New Fasenra data from the PONENTE trial show sustained, robust oral corticosteroid reductions in largest ever steroid-sparing trial in severe asthma
97% of patients across a broad range of blood eosinophil counts maintained their lowest OCS dose over approximately six months
New findings from the PONENTE Phase IIIb open-label trial showed that oral corticosteroid (OCS)-dependent asthma patients treated with?Fasenra?(benralizumab) eliminated maintenance OCS or achieved a daily dose of 5mg or below using a personalised tapering schedule.1?These outcomes were sustained?during the six-month trial maintenance phase.1
These findings were presented today at the?European Respiratory Society (ERS) International Congress 2021.1,2
Severe asthma is an often debilitating condition affecting approximately 34 million people worldwide.3,4?Between 20 and 60% of these patients currently use chronic or intermittent OCS on top of other therapies to control their symptoms and exacerbations.5-8?However, frequent or chronic OCS use can lead to serious adverse effects, including adrenal insufficiency,4,9-11?a condition in which the adrenal?glands do not produce adequate amounts of steroid hormones.12,13
During the maintenance phase, no change in median daily OCS dosage (0 mg) was observed from the end of the OCS reduction phase and only 3% (18/593) of patients who completed the reduction phase increased their maintenance OCS dosage.1?Most patients had an improvement (18%) or no change (39%) in their asthma control from the end of the OCS-reduction phase to the end of the maintenance phase (assessed by the Asthma Control Questionnaire [ACQ-6]) and most were exacerbation free (85%) during the maintenance phase, versus 16% exacerbation free at baseline in the 12 months before enrolment.1,14?At the end of the maintenance phase, compared to baseline, there was also a substantial improvement in quality of life (QoL) with an adjusted mean change from baseline in the St. George?s Respiratory Questionnaire (SGRQ) total score of ?19.7 units.1
Adrenal insufficiency is commonly associated with OCS use.10,11?As expected with OCS reduction or elimination, there were more patients with normal adrenal function (55.5%) at the end of maintenance phase, as compared with 51% at end of the OCS reduction phase and 40% at initial testing.2
Professor Andrew Menzies-Gow, Director of the Lung Division, Royal Brompton Hospital, London, UK, the principal investigator of the PONENTE trial, said: ?Having previously demonstrated that almost all patients on?Fasenra?reduced or eliminated their daily OCS use during the reduction phase of PONENTE, we can now confidently affirm that these positive outcomes can be sustained for approximately six months. Importantly, these data from the largest-ever steroid sparing trial in severe asthma address a longstanding knowledge gap around OCS tapering and should help advance much needed changes in clinical practice.?
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: ?We know that among the 34 million people worldwide living with severe asthma, many continue to rely on OCS, which can lead to severe and potentially life-threatening side effects. These new data from the maintenance phase of the PONENTE trial reinforce?Fasenra?s ability to sustain OCS elimination or dosage reductions among patients with a broad range of baseline blood eosinophil counts.?
The safety profile and tolerability of?Fasenra?in this trial were consistent with the known profile of the medicine.14
These maintenance phase data build on previously reported?high-level results?from the PONENTE OCS reduction phase that were presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) 2021 Virtual Annual Meeting.14?Full results from the OCS reduction phase have been submitted for publication in a peer-reviewed medical journal.
The trial expands on OCS-sparing data previously seen in the ZONDA Phase III trial, by using a faster steroid-tapering schedule.15,16?The PONENTE trial also has a longer maintenance phase of approximately 24-32 weeks than in ZONDA and all other published trials for biologic medicines.15,16
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 July 2021, AstraZeneca announced?Fasenra?is being evaluated in?10 eosinophilic diseases?beyond severe asthma.17-26
Severe asthma
Severe asthma is an often-debilitating, potentially fatal condition affecting approximately 34 million people worldwide.3,4,27?Patients may be uncontrolled despite high dosages of standard of care asthma controller medicines, experiencing frequent exacerbations and significant limitations on lung function and health-related quality of life as a result.4,27,28
Between 20 and 60% of patients with severe asthma currently use chronic or intermittent OCS on top of other therapies to control their symptoms and exacerbations.5-8?However, frequent, or chronic OCS use can lead to serious adverse effects.4,9-11
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.4,9,29-31?OCS over-reliance can also place additional strain on health systems; a UK analysis identified OCS-dependent asthma patients have an average of 43% greater associated direct healthcare treatment costs than patients not receiving maintenance OCS.32
Adrenal insufficiency is a condition in which the adrenal?glands do not produce adequate amounts of steroid hormones.12,13?Steroid hormones are important to help control metabolism, inflammation, immune functions and salt and water balance, among other critical functions.13?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.12,13
PONENTE
PONENTE is a multicentre, 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).15?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/?L or baseline eosinophils below 150 cells/?L with a documented eosinophil count of =300 cells/?L in the past 12 months.15?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.15
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.15
Adult patients in the trial continued on the lowest stable daily OCS dosage or OCS elimination achieved during the reduction phase plus?Fasenra?30 mg every 8 weeks for 3 doses. Changes in OCS dosage and asthma control were measured from the end of the reduction phase and changes in QoL from baseline.1?Adrenal function was assessed upon reaching 5mg stable OCS dosage during the reduction phase and repeated through to the end of the maintenance phase.2
Compared to published trials, PONENTE has a personalised OCS tapering schedule that allows for more rapid OCS tapering from high OCS doses ?7.5 mg/day initiated 1 month after the first dose of?Fasenra.15?Once the OCS dose reaches a level equivalent to 5mg of prednisone a day, individualised OCS tapering from 5mg to 0mg is based on assessment of adrenal function as part of the decision-making to manage the risk of adrenal insufficiency.15?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.15,16,33,34
PONENTE included nearly 600 patients in Europe, North America, South America, and Taiwan.15?Of the patients who entered PONENTE, 90% completed both the OCS-reduction and the 24- to 32-week maintenance phases.1?In the reduction phase of the trial,?Fasenra?eliminated maintenance OCS use in 62% of OCS-dependent severe asthma patients across a broad range of blood eosinophil counts.14?Overall, 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.14?Nearly all patients (91%) eliminated OCS use or achieved a final daily OCS dose of 5mg or less regardless of the reason for stopping the reduction.14?In addition, 74% of patients during the reduction phase did not experience asthma exacerbations. At baseline, 16% of patients were exacerbation free in the 12 months before enrolment.14
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).35,36
Fasenra?is in development for other eosinophilic diseases and chronic obstructive pulmonary disease.17-26?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, 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 (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 Twitter?@AstraZeneca.
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References
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Veeva ID: Z4-36055
Date of Preparation: September 2021
