62% of patients stopped OCS use in largest
ever steroid sparing trial in severe asthma
High-level results from the PONENTE Phase IIIb open-label trial
showed FASENRA® (benralizumab) eliminated the use of
maintenance oral corticosteroids (OCS) in OCS-dependent asthma
patients with a broad range of blood eosinophil counts.
Severe asthma is an often debilitating condition affecting
approximately 34 million people worldwide.1,2 More than one-third
of these patients currently use chronic or intermittent OCS on top
of other therapies to control their symptoms and exacerbations.3
However, frequent or chronic OCS use can lead to serious adverse
effects.4-6
On the first primary endpoint, 62% of patients achieved complete
elimination of daily OCS use. On the second primary endpoint, 81%
of patients achieved complete elimination or were able to reduce
their daily OCS dose to 5mg or less when further reduction was not
possible due to adrenal insufficiency. Both primary endpoints were
sustained for at least four weeks while maintaining asthma control.
PONENTE included nearly 600 patients in Europe, North America,
South America, and Taiwan.
Professor Andrew Menzies-Gow, Director of the Lung Division,
Royal Brompton Hospital, London, UK, the principal investigator of
the PONENTE trial, said: “These exciting results demonstrate
FASENRA’s impact in eliminating or reducing oral corticosteroid
use. The reductions achieved with the personalized oral
corticosteroid tapering schedule are particularly important because
adrenal insufficiency can be a barrier to safe and meaningful oral
corticosteroid reduction. These data should inform severe asthma
treatment guidelines and strengthen physicians’ confidence to more
safely eliminate chronic oral corticosteroid use in their
patients.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, said: "Around 13.5 million people worldwide with severe
asthma currently rely on oral corticosteroids to control
exacerbations and prevent hospitalizations. However, over-reliance
on oral corticosteroids can also cause significant health risks for
patients, as well as additional strain on health systems. These
data further support FASENRA’s clinical profile in eliminating oral
corticosteroid use across a broader population of severe asthma
patients.”
The trial expands on OCS-sparing data previously seen in the
ZONDA Phase III trial by using a faster steroid tapering schedule
in patients who did not experience adrenal insufficiency to reduce
OCS use from higher doses. The PONENTE trial also has a longer
maintenance phase of approximately 24–32 weeks, which shows more
durable OCS reduction and asthma control than was shown in ZONDA
and all other published trials for biologic medicines.7,8 The
safety profile and tolerability of FASENRA in PONENTE were
consistent with the known profile of the medicine. The trial
results will be presented at a forthcoming medical meeting.
FASENRA is currently approved as an add-on maintenance treatment
for severe eosinophilic asthma in the US, EU, Japan and other
countries, and is approved for self-administration in the US, EU
and other countries. In January 2020, AstraZeneca announced FASENRA
is being evaluated in eight eosinophil-driven diseases beyond
severe asthma.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS Known hypersensitivity to benralizumab
or excipients.
WARNINGS AND PRECAUTIONS Hypersensitivity Reactions
Hypersensitivity reactions (eg, anaphylaxis, angioedema, urticaria,
rash) have occurred after administration of FASENRA. These
reactions generally occur within hours of administration, but in
some instances have a delayed onset (ie, days). Discontinue in the
event of a hypersensitivity reaction.
Acute Asthma Symptoms or Deteriorating Disease FASENRA
should not be used to treat acute asthma symptoms, acute
exacerbations, or acute bronchospasm.
Reduction of Corticosteroid Dosage Do not discontinue
systemic or inhaled corticosteroids abruptly upon initiation of
therapy with FASENRA. Reductions in corticosteroid dose, if
appropriate, should be gradual and performed under the direct
supervision of a physician. Reduction in corticosteroid dose may be
associated with systemic withdrawal symptoms and/or unmask
conditions previously suppressed by systemic corticosteroid
therapy.
Parasitic (Helminth) Infection It is unknown if FASENRA
will influence a patient’s response against helminth infections.
Treat patients with pre-existing helminth infections before
initiating therapy with FASENRA. If patients become infected while
receiving FASENRA and do not respond to anti-helminth treatment,
discontinue FASENRA until infection resolves.
ADVERSE REACTIONS The most common adverse reactions
(incidence ≥ 5%) include headache and pharyngitis.
Injection site reactions (eg, pain, erythema, pruritus, papule)
occurred at a rate of 2.2% in patients treated with FASENRA
compared with 1.9% in patients treated with placebo.
USE IN SPECIFIC POPULATIONS A pregnancy exposure registry
monitors pregnancy outcomes in women exposed to FASENRA during
pregnancy. To enroll call 1-877-311-8972 or visit
www.mothertobaby.org/fasenra.
