease more than men, the reimbursement of tezepelumab across a broad severe asthma patient population, regardless of biomarkers, helps to address the current inequality that exists in terms of biologic treatment options for women.

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B.2 Clinical effectiveness

SUMMARY

• The pivotal evidence for tezepelumab for the treatment of severe asthma comes from one Phase 2 RCT, PATHWAY (42, 107), and two Phase 3 RCTs, NAVIGATOR (43, 108, 109) and SOURCE (110)

• In PATHWAY and NAVIGATOR, tezepelumab treatment over 52 weeks resulted in clinically meaningful and statistically significant reductions in exacerbation rates of 71% and 56%, respectively, versus placebo (both p<0.001)

• In both studies,

• Treatment with tezepelumab resulted in clinically meaningful reductions in AAER versus placebo irrespective of baseline EOS levels, FeNO levels, allergic status, and serum IgE

• Tezepelumab treatment was also shown to result in clinically meaningful improvements over 52 weeks in lung function (pre-BD FEV1), quality of life (AQLQ(S)+12), asthma control (ACQ-6), and asthma symptoms (ASD) compared with placebo

• By preventing exacerbations, tezepelumab prevents patients from requiring either short bursts or chronic OCS use, reduces the need for OCS in OCS-dependent patients and demonstrates clinically meaningful improvements in key outcomes for OCS-dependent patients

• Although SOURCE did not meet its primary endpoint, it did demonstrate a numerical improvement in the odds of achieving a categorical reduction in mOCS dose with tezepelumab treatment versus placebo

• Tezepelumab 210 mg SC Q4W is well tolerated in adults and adolescents 12 years and older with severe asthma

B.2.1 Identification and selection of relevant studies

Full details of the process and methods used to identify and select the clinical evidence relevant to the technology being appraised are provided in Appendix D.

A systematic literature review (SLRs) were conducted to identify RCT evidence reporting on the efficacy and safety of tezepelumab for the treatment of patients with severe, uncontrolled asthma. The SLR was originally conducted in October 2020 and then updated in November 2021.

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B.2.2 List of relevant clinical effectiveness evidence

A summary of the clinical effectiveness evidence for tezepelumab for the treatment of patients with severe, uncontrolled asthma is provided in Table 6 (PATHWAY), Table 7 (NAVIGATOR), and Table 8 (SOURCE).

The primary references used for writing up each of the three pivotal trials are as follows:

• PATHWAY: Corren et al 2017 (42), Clinical Study Report (107)

• NAVIGATOR: Menzies-Gow et al 2020 (43), Menzies-Gow et al 2021 (109) Clinical Study Report (108)

• SOURCE: Clinical Study Report (110)

Table 6: Clinical effectiveness evidence – PATHWAY

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Lung function:  FEV1, FEF25–75%, home PEF Adverse effects of treatment/mortality:  AEs Time to discontinuation:  Duration of study/AEs Health-related quality of life:  EQ-5D-5L , AQLQ(S)+12, SGRQ, WPAI+CIQ

Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AE, adverse event; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; CGI-I, Clinician Global Impression of Change; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; ER, emergency room; FEF25–75%, forced expiratory flow over 25–75% of the vital capacity; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; NMA, network meta-analysis; OCS, oral corticosteroid; PEF, peak expiratory flow; PGI-C, Patient Global Impression of Change; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SC, subcutaneous; SCS, systemic corticosteroid; SGRQ, St George’s Respiratory Questionnaire; WPAI-CIQ, Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire.

† PATHWAY informs the economic model indirectly via the NMA.

Table 7: Clinical effectiveness evidence – NAVIGATOR

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Adverse effects of treatment/mortality:  AEs Time to discontinuation:  Duration of study/AEs Health-related quality of life:  EQ-5D-5L , AQLQ(S)+12, SGRQ, WPAI+CIQ

Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AE, adverse event; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; CGI-I, Clinician Global Impression of Change; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; ER, emergency room; FEF25–75%, forced expiratory flow over 25–75% of the vital capacity; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; OCS, oral corticosteroid; PEF, peak expiratory flow; PGI-C, Patient Global Impression of Change; Q4W, once every 4 weeks; SC, subcutaneous; SCS, systemic corticosteroid; SGRQ, St George’s Respiratory Questionnaire; WPAI-CIQ, Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire.

Table 8: Clinical effectiveness evidence – SOURCE

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 FeNO, ASD, peripheral blood eosinophils, and total IgE Lung function:  FEV1, FEF25–75%, home PEF Adverse effects of treatment/mortality:  AEs Time to discontinuation:  Duration of study/AEs Health-related quality of life:  EQ-5D-5L , AQLQ(S)+12, SGRQ, WPAI+CIQ

Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AE, adverse event; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; ER, emergency room; FEF25–75%, forced expiratory flow over 25–75% of the vital capacity; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; mOCS, maintenance oral corticosteroid treatment; OCS, oral corticosteroid; PEF, peak expiratory flow; Q4W, once every 4 weeks; SC, subcutaneous; SCS, systemic corticosteroid; SGRQ, St George’s Respiratory Questionnaire; WPAI-CIQ, Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire.

B.2.3 Summary of methodology of the relevant clinical effectiveness evidence

B.2.3.1 Comparative summary of trial methodology

The methodologies of the pivotal Phase 2 RCT, PATHWAY, and that of its follow-on, pivotal Phase 3 RCT, NAVIGATOR, are summarised in Table 9.

The methodology of the pivotal Phase 3 RCT, SOURCE, is summarised in Table 10.

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Table 9: Comparative summary of PATHWAY and NAVIGATOR methodology

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NCT02054130 NCT03347279
(PATHWAY) (NAVIGATOR)
investigator during the conduct of this study. During the  All asthma controller medications for the 3 months prior to
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NCT02054130 NCT03347279
(PATHWAY) (NAVIGATOR)
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Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AE, adverse event; AER, asthma exacerbation rate; AQLQ, Asthma Quality of Life Questionnaire; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; BD, bronchodilator; BMI, body mass index; CFB, change from baseline; CGI-I, Clinician Global Impression of Change; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; EOS, eosinophil; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; ER, emergency room; FEF25–75%, forced expiratory flow over 25–75% of the vital capacity; FEIA, fluorescent enzyme immunoassay; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; ICS, inhaled corticosteroid; IgE, Immunoglobulin E; IU, International Unit; IWRS, Interactive Web Response System; LABA, long-acting beta agonist; mOCS, maintenance oral corticosteroid treatment; OCS, oral corticosteroid; PEF, peak expiratory flow; PGI-C, Patient Global Impression of Change; PGI-S, Patient Global Impression of Severity; ppb, parts per billion; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SABA, short-acting beta agonist; SC, subcutaneous; SCS, systemic corticosteroid; SGRQ, St George’s Respiratory Questionnaire; WPAI-CIQ, Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire.

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Table 10: Summary of SOURCE methodology

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NCT03406078
(SOURCE)
Study objective To evaluate the effect of a 210 mg dose of tezepelumab SC Q4W on mOCS dose
reduction in adult subjects with severe, mOCS-dependent asthma
Trial design Phase 3 multicentre, global, randomised, double-blind, placebo-controlled, parallel
group study (see Figure 8)
Duration of study The study consisted of a 2-week screening/run-in period followed by an mOCS
optimisation phase of up to 8 weeks, a treatment period of 48 weeks (comprising a
4-week induction phase, a 36-week mOCS reduction phase, and an 8-week
maintenance phase), and a post-treatment follow-up period of 12 weeks (see
Figure 8)
Method of Randomisation (1:1) was achieved via an IWRS with subject randomisation codes
randomisation grouped in blocks. All subjects were stratified at randomisation by region.
Method of blinding Tezepelumab and placebo were not visually distinct from each other. All packaging
(care provider, and labelling of investigational products was done in such way as to ensure
patient and outcome blinding for all sponsor and investigational site staff. Neither the subject nor any of
assessor)- the investigators or sponsor staff who were involved in the treatment or clinical
evaluation and monitoring of the subjects were aware of the treatment received. To
further prevent unblinding, blood eosinophil, basophils and monocyte numbers
from the visits after randomisation visit were redacted from the central laboratory
reports. In addition, FeNO results were blinded throughout the study.
Eligibility criteria for (The full inclusion and exclusion criteria are provided in Appendix N)
participants  Aged 18–80 (inclusive)
 Physician-diagnosed asthma for ≥12 months prior to Visit 1
 Physician-prescribed medium- or high-dose ICS as per GINA guidelines for ≥12
months prior to Visit 1
 Physician-prescribed LABA and high-dose ICS for ≥3 months prior to Visit 1
 mOCS for asthma for ≥6 months prior to Visit 1 and a stable dose of between
≥7.5 and ≤30 mg (prednisone or prednisolone)
 ≥1 asthma exacerbation event within 12 months prior to Visit 1
Settings and Subjects were enrolled at 60 centres in 7 countries (Argentina, Germany, South
locations where the Korea, Turkey, Poland, Ukraine, and USA)
data were collected
Trial drugs (the In addition to standard of care:
interventions for  Tezepelumab 210 mg SC Q4W plus ICS/LABA and mOCS (n=74)
each group with
sufficient details to  Placebo SC Q4W plus ICS/LABA and mOCS (n=76)
allow replication,
including how and
when they were
administered)
Intervention(s)
(n=[x]) and
comparator(s)
(n=[x])
Permitted and Use of the following concomitant medications was permitted and documented:
disallowed  Physician-prescribed medium- or high-dose ICS as per GINA guidelines for ≥12
concomitant
months prior to Visit 1
medications
 Physician-prescribed LABA and high-dose ICS (total daily dose >500 μg
fluticasone propionate dry powder formulation equivalent) for ≥3 months prior to
Visit 1
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NCT03406078 (SOURCE)

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 Additional maintenance asthma controller medications according to standard
practice of care; use of these medications must have been documented for ≥3
months prior to Visit 1
 mOCS for the treatment of asthma for ≥6 months prior to Visit 1 and a stable
dose of between ≥7.5 mg to ≤30 mg (prednisone or prednisolone) daily or daily
equivalent for ≥1 month prior to Visit 1
Subjects who were maintained on LAMA, theophylline, or LTRA were required to
continue treatment with these medications throughout the study.
Restricted medications:
The following medications were not permitted from Visit 1, throughout the treatment
period, and preferably not until 4 weeks after the last dose of investigational
product:
 Maintenance treatment with long-acting bronchodilators (including ICS/LABA
combinations)
 SABAs (regular, scheduled use; prn use was permitted with restrictions)
 Additional maintenance controllers
 Short-acting anticholinergics (e.g., ipratropium), except for managing an asthma
exacerbation event
Inactive/killed vaccinations were permitted provided they were administered within
5 days before or after any study visit.
Allergen immunotherapy was allowed if on stable therapy for ≥30 days prior to Visit
1 with no anticipated change during treatment period
Prohibited medications:
LABAs as a reliever; suplatast tosilate; any immunomodulators or
immunosuppressives (corticosteroids with systemic effects such as oral,
parenteral, or intra-articular administration for reasons other than asthma were not
allowed; however, corticosteroid treatment of adrenal insufficiency and acute
anaphylaxis was allowed); immunoglobulin or blood products; any marketed or
investigational biologic treatment; other investigational product; herbal remedies for
the treatment of allergic, inflammatory, or respiratory diseases; medications not
currently licensed for use in the treatment of asthma, e.g., medications approved
for COPD and not part of standard of care; live attenuated vaccines;
spironolactone; eplerenone; ephedrine; opiates.
Rescue mediation use:
SABA was to be withheld for ≥6 hours prior to scheduled site visit spirometry,
FeNO, ECG tests and home lung function assessments with the exception of any
unscheduled visits due to asthma worsening.
Regularly scheduled SABA use in the absence of any asthma symptoms was not
allowed from enrolment (Visit 1) and for the remainder of the study duration.
Prophylactic use of SABA, or any other use than to curb worsening of asthma
symptoms, was to be documented.
Rescue use of SABA administered via nebulisation was to be discouraged, except
as treatment during an asthma exacerbation, in which case its use was to be
documented.
Primary outcome Categorised percent reduction from baseline in the daily OCS at Week 48 while not
(including scoring losing asthma control. [†] The categories for percent change from baseline in daily
methods and OCS dose were defined as:
timings of  ≥90% to ≤100% reduction
assessments)
 ≥75% to <90% reduction
 ≥50% to <75% reduction
 >0% to <50% reduction
 No change or any increase
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Company evidence submission template for tezepelumab for treating severe asthma (ID3910)

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Company evidence submission template for tezepelumab for treating severe asthma (ID3910)

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NCT03406078 (SOURCE)  Country

Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AE, adverse event; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; BD, bronchodilator; BMI, body mass index; CFB, change from baseline; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; EOS, eosinophil; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; ER, emergency room; FEIA, fluorescent enzyme immunoassay; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; IgE, Immunoglobulin E; IWRS, Interactive Web Response System; LABA, long-acting beta agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; PEF, peak expiratory flow; ppb, parts per billion; Q4W, once every 4 weeks; SABA, short-acting beta agonist; SC, subcutaneous; SGRQ, St George’s Respiratory Questionnaire; Th, T helper cell; WPAI+CIQ, Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire.

† Repeated attempts at OCS reduction were permitted. If a subject could not reduce OCS because of loss of asthma control, they could try again at a later visit after control was regained.

B.2.3.2 Trial design schematics

Schematics illustrating the trial designs of PATHWAY, NAVIGATOR, and SOURCE are provided in Sections B.2.3.2.1, B.2.3.2.2, and B.2.3.2.3, respectively.

B.2.3.2.1 PATHWAY

Figure 6: Schematic of PATHWAY trial design

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Abbreviations: EOS, eosinophil; ICS, inhaled corticosteroid; MEDI9929, tezepelumab; Q4W, once every 4 weeks; SC, subcutaneous.

• Current post-BD FEV1 reversibility was defined as post-BD change in FEV1 of ≥12% and ≥200 mL at one of the screening visits.

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B.2.3.2.2 NAVIGATOR

Figure 7: Schematic of NAVIGATOR trial design

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Abbreviations: ICS, inhaled corticosteroid; OCS, oral corticosteroid; Q4W, once every 4 weeks; SC, subcutaneous. † DESTINATION is a long-term (1-year) extension study.

B.2.3.2.3 SOURCE

Figure 8: Schematic of SOURCE trial design

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Abbreviations: OCS, oral corticosteroid; Q4W, once every 4 weeks; SC, subcutaneous. † DESTINATION is a long-term (1-year) extension study.

B.2.3.3 Baseline characteristics and demographics

B.2.3.3.1 PATHWAY

Baseline demographic, clinical characteristics, and asthma history of subjects enrolled in PATHWAY are summarised in Table 11, Table 12, and Table 13, respectively.

Subject demographic and clinical characteristics were generally well balanced between the tezepelumab and placebo trial arms. Overall, the study population represented the intended population of severe, uncontrolled asthma.

The majority of subjects in the intent-to-treat (ITT) population (see Section B.2.4.2 for definitions of analysis sets) were white (91.6%), female (65.6%), and not Hispanic or

Latino (******* The mean age was 51.55 years (range: 20–75 years), and the average body mass index (BMI) was 28.20 (Table 11).

