TIDMAZN
RNS Number : 0599M
AstraZeneca PLC
11 September 2023
11 September 2023
Fasenra met the primary endpoint in the MANDARA Phase III trial
in eosinophilic granulomatosis with polyangiitis (EGPA)
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 randomised 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)
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 randomised, 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 randomised 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.
Respiratory & Immunology
Respiratory & Immunology, part of AstraZeneca
BioPharmaceuticals, is a key disease area and growth driver to the
Company.
AstraZeneca is an established leader in respiratory care with a
50-year heritage and a growing portfolio of medicines in
immune-mediated diseases. The Company is committed to addressing
the vast unmet needs of these chronic, often debilitating, diseases
with a pipeline and portfolio of inhaled medicines, biologics and
new modalities aimed at previously unreachable biologic targets.
Our ambition is to deliver life-changing medicines that help
eliminate COPD as a leading cause of death, eliminate asthma
attacks and achieve clinical remission in immune-mediated
diseases.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialisation of prescription medicines in
Oncology, Rare Diseases, 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. Please visit astrazeneca.com and follow the
Company on social media @AstraZeneca .
References
1. 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].
2. Mepolizumab US prescribing information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125526Orig1s021,761122Orig1s011Corrected_lbl.pdf [Last accessed: September 2023].
3. 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].
4. Furuta S, Iwamoto T, Nakajima H. Update on eosinophilic
granulomatosis with polyangiitis. Allergol Int.
2019;68:430-436.
5. Cottin V, et al. Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Eur Respir J. 2016;48:1429-1441.
6. Baldini C, et al. Clinical Manifestations and Treatment of
Churg-Strauss Syndrome. Rheum Dis Clin N Am. 2010;36:527-543.
7. 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.
8. Pham TH, et al. Reductions in eosinophil biomarkers by
benralizumab in patients with asthma. Respir Med.
2016;111:21-29.
9. 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].
10. 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].
11. 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].
12. 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].
13. 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].
14. 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].
15. AstraZeneca Data on file. 2022. REF-167820.
16. 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.
17. AstraZeneca Data on file. 2023. REF-196096.
18. Bleecker ER, et al. Efficacy and safety of benralizumab for
patients with severe asthma uncontrolled with high-dosage inhaled
corticosteroids and long-acting <BETA> 2-agonists (SIROCCO):
a randomised, multicentre, placebo-controlled phase 3 trial.
Lancet. 2016;388:2115-2127.
19. FitzGerald JM, et al. Benralizumab, an anti-interleukin-5
receptor <ALPHA> monoclonal antibody, as add-on treatment for
patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a
randomised, double-blind, placebo-controlled phase 3 trial. Lancet.
2016;388:2128-2141.
20. Nair P, et al. Oral Glucocorticoid-Sparing Effect of
Benralizumab in Severe Asthma. N Engl J Med.
2017;376:2448-2458.
21. 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.
22. 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 randomised, controlled,
phase 3b trial. Lancet Respir Med. 2021;9:260-274.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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