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 meaningful1 reduction in
the annualized 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 microliter.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 microliter and 70% in patients with greater than
or equal to 300 cells per microliter.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 randomized 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
microliter 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 hospitalizations.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 program
Building on the Phase IIb PATHWAY trial, the Phase III
PATHFINDER program included two trials, NAVIGATOR and SOURCE.22,23
The program includes additional planned mechanistic and long-term
safety trials.
NAVIGATOR is a Phase III, randomized, 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
NAVIGATOR primary endpoints2
Endpoint
Timepoint
Results
Tezepelumab added to SoC vs placebo added
to SoC
AAER – overall patient population
Over 52 weeks
56% reduction (95% CI: 47, 63;
p<0.001)
AAER – baseline eosinophil counts < 300
cells/µL
Over 52 weeks
41% reduction (95% CI: 25, 54;
p<0.001)
CI: confidence interval
As part of prespecified analyses, the AAER over 52 weeks was
also assessed in patients grouped by baseline blood eosinophil
count, fractional exhaled nitric oxide (FeNO) level, 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 multicenter, randomized, double-blinded,
parallel-group, placebo-controlled 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
categorized 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 pro-inflammatory 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 commercialize 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 recognized as collaboration revenue. In all
countries outside the US and Canada, AstraZeneca will solely
commercialize 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 biology-led 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 eosinophilic-driven
diseases. AstraZeneca’s ambition in Respiratory & Immunology is
to achieve disease modification and durable remission for millions
of patients worldwide.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, Cardiovascular, Renal &
Metabolism and Respiratory & Immunology. AstraZeneca operates
in over 100 countries and its innovative medicines are used by
millions of patients worldwide. For more information, please visit
www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.
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