In terms of asthma characteristics at baseline, overall:

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• ************* of subjects in the tezepelumab (any dose) and placebo arms, respectively, were receiving mOCS at baseline

• ************** of subjects in the tezepelumab (any dose) and placebo arms, respectively, had positive aeroallergen-specific IgE status (fluorescent enzyme immunoassay [FEIA])

• ************** of subjects in the tezepelumab (any dose) and placebo arms, respectively, had experienced ≥2 exacerbations in the prior 12 months

• ************** of subjects in the tezepelumab (any dose) and placebo arms, respectively, had experienced ≥3 exacerbations in the prior 12 months

• ************* of subjects in the tezepelumab (any dose) and placebo arms, respectively, had experienced ≥4 exacerbations in the prior 12 months

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Table 11: PATHWAY baseline demographic characteristics (ITT)

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NCT02054130 (PATHWAY) Tezepelumab Placebo Q2W Total
Baseline characteristics (n=138) (N=550)
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
(n=138) (n=137) (n=137) (n=412)
Age, years
Mean (SD) 50.80 (12.36) 52.66 (12.67) 50.43 (12.25) 51.30 (12.43) 52.32 (11.71) 51.55 (12.25)
Min, Max 20, 74 21, 75 21, 72 20, 75 20, 74 20, 75
Sex, n (%)
Male 49 (35.5) 50 (36.5) 46 (33.6) 145 (35.2) 44 (31.9) 189 (34.4)
Female 89 (64.5) 87 (63.5) 91 (66.4) 267 (64.8) 94 (68.1) 361 (65.6)
Ethnicity, n (%)
Hispanic or Latino * ******** ******* ******* ******* *******
Not Hispanic or Latino ********* ********** ********** ********** ********** **********
Race, n (%) [†]
Asian ******** ******* ******* ******** ******* ********
Black or African American ******** ******* ******* ******** ******* ********
White ********** ********** ********** ********** ********** **********
Other * * ********* ******** ******* *******
Multiple categories checked * ******** ******** ******** ******* *******
BMI, kg/m [2]
Mean (SD) 28.30 (5.05) 28.50 (4.91) 27.56 (5.00) 28.12 (4.99) 28.45 (5.55) 28.20 (5.14)
Min, Max 18.5, 39.8 19.8, 39.5 18.3, 39.5 18.0, 39.8 18.0, 44.4 18.0, 44.4
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Abbreviations: BMI, body mass index; ITT, intent-to-treat; max, maximum; min, minimum; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SD, standard deviation. † Each race category counted subjects who selected only that category. “Multiple categories checked” counted subjects who selected more than one race category.

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Table 12: PATHWAY baseline disease characteristics (ITT)

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NCT02054130 (PATHWAY) Tezepelumab Placebo Q2W
Baseline characteristics (n=138)
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
(n=138) (n=137) (n=137) (n=412)
Blood EOS count, n (%)
≥250 cells/μL ********** ********* ********* ********** *********
<250 cells/μL ********* ********* ********* ********** *********
ICS level, n (%)
Medium ********* ********* ********* ********** *********
High ********** ********* ********* ********** *********
Study site, n (%)
Non-Japanese *********** ********** ********** ********** **********
Japanese ******* ******* ******* ******** *******
Maintenance OCS use, n (%)
Yes ********** ******* ******** ******** *********
No *********** ********** ********** ********** **********
Pre-BD FEV1, L
Mean (SD) ************* ************* ************* ************* *************
Pre-BD FEV1, % predicted
Mean (SD) ************* ************* ************* ************* *************
Post-BD FEV1 reversibility, %
Mean (SD) ************** ************** ************* ************* *************
Number of asthma exacerbations in the past 12 months, n (%)
1 or 2 *********** ********** ********** ********** **********
≥3 ********* ********* ********* ********* *********
ACQ-6
Mean (SD) *********** *********** *********** *********** ***********
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NCT02054130 (PATHWAY) Tezepelumab Placebo Q2W
Baseline characteristics (n=138)
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
(n=138) (n=137) (n=137) (n=412)
Overall AQLQ(S)+12
Mean (SD) *********** *********** *********** *********** ***********
Overall Asthma Symptom Score
Mean (SD) *********** *********** *********** *********** ***********
Central blood EOS count, cells/μL
≥300, n (%) ********** ********* ********* ********** *********
<300, n (%) ********** ********* ********* ********** *********
Mean (SD) ************* ************* ************* ************* *************
Median ****** ***** ***** ***** *****
Th2 Status, n (%)
High ********** ********* ********* ********** *********
Low ********** ********* ********* ********** *********
Total Serum IgE, IU/mL
Mean (SD) *************** **************** *************** **************** ****************
Median ******* ******* ****** ******* ******
FeNO, ppb
≥24, n (%) ********** ********* ********* ********** *********
<24, n (%) ********** ********* ********* ********** *********
Mean (SD) ************* ************* ************* ************* *************
Median ****** ***** ***** ***** *****
Allergic asthma status, n (%)
Allergic ********** ********* ********* ********** *********
Non-allergic ********** ********* ********* ********** *********
Geographical Region, n (%)
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Table 13: PATHWAY baseline asthma history (ITT)

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NCT02054130 (PATHWAY) Tezepelumab Placebo Q2W Total
Baseline characteristics (n=138) (N=550)
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
(n=138) (n=137) (n=137) (n=412)
Childhood asthma, n (%)
Yes ********** ********* ********* ********* ********* **********
No *********** ********** ********* ********** ********** **********
NA ******** ******* ******* ******** ******* ********
Age of onset, childhood asthma
n *** ** ** ** ** ***
Mean (SD) ********* ********* ********* ********* ********* *********
Median **** *** *** *** *** ***
Min, Max ******** ******* ******* ******* ******* *******
Age of adult asthma onset
n *** *** *** *** *** ***
Mean (SD) *********** *********** *********** *********** *********** ***********
Median **** **** **** **** **** ****
Min, Max ********* ******** ******** ******** ******** ********
Family history: parents, n (%)
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NCT02054130 (PATHWAY) Tezepelumab Placebo Q2W Total
Baseline characteristics (n=138) (N=550)
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
(n=138) (n=137) (n=137) (n=412)
Yes ********** ********* ********* ********* ********* *********
No *********** ********** ********** ********** ********** **********
NA ******** ******* ******** ******** ******** ********
Family history: siblings, n (%)
Yes ******** ******** ******* ******** ******* ********
No *********** ********** ********** ********** ********** **********
NA ******* ******** ******** ******** ******** ********
Exacerbation history: number of exacerbations in the past 12 months, n (%)
1 ******** ******* ******* ******* ******* ********
2 *********** ********** ********** ********** ********** **********
3 ********** ********* ********* ********* ******** *********
4 ******** ******* ******* ******* ******* ********
5 ******** ******* ******* ******* ******* ********
6 ******** ******* * ******* ******* ********
7 ******** * ******* ******* ******* *******
8 ******** * * ******* * *******
9 ** * ******* ******* * *******
10 ******** ******* * ******* ******* *******
11 * * * * * *
12 * * ******* ******* * *******
Night-time awakenings (last 3 months), n (%)
0–1/month ********** ********* ********* ********* ********* *********
3–4/month ********** ********* ********* ********** ********* **********
>2/week ********** ********* ********* ********** ********* **********
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Company evidence submission template for tezepelumab for treating severe asthma (ID3910)

© AstraZeneca (2022). All rights reserved

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NCT02054130 (PATHWAY) Tezepelumab Placebo Q2W Total
Baseline characteristics (n=138) (N=550)
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
(n=138) (n=137) (n=137) (n=412)
NA ******** ******* ******* ******* ******* *******
SABA use (last 3 months), n (%)
0–2 days/week ********** ********* ********* ********* ********* **********
3–6 days/week ********** ********* ********* ********** ********* **********
7 days/week ********** ********* ********* ********** ********* **********
NA ******** * ******* ******* ******* *******
Cough, wheeze, shortness of breath, chest tightness (last 3 months), n (%)
0–2 days/week ********** ********* ********* ********* ********* *********
3–6 days/week ********** ********* ********* ********** ********* **********
7 days/week ********** ********* ********* ********** ********* **********
NA ******** * ******* ******* ******* *******
Interference with normal activity (last 3 months), n (%)
None ********* ******** ******** ******** ********* ********
Minor ********** ********* ********* ********* ********* **********
Some ********** ********* ********* ********** ********* **********
Extremely ********* ******* ******* ******** ******* ********
NA ** ******* ******* ******* ******* *******
OCS bursts, last 3 months
Median ****** ****** ****** ****** ****** ******
Min, Max ****** ****** ****** ****** ****** ******
ICS use, n (%)
Subjects using ≥1 ICS ********** ********* ********* ********* ********* ***
Budesonide ********** ********* ********* ********** ********* ***
Fluticasone ********** ********* ********* ********** *********
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Company evidence submission template for tezepelumab for treating severe asthma (ID3910)

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NCT02054130 (PATHWAY) Tezepelumab Placebo Q2W Total
Baseline characteristics (n=138) (N=550)
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
(n=138) (n=137) (n=137) (n=412)
Fluticasone propionate ********** ********* ********* ********* ********* NR
Beclometasone dipropionate ********* ********* ********* ********* ********* NR
Beclometasone ******** ******* ******* ******** ******* NR
Fluticasone furoate ******** ******* ******* ******** ******* NR
Mometasone furoate ******** ******* ******* ******* *** NR
Ciclesonide ******** ******* ********* ******* ******* NR
Mometasone ******** ******* ******* ******* ******* NR
mOCS use, n (%)
Subjects using ≥1 OCS ********** ******* ******** ******** ******** NR
Methylprednisolone ********* ******* ******* ******** ******* NR
Prednisone ******** ******* ******* ******* ******* NR
Prednisolone ******** ******* ******* ******* ******* NR
Triamcinolone ******** ******* ******* ******* ******* NR
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Abbreviations: ICS, inhaled corticosteroid; ITT, intent-to-treat, max, maximum; min, minimum; mOCS, maintenance oral corticosteroid treatment; NA, not applicable; OCS, oral corticosteroid; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SABA, short-acting beta agonist; SD, standard deviation.

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B.2.3.3.2 NAVIGATOR

Baseline demographic and clinical characteristics of subjects enrolled in NAVIGATOR are summarised in Table 14 and Table 15, respectively. (Additional baseline characteristics of lesser importance are presented in Appendix M).

Subject demographic and clinical characteristics were generally balanced between the tezepelumab and placebo trial arms. Overall, the study population represented the intended population of severe, uncontrolled asthma.

The majority of subjects in the full analysis set (FAS) (see Section B.2.4.2 for definitions of analysis sets) were white (62.2%), female (63.5%), and not Hispanic or Latino (84.5%). The mean age was 49.5 years (range: 12–80 years), and the average BMI was 28.49. A total of 82 subjects were aged ≥12 to 17 years (i.e. adolescents [7.7%]) and the remaining subjects were adults, 170 of whom (16.1%) were aged ≥65 to 80 years (Table 14).

In terms of asthma characteristics at baseline, overall:

• 9.4% of subjects were receiving mOCS at baseline

• 58.4% of subjects had EOS<150 cells/µL and 41.6% had EOS ≥300 cells/µL

• 68.5% of subjects had positive aeroallergen-specific IgE status (FEIA)

• 99.9% of subjects had experienced ≥2 exacerbations in the prior 12 months

• 40.0% of subjects had experienced ≥3 exacerbations in the prior 12 months

• 16.8% of subjects had experienced ≥4 exacerbations in the prior 12 months.

Table 14: NAVIGATOR baseline demographic characteristics (FAS)

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NCT03347279 (NAVIGATOR) Tezepelumab Placebo Total
Baseline [†] characteristics (n=528) (n=531) (N=1,059)
Age, years
Mean (SD) 49.9 (16.3) 49.0 (15.9) 49.5 (16.1)
Median **** **** ****
Min, Max ****** ****** ******
Age group, n (%)
Adolescent (≥12 to <18 years) ******** ******** ********
Adult (≥18 to <65 years) ********** ********** **********
Adult (≥65 years) ********* ********* **********
Adult (≥18 years) ********** ********** **********
Sex, n (%)
Male 193 (36.6) 194 (36.5) 387 (36.5)
Female 335 (63.4) 337 (63.5) 672 (63.5)
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NCT03347279 (NAVIGATOR) Tezepelumab Placebo Total
Baseline [†] characteristics (n=528) (n=531) (N=1,059)
Race, n (%)
White 332 (62.9) 327 (61.6) 659 (62.2)
Black or African American ******** ******** ********
Asian ********** ********** **********
Native Hawaiian or Other ******* ******* *******
Pacific Islander
American Indian or Alaska ******* ******* *******
Native
Other ******** ******** ********
Ethnic group, n (%)
Hispanic or Latino ********* ********* **********
Not Hispanic or Latino ********** ********** **********
BMI, kg/m [2]
Mean (SD) 28.69 (7.09) 28.30 (6.89) 28.49 (6.99)
Median ***** ***** *****
Min, Max ********** ********** **********
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Abbreviations: BMI, body mass index; FAS, full analysis set; max, maximum; min, minimum; SD, standard deviation. † Baseline was defined as the last non-missing measurement recorded on or prior to randomisation.

Table 15: NAVIGATOR baseline clinical characteristics (FAS)

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NCT03347279 (NAVIGATOR) Tezepelumab Placebo Total
Baseline [†] characteristics (n=528) (n=531) (N=1,059)
EOS, cells/µL
n 528 531 1,059
Mean (SD) 326.74 (293.33) 353.39 (488.40) 340.10 (403.15)
Median 250.00 250.00 250.00
Min, Max *********** *********** ************
EOS group, n (%)
<150 cells/µL ********** ********** **********
150 to <300 cells/µL ********** ********** **********
300 to <450 cells/µL ********* ********* **********
≥450 cells/µL ********** ********** **********
FeNO, ppb
n 522 527 1,049
Mean (SD) 41.38 (36.30) 46.27 (44.73) 43.83 (40.81)
Median 31.00 30.00 30.00
Min, Max 5.0, 235.0 5.0, 265.0 5.0, 265.0
FeNO group, n (%)
<25 ppb 213 (40.8) 220 (41.7) 433 (41.3)
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NCT03347279 (NAVIGATOR) Tezepelumab Placebo Total
Baseline [†] characteristics (n=528) (n=531) (N=1,059)
25 to <50 ppb ********** ********** **********
≥50 ppb ********** ********** **********
Number of exacerbations in the past 12 months, n (%)
0 ******* ******* *******
1 ******* ******* *******
2 ********** ********** **********
≥3 ********** ********** **********
Total IgE, IU/mL
n 528 531 1,059
Mean (SD) 515.68 (959.75) 614.05 (1159.49) 565.00 (1065.23)
Median 194.85 196.70 195.60
Min, Max ************* ************ *************
Aeroallergen-specific IgE status (FEIA), n (%)
Any FEIA positive ********** ********** **********
All FEIA negative ********** ********** **********
Unknown FEIA ******* ******** ********
Time since asthma diagnosis, years [‡]
n *** *** *****
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max ********* ********* *********
Time since asthma symptoms started, years [‡]
n *** *** *****
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max ********* ********* *********
Nasal polyps in the past 24 months, n (%)
Yes ******** ******** ********
No ********** ********** **********
FEV1 pre-BD, L
n *** *** *****
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max ********** ********** **********
FEV1 pre-BD, % PN
n *** *** *****
Mean (SD) *********** *********** ***********
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NCT03347279 (NAVIGATOR) Tezepelumab Placebo Total
Baseline [†] characteristics (n=528) (n=531) (N=1,059)
Median **** **** ****
Min, Max 18, 106 5, 127 15, 127
Reversibility in FEV1, L [§]
n *** *** *****
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max *********** *********** ***********
Reversibility in FEV1, % [§]
n *** *** *****
Mean (SD) *************** *************** ***************
Median ****** ****** ******
Min, Max ************** ************* **************
AQLQ(S)+12 total score [¶]
N *** *** *****
Mean (SD) *********** *********** ***********
Median **** **** ****
Min, Max ******** ******** ********
ACQ-6 score at baseline
n *** *** *****
Mean (SD) *********** *********** ***********
Median **** **** ****
Min, Max ******** ******** ********
Weekly mean daily ASD score [††]
n *** *** *****
Mean (SD) *********** *********** ***********
Median **** **** ****
Min, Max ******** ******** ********
ICS dose group, n (%)
Low ******* ******* *******
Medium ********** ********** **********
High ********** ********** **********
Taking OCS, n (%)
Yes 49 (9.3) 51 (9.6) 100 (9.4)
No 479 (90.7) 480 (90.4) 959 (90.6)
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Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; BD, bronchodilator; EOS, eosinophil; FAS, full analysis set; FEIA, fluorescent enzyme immunoassay; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IU, International Unit; max, maximum; min, minimum; OCS, oral corticosteroid; PN, predicted normal; ppb, parts per billion; SD, standard deviation. † Baseline was defined as the last non-missing measurement recorded on or prior to randomisation.

