Tezepelumab demonstrated superiority versus placebo across every primary and key
secondary endpoint in NAVIGATOR Phase III trial

Positive full results from the pivotal NAVIGATOR Phase III trial showed AstraZeneca and
Amgen’s tezepelumab demonstrated a statistically significant and clinically meaningful 1
reduction in the annualised asthma exacerbation rate (AAER) in severe, uncontrolled
asthma patients.
2 The results were presented at the American Academy of Asthma Allergy
& Immunology Virtual Annual Meeting.2

Tezepelumab, a potential first-in-class medicine, when added to standard of care (SoC) achieved a 56% reduction (p<0.001) in AAER over 52 weeks in the overall patient population, compared to placebo when added to SoC. 2 SoC was medium- or high-dose inhaled corticosteroids (ICS) plus at least one additional controller medication with or without oral corticosteroids (OCS).2

Tezepelumab is the only biologic medicine to consistently and significantly reduce AAER
in a broad population of severe asthma patients irrespective of baseline eosinophil count
across Phase II and Phase III clinical trials.2-9

In a pre-planned subgroup analysis, tezepelumab achieved a statistically significant and clinically meaningful 41% reduction (p<0.001) in AAER in patients with baseline eosinophil counts less than 300 cells per microlitre. 2 Importantly, clinically meaningful reductions in AAER were also observed in two additional subgroups: 39% in patients with baseline eosinophil counts less than 150 cells per microlitre and 70% in patients with greater than or equal to 300 cells per microlitre. 2 Additionally, clinically meaningful reductions in AAER compared to placebo were observed in the tezepelumab-treated patients irrespective of allergy status and fractional exhaled nitric oxide (FeNO) level, biomarkers used by clinicians to inform treatment options. 2

Professor Andrew Menzies-Gow, Director of the Lung Division, Royal Brompton Hospital,
London, UK, and principal investigator of the NAVIGATOR Phase III trial, said: “These
are ground-breaking results for the many patients with severe asthma who continue to
face debilitating symptoms despite receiving standard of care inhaled medicines and
currently approved biologics. Tezepelumab has the potential to transform treatment for a
broad population of patients with severe asthma regardless of their type of inflammation,
including those with and without an eosinophilic phenotype.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The
unprecedented results from the NAVIGATOR Phase III trial show tezepelumab is the first
and only asthma biologic to demonstrate in randomised trials clinically meaningful
exacerbation reductions, irrespective of blood eosinophil counts, allergy status and
fractional exhaled nitric oxide. There is now a strong body of evidence showing the benefit
of targeting the top of the inflammatory cascade with tezepelumab, and we look forward
to bringing this potential first-in-class medicine to a broad population of severe asthma
patients as soon as possible.”

Tezepelumab demonstrated statistically significant improvements in every key secondary
endpoint compared to placebo, including lung function measurements, asthma control
and health-related quality of life.2
There were no clinically meaningful differences in safety results between the tezepelumab
and placebo groups. The most frequently reported adverse events were nasopharyngitis,
upper respiratory tract infection and headache.2
NAVIGATOR is a pivotal Phase III trial that will form the basis of regulatory submission.
Tezepelumab blocks the action of thymic stromal lymphopoietin (TSLP), an epithelial
cytokine that plays a key role across the spectrum of asthma inflammation. 3,10
NAVIGATOR is the first Phase III trial to show benefit in severe asthma by targeting
TSLP.2

The statistically significant and clinically meaningful exacerbation rate reductions
demonstrated with tezepelumab in patients with baseline eosinophil counts less than 300
cells per microlitre support the US Food and Drug Administration Breakthrough Therapy
Designation granted to tezepelumab in September 2018 for patients with severe asthma,
without an eosinophilic phenotype.2,3 Tezepelumab is being developed by AstraZeneca in
collaboration with Amgen.
Severe asthma
Asthma is a heterogeneous disease affecting an estimated 339 million people worldwide.11,12
Approximately 10% of asthma patients have severe asthma.12,13 Despite the use of inhaled
asthma controller medicine, currently available biologic therapies and OCS, many severe
asthma patients remain uncontrolled.12-14 Due to the complexity of severe asthma, many
patients have unclear or multiple drivers of inflammation and may not qualify for or respond
well to a current biologic medicine.13-16

Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations,
significant limitations on lung function and a reduced quality of life.12,13,17 Patients with severe
asthma are at an increased risk of mortality and have twice the risk of asthma-related
hospitalisations.18-20 There is also a significant socio-economic burden, with these patients
accounting for 50% of asthma-related costs.21
NAVIGATOR and the PATHFINDER clinical trial programme
Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER programme included
two trials, NAVIGATOR and SOURCE.22,23 The programme includes additional planned
mechanistic and long-term safety trials.

