First head-to-head trial of biologics in
EGPA, comparing a single monthly injection of FASENRA to three
injections per month of mepolizumab
Positive high-level results from the MANDARA Phase III trial
showed AstraZeneca’s FASENRA (benralizumab) met the primary
endpoint of the trial and demonstrated non-inferior rates of
remission compared to mepolizumab in patients with eosinophilic
granulomatosis with polyangiitis (EGPA) who were receiving oral
corticosteroids (OCS) with or without stable immunosuppressive
therapy.
MANDARA is the first Phase III head-to-head trial of biologics
in EGPA and compared the efficacy and safety of FASENRA versus
mepolizumab, the only currently approved treatment.1,2 In the
blinded trial, patients were randomized to receive either a single
30mg subcutaneous injection of FASENRA or three separate 100mg
subcutaneous injections of mepolizumab once every four
weeks.1,2
EGPA is a rare, immune-mediated vasculitis that is caused by
inflammation of small to medium-sized blood vessels.3,4
Approximately half of patients with EGPA have concomitant
adult-onset severe eosinophilic asthma (SEA).5 EGPA can result in
damage to multiple organs, including lungs, skin, heart,
gastrointestinal tract and nerves, which accumulates over time and
without treatment can be fatal.3,6
Dr Michael Wechsler, Principal Investigator said: “The positive
MANDARA trial results are exciting because patients with
eosinophilic granulomatosis with polyangiitis today have limited
treatment options but face crippling symptoms, which can even be
fatal if not treated. This trial demonstrates that a biologic
medicine given in a single monthly injection could help patients
achieve remission rates comparable to the current standard of care,
adding to the importance of benralizumab as a potential treatment
option for eosinophilic granulomatosis with polyangiitis.”
Sharon Barr, Executive Vice President, BioPharmaceuticals
R&D, AstraZeneca, said: “The positive results from MANDARA
demonstrate that FASENRA, which has a unique mechanism of action
and directly targets eosinophils, can help patients achieve
remission from the debilitating impacts of this inflammatory
disease with a more convenient single monthly subcutaneous
injection.”
The safety and tolerability profile for FASENRA in the trial was
consistent with the known profile of the medicine.
Full results from MANDARA will be presented at an upcoming
medical meeting and data will be shared with health authorities
around the world.
FASENRA 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 blood and tissue
eosinophils in most patients via apoptosis (programmed cell
death).7,8
FASENRA is currently approved as an add-on maintenance treatment
for SEA in the US, EU, Japan and other countries, and is approved
for self-administration in the US, EU and other countries.9,10 The
FDA granted Orphan Drug Designation for FASENRA for EGPA in 2018
and AstraZeneca continues to explore FASENRA’s potential beyond
severe asthma, as a treatment across many diseases where
eosinophils are expected to play a role.11-14
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 and Instructions for Use. You may report side
effects related to AstraZeneca products.
Notes
EGPA EGPA, formerly known as Churg-Strauss Syndrome, is a
rare, immune-mediated inflammatory disease that is caused by
inflammation of small to medium-sized blood vessels.3,4 It is
estimated that 118,000 people throughout the world live with
EGPA.15
EGPA can result in damage to multiple organs, including lungs,
skin, heart, gastrointestinal tract and nerves.3 The most common
symptoms and signs include extreme fatigue, weight loss, muscle and
joint pain, rashes, nerve pain, sinus and nasal symptoms, and
shortness of breath.3,6 Without treatment, the disease may be
fatal.3,6
Elevated levels of eosinophils play a central role in EGPA
disease pathophysiology.4 All patients with EGPA have very high
levels of eosinophils at some point in their disease, both in
peripheral blood and in affected tissues or organs.3,6
Approximately half of patients with EGPA have concomitant
adult-onset SEA, and often have sinus and nasal symptoms.3,5
There are limited treatment options for EGPA. Patients are often
treated with chronic high-dose OCS and can experience recurrent
relapses when attempting to taper off OCS.6,16 Mepolizumab is
currently the only approved treatment for EGPA.2
MANDARA MANDARA was a randomized, double blind,
double-dummy, active-controlled, parallel group, multicentre
52-week Phase III trial which compared the efficacy and safety of
FASENRA to mepolizumab in adult patients with relapsing or
refractory EGPA.1 In the blinded trial, 140 patients were
randomized 1:1 (70 per treatment group) to receive either a single
30mg subcutaneous injection of FASENRA or three separate 100mg
subcutaneous injections of mepolizumab once every four weeks.1
The primary endpoint was the proportion of patients who were in
remission at both weeks 36 and 48.1 Remission is defined as
Birmingham Vasculitis Activity Score (BVAS)=0 and OCS dose less
than or equal to 4mg/day.1 FASENRA remission was compared to the
historical placebo rate from mepolizumab’s Phase III trial,
MIRRA.17 The primary statistical analysis was to demonstrate
non-inferiority of FASENRA versus mepolizumab based on the primary
endpoint.
