AIRSUPRA™ (PT027) approved in the US for asthma

First and only rescue medication approved in the US for as-needed use to reduce risk of asthma exacerbations

WILMINGTON, Del.–(BUSINESS WIRE)–AIRSUPRA™ (albuterol/budesonide), formerly known as PT027, has been approved in the US for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in people with asthma aged 18 years and older.

The approval by the Food and Drug Administration (FDA) was based on results from the MANDALA and DENALI Phase III trials.^1,2 In MANDALA, AIRSUPRA significantly reduced the risk of severe exacerbations compared to albuterol in patients with moderate to severe asthma when used as an as-needed rescue medication in response to symptoms.¹ Importantly, in the secondary endpoint of mean annualized total systemic corticosteroid exposure, AIRSUPRA demonstrated a significant reduction compared to albuterol at the approved dose of 180mcg albuterol/160mcg budesonide.¹ In DENALI, AIRSUPRA significantly improved lung function compared to the individual components albuterol and budesonide in patients with mild to moderate asthma.²

AIRSUPRA is a first-in-class, pressurized metered-dose inhaler (pMDI), fixed-dose combination rescue medication containing albuterol, a short-acting beta2-agonist (SABA), and budesonide, an anti-inflammatory inhaled corticosteroid (ICS) in the US. It is being developed by AstraZeneca and Avillion.

Bradley E. Chipps, Past President of the American College of Allergy, Asthma & Immunology and Medical Director of Capital Allergy & Respiratory Disease Center in Sacramento, US, said: “People with asthma are at risk of severe exacerbations regardless of their disease severity or level of control. Current albuterol rescue inhalers alleviate acute symptoms, but do not treat the underlying inflammation in asthma. The approval of AIRSUPRA means that for the first time, adults with asthma in the US have a rescue treatment to manage both their symptoms and the inflammatory nature of their disease.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “With patients experiencing more than 10 million asthma exacerbations each year in the US and uncontrolled asthma expected to cost the US economy billions of dollars in direct medical costs alone over the next 20 years, today’s positive decision is good news for those adults with asthma who make up more than 80% of asthma patients in the US. Physicians will be able to offer their patients AIRSUPRA, an important new rescue treatment that reduces the risk of asthma exacerbations.”

Asthma is a chronic, inflammatory respiratory disease with variable symptoms that affects as many as 262 million people worldwide.³ In the US over 21 million adults have asthma, representing more than 80% of the total number of people with asthma.⁴ Adults have 8.5 million exacerbations each year in the US.⁴ Uncontrolled asthma will cost the US economy an estimated $300 billion (in 2018 dollar values) in the next 20 years in direct medical costs alone.⁵

The safety and tolerability of AIRSUPRA in both trials were consistent with the known profiles of the components,^1,2 with the most common adverse events including headache, oral candidiasis, cough and dysphonia.⁶

Results from the MANDALA trial were published in the New England Journal of Medicine in May 2022.¹

INDICATION

AIRSUPRA is a combination of albuterol, a beta₂-adrenergic agonist and budesonide, a corticosteroid, indicated for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years of age and older.

IMPORTANT SAFETY INFORMATION

• Contraindications: Hypersensitivity to albuterol, budesonide, or to any of the excipients
• Deterioration of Asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient continues to experience symptoms after using AIRSUPRA or requires more doses of AIRSUPRA than usual, it may be a marker of destabilization of asthma and requires evaluation of the patient and their treatment regimen
• Paradoxical Bronchospasm: AIRSUPRA can produce paradoxical bronchospasm, which may be life threatening. Discontinue AIRSUPRA immediately and institute alternative therapy if paradoxical bronchospasm occurs. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister
• Cardiovascular Effects: AIRSUPRA, like other drugs containing beta₂-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by pulse rate, blood pressure, and/or other symptoms. If such effects occur, AIRSUPRA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST-segment depression. Therefore, AIRSUPRA, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension
• Do Not Exceed Recommended Dose: Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs
• Hypersensitivity Reactions, Including Anaphylaxis: Can occur after administration of albuterol sulfate and budesonide, components of AIRSUPRA, as demonstrated by cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, rash, and urticaria. Discontinue AIRSUPRA if such reactions occur
• Risk of Sympathomimetic Amines with Certain Coexisting Conditions: AIRSUPRA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines
• Hypokalemia: Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients. The decrease in serum potassium is usually transient, not requiring supplementation
• Immunosuppression and Risk of Infections: Due to possible immunosuppression from use of ICS, potential worsening of infections could occur. Use with caution. A more serious or fatal course of chickenpox or measles can occur in susceptible patients
• Oropharyngeal Candidiasis: Has occurred in patients treated with ICS agents. Monitor patients periodically. Advise patients to rinse his/her mouth with water, if available, without swallowing after inhalation
• Hypercorticism and Adrenal Suppression: May occur with very high doses in susceptible individuals. If such changes occur, consider appropriate therapy
• Reduction in Bone Mineral Density: Decreases in bone mineral density have been observed with long-term administration of ICS. For patients at high risk for decreased bone mineral density, assess initially and periodically thereafter
• Glaucoma and Cataracts: Have been reported following the long-term administration of ICS, including budesonide, a component of AIRSUPRA
• Effects on Growth: Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of AIRSUPRA have not been established in pediatric patients, and AIRSUPRA is not indicated for use in this population
• Most common adverse reactions (incidence ≥ 1%) are headache, oral candidiasis, cough, and dysphonia
• Drug Interactions: AIRSUPRA should be administered with caution to patients being treated with:
  • Strong cytochrome P450 3A4 inhibitors (may cause systemic corticosteroid effects)
  • Short-acting bronchodilators (concomitant use of additional beta-agonists with AIRSUPRA should be used judiciously to prevent beta-agonist overdose)
  • Beta-blockers (may block pulmonary effects of beta-agonists and produce severe bronchospasm)
  • Diuretics or non-potassium-sparing diuretics (may potentiate hypokalemia or ECG changes). Consider monitoring potassium levels
  • Digoxin (may decrease serum digoxin levels). Consider monitoring digoxin levels
  • Monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants (Use AIRSUPRA with extreme caution; may potentiate effect of albuterol on the cardiovascular system)
• Use AIRSUPRA with caution in patients with hepatic impairment, as budesonide systemic exposure may increase. Monitor patients with hepatic disease