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‡ Calculated as (date of randomisation – date of asthma diagnosis/date asthma symptoms started +1) / 365.25. § Reversibility in FEV1 (L) was calculated as post-BD FEV1 (L) – pre-BD FEV1 (L). Reversibility in FEV1 (%) was calculated as (post-BD FEV1 (L) – pre-BD FEV1 (L)) / pre-BD FEV1 (L) × 100%. Current post-BD reversibility was defined as FEV1 ≥12% and ≥200 mL during screening (15–30 mins after administration of four puffs of albuterol/salbutamol). If both Visit 2 and Visit 2a values were available, the highest of the reversibility values, i.e. the largest difference (post-BD FEV1 – pre-BD FEV1) across the two visits was used to determine ‘Yes’ and ‘No.’ Inclusion into the study was based on current post-BD FEV1 reversibility or on documented historical reversibility.

¶ ACQLQ(S)+12 was defined as the unweighted mean of the responses to all questions in the questionnaire. ACQ-6 score was defined as the unweighted mean of the responses to six questions. If responses to any of the ACQLQ(S)+12 or ACQ-6 questions were missing, the total score for the tool was considered missing. If more than 3 days were missing within a week, the weekly mean was set to missing. No imputation was made for missing values.

†† Daily ASD score was defined as the mean of the 10 items recorded in the evening (five items) and the following morning (five items).

B.2.3.3.3 SOURCE

Baseline demographic and clinical characteristics of subjects enrolled in SOURCE are summarised in Table 16 and Table 17, respectively. (Additional baseline characteristics of lesser importance are presented in Appendix N).

The majority of subjects in the FAS (see Section B.2.4.2 for definitions of analysis sets) were White (84.0%), female (62.7%), *********************************** The mean age was 53.4 years (range 22–76 years) and the mean BMI was 29.37. All patients were aged ≥18 years and 20.0% were aged ≥65 years.

Overall, the study population represented the intended population of adults with severe, mOCS-dependent asthma, and characteristics were generally well balanced between trial arms.

In terms of asthma characteristics at baseline, overall:

• 100% of subjects were receiving mOCS at baseline

 ************************************************************************************************* ************************************************************************************************* ************************************************************************************************* *************************************************************************************************

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Table 16: SOURCE baseline demographic characteristics (FAS)

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NCT03406078 (SOURCE) Tezepelumab Placebo Total
Baseline [†] characteristics (n=74) (n=76) (N=150)
Age, years
n 74 76 150
Mean (SD) 53.5 (12.1) 53.4 (11.9) 53.4 (12.0)
Median **** **** ****
Min, Max ****** ****** ******
Age group, n (%)
Adult (≥18 to <65 years) ********* ********* **********
Adult (≥65 years) ********* ********* *********
Sex, n (%)
Male 25 (33.8) 31 (40.8) 56 (37.3)
Female 49 (66.2) 45 (59.2) 94 (62.7)
Race, n (%)
White 62 (83.8) 64 (84.2) 126 (84.0)
Black or African American 1 (1.4) 0 (0.0) 1 (0.7)
Asian 11 (14.9) 11 (14.5) 22 (14.7)
Native Hawaiian or Other ******* ******* *******
Pacific Islander
American Indian or Alaska ******* ******* *******
Native
Other ******* ******* *******
Ethnic group, n (%)
Hispanic or Latino ********* ********* *********
Not Hispanic or Latino ********* ********* **********
BMI, kg/m [2]
n 74 76 150
Mean (SD) 29.29 (6.67) 29.44 (7.44) 29.37 (7.04)
Median ***** ***** *****
Min, Max ********** ********** **********
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Abbreviations: BMI, body mass index; FAS, full analysis set; max, maximum; min, minimum; SD, standard deviation. † Baseline was defined as the last non-missing measurement recorded on or prior to randomisation.

Table 17: SOURCE baseline clinical characteristics (FAS)

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NCT03406078 (SOURCE) Tezepelumab Placebo Total
Baseline [† ] characteristics (n=74) (n=76) (N=150)
EOS, cells/µL
n 74 76 150
Mean (SD) 253.25 (203.12) 231.84 (153.81) 242.40 (179.55)
Median 215.00 200.00 200.00
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NCT03406078 (SOURCE) Tezepelumab Placebo Total
Baseline [† ] characteristics (n=74) (n=76) (N=150)
Min, Max ************* *********** ************
EOS group (cells/µL), n (%)
<150 27 (36.5) 24 (31.6) 51 (34.0)
150 to <300 19 (25.7) 28 (36.8) 47 (31.3)
300 to <450 ********* ********* *********
≥450 ******** ******** *********
FeNO (ppb)
n 68 69 137
Mean (SD) 38.71 (40.82) 42.35 (37.44) 40.54 (39.05)
Median 26.00 28.00 27.00
Min, Max ********** ********** **********
FeNO group (ppb), n (%)
<25 32 (47.1) 26 (37.7) 58 (42.3)
25 to <50 ********* ********* *********
≥50 ********* ********* *********
Total IgE (IU/mL)
n 73 76 149
Mean (SD) 298.71 (576.28) 300.89 (521.39) 299.82 (547.10)
Median 109.40 122.65 109.70
Min, Max ************ ************
Aeroallergen-specific IgE status (FEIA), n (%)
Any FEIA positive ********* ********* *********
All FEIA negative ********* ********* *********
Unknown FEIA ******* ******* *******
FEV1 pre-BD, L
n ** ** ***
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max ********** ********** **********
FEV1 pre-BD, % PN
n ** ** ***
Mean (SD) *********** *********** ***********
Median **** **** ****
Min, Max ******* ****** *******
FEF25–75% pre-BD, L/s
n ** ** ***
Mean (SD) ************* ************* *************
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NCT03406078 (SOURCE) Tezepelumab Placebo Total
Baseline [† ] characteristics (n=74) (n=76) (N=150)
Median ***** ***** *****
Min, Max ********** ********** **********
FVC pre-BD, L
n ** ** ***
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max ********** ********** **********
FEV1/FVC pre-BD, %
n ** ** ***
Mean (SD) *************** *************** ***************
Median ****** ****** ******
Min, Max ************ ************ ************
Post-BD FEV1 reversibility, n (%) [‡]
Yes (current) ********* ********* **********
No (historical) ********* ********* *********
Reversibility in FEV1, L [‡]
n ** ** ***
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max *********** *********** ***********
Reversibility in FEV1, % [‡]
n ** ** ***
Mean (SD) *************** *************** ***************
Median ****** ****** ******
Min, Max ************ ************* *************
Reversibility in FEV1, n (%) [‡]
n ** ** ***
<12% ********* ********* *********
≥12 and <15% ********* ******* *********
≥15% ********* ********* *********
Time since asthma diagnosis, years [§]
n ** ** ***
Mean (SD) ************* ************* *************
Median ***** ***** *****
Min, Max ********* ********* *********
Number of exacerbations per subject in the last 12 months, n (%)
1 ********* ********* *********
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NCT03406078 (SOURCE) Tezepelumab Placebo Total
Baseline [† ] characteristics (n=74) (n=76) (N=150)
2 ********* ********* *********
3 ******** ********* *********
4 ******* ******* *******
5 ******* ******* *******
7 ******* * *******
15 ******* * *******
n ** ** ***
Mean (SD) ********* ********* *********
Median *** *** ***
Min, Max ***** **** *****
Number of exacerbations per subject in the last 12 months resulting in temporary increase in maintenance
OCS dose for ≥3 consecutive days, n (%)
0 ********* ********* *********
1 ********* ********* *********
2 ********* ********* *********
3 ******* ********* *********
4 ******* ******* *******
n ** ** ***
Mean (SD) ********* ********* *********
Median *** *** ***
Min, Max **** **** ****
Number of exacerbations per subject in the last 12 months resulting in emergency room visit with SCS
treatment, n (%)
0 ********* ********* **********
1 ******* ******* *******
2 ******* ******* *******
3 * ******* *******
n ** ** ***
Mean (SD) ********* ********* *********
Median *** *** ***
Min, Max **** **** ****
Number of exacerbations per subject in the last 12 months resulting in hospitalisation with/without SCS
treatment, n (%)
0 ********* ********* **********
1 ********* ******* *********
2 ******* ******* *******
n ** ** ***
Mean (SD) ********* ********* *********
Median *** ***
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NCT03406078 (SOURCE) Tezepelumab Placebo Total
Baseline [† ] characteristics (n=74) (n=76) (N=150)
Min, Max **** **** ****
ICS dose group, n (%)
Low ******* ******* *******
Medium ******* ******* *******
High ********* ******** **********
OCS, n (%)
Yes 74 (100) 76 (100) 150 (100)
No 0 (0.0) 0 (0.0) 0 (0.0)
Daily OCS dose, n (%)
≤10 mg ********* ********* **********
>10 mg ********* ********* *********
7.5 mg ********* ********* *********
9 mg ******* ******* *******
10 mg ********* ********* *********
12.5 mg ******* ******* *******
15 mg ******* ******** *********
20 mg ******* ******* ********
25 mg ******* ******* *******
30 mg ******* ******* *******
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Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; BD, bronchodilator; EOS, eosinophil; FAS, full analysis set; FEIA, fluorescent enzyme immunoassay; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IU, International Unit; max, maximum; min, minimum; OCS, oral corticosteroid; PN, predicted normal; ppb, parts per billion; SCS, systemic corticosteroid; SD, standard deviation.

† Baseline was defined as the last non-missing measurement recorded on or prior to randomisation.

‡ Reversibility in FEV1 (L) was calculated as post-BD FEV1 (L) – pre-BD FEV1 (L). Reversibility in FEV1 (%) was calculated as (post-BD FEV1 (L) – pre-BD FEV1 (L)) / pre-BD FEV1 (L) × 100%. Current post-BD reversibility was defined as FEV1 ≥12% and ≥200 mL during screening (15–30 mins after administration of four puffs of albuterol/salbutamol). If both Visit 1 and Visit 2 values were available, the highest of the reversibility values, i.e., the largest difference (post-BD FEV1 – pre-BD FEV1) across the two visits was used to determine ‘Yes’ and ‘No.’ Inclusion into the study was based on current post-BD FEV1 reversibility or on documented historical reversibility.

§ Time since asthma diagnosis was calculated as (date of randomisation – date of diagnosis/date asthma symptoms started + 1) / 365.2.

B.2.4 Statistical analysis and definition of study groups in the relevant clinical effectiveness evidence

B.2.4.1 Hypotheses and methods for statistical analysis

Overviews of the approaches to statistical analysis in the pivotal Phase 2 RCT,

PATHWAY, and that of its follow-on, pivotal Phase 3 RCT, NAVIGATOR, are provided in Table 18 and Table 19, respectively.

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A summary of the approach to statistical analysis in the Phase 3 SOURCE trial is provided in Table 20.

Schematics of the multiple testing procedures used in the NAVIGATOR and SOURCE trials are provided in Figure 9 and Figure 10.

B.2.4.1.1 PATHWAY

Table 18: Summary of statistical analysis approach in PATHWAY

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PATHWAY
Hypothesis objective The primary analysis was based on the ITT population. The three primary
comparisons were as follows:
 Tezepelumab 280 mg Q2W versus placebo
 Tezepelumab 210 mg Q4W versus placebo
 Tezepelumab 70 mg Q4W versus placebo
Statistical analysis The primary endpoint was tested using a stepdown method for the three
hypotheses (from the high dose [280 mg] to the medium dose [210 mg] to the
low dose [70 mg] when compared with placebo) to maintain the overall Type I
error rate at 0.1 (2-sided). No multiplicity adjustments were applied for
secondary endpoints and supportive subgroup analyses of the primary and
secondary endpoints.
Sample size, power Sample size calculations were performed for the primary endpoint of AAER,
calculation based on the negative binomial distribution. Approximately 552 subjects were
to be randomised in the study, with approximately 85% of the total number of
subjects designated as non-Japanese subjects (i.e. subjects enrolled at sites
outside of Japan) and approximately 15% of the total number of subjects
designated as Japanese subjects (i.e. subjects enrolled at sites in Japan).
A total of 124 subjects per treatment group were required to detect a 40%
reduction in AAER for each tezepelumab dose group compared with placebo
group, assuming an AER of 0.7 in the placebo group, a 2-sided significance
level of 0.1, 80% power, and a dispersion parameter of 0.7 based on the
negative binomial distribution. The 2-sided significance level of 0.1 was applied
to a hypothesis of comparing a single tezepelumab dose group to placebo
group. The AER of 0.7 in the placebo group was estimated based on internal
and external studies with a similar subject population (before considering
dropouts). The dispersion parameter of 0.7 was selected from the
mepolizumab study in subjects with severe, eosinophilic asthma (111). The
sample size was increased to 138 per treatment group to accommodate a 10%
loss of information due to dropouts. The minimal detectable difference was
approximately a 28% reduction in AAER. The minimum acceptable reduction in
the AAER of 40% for the study population was based upon an expected
reduction of approximately 50% in a Th2-driven asthma population, which
appeared to be achievable in competitors which targeted Th2 cytokines (e.g.
IL-13, IL-5) and a more modest reduction in a non-Th2 asthma population for
which there were little data and no current competitors.
Stratification of subjects Prior to randomisation, subjects were stratified by study site (non-Japanese
and Japanese), and then blood EOS count (≥ or <250 cells/μL) and by ICS
dose level (medium or high). Subjects taking mOCS were automatically
assigned to the high-dose ICS strata.
There was a total of eight strata: four strata for non-Japanese subjects and four
identical strata for Japanese subjects. Subjects were stratified as follows:
 High blood EOS count (≥250 cells/μL) and medium ICS dose level
 High blood EOS count (≥250 cells/μL) and high ICS dose level
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Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; BD, bronchodilator; CFB, change from baseline; EOS, eosinophil; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; mOCS, maintenance oral corticosteroid treatment; PBO, placebo; teze, tezepelumab.