All patients who complete the 52-week double-blind treatment
period may be eligible to continue into an open label extension
(OLE) period, intended to allow each patient at least one year of
treatment with open-label FASENRA.1
Mepolizumab is a humanized IL-5 antagonist monoclonal
antibody.2
FASENRA FASENRA (benralizumab) is currently approved as
an add-on maintenance treatment for SEA in the US, EU, Japan and
other countries, and is approved for self-administration in the US,
EU and other countries.9,10 FASENRA has been studied in almost
4,000 patients in global clinical trials.18-22
FASENRA is in development for other eosinophilic diseases
including chronic obstructive pulmonary disease, chronic
rhinosinusitis with nasal polyps and hypereosinophilic
syndrome.12-14
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 and Immunology Respiratory
& Immunology, part of BioPharmaceuticals, is one of
AstraZeneca’s main disease areas and is a key growth driver for the
Company.
AstraZeneca is an established leader in respiratory care with 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.
AstraZeneca AstraZeneca is a global, science-led
biopharmaceutical company that focuses on the discovery,
development and commercialization of prescription medicines in
Oncology and BioPharmaceuticals, including 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.
For more information, please visit www.astrazeneca-us.com and
follow the Company on social media @AstraZeneca.
References
- Clinicaltrials.gov. Efficacy and Safety of Benralizumab in EGPA
Compared to Mepolizumab. (MANDARA). Available at:
https://classic.clinicaltrials.gov/ct2/show/NCT04157348. [Last
accessed: September 2023].
- Mepolizumab US prescribing information. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125526Orig1s021,761122Orig1s011Corrected_lbl.pdf
[Last accessed: September 2023].
- American Partnership for Eosinophilic Disorders. Eosinophilic
Granulomatosis with Polyangiitis (EGPA). Available at:
https://apfed.org/about-ead/eosinophilic-granulomatosis-with-polyangiitis/.
[Last accessed: September 2023].
- Furuta S, Iwamoto T, Nakajima H. Update on eosinophilic
granulomatosis with polyangiitis. Allergol Int.
2019;68:430-436.
- Cottin V, et al. Respiratory manifestations of eosinophilic
granulomatosis with polyangiitis (Churg–Strauss). Eur Respir J.
2016;48:1429-1441.
- Baldini C, et al. Clinical Manifestations and Treatment of
Churg-Strauss Syndrome. Rheum Dis Clin N Am. 2010;36:527–543.
- Kobleck R, 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;125:1344-1353.e2.
- Pham TH, et al. Reductions in eosinophil biomarkers by
benralizumab in patients with asthma. Respir Med.
2016;111:21-29.
- AstraZeneca news release. Available at:
https://www.astrazeneca.com/media-centre/press-releases/2019/fasenra-approved-in-the-us-for-self-administration-in-a-new-pre-filled-auto-injector-the-fasenra-pen-04102019.html.
[Last accessed: September 2023].
- AstraZeneca news release. Available at:
https://www.astrazeneca.com/media-centre/press-releases/2019/fasenra-receives-positive-eu-chmp-opinion-for-self-administration-and-the-new-fasenra-pen-a-pre-filled-single-use-auto-injector-01072019.html.
[Last accessed: September 2023].
- AstraZeneca news release. Available at:
https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-grants-fasenra-orphan-drug-designation-for-eosinophilic-granulomatosis-with-polyangiitis-26112018.html.
[Last accessed: September 2023].
- 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 from: https://clinicaltrials.gov/ct2/show/NCT04053634.
[Last accessed: September 2023].
- Clinicaltrials.gov. Efficacy and Safety Study of Benralizumab
in Patient With Eosinophilic Chronic Rhinosinusitis With Nasal
Polyps (ORCHID). Available at:
https://clinicaltrials.gov/ct2/show/NCT04157335. [Last accessed:
September 2023].
- Clinicaltrials.gov. A Phase 3 Study to Evaluate the Efficacy
and Safety of Benralizumab in Patients With Hypereosinophilic
Syndrome (HES) (NATRON). Available from:
https://clinicaltrials.gov/ct2/show/NCT04191304. [Last accessed:
September 2023].
- AstraZeneca Data on file. 2022. REF-167820.
- Bell CF, et al. Burden of illness and costs associated with
eosinophilic granulomatosis with polyangiitis: evidence from a
managed care database in the United States. J Manag Care Spec
Pharm. 2021;27:1249-1259.
- AstraZeneca Data on file. 2023. REF-196096.
- Bleecker ER, et al. Efficacy and safety of benralizumab for
patients with severe asthma uncontrolled with high-dosage inhaled
corticosteroids and long-acting β 2-agonists (SIROCCO): a
randomized, multicentre, placebo-controlled phase 3 trial. Lancet.
2016;388:2115-2127.
- FitzGerald JM, et al. Benralizumab, an anti-interleukin-5
receptor α monoclonal antibody, as add-on treatment for patients
with severe, uncontrolled, eosinophilic asthma (CALIMA): a
randomized, double-blind, placebo-controlled phase 3 trial. Lancet.
2016;388:2128-2141.
- Nair P, et al. Oral Glucocorticoid-Sparing Effect of
Benralizumab in Severe Asthma. N Engl J Med.
2017;376:2448-2458.
- Menzies-Gow A, et al. Oral corticosteroid elimination via a
personalised reduction algorithm in adults with severe,
eosinophilic asthma treated with benralizumab (PONENTE): a
multicentre, open-label, single-arm study. Lancet Respir Med.
2022;10:47-58.
- Harrison TW, et al. Onset of effect and impact on
health-related quality of life, exacerbation rate, lung function,
and nasal polyposis symptoms for patients with severe eosinophilic
asthma treated with benralizumab (ANDHI): a randomized, controlled,
phase 3b trial. Lancet Respir Med. 2021;9:260-274.
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