The data on pregnancy exposure from the clinical trials are
insufficient to inform on drug-associated risk. Monoclonal
antibodies such as benralizumab are transported across the placenta
during the third trimester of pregnancy; therefore, potential
effects on a fetus are likely to be greater during the third
trimester of pregnancy.
INDICATION FASENRA is indicated for the add-on
maintenance treatment of patients with severe asthma aged 12 years
and older, and with an eosinophilic phenotype.
- FASENRA is not indicated for treatment of other eosinophilic
conditions
- FASENRA is not indicated for the relief of acute bronchospasm
or status asthmaticus
Please read full Prescribing Information, including Patient
Information.
Severe asthma Asthma affects approximately 339 million
individuals worldwide.1 Approximately 10% of asthma patients have
severe asthma, which may be uncontrolled despite high dosages of
standard of care asthma controller medicines and can require the
long-term use of OCS.2,9,10 Severe, uncontrolled asthma is
debilitating and potentially fatal, with patients experiencing
frequent exacerbations and significant limitations on lung function
and health-related quality of life.2,10 Severe, uncontrolled asthma
has a greater risk of mortality than severe asthma.10 70% or more
of people with severe asthma have elevated counts of eosinophils,
white blood cells that are a normal part of the immune system and
can drive airway inflammation in some patients.3, 9, 10
Severe, uncontrolled asthma can lead to a dependence on OCS,
with cumulative steroid exposure leading to serious short- and
long-term adverse effects including weight gain, diabetes,
osteoporosis, glaucoma, anxiety, depression, cardiovascular disease
immunosuppression and adrenal insufficiency.4-6
Adrenal insufficiency is a condition in which the adrenal glands
do not produce adequate amounts of steroid hormones.11 Steroid
hormones are important to help control metabolism, inflammation,
immune functions and salt and water balance, among other critical
functions.11 Adrenal insufficiency can develop as a result of
taking chronic OCS and may persist following steroid reduction or
discontinuation, potentially causing serious clinical consequences
including shock, seizure, coma and even death in cases of an acute
adrenal crisis.11
PONENTE PONENTE is a multicenter, open-label, single-arm,
Phase IIIb trial to evaluate the efficacy and safety of reducing
daily OCS use after initiation of 30 mg dose of FASENRA
administered subcutaneously (SC) in adult patients with severe
eosinophilic asthma on high-dose inhaled corticosteroids (ICS) plus
long-acting beta2-agonist (LABA) and long-term use of OCS therapy
with or without additional asthma controller(s). Patients recruited
into the study had been on maintenance OCS dose of ≥5 mg of
prednisone for at least three months and had a baseline peripheral
blood eosinophil count of ≥150 cells/μL or baseline eosinophils
below 150 cells/μL with a documented eosinophil count of ≥300
cells/μL in the past 12 months. The treatment period consisted of a
four-week induction phase with no OCS adjustments, a variable OCS
tapering phase and an ongoing 24-32-week maintenance phase.7
The primary outcome measures of the trial were the proportion of
patients achieving a 100% reduction in daily OCS dose and the
proportion of patients achieving a 100% reduction or a daily OCS
dose of ≤5 mg if the reason for no further OCS reduction was
adrenal insufficiency, both sustained for at least four weeks
without worsening of asthma.7,12
Compared to published trials, PONENTE has a personalized OCS
tapering schedule that allows for more rapid OCS tapering from high
OCS doses, followed by an assessment of the adrenal function as
part of decision-making to manage the risk of adrenal
insufficiency. PONENTE also has a significantly longer maintenance
phase, (approximately 24-32 weeks versus four weeks for published
trials of other biologics) allowing assessment of the durability of
OCS reduction.7
FASENRA FASENRA® (benralizumab) is a monoclonal
antibody that binds directly to IL-5 receptor alpha on eosinophils
and attracts natural killer cells to induce rapid and near-complete
depletion of eosinophils via apoptosis (programmed cell death).13,
14
FASENRA is in development for other eosinophilic diseases and
chronic obstructive pulmonary disease.15-19 The Food and Drug
Administration granted Orphan Drug Designation for FASENRA for the
treatment of eosinophilic granulomatosis with polyangiitis in 2018,
and hypereosinophilic syndrome and eosinophilic oesophagitis in
2019.
FASENRA was developed by AstraZeneca and is in-licensed from
BioWa, Inc., a wholly-owned subsidiary of Kyowa Kirin Co., Ltd.,
Japan.
AstraZeneca in Respiratory & Immunology Respiratory
& Immunology is one of AstraZeneca’s three therapy areas and is
a key growth driver for the Company.
Building on a 50-year heritage, AstraZeneca is an established
leader in respiratory care across inhaled and biologic medicines.