B.2.4.1.2 NAVIGATOR

Table 19: Summary of statistical analysis approach in NAVIGATOR

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NAVIGATOR
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NAVIGATOR
 H04a: Diff in mean CFB in AQLQ(S)+12 total score at 52 weeks (teze–PBO) = 0
 H14a: Diff in mean CFB in AQLQ(S)+12 total score at 52 weeks (teze–PBO) ≠ 0
A diff in means >0 indicates superiority of teze.
 H04b: Diff in mean CFB in ACQ-6 score at 52 weeks (teze–PBO) = 0
 H14b: Diff in mean CFB in ACQ-6 score at 52 weeks (teze–PBO) ≠ 0
A diff in means <0 indicates superiority of teze.
 H05: Diff in mean CFB in weekly mean ASD score at 52 weeks (teze–PBO) = 0
 H15: Diff in mean CFB in ASD score at 52 weeks (teze–PBO) ≠ 0
A diff in means <0 indicates superiority of teze.
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NAVIGATOR
subjects in the screening/run-in period in the closed subgroup were not randomised and
were considered screen failures.
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NAVIGATOR interaction were included as factors in this model. Baseline of the corresponding endpoint was also included in the model as a continuous linear covariate. Unstructured covariance was assumed to model the relationship between pairs of response variables taken at different visits on the same subject. If the MMRM model failed to converge with unstructured covariance, a pre-specified approach for selecting a simpler covariance structure was used. The Kenward-Roger approximation to estimating the degrees of freedom was used for tests of fixed effects derived from the MMRM model. The consistency of treatment effects across continuous and categorical demographic/baseline variables was investigated in a similar manner to the primary endpoint. In the case of categorical variables, appropriate terms were added to the MMRM model, including a treatment by visit by subgroup interaction term, to enable the treatment effects within each subgroup category at Week 52 to be estimated.

Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; BD, bronchodilator; CFB, change from baseline; diff, difference; EOS, eosinophil; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IWRS, Interactive Web Response System; MMRM, mixed-effects model for repeated measures; mOCS, maintenance oral corticosteroid treatment; PBO, placebo; teze, tezepelumab.

† This was to support US FDA breakthrough designation in patients without an eosinophilic phenotype.

Figure 9: Multiple testing procedure used in NAVIGATOR

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Abbreviations: AAER, annualised asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire 6-item; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; BD, bronchodilator; FEV1, forced expiratory volume in the first second.

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B.2.4.1.3 SOURCE

Table 20: Summary of statistical analysis approach in SOURCE

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SOURCE
Hypothesis The following 2-sided hypotheses were evaluated:
objective Primary endpoint (all subjects):
 H01: Cumulative odds ratio of percentage reduction category from baseline in daily
OCS dose at 48 weeks whilst not losing asthma control (teze/PBO) = 1, vs
 H11: Cumulative odds ratio of percentage reduction category from baseline in daily
OCS dose at 48 weeks whilst not losing asthma control (teze/PBO) ≠ 1
For five ordered categories, there were four possible cumulative odds for each treatment
group, corresponding to the four different possible binary splits, which were defined as
follows:
 Category 1 vs categories 2, 3, 4, 5
 Categories 1, 2 vs categories 3, 4, 5
 Categories 1, 2, 3 vs categories 4, 5
 Categories 1, 2, 3, 4 vs category 5
Where the ordered categories for OCS daily dose reduction were in turn defined as:
 Category 1: 90–100% reduction
 Category 2: 75–<90% reduction
 Category 3: 50–<75% reduction
 Category 4: >0–<50% reduction
 Category 5: no reduction or an increase
This hypothesis assumed that the four possible odds ratios between the two treatments
as defined above were the same (proportional odds assumption).
The direction of superiority of teze is indicated by an odds ratio >1.
Key secondary endpoints (all subjects):
 H02: AAER ratio over 52 weeks (teze/PBO) = 1, vs
 H12: AAER ratio over 52 weeks (teze/PBO) ≠ 1
Statistical A hierarchical testing strategy (illustrated in Figure 10) was implemented to test for
analysis superiority of tezepelumab over placebo in the primary and key secondary endpoints,
whilst controlling the overall Type 1 error rate at 0.05 (2-sided).
The 2-sided hypotheses outlined above were evaluated at the 0.05 significance level. All
other hypothesis testing in the study was considered exploratory.
To account for multiplicity when testing the primary and secondary endpoints, a
hierarchical testing procedure was applied, with the hypotheses tested as outlined above:
Level 1:
The null hypothesis H01 was tested at a 2-sided significance with regard to the primary
endpoint (percentage reduction category from baseline in daily OCS dose at 48 weeks
whilst not losing asthma control).
Level 2:
If H01 was rejected, the null hypothesis H02 was tested at a 2-sided significance level
with regard to the key secondary endpoint (AAER ratio over 48 weeks).
Sample size, Approximately 152 subjects were to be randomly assigned to study treatment using 1:1
power allocation between the two treatments. Since the primary analysis of the primary endpoint
calculation was to include all randomised subjects as far as possible, no need was envisaged to
adjust the number of subjects planned to be randomised in order to obtain a number of
evaluable subjects.
With 76 subjects per treatment group, it was estimated that, using a 2-sided 5%
significance level, the power to reject the null hypothesis for the primary endpoint of OCS
reduction would be at least 90%, assuming:
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SOURCE actually received. This analysis therefore included all available data after treatment discontinuation until the end of the planned treatment period. Subjects were encouraged to continue to undergo applicable study-related visits/procedures for the full 48-week period even after premature discontinuation of investigational product. Consequently, subjects lost to follow-up, subjects who died, and subjects who withdraw their consent were the only source of missing information for the primary analysis. Missing data from early study withdrawal were modelled based on what was observed during the study using direct likelihood approaches – a valid approach under the assumption that data were missing at random. AAER in the tezepelumab group was compared with that seen in the placebo group using a negative binomial model. This model was used to estimate the rate ratio and its 95% confidence interval. The response variable in the model was the number of asthma exacerbations experienced by a subject over the 48-week planned treatment period (or shorter duration if not followed up for the full 48 weeks). Treatment, region and history of exacerbations (≤2 or >2 in previous 12 months) were included as factors in this model. The logarithm of the time at risk (in years) for exacerbation in the study was used as an offset variable in the model, to adjust for subjects having different follow-up times during which the events occurred. Time during an exacerbation and the 7 days following an exacerbation in which a new exacerbation cannot occur, were not included in the calculation of time at risk for exacerbation.

Abbreviations: AAER, annualised asthma exacerbation rate; EOS, eosinophil; IWRS, Interactive Web Response System; OCS, oral corticosteroid; PBO, placebo; teze, tezepelumab.

Figure 10: Testing procedure used in SOURCE

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Abbreviations: AAER, annualised asthma exacerbation rate.

B.2.4.2 Definitions of analysis sets

Analysis sets used in the PATHWAY, NAVIGATOR, and SOURCE trials are defined in Table 21, Table 22, and

Table 23, respectively

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Table 21: Definitions of analysis sets (PATHWAY)

Abbreviations: ITT, intent-to-treat.

Table 22: Definitions of analysis sets (NAVIGATOR)

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Analysis set
All subjects analysis All enrolled subjects who signed the informed consent form, including screening
set failures.
Randomised All subjects randomised to study treatment, irrespective of whether investigational
subjects analysis set product was subsequently taken.
Full analysis set All subjects randomised to study treatment who received at least one dose of
investigational product, irrespective of their protocol adherence, and continued
participation in the study.
Safety analysis set All subjects who received at least one dose of investigational product.
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Table 23: Definitions of analysis sets (SOURCE)

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----- Start of picture text -----
Analysis set
All subjects analysis All enrolled subjects who signed the informed consent form, including screening
set failures.
Randomised All subjects randomised to study treatment, irrespective of whether investigational
subjects analysis set product was subsequently taken.
Full analysis set All subjects randomised to study treatment who received at least one dose of
investigational product, irrespective of their protocol adherence, and continued
participation in the study.
Safety analysis set All subjects who received at least one dose of investigational product.
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B.2.4.3 Participant flow in the relevant randomised controlled trials

B.2.4.3.1 PATHWAY

A total of 918 subjects were enrolled in PATHWAY, of which 550[a] were randomised to treatment with either:

a A total of 584 subjects were actually randomised; however 34 subjects from one site in the US were excluded from the study due to anomalous data and noncompliance with good clinical practice

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• Tezepelumab 70 mg once every 4 weeks (Q4W) (n=138), or

• Tezepelumab 210 mg Q4W (n=137), or

• Tezepelumab 280 mg once every two weeks (Q2W) (n=137), or

• Placebo (n=138)

Subject numbers in each analysis set of PATHWAY are presented in Table 24.

Of the 550 subjects randomised to treatment, 496 subjects (90.2%) completed treatment, and the remaining 54 subjects (9.8%) did not complete treatment. A total of 494 subjects (89.8%) completed the study (Table 25).

Table 24: Numbers of subjects in each analysis set in PATHWAY

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Population Tezepelumab Placebo Total
70 mg 210 mg 280 mg Total
Q4W Q4W Q2W
Subjects randomised 138 137 137 412 138 550
ITT population [†] 138 137 137 412 138 550
As-treated population [‡] 138 137 137 412 138 550
Per-protocol population [§] 114 106 108 328 121 449
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Abbreviations: ITT, intent-to-treat; Q2W, once every 2 weeks; Q4W, once every 4 weeks. † Subjects who were randomised and received any investigational product were included in the ITT population, and subjects were analysed according to their randomised treatment group. This was the primary efficacy population. ‡ Subjects who received any investigational product were included in the as-treated population and subjects were analysed according to the treatment they actually received. § Subjects who did not have significant protocol violations and received at least 80% of the intended doses of investigational product were included in the per-protocol population, and subjects were analysed according to the treatment they actually received.

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Table 25: Completions/withdrawals in PATHWAY

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Tezepelumab Placebo Total
70 mg Q4W 210 mg Q4W 280 mg Q2W Total
Randomised and received treatment, n (%) 138 137 137 412 138 550
Completed treatment, n (%) 129 (93.5) 121 (88.3) 117 (85.4) 367 (89.1) 129 (93.5) 496 (90.2)
Did not complete treatment, n (%) 9 (6.5) 16 (11.7) 20 (14.6) 45 (10.9) 9 (6.5) 54 (9.8)
Reasons for not completing treatment, n (%)
Lost to follow-up 0 1 (0.7) 2 (1.5) 3 (0.7) 0 3 (0.5)
Other [†] 6 (4.3) 6 (4.4) 7 (5.1) 19 (4.6) 3 (2.2) 22 (4.0)
Withdrawal of consent 3 (2.2) 7 (5.1) 8 (5.8) 18 (4.4) 5 (3.6) 23 (4.2)
Adverse event 0 2 (1.5) 3 (2.2) 5 (1.2) 1 (0.7) 6 (1.1)
Completed study, n (%) [‡] 127 (92.0) 122 (89.1) 115 (83.9) 364 (88.3) 130 (94.2) 494 (89.8)
Reasons for not completing study, n (%)
Withdrawal of consent 4 (2.9) 7 (5.1) 10 (7.3) 21 (5.1) 4 (2.9) 25 (4.5)
Death 1 (0.7) 0 0 1 (0.2) 0 1 (0.2)
Lost to follow-up 0 1 (0.7) 2 (1.5) 3 (0.7) 0 3 (0.5)
Other [§] 6 (4.3) 7 (5.1) 10 (7.3) 23 (5.6) 4 (2.9) 27 (4.9)
Non-Japanese, n (%) 135 (97.8) 132 (96.4) 132 (96.4) 399 (96.8) 132 (95.7) 531 (96.5)
Japanese, n (%) 3 (2.2) 5 (3.6) 5 (3.6) 13 (3.2) 6 (4.3) 19 (3.5)
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Abbreviations: AE, adverse event; Q2W, every 2 weeks; Q4W, every 4 weeks; SAE, serious adverse event.

† Other reasons included subject’s decision, adverse event, failure to meet eligibility criteria, visit out of window, sponsor decision, lack of available investigational product, pregnancy, use of prohibited medication, and missed dose.

‡ Completion of study was defined as the treated subject was followed through to the last protocol-specified visit/assessment.

§ Other reasons included missed dose, subject’s decision, adverse event, serious adverse event, failure to meet eligibility criteria, lack of available investigational product, sponsor decision, pregnancy, and use of prohibited medication.

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B.2.4.3.2 NAVIGATOR

A total of 2,420 subjects were enrolled in NAVIGATOR, of which 1,061 were randomised to treatment during the double-blind phase with either:

• Tezepelumab 210 mg Q4W (n=529), or

• Placebo (n=532)

Subject numbers in each analysis set of NAVIGATOR are presented in Table 26.

Table 26: Numbers of subjects in each analysis set in NAVIGATOR

Abbreviations: Q4W, once every 4 weeks. † All subjects randomised to study treatment who received at least one dose of investigational product, irrespective of their protocol adherence and continued participation in the study. ‡ All subjects who received at least one dose of investigational product.

A CONSORT flow chart for NAVIGATOR is presented in Figure 11. Of the 1,061 subjects randomly assigned to treatment, 1,059 proceeded to receive treatment. A total of 966 (91.0%) subjects completed treatment and 93 (8.7%) subjects withdrew (Table 27). Two randomised patients (one in each treatment group) did not receive any treatment. A total of 60 (5.7%) subjects discontinued treatment but completed study assessments. The most common reason for treatment discontinuation was withdrawal by the subject. A total of 954 (89.9%) subjects completed the whole trial (i.e. completed treatment and study).

In the tezepelumab group, a total of 415 (78.0%) subjects entered an extension study (DESTINATION) while 72 (14.8%) in this group completed the follow-up period but did not enter the extension study.

Table 27: Completions/withdrawals in NAVIGATOR

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Tezepelumab Placebo Total
210 mg Q4W
Randomised, n (%) 529 (100.0) 532 (100.0) 1,061 (100.0)
Received treatment, n (%) 528 (99.8) 531 (99.8) 1,059 (99.8)
Completed treatment, n (%) 492 (93.0) 474 (89.1) 966 (91.0)
Discontinued treatment, n (%) 36 (6.8) 57 (10.7) 93 (8.8)
Withdrawal by subject 14 (2.6) 26 (4.9) 40 (3.8)
Adverse event 7 (1.3) 14 (2.6) 21 (2.0)
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Tezepelumab Placebo Total
210 mg Q4W
Protocol deviation 2 (0.4) 1 (0.2) 3 (0.3)
Development of study-specific withdrawal criteria 4 (0.8) 5 (0.9) 9 (0.8)
Lost to follow-up 5 (0.9) 0 (0.0) 5 (0.5)
Other 4 (0.8) 11 (2.1) 15 (1.4)
Due to COVID-19 pandemic 0 (0.0) 0 (0.0) 0 (0.0)
Discontinued treatment but completed study 22 (4.2) 38 (7.1) 60 (5.7)
assessments
Completed study, n (%) [†] 509 (96.2) 505 (94.9) 1,014 (95.6)
Withdrew from study, n (%) 16 (3.0) 23 (4.3) 39 (3.7)
Death 0 (0.0) 2 (0.4) 2 (0.2)
Lost to follow-up 5 (0.9) 2 (0.4) 7 (0.7)
Withdrawal by subject 8 (1.5) 15 (2.8) 23 (2.2)
Other 3 (0.6) 4 (0.8) 7 (0.7)
Due to COVID-19 pandemic 0 (0.0) 0 (0.0) 0 (0.0)
Completed treatment and completed study, n (%) 487 (92.1) 467 (87.8) 954 (89.9)
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Abbreviations: Q4W, once every 4 weeks.

† Includes subjects who completed treatment and study, and subjects who discontinued treatment but completed study assessments. A subject who did not participate in the extension study after the planned treatment period, and who did not complete the follow-up visits, was considered not to have completed the study (but to have completed treatment). Subjects discontinuing investigational product due to protocol deviation were those with severe non-compliance to the protocol.

