Avillion announces publication of positive full results from MANDALA Phase III trial of AstraZeneca’s PT027 in asthma patients in the New England Journal of Medicine

• First time an albuterol/budesonide fixed-dose combination rescue medication used as needed has been shown to reduce severe asthma exacerbations 

• Results from both positive MANDALA and DENALI Phase III trials to be presented at ATS 2022 
• Complex global pivotal trial programme in more than 4,000 patients delivered by Avillion, maintaining 100% success rate from its clinical co-development partnerships 

London, UK, 15 May 2022 – Avillion LLP, a drug development company focused on the co-development and financing of pharmaceutical candidates from proof-of-concept through to regulatory approval, announces that full results from the positive MANDALA Phase III trial of AstraZeneca’s PT027, a novel fixed-dose combination of albuterol and budesonide, have been published in the New England Journal of Medicine and will be presented at the American Thoracic Society (ATS) 2022 International Conference.^1.2,3 The results show that PT027 at two different strengths of budesonide, used as an as-needed rescue medicine, demonstrated a statistically significant reduction in the risk of a severe exacerbation versus albuterol rescue in patients with moderate to severe asthma.^1,2  

PT027 is a potential first-in-class inhaled, fixed-dose combination of albuterol, a short-acting beta2-agonist (SABA), and budesonide, an inhaled corticosteroid (ICS), in the US, being developed by Avillion and AstraZeneca under a 2018 clinical co-development agreement. Under the terms of the agreement, Avillion became the trial sponsor responsible for executing and funding the multicentre, global clinical trial programme for PT027 through NDA filing to a regulatory decision in the US. Following the successful approval of PT027, AstraZeneca has the option, upon certain financial payments, to commercialise the medicine in the US. 

Globally, more than 176 million asthma attacks are experienced each year.¹⁰ 

The full results from MANDALA demonstrate that, compared with albuterol rescue, PT027 at the 180mcg albuterol/160mcg budesonide dose reduced the risk of a severe exacerbation by 27% (p<0.001) in adults and adolescents.^1,2 In the trial, patients were randomised to receive PT027 or albuterol rescue, on top of their usually prescribed maintenance ICS, with or without additional controller medicines.^1,2  

In secondary endpoints, PT027 (180mcg albuterol/160mcg budesonide) demonstrated a 33% reduction in mean annualised total systemic corticosteroid exposure (p=0.002) and a 24% reduction in annualised severe exacerbation rate (p=0.008).^1,2 A numerically higher odds of patients experiencing an improvement in symptom control and quality of life was also observed after 24 weeks of treatment with PT027 compared to albuterol rescue.^1,2 

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  

Allison Jeynes, MD, Chief Executive Officer of Avillion, said: “Building on the positive high-level results for MANDALA and DENALI announced in September last year, it’s fantastic to receive further confirmation of PT027’s potential in reducing the significant burden that asthma presents to millions of people worldwide. With the completion of this pivotal programme, Avillion maintains its 100% trial success rate across multiple therapy areas. This is an impressive achievement and demonstrates the power of our clinical co-development model and the quality of our international team in advancing vital drugs in partnership with pharma and biotech companies. We have enjoyed an excellent collaboration with AstraZeneca, under which we have delivered these large and complex trials during a pandemic and have ongoing regulatory responsibility for the NDA filing. Furthermore, this partnership has recently expanded to include a new decentralized, randomised trial in patients with mild asthma, which is anticipated to kick off in the coming months.” 

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: “The MANDALA Phase III trial results demonstrated that PT027, a novel fixed-dose combination of albuterol/budesonide, used as-needed, provided additional anti-inflammatory treatment in response to patient symptoms, which led to a reduced risk of severe exacerbations compared with albuterol alone. These data further strengthen the growing body of evidence around the value of as-needed anti-inflammatory treatment in asthma and support PT027’s potential to transform the current rescue treatment approach.” 

In the MANDALA trial, PT027 at a lower budesonide dose (180mcg albuterol/80mcg budesonide) also demonstrated a statistically significant reduction of 17% in the risk of severe exacerbation versus albuterol rescue (p=0.041), when used as an as-needed rescue medicine in adults, adolescents and children aged 4–11 years.^1,2  

Also being presented at the ATS International Conference this week are the positive DENALI Phase III trial results. In this trial, PT027 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 PT027 and albuterol. The safety and tolerability of PT027 in DENALI was consistent with the known profiles of the components.⁴ 

The PT027 clinical co-development programme was funded by Blackstone Life Sciences, Royalty Pharma (Nasdaq: RPRX) and Abingworth. 