AstraZeneca aims to transform the treatment of asthma and chronic
obstructive pulmonary disease (COPD) by eliminating preventable
asthma attacks across all severities and removing COPD as leading
cause of death through earlier, biology-led treatment. 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 immune-driven diseases. The Company’s
growing presence in immunology is focused on five mid- to
late-stage franchises with multi-disease potential in rheumatology
(including systemic lupus erythematosus), dermatology,
gastroenterology and systemic eosinophilic-driven diseases.
AstraZeneca’s ambition in immunology is to achieve disease control
and ultimately clinical remission in targeted immune-driven
diseases.
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.
References
- The Global Asthma Network. The Global Asthma Report 2018.
[Online]. Available at: http://www.globalasthmareport.org/Global
Asthma Report 2018.pdf. Last accessed: October 2020.
- Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS
guidelines on definition, evaluation and treatment of severe
asthma. Eur Respir J 2014; 43: 343–73.
- Wang E, Wechsler ME, Tran TN, et al. Characterization of Severe
Asthma Worldwide Data From the International Severe Asthma
Registry. Chest. 2020;157 (4): 790-804.
- Sweeney J, Patterson CC, Menzies-Gow A, et al. Comorbidity in
severe asthma requiring systemic corticosteroid therapy:
cross-sectional data from the Optimum Patient Care Research
Database and the British Thoracic Difficult Asthma Registry.
Thorax. 2016; 71 (4): 339-346.
- Sullivan PW, Ghushchyan VH, Globe G, Schatz M. Oral
corticosteroid exposure and adverse effects in asthmatic patients.
J Allergy Clin Immunol. 2018; 141 (1): 110-116.e7
- Hyland ME, Whalley B, Jones RC, et al. A qualitative study of
the impact of severe asthma and its treatment showing that
treatment burden is neglected in existing asthma assessment scales.
Quality of Life Research. 2015: 24 (3) 631-619.
- Menzies-Gow A, Corren J, Bel EH, et al. Corticosteroid tapering
with benralizumab treatment for eosinophilic asthma: PONENTE Trial.
ERJ Open Res 2019; 5: 00009-2019.
- Nair P, Wenzel S, Rabe KF, et al, on behalf of the ZONDA trial
investigators. Oral glucocorticoid–sparing effect of benralizumab
in severe asthma. N Engl J Med 2017; 376: 2448-2458.
- Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med.
2005; 172; 149–60.
- Peters SP, Ferguson G, Deniz Y, et al. Uncontrolled asthma: a
review of the prevalence, disease burden and options for treatment.
Respir Med 2006: 100 (7): 1139-51.
- Liu D, Ahmet A, Ward L, et al. A practical guide to the
monitoring and management of the complications of systemic
corticosteroid therapy. Allergy & Clinical Immunology. 2013;
9:30.
- Clinicaltrials.gov. Study to Evaluate Efficacy and Safety of
Benralizumab in Reducing Oral Corticosteroid Use in Adult Patients
With Severe Asthma (PONENTE). Available at:
https://clinicaltrials.gov/ct2/show/NCT03557307 Last accessed:
October 2020.
- Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized
anti–IL-5 receptor a mAb with enhanced antibody-dependent
cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;
125 (6): 1344-1353.e2.
- Pham TH, Damera G, Newbold P, Ranade K. Reductions in
eosinophil biomarkers by benralizumab in patients with asthma.
Respir Med. 2016; 111: 21-29.
- Clinicaltrials.gov. Effect of Benralizumab in Atopic
Dermatitis. Available at:
https://clinicaltrials.gov/ct2/show/NCT03563066 Last accessed:
October 2020.
- Data on file, REF-84445, AstraZeneca Pharmaceuticals LP.
- Clinicaltrials.gov. A Study to Evaluate if Benralizumab
Compared to Mepolizumab May be Beneficial in the Treatment of
Eosinophilic Granulomatosis With Polyangiitis (EGPA) (MANDARA).
Available at: https://clinicaltrials.gov/ct2/show/NCT04157348. Last
accessed: October 2020.
- Clinicaltrials.gov. A Phase 3 Study to Evaluate the Efficacy
and Safety of Benralizumab in Patients With Hypereosinophilic
Syndrome (HES) (NATRON). Available at:
https://clinicaltrials.gov/ct2/show/NCT04191304 Last accessed:
October 2020.
- Clinicaltrials.gov. Efficacy and Safety of Benralizumab in
Moderate to Very Severe Chronic Obstructive Pulmonary Disease
(COPD) With a History of Frequent Exacerbations (RESOLUTE).
Available at: https://clinicaltrials.gov/ct2/show/NCT04053634 Last
accessed: October 2020.
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