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Figure 11: CONSORT diagram for NAVIGATOR

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Abbreviations: teze, tezepelumab; Q4W, once every 4 weeks.

a Informed consent received.

b Subjects who completed treatment and entered either the extension study or post-study follow-up. Four subjects in each treatment group completed treatment but were ongoing in safety follow-up at the time of the primary database lock.

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B.2.4.3.3 SOURCE

A total of 243 subjects were enrolled in SOURCE of which 150 were randomised to treatment with either:

• Tezepelumab 210 mg Q4W (n=74), or

• Placebo (n=76)

Subject numbers in each analysis set of SOURCE are presented in Table 28.

Table 28: Numbers of subjects in each analysis set in SOURCE

Abbreviations: Q4W, once every 4 weeks. † All subjects randomised to study treatment who received at least one dose of investigational product, irrespective of their protocol adherence and continued participation in the study. ‡ All subjects who received at least one dose of investigational product.

A CONSORT flow chart for SOURCE is presented in Figure 12. Of the 150 subjects randomly assigned to treatment, 137 (91.3%) subjects completed treatment and 13 (8.7%) subjects withdrew (Table 29). A total of six (4.0%) subjects discontinued treatment but completed study assessments. The most common reason for treatment discontinuation was withdrawal by the subject. A total of 135 (90.0%) subjects completed the whole trial (i.e. completed treatment and study).

Table 29: Completions/withdrawals in SOURCE

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Tezepelumab Placebo Total
210 mg Q4W
Randomised, n (%) 74 (100.0) 76 (100.0) 150 (100.0)
Received treatment, n (%) 74 (100.0) 76 (100.0) 150 (100.0)
Completed treatment, n (%) 66 (89.2) 71 (93.4) 137 (91.3)
Discontinued treatment, n (%) 8 (10.8) 5 (6.6) 13 (8.7)
Withdrawal by subject 4 (5.4) 2 (2.6) 6 (4.0)
Adverse event 1 (1.4) 2 (2.6) 3 (2.0)
Development of study-specific withdrawal criteria 1 [†] (1.4) 0 (0.0) 1 (0.7)
Lost to follow-up 0 (0.0) 1 (1.3) 1 (0.7)
Other 2 (2.7) 0 (0.0) 2 (1.3)
Due to COVID-19 pandemic 0 (0.0) 0 (0.0) 0 (0.0)
Discontinued treatment but completed study 4 (5.4) 2 (2.6) 6 (4.0)
assessments
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Tezepelumab Placebo Total
210 mg Q4W
Completed study, n (%) [‡] 68 (91.9) 73 (96.1) 141 (94.0)
Withdrew from study, n (%) 6 (8.1) 3 (3.9) 9 (6.0)
Death 1 (1.4) 0 (0.0) 1 (0.7)
Lost to follow-up 0 (0.0) 1 (1.3) 1 (0.7)
Withdrawal by subject 5 (6.8) 2 (2.6) 7 (4.7)
Due to COVID-19 pandemic 0 (0.0) 0 (0.0) 0 (0.0)
Completed treatment and completed study, n (%) 64 (86.5) 71 (93.4) 135 (90.0)
----- End of picture text -----

Abbreviations: Q4W, once every 4 weeks.

† Subject withdrew from the study as they were unable to continue due to an adverse event (preferred term: invasive breast carcinoma).

‡ Includes subjects who completed treatment and study, and subjects who discontinued treatment but completed study assessments. A subject who did not participate in the extension study after the planned treatment period, and who did not complete the follow-up visits, was considered not to have completed the study (but to have completed treatment). Subjects discontinuing investigational product due to protocol deviation were those with severe non-compliance to the protocol. Subjects who were not randomised included subjects not eligible to start the optimisation phase as well as subjects for whom oral corticosteroids optimisation was not achieved.

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Figure 12: CONSORT diagram for SOURCE

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Abbreviations: teze, tezepelumab; Q4W, once every 4 weeks. a Informed consent received.

b Subjects who completed treatment and entered either the extension study or post-study follow-up.

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B.2.5 Quality assessment of the relevant clinical effectiveness evidence

The results of the quality assessments of each of the three pivotal trials (PATHWAY, NAVIGATOR, and SOURCE) are presented in Table 30.

The trials were well conducted and methodologically robust. Randomisation to tezepelumab or placebo was achieved via a central Interactive Web Response System (IWRS), and packaging and preparation of investigational products was undertaken by an independent product manager (e.g. a pharmacist or study nurse) to ensure all sponsor and investigational site staff were blinded with regard to the treatment administered.

PATHWAY was a Phase 2, randomised, double-blind, placebo-controlled dose-ranging study. Patients were appropriately randomised and demographics/characteristics were balanced between the trial arms. Staff administering the trial agents were unaware of trial arm assignments; however, it was unclear who was blinded across the entire study, despite it being described as double-blind. The study withdrawal rate was higher in the high dose tezepelumab arm than in the medium/low dose and placebo arms. Efficacy and safety analyses were conducted appropriately (Table 30).

NAVIGATOR was a Phase 3, randomised, double-blind, placebo-controlled study. Patients were appropriately randomised and demographics/characteristics were balanced between trial arms. All participants, sponsor staff, and investigational site staff were blinded. More patients discontinued treatment or the study in the placebo arm versus the tezepelumab arm. Efficacy and safety analyses were conducted appropriately and sensitivity analyses showed that missing data did not impact the overall result (Table 30).

SOURCE was a Phase 3, randomised, double-blind, placebo-controlled study. Patients were appropriately randomised and demographics/characteristics were balanced between the trial arms. All participants, sponsor staff, and investigational site staff were blinded. Study withdrawals were balanced between the trial arms. Efficacy and safety analyses were conducted appropriately and sensitivity analyses showed that missing data did not impact the overall result (Table 30).

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B.2.5.1 Relevance of trial populations to patients in England

Subjects enrolled in the PATHWAY, NAVIGATOR, and SOURCE trials were broadly reflective of severe asthma patients seen in clinical practice in England (70, 73). The majority of enrolled subjects (~60%) were female, 50–60% had baseline EOS <300 cells/μL, and 40–75% had experienced two exacerbations in the 12 months prior to enrolment (see Section B.2.3.3).

While none of the randomised subjects PATHWAY, NAVIGATOR, and SOURCE were from the UK, subgroup analysis of the primary efficacy outcome in each trial suggested there was little to no effect of subject ethnicity or geographic region on tezepelumab treatment response.

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Table 30: Quality assessment results for PATHWAY, NAVIGATOR, and SOURCE

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Trial number (acronym) PATHWAY (NCT02054130) NAVIGATOR (NCT03347279) SOURCE
Was randomisation carried Yes. Patients were randomly assigned Yes. Patients were randomly assigned in a Yes. Patients were randomly assigned
out appropriately? (1:1:1:1 ratio) according to a central 1:1 ratio via the interactive web response in a 1:1 ratio via an interactive web
interactive voice response or web- system/interactive voice response system. response system/interactive voice
response system and stratified Patients were stratified according to response system. Patients were
according to location, blood eosinophil location and age. stratified according to location.
count, and dose level of inhaled
glucocorticoids.
Was the concealment of Yes. Trial agents were similar in Yes. The randomisation code was assigned Yes. The randomisation code was
treatment allocation appearance and were administered by from a randomisation list prepared by a assigned from a randomisation list
adequate? staff who were unaware of the trial computerised system. prepared by a computerised system.
group assignments.
Were the groups similar at Yes. Demographics and disease Yes. Demographics and disease Yes. Demographics and disease
the outset of the study in characteristics were balanced between characteristics were balanced between the characteristics were balanced
terms of prognostic factors? the groups. groups. between the groups.
Were the care providers, Unclear. Study was reported as double- Yes. Study was reported as double-blind. Yes. Study was reported as double-
participants and outcome blind, but it was unclear who was All packaging and labelling of blind. All packaging and labelling of
assessors blind to blinded. investigational product was done in such investigational product was done in
treatment allocation? way as to ensure blinding for all sponsor such a way as to ensure blinding for
and investigational site staff. subject and all sponsor and
investigational site staff.
Were there any unexpected Yes. Patient disposition indicates that Yes. Patient disposition indicates that more No. Patient disposition indicated the
imbalances in drop-outs more patients withdrew from high dose patients discontinued treatment in the overall drop-outs were generally well-
between groups? (n=22) compared with medium dose placebo group (n=57) compared with balanced between treatment arms.
(n=15), low dose (n=11), and placebo tezepelumab (n=36). More patients
(n=8). discontinued the study in the placebo group
(n=23) compared with the tezepelumab
group (n=16).
Is there any evidence to No. Based on the manuscript (by Corren No. Based on the manuscript (by Menzies- No. Based on the clinical study report
suggest that the authors 2017) all outcomes are reported in Gow 2021) all outcomes are reported in all outcomes are reported in detail.
measured more outcomes detail. detail.
than they reported?
Did the analysis include an Yes. Efficacy analyses were based on Yes. Efficacy analysis of the primary Yes. Efficacy analysis of the primary
intention-to-treat analysis? ITT analysis, defined as all randomised outcome was based on all randomised outcome was based all subjects
If so, was this appropriate patients who received at least one dose patients who received at least one dose of randomised to study treatment who
and were appropriate of tezepelumab or placebo. tezepelumab or placebo. received at least one dose of
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----- Start of picture text -----
Trial number (acronym) PATHWAY (NCT02054130) NAVIGATOR (NCT03347279) SOURCE
methods used to account The safety analysis set was defined as The safety analysis set was defined as the tezepelumab or placebo, irrespective
for missing data? the as-treated population and included patients who received at least one dose of of their protocol adherence and
all the patients who received at least tezepelumab or placebo. continued participation in the study.
one dose of tezepelumab or placebo. Sensitivity analyses to assess the impact of The safety analysis set was defined
missing data were performed and did not as all patients who received at least
impact the overall result. one dose of tezepelumab or placebo.
For both analyses this was all patients
randomised.
Sensitivity analyses explored the
effect of missing data on the reliability
of the results using multiple imputation
and determined that they did not affect
the conclusions.
Adapted from Systematic reviews: CRD's guidance for undertaking reviews in health care (University of York Centre for Reviews and Dissemination)
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Abbreviations: ITT, intent-to-treat.

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B.2.6 Clinical effectiveness results of the relevant trials

B.2.6.1 PATHWAY

SUMMARY

• In a broad population of adult subjects with severe, uncontrolled asthma, treatment with tezepelumab (any dose group) resulted in a significant reduction in the primary endpoint, AAER, compared with placebo at Week 52.

• At Week 52, AAER reductions of 62, 71, and 66% in the 70 mg Q4W, 210 mg Q4W, and 280 mg Q2W tezepelumab arms, respectively (compared with placebo) were observed in the ITT population (p<0.001).

• With all three tezepelumab doses, considerable improvements from baseline to Week 52 were observed for key secondary endpoints, including pre-BD FEV1, ACQ6, AQLQ(S)+12, and asthma symptom daily diary score, compared with placebo.

B.2.6.1.1 Primary efficacy outcome: AAER

Tezepelumab 70 mg Q4W, 210 mg Q4W, and 280 mg Q2W treatment resulted in statistically significant reductions of 62, 71, and 66%, respectively, in the rate of asthma exacerbations over 52 weeks compared with placebo (Table 31). Numerically higher reductions in the exacerbation rate were observed with the two higher doses of tezepelumab (Please note that the tezepelumab 210 mg Q4W is the intended licensed dose).

Table 31: AAER over 52 weeks (ITT)

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Tezepelumab Placebo (n=138)
70 mg Q4W 210 mg Q4W 280 mg Q2W
(n=138) (n=137) (n=137)
AAER (95% CI) 0.27 (0.19, 0.38) 0.20 (0.13, 0.30) 0.23 (0.16, 0.34) 0.72 (0.59, 0.88)
Rate ratio (95% CI) 0.38 (0.23, 0.63) 0.29 (0.16, 0.51) 0.34 (0.20, 0.58) -
p-value <0.001 <0.001 <0.001 -
----- End of picture text -----

Abbreviations: AAER, annualised asthma exacerbation rate; CI, confidence interval; ICS, inhaled corticosteroids; ITT, intent-to-treat; Q2W, once every 2 weeks; Q4W, once every 4 weeks.

Rate = total number of asthma exacerbations in each group/total person-year follow-up in each group; 95% CI for rate was based on the exact 95% Poisson CI. Rate ratio and 95% CI for rate ratio were estimated from negative binomial regression with treatment group, and the stratification factors - baseline blood eosinophil count (≥ or < 250 cells/μL) and baseline ICS dose level (medium or high) as the covariates. A rate ratio <1 favoured tezepelumab. Nominal p-value was from the negative binomial regression based on pairwise comparisons against the placebo group.

B.2.6.1.2 Other efficacy outcomes

Results of the remaining efficacy outcomes of the Phase 2 PATHWAY trial are presented in Appendix L.

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For secondary endpoints of lung function, including pre-bronchodilator (BD) FEV1 and forced vital capacity (FVC), improvements from baseline were observed in all three tezepelumab dose arms compared with placebo at Week 52. Increases (indicating improvement) from baseline in pre-BD FEV1 and FVC were observed as early as Week 4 (first time point assessed) in all three tezepelumab dose arms compared with placebo, and these increases were generally maintained over time for the duration of the study.

For the patient-reported outcomes, Asthma Control Questionnaire 6-item (ACQ-6), Asthma Quality of Life Questionnaire (Standardised) for 12 years and older (AQLQ(S)+12), and asthma symptom daily diary score, improvements from baseline were observed in all three tezepelumab dose groups compared with placebo at Week 52. Full details are provided in Appendix L.

B.2.6.2 NAVIGATOR

SUMMARY

In the Phase 3 NAVIGATOR trial, which enrolled a broad population of subjects with severe asthma, treatment with 210 mg tezepelumab SC Q4W resulted in statistically significant improvements over placebo in all primary and key secondary endpoints.

Compared with placebo, over the course of the 52-week study period, tezepelumab was shown to:

• Reduce AAER (the primary efficacy endpoint) by 56% (rate ratio: 0.44; 95% CI: 0.37, 0.53; p<0.001)

• Reduce the annualised rate of exacerbations associated with an ER visit or hospitalisation by 79% versus placebo (p<0.001)

• Reduce the annualised rate of exacerbations associated with a hospitalisation by 85% versus placebo (p<0.001)

• Improve FEV1 at Week 52 by 0.13 L versus placebo (0.23 L versus 0.10 L; 95% CI: 0.08, 0.18; p<0.001)

  • Improvement in FEV1 was observed at the first post-baseline time point it was assessed (2 weeks) and maintained to 52 weeks

• Improve patient QoL (AQLQ(S)+12), asthma control (ACQ-6), and asthma symptoms (ASD)

  • Improvements in each of these endpoints were observed at their first post-baseline assessment time points (between Weeks 1 and 4)

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B.2.6.2.1 Primary efficacy outcome: AAER

Tezepelumab 210 mg SC Q4W treatment resulted in a clinically meaningful and statistically significant 56% reduction in the rate of asthma exacerbations over 52 weeks compared with placebo (rate ratio: 0.44 [95% CI: 0.37, 0.53]; p<0.001) (Table 32).