NAVIGATOR is a Phase III, randomised, double-blinded, placebo-controlled trial in adults (18– 80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma, who were receiving treatment with medium- or high-dose ICS plus at least one additional controller medication with or without OCS. The trial population included approximately equal proportions of patients with high (≥ 300 cells/µL) and low (< 300 cells/µL) blood eosinophil counts. The trial comprised a five to six week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients received their prescribed controller medications without change throughout the trial.22 The primary efficacy endpoint was the AAER during the 52-week treatment period. Key secondary endpoints included the effect of tezepelumab on lung function, asthma control and health-related quality of life.22

As part of prespecified analyses, the AAER over 52 weeks was also assessed in patients
grouped by baseline blood eosinophil count, FeNO level and serum specific immunoglobin E
(IgE) status (perennial allergen sensitivity positive or negative). These are inflammatory
biomarkers used by clinicians to inform treatment options and involve tests analysing a
patient’s blood (eosinophils / IgE) and exhaled air (FeNO).
SOURCE is a Phase III multicentre, randomised, double-blinded, parallel-group, placebocontrolled trial for 48 weeks in adult patients with severe asthma who require continuous
treatment with ICS plus long-acting beta2-agonists (LABA), and chronic treatment with
maintenance OCS therapy. The primary endpoint is the categorised percentage reduction
from baseline in the daily OCS dose, while not losing asthma control.
23
Patients who participated in the NAVIGATOR and SOURCE trials were eligible to continue in
DESTINATION, a Phase III extension trial assessing long-term safety and efficacy.24

Tezepelumab
Tezepelumab is a potential first-in-class human monoclonal antibody that inhibits the action of
TSLP, a key epithelial cytokine that sits at the top of multiple inflammatory cascades and is
critical in the initiation and persistence of allergic, eosinophilic and other types of airway
inflammation associated with severe asthma.3,10 TSLP is released in response to multiple
triggers associated with asthma exacerbations, including allergens, viruses and other airborne
particles.3,10 Expression of TSLP is increased in the airways of patients with asthma and has

been correlated with disease severity.3,25 Blocking TSLP may prevent the release of proinflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations
and improved asthma control.3,25 Tezepelumab acts at the top of the inflammation cascade
and has the potential to treat a broad population of severe asthma patients regardless of their
type of inflammation.3,25

AstraZeneca and Amgen collaboration
In 2020, Amgen and AstraZeneca updated the 2012 collaboration agreement for tezepelumab.
Both companies will continue to share costs and profits equally after payment by AstraZeneca
of a mid single-digit inventor royalty to Amgen. AstraZeneca continues to lead development
and Amgen continues to lead manufacturing. All aspects of the collaboration are under the
oversight of joint governing bodies. Under the amended agreement in North America, Amgen
and AstraZeneca will jointly commercialise tezepelumab; Amgen will record sales in the US
and AstraZeneca will record sales in Canada. AstraZeneca’s share of gross profits from
tezepelumab in the US will be recognised as collaboration revenue. In all countries outside
the US and Canada, AstraZeneca will solely commercialise tezepelumab. AstraZeneca will
record all sales outside of the US as product sales and recognise Amgen’s share of gross
profit as cost of sales.

AstraZeneca in Respiratory & Immunology
Respiratory & Immunology is one of AstraZeneca’s three therapy areas and is a key growth
driver for the Company.
AstraZeneca is an established leader in respiratory care, and its inhaled and biologic
medicines reached more than 53 million patients in 2019. Building on a 50-year heritage, the
Company aims to transform the treatment of asthma and COPD by focusing on earlier biologyled treatment, eliminating preventable asthma attacks, and removing COPD as a top-three
leading cause of death. The Company’s early respiratory research is focused on emerging
science involving immune mechanisms, lung damage and abnormal cell-repair processes in
disease and neuronal dysfunction.
With common pathways and underlying disease drivers across respiratory and immunology,
AstraZeneca is following the science from chronic lung diseases to immunology-driven
disease areas. The Company’s growing presence in immunology is focused on five mid- to
late-stage franchises with multi-disease potential, in areas including rheumatology (including
Systemic Lupus Erythematosus), dermatology, gastroenterology, and systemic eosinophilicdriven diseases. AstraZeneca’s ambition in Respiratory & Immunology is to achieve disease
modification and durable remission for millions of patients worldwide.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialisation of prescription medicines,
primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular,
Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca
operates in over 100 countries and its innovative medicines are used by millions of patients
worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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