FDA approves first rescue treatment of asthma for adults

The US Food and Drug Administration (FDA) has approved albuterol/budesonide (Airsupra) for prevention and treatment of bronchoconstriction and to reduce the risk of exacerbations in people with asthma aged 18 years and older.

Airsupra is a first-in-class, pressurised 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).

The US approval was based on positive results from a global Phase III clinical trial programme for Airsupra comprising four studies involving more than 4,000 patients (including the MANDALA and DENALI trials1,2), which was conducted successfully by Avillion under an exclusive clinical co-development agreement with AstraZeneca.

Under its 2018 agreement, Avillion had regulatory responsibility including filing the New Drug Application (NDA) through to FDA approval in the US. Following this approval, AstraZeneca has the option, upon making certain financial payments to Avillion, to commercialise Airsupra in the US.

This milestone continues Avillion's 100% successful rate in clinical co-development partnerships for the global pharmaceutical and biotech industry.

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 The results from the MANDALA trial were published in the New England Journal of Medicine in May 2022.1 In DENALI, Airsupra significantly improved lung function compared to the individual components, albuterol and budesonide, in patients with mild to moderate asthma.2 The safety and tolerability of Airsupra in both trials were consistent with the known profiles of the components with the most common adverse events including headache, oral candidiasis, cough and dysphonia.

The co-development partnership between AstraZeneca and Avillion has recently expanded to include the BATURA study, a randomised Phase IIIb decentralised trial to further assess the role of Airsupra in reducing the risk of asthma exacerbations.

The Airsupra clinical co-development programme was funded by Blackstone Life Sciences, Royalty Pharma and Abingworth.

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."

Allison Jeynes, MD, Chief Executive Officer of Avillion, said: "We're delighted that our clinical co-development programme with AstraZeneca has been successful and that Airsupra has been approved in the US as a new treatment option for asthma patients. The Airsupra approval continues our 100% success rate facilitating clinical co-development programmes with pharma companies, demonstrating the strong value our innovative model can provide to partners and the excellence and dedication of our international team. We've had an excellent working relationship with AstraZeneca and are excited to continue our partnership with the BATURA Phase IIIb study, which is looking to continue building the evidence base of Airsupra to reduce the risk of asthma exacerbations."

Asthma

Asthma is a chronic, inflammatory respiratory disease with variable symptoms that affects as many as 262 million people worldwide,4 including over 25 million in the US.5

Patients with asthma experience recurrent breathlessness and wheezing, which varies over time, and in severity and frequency.6 These patients are at risk of severe exacerbations regardless of their disease severity, adherence to treatment or level of control.

There are an estimated 136 million asthma exacerbations globally per year,9 including 10 million in the US;5 these are physically threatening and emotionally significant for many patients11 and can be fatal.

Inflammation is central to both asthma symptoms7 and exacerbations.12 Many patients experiencing asthma symptoms use a SABA (e.g. albuterol) as a rescue medicine;13-15 however, taking a SABA alone does not address inflammation, leaving patients at risk of severe exacerbations,16 which can result in impaired quality of life,17 hospitalisation18 and frequent oral corticosteroid (OCS) use.18 Treatment of exacerbations with as few as 1-2 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.19 International recommendations from the Global Initiative for Asthma no longer recommend SABA alone as the preferred rescue therapy.

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

The CREST clinical trial programme studied the efficacy and safety of PT027 and included the MANDALA,1,20,21 DENALI2,22,23 and TYREE25 Phase III trials.

MANDALA1,20,21 was a Phase III, randomised, double-blind, multicentre, 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 (annualised), total systemic corticosteroid exposure (annualised), 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 asthma1,21. 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

Primary and secondary endpoint results in adults and adolescents

(pre-planned on-treatment efficacy analysis)

Deterioration of asthma requiring use of SCS for ≥3 days, or inpatient hospitalisation, or emergency room visit, that required SCS. bBefore discontinuation of randomised treatment or change in maintenance therapy.

CI, confidence interval; SCS, systemic corticosteroid; SD, standard deviation

Primary endpoint results in adults, adolescents, and children

(pre-planned on-treatment efficacy analysis)

Deterioration of asthma requiring use of SCS for ≥3 days, or inpatient hospitalisation, or emergency room visit, that required SCS. bBefore discontinuation of randomised 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.

DENALI2,23,24 was a Phase III, randomised, double-blind, placebo-controlled, multicentre, 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.