WILMINGTON, Del.–(BUSINESS WIRE)–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
Known hypersensitivity to benralizumab or excipients.
WARNINGS AND PRECAUTIONS
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.
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.
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
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 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® (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 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.
- 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.