REG - AstraZeneca PLC - Fasenra Phase III EGPA trial met primary endpoint

AstraZenecaAnnouncement

11/09/2023 16:00

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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 (http://www.astrazeneca.com/) and follow the
Company on social media @AstraZeneca
(https://www.linkedin.com/company/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 β 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 α
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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