Please see full Prescribing Information, including Patient Information.

Notes

Asthma

Asthma is a chronic, inflammatory respiratory disease with variable symptoms that affects as many as 262 million people worldwide,³ including over 25 million in the US.⁴

Patients with asthma experience recurrent breathlessness and wheezing, which varies over time, and in severity and frequency.⁷ These patients are at risk of severe exacerbations regardless of their disease severity, adherence to treatment or level of control.^8,9

There are an estimated 136 million asthma exacerbations globally per year,¹⁰ including more than 10 million in the US;⁴ these are physically threatening and emotionally significant for many patients¹¹ and can be fatal.^3,12

Inflammation is central to both asthma symptoms⁸ and exacerbations.¹³ Many patients experiencing asthma symptoms use a SABA (e.g. albuterol) as a rescue medicine;^14-16 however, taking a SABA alone does not address inflammation, leaving patients at risk of severe exacerbations,¹⁷ which can result in impaired quality of life,¹⁸ hospitalization¹⁹ and frequent oral corticosteroid (OCS) use.¹⁹ Treatment of exacerbations with as few as 1-3 short courses of OCS are associated with an increased risk of adverse health conditions including type 2 diabetes, depression/anxiety, renal impairment, cataracts, cardiovascular disease, pneumonia and fracture.²⁰ International recommendations from the Global Initiative for Asthma no longer recommend SABA alone as the preferred rescue therapy.⁷

MANDALA, DENALI and the CREST (Combination REliever STudies) program

The CREST clinical trial program studied the efficacy and safety of PT027 and included the MANDALA,^1,21,22 DENALI^2,23,24 and TYREE²⁵ Phase III trials.

MANDALA^1,21,22 was a Phase III, randomized, double-blind, multicenter, parallel-group, event-driven trial evaluating the efficacy and safety of AIRSUPRA compared to albuterol on the time to first severe asthma exacerbation in 3,132 adults, adolescents, and children (aged 4–11 years) with moderate to severe asthma taking ICS alone or in combination with a range of asthma maintenance therapies, including long-acting beta2-agonists (LABA), leukotriene receptor antagonists (LTRA), long-acting muscarinic antagonists (LAMA) or theophylline. The trial comprised a two-to-four-week screening period, at least a 24-week treatment period and a two-week post-treatment follow-up period.

Patients were randomly assigned to one of the following three treatment groups in a 1:1:1 ratio: AIRSUPRA 180/160mcg (excluding children aged 4–11 years), albuterol/budesonide 180/80mcg or albuterol 180mcg, taken as an as-needed rescue medicine. AIRSUPRA and the albuterol comparator were delivered in a pMDI using AstraZeneca’s Aerosphere delivery technology. The primary efficacy endpoint was the time to first severe asthma exacerbation during the treatment period. Secondary endpoints included severe exacerbation rate (annualized), total systemic corticosteroid exposure (annualized), asthma control and health-related quality of life.