Table 32: AAER over 52 weeks (FAS)

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----- Start of picture text -----
Tezepelumab (n=528) Placebo (n=531)
Number of events *** ***
Total time at-risk (years) ***** *****
Crude rate **** ****
AAER (95% CI) 0.93 (0.80, 1.07) 2.10 (1.84, 2.39)
Absolute diff from placebo (95% CI) ********************
Rate ratio (95% CI) 0.44 (0.37, 0.53)
p-value <0.001
----- End of picture text -----

Abbreviations: AAER, annualised asthma exacerbation rate; CI, confidence interval; FAS, full analysis set. A rate ratio <1 favoured tezepelumab. The overdispersion parameter was estimated to be 1.41. Model: A negative binomial regression analysis with treatment, region, age group, and history of exacerbations as covariates. The logarithm of the time at risk was used as an offset variable. Annual exacerbation rates displayed are estimated marginal rates from the model. Absolute difference was the difference between the marginal rates. CIs for annual exacerbation rates and absolute differences were estimated via the delta method.

B.2.6.2.2 Key secondary outcome: Pre-BD FEV1

Subjects treated with tezepelumab demonstrated a statistically significant and clinically meaningful improvement in pre-BD FEV1 from baseline to 52 weeks compared with subjects treated with placebo (0.23 L versus 0.10 L; least squares [LS] mean difference: 0.13 L [95% CI: 0.08, 0.18]; p<0.001) (Table 33).

Onset of the effect of tezepelumab on FEV1 was seen at the first post-baseline assessment at 2 weeks and was maintained over 52 weeks, as shown in Figure 13.

Table 33: pre-BD FEV1 change from baseline at 52 weeks (FAS)

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----- Start of picture text -----
Tezepelumab (n=528) Placebo (n=531)
n1 *** ***
n2 *** ***
Change from baseline (L) **** ****
LS mean difference (95% CI) 0.13 (0.08, 0.18)
p-value <0.001
Reject H0?
----- End of picture text -----*

Abbreviations: BD, bronchodilator; CI, confidence interval; FAS, full analysis set; FEV1, forced expiratory volume in the first second; LS, least squares.

n1 = number of subjects contributing to the analysis, i.e. the number of subjects with at least one change from baseline value at any post baseline visit.

n2 = number of subjects with a change from baseline value at each timepoint.

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Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. Estimate of the mean change from baseline at each week in tezepelumab was compared with placebo using a repeated measures analysis. Estimates are least squares means. The model with unstructured covariance structure was: Change from baseline in FEV1 = Treatment group + region + age + baseline FEV1 + visit + treatment * visit.

Figure 13: Adjusted mean (95% CI) change from baseline in pre-BD FEV1 (FAS)

==> picture [477 x 201] intentionally omitted <==

Abbreviations: BD, bronchodilator; CI, confidence interval; FAS, full analysis set; FEV1, forced expiratory volume in the first second; LS, least squares; Pbo, placebo; Q4W, once every 4 weeks; teze, tezepelumab. Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. Estimate of the mean change from baseline at each week in tezepelumab was compared with placebo using a repeated measures analysis. Estimates are least squares means. The model with unstructured covariance structure was: Change from baseline in FEV1 = Treatment group + region + age + baseline FEV1 + visit + treatment * visit.

B.2.6.2.3 Key secondary outcome: ACQ-6

Tezepelumab treatment resulted in a clinically meaningful improvement from baseline in ACQ-6, and a statistically significant improvement compared with placebo at 52 weeks (– 1.53 versus –1.20, respectively; LS mean difference: –0.33 [95% CI: –0.46, –0.20]; p<0.001) (Table 34).

Table 34: ACQ-6 score change from baseline at 52 weeks (FAS)

==> picture [483 x 110] intentionally omitted <==

----- Start of picture text -----
Tezepelumab (n=528) Placebo (n=531)
n *** ***
Change from baseline ***** *****
LS mean difference (95% CI) –0.33 (–0.46, –0.20)
p-value <0.001
Reject H0?
----- End of picture text -----*

Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; CI, confidence interval; FAS, full analysis set; LS, least squares.

The ACQ-6 score was computed as the unweighted mean of the responses to the six questions. If response to any of the questions was missing, the ACQ-6 was missing. Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. Calculation of percentages was based on the number of subjects in the FAS with a completed assessment at each time point. The estimate of the odds ratio was obtained using a GEE model for repeated measures binary data with unstructured covariance structure and treatment, region, age, visit, visit * treatment, and baseline ACQ-6 score as covariates. Unadjusted CI and nominal p-values are presented, as the analysis was not included in the multiple testing procedure.

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In the responder analysis (a subject was classified as a responder if their change from baseline in ACQ-6 score was ≥0.5), a greater proportion of subjects in the tezepelumab arm achieved clinically meaningful improvements in ACQ-6 score compared with those in the placebo arm at Week 52 (************************************************************ (Table 35).

Improvements in ACQ-6 were seen as early as 2 weeks after administration and maintained to 52 weeks (Figure 14).

Table 35: GEE analysis of ACQ-6 responders (FAS)

==> picture [483 x 236] intentionally omitted <==

----- Start of picture text -----
Time point Tezepelumab (n=528) Placebo (n=531)
Week 4 n *** ***
Responders, n (%) [†] ********** **********
OR (95% CI) *****************
p-value *****
Week 12 n *** ***
Responders, n (%) [†] ********** **********
OR (95% CI) *****************
p-value *****
Week 52 n *** ***
Responders, n (%) [†] ********** **********
OR (95% CI) *****************
p-value ******
----- End of picture text -----

Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; CI, confidence interval; FAS, full analysis set; GEE, generalised estimating equations; OR, odds ratio.

The ACQ-6 score was computed as the unweighted mean of the responses to the six questions. If response to any of the questions was missing, the ACQ-6 was missing. Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. Calculation of percentages was based on the number of subjects in the FAS with a completed assessment at each time point. The estimate of the odds ratio was obtained using a GEE model for repeated measures binary data with unstructured covariance structure and treatment, region, age, visit, visit * treatment, and baseline ACQ-6 score as covariates. Unadjusted CI and nominal p-values are presented, as the analysis was not included in the multiple testing procedure.

† A subject was classified as a responder if their change from baseline in ACQ-6 score was ≥0.5.

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Figure 14: Adjusted mean (95% CI) change from baseline in ACQ-6 score (FAS)

==> picture [483 x 241] intentionally omitted <==

Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; CI, confidence interval; FAS, full analysis set; Pbo, placebo; Q4W, once every 4 weeks; teze, tezepelumab. Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. The model with unstructured covariance structure was: Change from baseline in ACQ-6 = Treatment group + region + age + baseline ACQ-6 + visit + treatment * visit.

B.2.6.2.4 Key secondary outcome: AQLQ(S)+12

Tezepelumab treatment resulted in a clinically meaningful improvement from baseline in AQLQ(S)+12, and a statistically significant improvement compared with placebo (1.48 versus 1.14, respectively; LS mean difference: 0.33 [95% CI: 0.20, 0.47]; p<0.001) (Table 36). An improvement from baseline was also observed in the placebo arm.

Table 36: AQLQ(S)+12 score change from baseline at 52 weeks (FAS)

==> picture [483 x 109] intentionally omitted <==

----- Start of picture text -----
Tezepelumab (n=528) Placebo (n=531)
n *** ***
Change from baseline **** ****
LS mean difference (95% CI) 0.33 (0.20, 0.47)
p-value <0.001
Reject H0?
----- End of picture text -----*

Abbreviations: AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; CI, confidence interval; FAS, full analysis set; LS, least squares.

Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. AQLQ(S)+12 total score was defined as the unweighted mean of the responses to all questions in the questionnaire. If response to any of the questions was missing, the total score was missing. If a response to a question within a domain was missing, the score for that domain was missing. Estimate of the mean change from baseline at each week in tezepelumab was compared with placebo using a repeated measures analysis. Estimates are least squares means. The model with unstructured covariance structure was: Change from baseline in AQLQ(S)+12 = Treatment group + region + age + baseline AQLQ(S)+12 + visit + treatment * visit.

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In the responder analysis (a subject was classified as a responder if their change from baseline in AQLQ(S)+12 total score was ≥0.5), a greater proportion of subjects in the tezepelumab arm achieved clinically meaningful improvements in AQLQ(S)+12 score compared with those in the placebo arm at Week 52

************************************************************ (Table 37).

Improvements in AQLQ(S)+12 were seen as early as 4 weeks after administration (the first time point at which AQLQ(S)+12 was assessed) and maintained to 52 weeks (Figure 15).

Table 37: GEE analysis of AQLQ(S)+12 responders (FAS)

==> picture [483 x 236] intentionally omitted <==

----- Start of picture text -----
Time point Tezepelumab (n=528) Placebo (n=531)
Week 4 n *** ***
Responders, n (%) [†] ********** **********
OR (95% CI) *****************
p-value *****
Week 12 n *** ***
Responders, n (%) [†] ********** **********
OR (95% CI) *****************
p-value *****
Week 52 n *** ***
Responders, n (%) [†] ********** **********
OR (95% CI) *****************
p-value *****
----- End of picture text -----

Abbreviations: AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; CI, confidence interval; FAS, full analysis set; GEE, generalised estimating equations; OR, odds ratio. AQLQ(S)+12 total score was defined as the unweighted mean of the responses to all questions in the questionnaire. If response to any of the questions was missing, the total score was missing. Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. Calculation of percentages was based on the number of subjects in the FAS with a completed assessment at each time point. The estimate of the odds ratio was obtained using a GEE model for repeated measures binary data with unstructured covariance structure and treatment, region, age, visit, visit*treatment and baseline AQLQ(S)+12 score as covariates. Unadjusted CI and nominal p-values are presented, as analysis was not included in the multiple testing procedure.

† A subject was classified as a responder if their change from baseline in AQLQ(S)+12 total score was ≥0.5.

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Figure 15: Adjusted mean (95% CI) change from baseline in AQLQ(S)+12 total score (FAS)

==> picture [483 x 224] intentionally omitted <==

Abbreviations: AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; CI, confidence interval; FAS, full analysis set; Pbo, placebo; Q4W, once every 4 weeks; teze, tezepelumab. Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. The model with unstructured covariance structure was: Change from baseline in AQLQ(S)+12 = Treatment group + region + age + baseline AQLQ(S)+12 + visit + treatment * visit.

B.2.6.2.5 Key secondary outcome: Asthma Symptom Diary (ASD) score (Weekly Mean Daily Score)

Tezepelumab treatment resulted in clinically meaningful improvements from baseline in

ASD score and a statistically significant improvement compared with placebo at 52 weeks (–0.70 versus –0.59, respectively; LS mean difference: –0.11 [95% CI: –0.19, –0.04]; p=0.004) (Table 38).

Table 38: ASD[†] score change from baseline at 52 weeks (FAS)

==> picture [483 x 109] intentionally omitted <==

----- Start of picture text -----
Tezepelumab (n=528) Placebo (n=531)
n *** ***
Change from baseline ***** *****
LS mean difference (95% CI) –0.11 (–0.19, –0.04)
p-value 0.004
Reject H0?
----- End of picture text -----*

Abbreviations: ASD, Asthma Symptom Diary; CI, confidence interval; FAS, full analysis set; LS, least squares. Baseline was defined as the mean of the available data in the most recent week prior to the date of randomisation. Each period was defined from the evening of the first day (1 week prior to the time point displayed) to the morning of the last day (at the time point displayed). If more than 3 days were missing within a week, then the weekly mean was set to missing. No imputation was made for missing values. Estimate of the mean change from baseline at each week in tezepelumab was compared with placebo using a repeated measures analysis. Estimates are least squares means. The model with First Order Regressive covariance structure was: Change from baseline in Asthma Symptom Diary score = Treatment group + region + age + baseline Asthma Score + week + treatment * week.

† Completed by subjects twice daily. The ASD consists of 10 items. Five morning items assess night-time symptom severity in relation to: wheezing, shortness of breath, cough, chest tightness, and the frequency of night-time awakening. Five evening items assess daytime symptom severity in relation to: wheezing, shortness of breath, cough, chest tightness, and activity limitation since waking (6).

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In the responder analysis (a subject was classified as a responder if their change from baseline in ASD was ≥0.5), a greater proportion of subjects in the tezepelumab arm achieved clinically meaningful improvements in ASD score compared with those in the placebo arm at Week 52 ***************************** (Table 39).

Improvements in ASD score were seen as early as 2 weeks after administration and maintained to 52 weeks (Figure 16).

Table 39: ASD score responders by time point (FAS)

==> picture [473 x 127] intentionally omitted <==

----- Start of picture text -----
Time point Tezepelumab (n=528) Placebo (n=531)
Week 1 n *** ***
Responders, n (%) [†] ********* *********
Non-responder, n (%) ********** **********
Week 52 n *** ***
Responders, n (%) [†] ********** **********
Non-responder, n (%) ********** **********
----- End of picture text -----

Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; FAS, full analysis set. Baseline was defined as the mean of the available ASD scores in the most recent week prior to the date of randomisation. Calculation of percentages was based on the number of subjects in the FAS with a completed assessment at each time point. † A subject was classified as a responder if their change from baseline in weekly ASD total score was ≥–0.5.

Figure 16: Adjusted mean (95% CI) change from baseline in ASD score (FAS)

==> picture [483 x 245] intentionally omitted <==

Abbreviations: ASD, Asthma Symptom Diary score; CI, confidence interval; FAS, full analysis set; Pbo, placebo; Q4W, once every 4 weeks; teze, tezepelumab.

Baseline was defined as the mean of the available data in the most recent week prior to the date of randomisation. The model, First Order Regressive covariance structure, was: Change from baseline in Asthma Symptom Diary score = Treatment group + region + age + baseline Asthma Score + week + treatment * week.

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B.2.6.2.6 Other secondary efficacy outcomes

The below section includes other secondary efficacy outcomes that inform the model. Additional secondary efficacy outcomes that do not inform the model are presented in Appendix M.

Time to first asthma exacerbation

 The time to first exacerbation was nominally statistically significantly longer in the tezepelumab versus the placebo arm (HR: ******************************************), as shown in Figure 17.

Figure 17: Time to first asthma exacerbation (Kaplan–Meier plot; FAS)

==> picture [483 x 233] intentionally omitted <==

Abbreviations: FAS, full analysis set; Pbo, placebo; Q4W, once every 4 weeks; teze, tezepelumab. Time to first exacerbation was calculated as date of first asthma exacerbation - date of randomisation + 1. Subjects with no observed event (asthma exacerbation) were censored at the end of the time at risk. Time during an exacerbation and the 7 days following an exacerbation in which a new exacerbation could not occur, were not included in the calculation of time at risk for exacerbation. Censoring symbols indicate time when a subject completed planned treatment or withdrew from study during planned treatment without an asthma exacerbation.

Proportion of subjects experiencing no asthma exacerbations over 52 weeks

 A *****************************************************************************************

************************************************************************************************* *********************************************************************************)*************** ******************************************************************)

Annualised rate of exacerbations associated with ER visit or hospitalisation

Compared with placebo, tezepelumab treatment resulted in a *******************

****************************** in the annualised rate of exacerbations associated with an

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ER visit or hospitalisation, and an ************************************************

***************, as shown in Table 40

• The proportion of subjects followed for 52 weeks and who did not experience an asthma exacerbation requiring an ER visit or hospitalisation was

  • ---

Table 40: Annual exacerbations associated with an ER visit or hospitalisation over 52 weeks

(FAS)

==> picture [483 x 308] intentionally omitted <==

----- Start of picture text -----
Tezepelumab (n=528) Placebo (n=531)
Annual n *** ***
exacerbations
Number of events ** ***
associated
with an ER Total time at-risk, years ***** *****
visit or
Crude rate **** ****
hospitalisation [†]
AAER (95% CI) ***************** *****************
Absolute diff from placebo (95% CI) ********************
Rate ratio (95% CI) *****************
p-value ***************
Annual n *** ***
exacerbations
Number of events ** **
associated
with a Total time at-risk, years ***** *****
hospitalisation [‡]
Crude rate **** ****
AAER (95% CI) ***************** *****************
Absolute diff from placebo (95% CI) ********************
Rate ratio (95% CI) *****************
p-value ***************
----- End of picture text -----

Abbreviations: AAER, annualised asthma exacerbation rate; CI, confidence interval; ER, emergency room; FAS, full analysis set.