Notes 

PT027 

PT027 is a potential 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 is being developed in a pMDI using AstraZeneca’s Aerosphere delivery technology. 

Asthma 

Asthma is a chronic, inflammatory, variable respiratory disease that affects as many as 339 million adults and children worldwide,⁵ including over 25 million in the US.⁶  

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 176 million asthma exacerbations globally per year,¹⁰ including more than 10 million in the US;⁶ these are physically threatening and emotionally significant for many patients¹¹ and can be fatal.^5,12 

Inflammation is central to both asthma symptoms⁷ and exacerbations.¹³ Many patients experiencing asthma symptoms use a SABA as a rescue medicine, however, taking a SABA alone does not address inflammation, leaving patients at risk of severe exacerbations,¹⁴ which can result in impaired quality of life,¹⁵ hospitalisation¹⁶ and frequent oral corticosteroid (OCS) use.¹⁵ 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.^7,17,18 International recommendations from the Global Initiative for Asthma no longer recommend SABA alone as the preferred rescue therapy.⁷ 

MANDALA 

MANDALA^1,19 was a Phase III, randomised, double-blind, multicentre, parallel-group, event-driven trial evaluating the efficacy and safety of PT027 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: PT027 180/160mcg (excluding children aged 4–11 years), PT027 180/80mcg or albuterol 180mcg, taken as an as-needed rescue medicine. PT027 and the albuterol comparator were delivered in a pressurised metered-dose inhaler (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. 

Primary and secondary endpoint results in adults and adolescents^1,2 
(pre-planned on-treatment efficacy analysis) 

aDeterioration 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^1,2 

(pre-planned on-treatment efficacy analysis) 

aDeterioration 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 

DENALI 

DENALI^4,20,21 was a Phase III, randomised, double-blind, placebo-controlled, multicentre, parallel-group trial evaluating the efficacy and safety of PT027 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: PT027 180/160mcg four times daily (excluding children aged 4-11 years), PT027 180/80mcg four times daily, albuterol 180mcg four times daily, budesonide 160mcg four times daily and placebo four times daily (excluding children aged 4-11 years). PT027 and 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 PT027 compared to budesonide to assess the effect of albuterol and change from baseline in trough FEV1 at Week 12 of PT027 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. 

About Avillion  

Avillion offers pharma partners an innovative model providing additional funding and clinical development expertise, to maximise the potential of new and existing assets. With deal sizes ranging from $50M–$600M, Avillion takes on the full clinical and regulatory risk, focusing on the speed and quality of trial execution. Typically supporting programs post proof-of-concept through to registration and with an agnostic approach to therapy area, Avillion prides itself in adding value around operational expertise while being backed by established long-term investors.  

Avillion was founded in 2012 and is backed by Abingworth and Blackstone Life Sciences (previously Clarus Ventures). The PT027 clinical co-development programme was funded by Blackstone Life Sciences, Royalty Pharma (Nasdaq: RPRX) and Abingworth. 

For more information, please visit us at www.avillionllp.com 

References  

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3. AstraZeneca Pharmaceuticals. Data on File. Budesonide/formoterol Data on File: Annual Rate of Asthma Exacerbations Globally. (ID: SD-3010-ALL-0017). 
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19. Chipps BE, et al. Evaluation of the Efficacy and Safety of As-Needed PT027 Budesonide/Albuterol MDI) Compared to As-Needed Albuterol MDI in Adults and Children 4 Years of Age or Older with Uncontrolled Moderate to Severe Asthma: Design of the MANDALA Study. Am. J. Respir. Crit. Care Med. 2020; 201: A3015. 
20. Clinicaltrials.gov. A Study to Assess the Efficacy and Safety of Budesonide/Albuterol Metered-dose Inhaler (BDA MDI/PT027) Used 4 Times Daily in Adults and Children 4 Years of Age or Older With Asthma (DENALI). Available at https://clinicaltrials.gov/ct2/show/NCT03847896. [Last accessed: 4 May 2022]. 
21. AstraZeneca Pharmaceuticals. Data on File. DENALI clinical trial protocol Data on File (ID: 121792).