Results from the positive MANDALA Phase III trial showed that AIRSUPRA demonstrated a statistically significant reduction in the risk of a severe exacerbation versus albuterol rescue in patients with moderate to severe asthma.^1,22 Compared with albuterol rescue, AIRSUPRA at the 180mcg albuterol/160mcg budesonide dose reduced the risk of a severe exacerbation by 27% (p<0.001) in adults and adolescents.^1,22

Primary and secondary endpoint results in adults and adolescents^1,22

(pre-planned on-treatment efficacy analysis)

Treatment Group			Comparison versus albuterol 180mcg
Time to first severe exacerbation	n	Number (%) of Patients with a Severe Exacerbation a, b	Hazard Ratio (95% CI)	p value (2‑sided)
AIRSUPRA 180/160mcg	1013	207 (20.4)	0.73 (0.61, 0.88)	<0.001
Albuterol 180mcg	1014	266 (26.2)
Annualized severe exacerbation rate (rate ratio)	n	Number of Severe Exacerbations a, b	Annualized rate (95% CI)	Rate Ratio (95% CI)
AIRSUPRA 180/160mcg	1013	334	0.45 (0.34, 0.60)	0.76 (0.62, 0.93)
Albuterol 180mcg	1014	413	0.59 (0.44, 0.78)
Annualized total SCS dose (mg/year)	n	Mean (SD) b	% reduction in mean
AIRSUPRA 180/160mcg	1012	86.2 (262.86)	33.4%
Albuterol 180mcg	1011	129.3 (657.19)
aDeterioration of asthma requiring use of SCS for ≥3 days, or inpatient hospitalization, or emergency room visit, that required SCS. bBefore discontinuation of randomized treatment or change in maintenance therapy. CI, confidence interval; SCS, systemic corticosteroid; SD, standard deviation

Primary endpoint results in adults, adolescents, and children^1,22

(pre-planned on-treatment efficacy analysis)

Treatment Group			Comparison versus albuterol 180mcg
Time to first severe exacerbation	n	Number (%) of Patients with a Severe Exacerbation a, b	Hazard Ratio (95% CI)	p value (2‑sided)
Albuterol/budesonide 180/80mcg	1054	241 (22.9)	0.83 (0.70, 0.99)	0.041
Albuterol 180mcg	1056	276 (26.1)
aDeterioration of asthma requiring use of SCS for ≥3 days, or inpatient hospitalization, or emergency room visit, that required SCS. bBefore discontinuation of randomized treatment or change in maintenance therapy. CI, confidence interval

Adverse events (AEs) were similar across the treatment groups in the trial and consistent with the known safety profiles of the individual components, with the most common AEs including nasopharyngitis and headache.^1,22

DENALI^2,23,24 was a Phase III, randomized, double-blind, placebo-controlled, multicenter, parallel-group trial evaluating the efficacy and safety of AIRSUPRA compared to its components albuterol and budesonide on improvement in lung function in 1,001 adults, adolescents, and children aged 4–11 years with mild to moderate asthma previously treated either with SABA as-needed alone or in addition to regular low-dose ICS maintenance therapy. The trial comprised a two-to-four-week screening period, a 12-week treatment period and a two-week post-treatment follow-up period.

Patients were randomly assigned to one of the following five treatment groups in a 1:1:1:1:1 ratio: AIRSUPRA 180/160mcg four times daily (excluding children aged 4–11 years), albuterol/budesonide 180/80mcg four times daily, albuterol 180mcg four times daily, budesonide 160mcg four times daily (excluding children aged 4–11 years) and placebo four times daily. AIRSUPRA, the albuterol and budesonide comparators and placebo were delivered in a pMDI using AstraZeneca’s Aerosphere delivery technology. The dual primary efficacy endpoints were change from baseline in FEV1 area under the curve 0-6 hours over 12 weeks of AIRSUPRA compared to budesonide to assess the effect of albuterol and change from baseline in trough FEV1 at Week 12 of AIRSUPRA compared to albuterol to assess the effect of budesonide. Secondary endpoints included the time to onset and duration of response on day one, number of patients who achieved a clinically meaningful improvement in asthma control from baseline at Week 12 and trough FEV1 at Week 1.

In the trial, AIRSUPRA demonstrated a statistically significant improvement in lung function measured by forced expiratory volume in one second (FEV1), compared to the individual components albuterol and budesonide, and compared to placebo in patients with mild to moderate asthma aged 12 years or older. Onset of action and duration of effect were similar for AIRSUPRA and albuterol. The safety and tolerability of AIRSUPRA in DENALI was consistent with the known profiles of the components.

AIRSUPRA

AIRSUPRA (albuterol/budesonide), formerly known as PT027, is a first-in-class SABA/ICS rescue treatment for asthma in the US, to be taken as needed. It is an inhaled, fixed-dose combination rescue medication containing albuterol (also known as salbutamol), a SABA, and budesonide, a corticosteroid, and has been developed in a pMDI using AstraZeneca’s Aerosphere delivery technology.

AstraZeneca and Avillion collaboration

In March 2018, AstraZeneca and Avillion signed an agreement to advance AIRSUPRA through a global clinical development program for the treatment of asthma. Under the terms of the agreement, Avillion became the trial sponsor responsible for executing and funding the multicenter, global clinical trial program for AIRSUPRA through NDA filing to a regulatory decision in the US. Following the successful approval of AIRSUPRA, AstraZeneca has the option, upon certain financial payments, to commercialize the medicine in the US.

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, 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. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

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