A rate ratio <1 favoured tezepelumab. Model: a negative binomial regression analysis with treatment, region, age group, and history of exacerbations as covariates. The logarithm of the time at risk was used as an offset variable. Annual exacerbation rates displayed are estimated marginal rates from the model. Absolute difference was the difference between the marginal rates. CIs for annual exacerbation rates and absolute differences were estimated via the delta method. Unadjusted CI and Nominal p-value are presented, as the analysis was not included in the multiple testing procedure. Exacerbations associated with hospitalisations and ER visits that were adjudicated not to be asthma related were removed; hospitalisations and ER visits that were adjudicated to be due to an asthma exacerbation were added. † The overdispersion parameter was estimated to be 7.48.

‡ The overdispersion parameter was estimated to be 11.63.

EQ-5D-5L

 Improvements in the current HRQoL of subjects treated with tezepelumab were observed at after Week 10, compared with placebo, as measured by EQ-5D-5L (Table 41)

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• Tezepelumab treatment improved scores and increased the percentage of subjects

***************************************** at Week 52 compared with placebo

Table 41: EQ-5D-5L score change from baseline at 52 weeks (FAS)

Abbreviations: CI, confidence interval; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; FAS, full analysis set; LS, least squares; SE, standard error.

Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. The Health State Valuation (an index-based value) for the EQ-5D-5L was derived from the five dimensions using the UK population-based preference weights. Estimate of the mean change from baseline at each week in tezepelumab was compared with placebo using a repeated measures analysis. Estimates are least squares means. The model with unstructured covariance structure was: Change from baseline in HSV index = Treatment group + region + age + baseline HSV index + visit + treatment * visit.

B.2.6.2.7 Conclusion

• The NAVIGATOR trial achieved its primary efficacy endpoint, demonstrating a statistically significant (and clinically meaningful) 56% reduction in the annualised asthma exacerbation rate (AAER) with tezepelumab versus placebo in the enrolled broad population of adults and adolescents with severe uncontrolled asthma

• Clinically meaningful reductions in exacerbations with tezepelumab treatment were observed irrespective of subject baseline levels of EOS, FeNO, or IgE, or baseline allergic/non-allergic status (see Section B.2.7.1.2)

• Tezepelumab treatment resulted in statistically significant and clinically meaningful improvements in lung function (pre-BD FEV1) versus placebo, with improvements seen by 2 weeks (the earliest time point assessed) and sustained to 52 weeks

• Tezepelumab treatment also resulted in clinically meaningful improvements from baseline in quality of life (AQLQ[S]+12), asthma control (ACQ-6), and asthma symptoms (ASD) that were statistically significant compared with placebo, with an onset of effect as early as the first assessment (between Week 1 and 4) and maintained to 52 weeks

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B.2.6.3 SOURCE

SUMMARY

• For the primary efficacy endpoint, the odds of reaching a category of greater percent mOCS reduction were numerically higher with tezepelumab 210 mg Q4W treatment versus placebo, with a cumulative OR of 1.28 (95% CI: 0.69, 2.35, p=0.434), but was not statistically significant

• A total of ***** of subjects in the tezepelumab arm (***** in the placebo arm) achieved a ≥90 to ≤100% reduction in mOCS dose at Week 48 without losing asthma control

• In addition, at Week 48, tezepelumab treatment also resulted in:

  • A ******************************************************* in AAER compared with placebo

  • o A ***************************************************** from baseline in pre-BD FEV1, compared with placebo

  • ******************* for the PROs of ASD, ACQ-6, and AQLQ(S)+12 scores compared with placebo

• Overall, efficacy results from SOURCE support observations from NAVIGATOR and PATHWAY in relation to the benefits of tezepelumab on exacerbations, lung function, and asthma control in mOCS-dependent patients, despite a considerable reduction in daily mOCS dose

• By preventing exacerbations, tezepelumab prevents patients from requiring either short bursts or chronic OCS use, reduces the need for OCS in OCS-dependent patients and demonstrates clinically meaningful improvements in key outcomes for OCS-dependent patients

B.2.6.3.1 Primary efficacy outcome: Categorised percent reduction in daily OCS dose while not losing asthma control

Results from the SOURCE trial favoured tezepelumab 210 mg SC Q4W over placebo, but the primary endpoint (categorised percent reduction in the daily OCS dose without loss of asthma control at Week 48 with tezepelumab plus standard of care compared with placebo plus standard of care) did not reach statistical significance and hence was not met (Section B.2.13.2.1 discusses the reasons why statistical significance was not met). The odds of reaching a category of greater percent OCS reduction was numerically higher with tezepelumab versus placebo, with a cumulative OR of 1.28 (95% CI: 0.69, 2.35; p=0.434) but was not statistically significant (Figure 18 and Table 42).

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The proportion of subjects achieving a ≥90 to ≤100% reduction in mOCS dose at Week 48 without losing asthma control was 54.1% in the tezepelumab group and 46.1% in the placebo group.

Figure 18: Proportion of subjects in different categories of reduction from baseline in final daily OCS dose at Week 48 (FAS)

==> picture [484 x 254] intentionally omitted <==

Abbreviations: AI, adrenal insufficiency; FAS, full analysis set; OCS, oral corticosteroid; Q4W, once every 4 weeks; teze, tezepelumab.

Derivation of daily OCS dose included a therapy reason of “asthma maintenance dose”, “titration, due to asthma”, and “other: AI”.

Table 42: Percent reduction from baseline in final daily OCS dose at Week 48 (FAS)

==> picture [483 x 182] intentionally omitted <==

----- Start of picture text -----
Tezepelumab ****** Placebo ******
Reduction from baseline in final daily OCS dose, n (%)
≥90 to ≤100% ********* *********
≥75 to <90% ******* *******
≥50 to <75% ********* *********
>0 to <50% ******* ********
No change or any increase ********* *********
Comparison between treatment groups
Cumulative OR (95% CI) *****************
p-value *****
----- End of picture text -----

Abbreviations: AI, adrenal insufficiency; CI, confidence interval; OCS, oral corticosteroid; OR, odds ratio; Q4W, once every 4 weeks; SAP, statistical analysis plan.

Baseline daily OCS dose was defined based on the prescribed dose per day at Visit 6. Final daily OCS dose was defined based on the prescribed dose per day at end of treatment visit. Derivation of daily OCS dose included a therapy reason of “asthma maintenance dose”, “titration, due to asthma”, and “Other: AI.” The estimate of the cumulative OR was obtained using a proportion odds model with treatment, region, and daily OCS dose at baseline as covariates.

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The mean change from baseline in daily OCS dose over time is presented in Figure 19. The separation of the curves was evident from Week 4 onwards.

Figure 19: Mean (± 1 SE) percentage change from baseline in daily OCS dose over time (FAS)

==> picture [484 x 254] intentionally omitted <==

Abbreviation: AI, adrenal insufficiency; CI, confidence interval; FAS, full analysis set; OCS, oral corticosteroid; Pbo, placebo; Q4W, once every 4 weeks; SE, standard error; Teze, tezepelumab.

Means +/- one standard error are presented. Derivation of daily OCS dose included a therapy reason of “asthma maintenance dose”, “titration, due to asthma”, and “Other: AI.”

Subjects in the tezepelumab arm had a

********************************************************************************* compared with

those in the placebo arm at Week 48, as shown in Table 43 and Figure 20.

Table 43: Percent reduction from baseline in final daily OCS dose at Week 48; van Elteren Test (FAS)

Abbreviations: AI, adrenal insufficiency; CI, confidence interval; FAS, full analysis set; OCS, oral corticosteroid. Baseline daily OCS dose was defined based on the prescribed dose per day at Visit 6. Final daily OCS dose was defined based on the prescribed dose per day at end of treatment visit. Derivation of daily OCS dose included a therapy reason of “asthma maintenance dose”, “titration, due to asthma”, and “Other: AI.” The CIs for the median in each treatment group were estimated using a distribution free procedure. The median difference in the percentage reduction of daily OCS dose between the tezepelumab and placebo arms and their respective 95% CIs were derived using an unadjusted bootstrap approach. The p-value was obtained using a Wilcoxon rank sum test stratified by region (van Elteren). The response variable was the percentage reduction from baseline in final daily OCS dose at Week 48.

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Figure 20: Median (95% CI) percentage change from baseline in daily OCS dose over time (FAS)

==> picture [484 x 202] intentionally omitted <==

Abbreviations: AI, adrenal insufficiency; CI, confidence interval; FAS, full analysis set; OCS, oral corticosteroid; Pbo, placebo; Q4W, once every 4 weeks; teze, tezepelumab.

CIs were calculated using a distribution free procedure. Derivation of OCS dose included a therapy reason of “asthma maintenance dose,” “titration, due to asthma,” and “other: AI.”

B.2.6.3.2 Key secondary outcome: AAER

Since the primary efficacy endpoint of SOURCE was not met (for the reasons described in Section B.2.13.2.1), the key secondary endpoint of SOURCE was not formally assessed. Subjects treated with tezepelumab

*******************************************************************************************************

**********************. Tezepelumab treatment reduced the rate of exacerbations by *** compared with placebo in subjects with mOCS-dependent severe asthma, despite the reductions in mOCS use (Table 44).

Table 44: AAER over 48 weeks (FAS)

==> picture [483 x 146] intentionally omitted <==

----- Start of picture text -----
Tezepelumab ****** Placebo ******
Number of events ** ***
Total time at-risk (years) **** ****
Crude rate **** ****
AAER (95% CI) ***************** *****************
Absolute diff from placebo (95% CI) *******************
Rate ratio (95% CI) *****************
p-value ***************
----- End of picture text -----

Abbreviations: AAER, annualised asthma exacerbation rate; CI, confidence interval; FAS, full analysis set; Q4W, once every 4 weeks.

The overdispersion parameter was estimated to be 1.16. A rate ratio <1 favoured tezepelumab. Model: A negative binomial regression analysis with treatment, region, and history of exacerbations as covariates. The logarithm of the time at risk was used as an offset variable. Annual exacerbation rates displayed are estimated marginal rates from the model. Absolute difference is the difference between the marginal rates. CIs for annual exacerbation rates and absolute differences are estimated via the delta method.

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B.2.6.3.3 Other secondary efficacy outcomes relevant to model and/or scope

The below section includes other secondary efficacy outcomes that inform the model. Additional secondary efficacy outcomes that do not inform the model are presented in Appendix N.

Time to first asthma exacerbation

• The Kaplan–Meier plot of time to first exacerbation is presented in Figure 21.

********************************************************************)

Figure 21: Time to first asthma exacerbation (Kaplan–Meier plot; FAS)

==> picture [484 x 253] intentionally omitted <==

Abbreviations: FAS, full analysis set; Pbo, placebo; Q4W, once every 4 weeks; teze, tezepelumab. Time to first exacerbation was calculated as start date of the first asthma exacerbation – date of randomisation + 1. Subjects with no observed event (asthma exacerbation) were censored at the end of the time at risk. Time during an exacerbation and the 7 days following an exacerbation in which a new exacerbation could not occur, were not included in the calculation of time at risk for exacerbation. Censoring symbols indicate time when a subject completed planned treatment or withdrew from the study during the planned treatment without an asthma exacerbation.

Annualised rate of exacerbations associated with ER visit or hospitalisation

• The numbers of exacerbations in the SOURCE study resulting in an ER visit or hospitalisation ********

• Subjects taking tezepelumab had a ************* in exacerbations requiring

hospitalisation or an ER visit when compared with placebo, despite the reduction in mOCS dose *********************************************** (Table 45)

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Table 45: Annual exacerbations associated with an ER visit or hospitalisation over 48 weeks

(FAS)

==> picture [483 x 164] intentionally omitted <==

----- Start of picture text -----
Tezepelumab ******* Placebo *******
n ** **
Number of events * **
Total time at-risk, years **** ****
Crude rate **** ****
AER (95% CI) ***************** *****************
Absolute diff from placebo (95% CI) *******************
Rate ratio (95% CI) *****************
p-value *****
----- End of picture text -----

Abbreviations: AER, annual exacerbation rate; CI, confidence interval; ER, emergency room; FAS, full analysis set. The overdispersion parameter was estimated to be 3.52. A rate ratio <1 favoured tezepelumab. Model: a negative binomial regression analysis with treatment, region, and history of exacerbations as covariates. The logarithm of the time at risk was used as an offset variable. Annual exacerbation rates displayed were estimated marginal rates from the model. Absolute difference was the difference between the marginal rates. CIs for annual exacerbation rates and absolute differences were estimated via the delta method.

Time to first asthma exacerbation associated with ER visit or hospitalisation

• The Kaplan–Meier plot for time to first asthma exacerbation associated with an ER visit or hospitalisation is presented in Figure 22.

• The risk of having an exacerbation leading to an ER visit or hospitalisation was numerically lower for subjects receiving tezepelumab than those receiving placebo, despite the reduction in mOCS dose, although the number of events was low (***************************************

Figure 22: Time to first asthma exacerbation associated with ER visit or hospitalisation (Kaplan–Meier plot; FAS)

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Abbreviations: ER, emergency room; FAS, full analysis set; Pbo, placebo; Q4W, once every 4 weeks; SCS, systemic corticosteroid; teze, tezepelumab.

Time to first exacerbation associated with ER visit or hospitalisation was calculated as the start date of the first asthma

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exacerbation associated with ER visit or hospitalisation – date of randomisation + 1. Subjects with no observed event (asthma exacerbation due to ER visit or hospitalisation) were censored at the end of the time at risk. The time during an exacerbation and the 7 days following an exacerbation in which a new exacerbation could not occur, were not included in the calculation of time at risk for exacerbation. An ER visit due to asthma required SCS bolus for at least 3 consecutive days or a single depot-injectable dose of corticosteroids. Censoring symbols indicate time when a subject completed planned treatment or withdrew from the study during the planned treatment without an asthma exacerbation associated with an ER visit or hospitalisation.

Proportion of subjects experiencing no asthma exacerbations over 48 weeks

• A numerically higher proportion of subjects in the tezepelumab arm (47.3%) did not experience an asthma exacerbation between baseline and Week 48 compared with

  • 34.2% of subjects in the placebo arm (OR: 1.68 [95% CI: 0.85, 3.31]; p=0.133)

Proportion of subjects with reduction in final mOCS dose

• The potential for tezepelumab to allow reduction of daily mOCS dose at Week 48 was assessed in multiple secondary endpoints (Table 46). No meaningful difference was observed between treatment groups. Only one subject could not reduce final mOCS dose by 100% due to adrenal insufficiency

Table 46: Proportion of subjects with reduction from baseline in final daily OCS dose at Week 48 (FAS)

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Endpoint Tezepelumab (n=74) Placebo (n=76)
100% reduction from baseline in daily OCS dose
n (%) 40 (54.1) 35 (46.1)
OR (95% CI) 1.35 (0.68, 2.68)
p-value 0.385
≥50% reduction from baseline in daily OCS dose
n (%) 55 (74.3) 53 (69.7)
OR (95% CI) 1.24 (0.60, 2.57)
p-value 0.559
Final daily OCS dose of ≤5 mg
n (%) 53 (71.6) 55 (72.4)
OR (95% CI) 0.88 (0.40, 1.94)
p-value 0.745
Final daily OCS dose of ≤5 mg and unable to achieve 100% reduction due to AI
n (%) 1 (1.4) 0 (0.0)
OR (95% CI) ND
p-value ND
Final daily OCS dose of ≤5 mg and unable to achieve 100% reduction due to AI and subjects with 100%
reduction in final daily OCS dose
n (%) 41 (55.4) 35 (46.1)
OR (95% CI) 1.44 (0.73, 2.86)
----- End of picture text -----

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Abbreviations: AI, adrenal insufficiency; CI, confidence interval; FAS, full analysis set; ND, not determined; OCS, oral corticosteroid; OR, odds ratio; Q4W, once every 4 weeks. Baseline daily OCS dose was defined based on the prescribed dose per day at Visit 6. Final daily OCS dose was defined based on the prescribed dose per day at end of treatment visit. Derivation of daily OCS dose included a therapy reason of “asthma maintenance dose”, “titration, due to asthma”, and “Other: AI.” An OR greater than 1 favoured tezepelumab. The estimate of the OR was obtained using a logistic regression model with treatment, region, and daily OCS dose at baseline as covariates.

ASD

• Compared with placebo, subjects who received tezepelumab had a numerically greater improvement in ASD total score from baseline at Week 48 (LS mean difference: –0.10 [95% CI: –0.29, 0.09]), with the difference apparent during the initial 4-week induction period (Week 0–4)

• A numerically greater number of subjects treated with tezepelumab had a clinically meaningful improvement in ASD score from baseline to Week 48 compared with placebo (proportion of responders: 43.1 vs 29.4%; OR: 8.98 [95% CI: 0.63, 127.41])

• Fewer symptomatic days were reported in the tezepelumab arm versus the placebo arm over 48 weeks (change from baseline: –27.94 versus –6.60, respectively)

ACQ-6

• A clinically meaningful change in ACQ-6 from baseline to Week 48 was observed in both the tezepelumab and placebo groups and the improvement from baseline was greater with tezepelumab than with placebo (LS mean difference: –0.37; [95% CI: – 0.71, –0.02])

• In the tezepelumab group, more patients achieved a clinically meaningful improvement in ACQ-6 (defined as ≥0.5 unit reduction from baseline) compared with placebo at Week 48 (65.2 vs 45.6%; OR: 2.30 [95% CI: 1.10, 4.81])

• More patients in the tezepelumab group achieved asthma control (ACQ-6 score ≤0.75) compared with placebo at Week 48 (30.3 vs 14.7%)

AQLQ(S)+12

• A clinically meaningful change in ALQ(S)+12 from baseline to Week 48 was observed in the tezepelumab and placebo groups and was greater in the tezepelumab group, with a total score LS mean change of 0.94 and 0.58 for tezepelumab and placebo, respectively (LS mean difference: 0.36 [95% CI 0.01, 0.70])

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• All domain score changes were greater in the tezepelumab group than the placebo group and the onset of effect was evident from Week 4 (first timepoint of AQLQ(S)+12 assessment)

EQ-5D-5L

• Subjects treated with tezepelumab had a greater improvement in EQ-5D-5L visual analogue scale scores versus placebo (LS mean difference: 7.21 [95% CI 1,01, 13.41]) (Table 47)

Table 47: EQ-5D-5L score change from baseline at 48 weeks (FAS)

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Tezepelumab (n=528) Placebo (n=531)
n 62 58
LS mean (SE) change from baseline to Week 52 9.21 (2.209) 2.00 (2.226)
LS mean difference (95% CI) 7.21 (1.01, 13.41)
p-value 0.023
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Abbreviations: CI, confidence interval; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels; FAS, full analysis set; LS, least squares; SE, standard error.

Baseline was defined as the last non-missing measurement recorded on or prior to randomisation. The Visual Analog Scale is a scale of 0–100 where subjects rate current health status, with 0 being the worst imaginable health state. Estimate of the mean change from baseline at each week in tezepelumab was compared with placebo using a repeated measures analysis. Estimates are least squares means. The model with unstructured covariance structure was: Change from baseline in VAS = Treatment group + region + baseline VAS + visit + treatment * visit.

Asthma-specific resource utilisation

• There was no meaningful difference between treatment groups in asthma-specific resource utilisation at Week 48

• The most common healthcare utilisation was ‘visit to specialist’ with a mean (SD) number of visits at baseline of 4.0 (4.1) and 4.8 (5.5) for tezepelumab and placebo, respectively and 1.0 (1.6) and 1.4 (2.1) at Week 48

B.2.6.3.4 Conclusion

Overall, efficacy results from SOURCE support observations from NAVIGATOR and PATHWAY in relation to the benefits of tezepelumab on exacerbations, lung function, and asthma control in mOCS-dependent patients, despite a considerable reduction in daily mOCS dose. SOURCE showed numerical benefits with tezepelumab treatment across secondary endpoints, including AAER, FEV1, and the PROs ASD, ACQ-6, and AQLQ(S)+12, while subjects were reducing their maintenance OCS dose.

By preventing exacerbations, tezepelumab prevents patients from requiring either short bursts or chronic OCS use, reduces the need for OCS in OCS-dependent patients and

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demonstrates clinically meaningful improvements in key outcomes for OCS-dependent patients.

Although SOURCE did not meet its primary endpoint, it did demonstrate a numerical improvement in the odds of achieving a categorical reduction in mOCS dose with tezepelumab treatment versus placebo.

The placebo response seen in the SOURCE trial was larger than expected and may be attributable to the trial design which had a long duration of the OCS reduction phase (36 weeks versus 16-20 weeks in other similar studies) and allowed multiple down titration attempts in the reduction phase. The placebo response suggests that some patients recruited may have been on OCS unnecessarily and were able to withdraw without a loss of control. These assumptions as to why SOURCE failed to reach significance have been validated with UK clinicians who commented that the trial design inadvertently introduced risk to achieving the primary endpoint and that in the real world, they would expect to see OCS sparing as a result of tezepelumab treatment in line with other biologics (96). A more detailed explanation of the data limitations of SOURCE are found in Section B.3.11.

B.2.7 Subgroup analyses

B.2.7.1 Pre-specified subgroup analyses

B.2.7.1.1 PATHWAY

Asthma exacerbation rate reduction (AERR) by pre-specified subgroups

• All three doses of tezepelumab reduced the rate of asthma exacerbations versus placebo over 52 weeks in the analysed subgroups, including blood EOS, FeNO, and Th2 status. The forest plot for the tezepelumab 210 mg dose arm (the intended licensed dose) is presented in Figure 23.

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Figure 23: AERR over 52 weeks by pre-planned subgroups (ITT): Tezepelumab 210 mg Q4W

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Abbreviations: AERR, asthma exacerbation rate reduction; CI, confidence interval; FEIA, fluorescent enzyme immunoassay; FeNO. fraction of exhaled nitric oxide; ICS, inhaled corticosteroids; ITT, intent-to-treat; MEDI9929, tezepelumab; ppb, parts per billion; Q4W, once every 4 weeks.

B.2.7.1.2 NAVIGATOR

AAER reduction by baseline biomarkers and other characteristics

Subgroups of subjects based on baseline biomarkers and other characteristics showed

broadly consistent AAER results as that seen in the overall analysis using the broad patient population. In subgroup analysis, tezepelumab treatment reduced the rate of asthma exacerbations versus placebo over 52 weeks, irrespective of the baseline levels of blood EOS, FeNO, total IgE, or perennial aeroallergen-specific IgE status at baseline when analysed categorically or along a continuum, and irrespective of other baseline characteristics.

AAER reduction by categorical baseline biomarkers

As shown in Figure 24, compared with placebo, tezepelumab treatment reduced AAER by:

• 39% in subjects with baseline blood EOS <150 cells/μL

• 41% in subjects with baseline blood EOS <300 cells/μL

• 70% in subjects with baseline blood EOS ≥300 cells/μL

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The benefit of tezepelumab over placebo in reducing AAER was similar in subjects with or without any positive baseline perennial aeroallergen-specific IgE FEIA result (Figure 24). Not shown in Figure 24, tezepelumab also reduced AAER in subjects irrespective of their baseline serum IgE levels. In the placebo arm, AAER increased with increasing baseline blood EOS count and FeNO levels.

Figure 24: AAER ratio over 52 weeks by baseline biomarker subgroup (FAS)

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Abbreviations: AAER, annualised asthma exacerbation rate; CI, confidence interval; FAS, full analysis set; FEIA, fluorescent enzyme immunoassay; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; teze, tezepelumab; Q4W, once every 4 weeks.

Rate ratio is displayed on the log scale. The dotted line represents no treatment difference. Model, including subgroups, was a negative binomial regression analysis with treatment, region, age, history of exacerbations, subgroup (if not already included), and treatment * subgroup as covariates. Time at risk was used as an offset variable in the model to adjust for subjects’ having different exposure times during which the events occur.

AAER reduction by baseline characteristics

As shown in Figure 25, tezepelumab treatment resulted in clinically meaningful reductions in AAER across most subgroups, including by baseline ICS dose, age, sex, race,

*****************************************************), OCS use, ********************** geographic

region (excluding Central/Eastern Europe), and nasal polyps in the 2 years before randomisation. Due to small numbers of subjects in certain subgroups, however (adolescents, Black or African American race, “Other” race, OCS present at baseline, and Central/Eastern Europe geography), the CIs for these subgroups did not exclude one. *******************************************************************************************************

***************************************************************************.

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Figure 25: AAER ratio over 52 weeks by baseline characteristic subgroup (FAS)

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Abbreviations: AAER, annualised asthma exacerbation rate; CI, confidence interval; FAS, full analysis set; ICS, inhaled corticosteroid; OCS, oral corticosteroid; teze, tezepelumab; Q4W, once every 4 weeks. Rate ratio is displayed on the log scale. The dotted line represents no treatment difference. Model, including subgroups, was a negative binomial regression analysis with treatment, region, age, history of exacerbations, subgroup (if not already included), and treatment * subgroup as covariates. Time at risk was used as an offset variable in the model to adjust for subjects’ having different exposure times during which the events occur.

B.2.7.1.3 SOURCE

OCS dose reduction by pre-specified subgroups

The results for the primary efficacy endpoint in SOURCE (OCS dose reduction) were ********************* the pre-planned baseline characteristic subgroup analyses as shown in Figure 26. The odds ratio point estimates

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******************************************************************************************************* ******************************************************************************************************* *********************************************************************************************). ******************************************************************************************************* *******************************************************************************************************

****************************. Although these analyses of the primary endpoint were prespecified, due to the small number of subjects, these results should be interpreted with caution.

Figure 26: Categorised percent reduction in daily OCS dose at Week 48 by baseline characteristic subgroup (FAS)

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Abbreviations: AI, adrenal insufficiency; BMI, body mass index; CI, confidence interval; FAS, full analysis set; FEIA, fluorescent enzyme immunoassay; FeNO, fractional exhaled nitric oxide; OCS, oral corticosteroid; ppb, parts per billion; Q4W, once every 4 weeks; Teze, tezepelumab.

Cumulative odds ratio is presented on the log scale. Dotted line represents no treatment difference. Derivation of OCS dose included a therapy reason of "Asthma maintenance dose", "Titration, due to asthma", and "Other: AI". Model: a proportional odds model with treatment group, region, OCS dose at baseline, subgroup (if not already included) and treatment * subgroup as covariates.

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B.2.7.2 Post hoc subgroup analyses

In order to inform the stratified patient population enrolled in the economic model (see Section B.3.2.1 for further information), a series of post hoc subgroup analyses for NAVIGATOR and SOURCE, were undertaken.

B.2.7.2.1 NAVIGATOR

Sum of all post hoc subgroups (3+ exacerbations OR mOCS)

This population aligns to the totality of the modelled populations. This includes the populations aligned to current NICE-approved biologics for benralizumab, mepolizumab, omalizumab, and dupilumab plus the residual patients with 3 or more exacerbations or mOCS who are not currently eligible for biologic treatment (see Table 97 in Section B.3.2.1 for more information). Table 48 to Table 51 present data specific for this subgroup from NAVIGATOR.

Table 48: Demographic characteristics: Sum of all post hoc subgroups (FAS)[†]

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Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; AQLQ(S)+12, Asthma Quality of Life Questionnaire (Standardised) for 12 years and older; ASD, Asthma Symptom Diary; ER, emergency room; FAS, full analysis set; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; LAMA, longacting muscarinic antagonist; LTRA, leukotriene receptor antagonist; max, maximum; min, minimum; OCS, oral corticosteroid; SD, standard deviation.

† Subjects who appeared in >1 of the post hoc subgroups described below were single counted in this subgroup.

• Calculated as (date of randomisation – date of asthma diagnosis/date asthma symptoms started +1) / 365.25.

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Table 49: AAER ratio over 52 weeks: Sum of all post hoc subgroups (negative binomial model; FAS)

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Abbreviations: AAER, annualised asthma exacerbation rate; CI, confidence interval; FAS, full analysis set. A rate ratio <1 favoured tezepelumab. A negative binomial regression analysis with treatment, region, age group, and history of exacerbations as covariates. The logarithm of the time at risk was used as an offset variable. Annual exacerbation rates and absolute differences displayed were estimated marginal rates from the model. Absolute difference was the difference between the marginal rates. Annual exacerbation rates displayed were estimated marginal rates from the model. Absolute difference was the difference between the marginal rates. CIs for annual exacerbation rates and absolute differences were estimated via the delta method.

Table 50: CFB to Week 52 in pre-BD FEV1: Sum of all post hoc subgroups (MMRM; FAS)

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Abbreviations: BD, bronchodilator; CFB, change from baseline; CI, confidence interval; FEV1, forced expiratory volume in the first second; LS, least squares; MMRM, mixed-effects model for repeated measures; SE, standard error. The model with unstructured covariance structure was: CFB in FEV1 = treatment group + region + age + baseline FEV1 + visit + treatment * visit. Subjects with data at baseline and at least one post-baseline time point were included in the analysis. n1 = number of subjects contributing to the analysis (i.e. the number of subjects with at least one CFB value at any post baseline visit). n2 = number of subjects with a CFB value at each timepoint.

Table 51: CFB to Week 52 in ACQ-6: Sum of all post hoc subgroups (MMRM; FAS)

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Abbreviations: ACQ-6, Asthma Control Questionnaire 6-item; CFB, change from baseline; CI, confidence interval; FAS, full analysis set; IL, interleukin; LS, least squares; MMRM, mixed-effects model for repeated measures.

The model with unstructured covariance structure was: CFB in ACQ-6 = treatment group + region + age + baseline ACQ6 + visit + treatment * visit. Subjects with data at baseline and at least one post-baseline time point were included in the analysis. n1 = number of subjects contributing to the analysis (i.e. the number of subjects with at least one CFB value at any post baseline visit). n2 = number of subjects with a CFB value at each timepoint.

Anti-IL-5 eligible subgroup

This population aligns with the NICE-recommended populations for benralizumab and

mepolizumab which includes adult patients who have 300+ EOS (4+ Exacs OR mOCS)

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OR (400+ EOS AND 3 Exacs) (see Table 97 in Section B.3.2.1 for more information). Table 52 to Table 55 present data specific for this subgroup from NAVIGATOR.

Table 52: Demographic characteristics: Anti-IL-5 eligible subgroup (FAS)

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