PT010 (budesonide/glycopyrronium/formoterol fumarate) significantly reduced rate of moderate or severe COPD exacerbations vs dual therapies in Phase III ETHOS trial

Trial results published in New England Journal of Medicine

 

Luton, UK, 26 June 2020 - Full results from the positive Phase III ETHOS trial showed AstraZeneca’s triple-combination therapy PT010 (budesonide/glycopyrronium/formoterol fumarate) demonstrated a statistically significant reduction in the rate of moderate or severe exacerbations compared with two dual-combination therapies in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).¹

 

The randomized, double-blind, multi-centre, parallel-group study assessed the efficacy and safety of PT010 relative to PT003 (glycopyrronium/formoterol fumarate) and PT009 (budesonide/formoterol fumarate) on COPD exacerbations over 52-weeks in people with moderate to very severe COPD.¹ The dual-combination therapies used as comparators in the trial represent recommended therapeutic classes for the treatment of COPD in appropriate patients.²

 

The trial met its primary endpoint demonstrating that PT010 reduced the rate of moderate or severe COPD exacerbations by 24% compared with PT003 (rate ratio, 0.76; 95% confidence interval [CI], 0.69–0.83; P<0.001 at dose 320/14.4/9.6 μg; model-estimated annual rate of moderate or severe COPD exacerbations 1.08 vs 1.42).¹

 

PT010 achieved a 13% reduction in moderate or severe COPD exacerbations compared with PT009 (rate ratio, 0.87; 95% CI, 0.79–0.95; P=0.003 dose 320/14.4/9.6 μg; model-estimated annual rate of moderate or severe COPD exacerbations 1.08 vs 1.24).¹

 

In a secondary endpoint*, PT010 showed a 46% reduction in the risk of all-cause mortality compared with PT003 (hazard ratio, 0.54; 95% CI, 0.34-0.87; at dose 320/14.4/9.6 μg; patient deaths — 28 (1.3%) vs 49 deaths (2.3%).¹

 

Professor Dave Singh, University of Manchester, Medical Director, Medicines Evaluation Unit said “COPD is a progressive disease where exacerbations can be fatal for many of the millions of people who suffer with this condition. The results from the phase III ETHOS trial clearly demonstrate that PT010 can reduce the rate of exacerbations and could potentially transform treatment goals in COPD.”

 

The results were published in the New England Journal of Medicine¹ and were presented at the American Thoracic Society virtual Scientific Symposium, Clinical Trial Results in Pulmonary Medicine.³ AstraZeneca continues to review these data with health authorities.

 

Dr Alexander de Giorgio-Miller, Vice President, Medical & Scientific Affairs, AstraZeneca UK said: “Chronic obstructive pulmonary disease affects almost 1.2 million people in the United Kingdom and is a leading cause of morbidity and mortality. For patients suffering from COPD, exacerbations can be devastating events - even a single exacerbation can

lead to a permanent loss of lung function. Results from ETHOS show the benefit of PT010 in reducing the rate of exacerbations compared with dual-combination therapies in symptomatic patients with a history of exacerbations.” 

 

The safety and tolerability of PT010 were consistent with the known profiles of the dual comparators. The most frequently reported adverse events overall were nasopharyngitis

(10.5%), COPD (10.4%), and upper respiratory tract infection (5.6%). The incidence of confirmed pneumonia was 4.2% with PT010, 2.3% with PT003 and 4.5% with PT009.¹

These results are based on PT010 at the standard dose of budesonide (budesonide/glycopyrronium/formoterol fumarate 320/14.4/9.6mcg), an inhaled corticosteroid (ICS). In the trial, PT010 at half the dose of budesonide (budesonide/glycopyrronium/formoterol fumarate 160/14.4/9.6mcg) also demonstrated a statistically significant reduction in the rate of moderate or severe exacerbations compared with PT003 (glycopyrronium/formoterol fumarate 14.4/9.6mcg) [(25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) model-estimated annual rate of moderate or severe COPD exacerbations 1.07 vs 1.42] and PT009 (budesonide/formoterol fumarate 320/9.6mcg) [(14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P=0.002) model-estimated annual rate of moderate or severe COPD exacerbations 1.07 vs 1.24].¹

 

PT010 is not licensed in Europe and is under regulatory review.

 

– ENDS –

CONTACTS

UK Media Enquires

Christian Petrovic, AstraZeneca: 07385 086354 / christian.petrovic@astrazeneca.com

 

About COPD

COPD is a progressive disease which can cause obstruction of airflow in the lungs resulting in debilitating bouts of breathlessness.² It affects an estimated 384 million people⁴ and is the third leading cause of death globally.⁵ It is estimated that 3 million people in the UK live with COPD and the UK has the 12^th highest recorded deaths from COPD in the world and 3^rd highest in Europe. ^6-8 COPD causes around 30,000 deaths a year in the UK each year, >5% of all annual deaths. ⁸ Improving lung function, reducing exacerbations and managing daily symptoms such as breathlessness are important treatment goals in the management of COPD.² Even a single COPD exacerbation may be associated with a significant increase in the rate of decline in lung function,⁹ a significant deterioration in quality of life,¹⁰ and can significantly reduce life expectancy and increase the risk of mortality.^11,12

 

About the trial interventions and arms

·         PT010 (budesonide/glycopyrronium/formoterol fumarate - 320/14.4/9.6 μg) is a single-inhaler, fixed dose triple-combination of budesonide, an inhaled corticosteroid (ICS), with glycopyrronium, a Long-Acting Muscarinic Antagonist (LAMA), and formoterol fumarate, a Long-Acting Beta Agonist (LABA)¹

·         PT010 (budesonide/glycopyrronium/formoterol fumarate - 160/14.4/9.6 μg) is a single-inhaler, fixed dose triple-combination of budesonide, an inhaled corticosteroid (ICS), with glycopyrronium, a Long-Acting Muscarinic Antagonist (LAMA), and formoterol fumarate, a Long-Acting Beta Agonist (LABA)¹

·         PT009 (budesonide, and formoterol fumarate - 320/9.6 μg) is a single inhaler, fixed-dose dual-combination therapy of budesonide, an ICS, and formoterol fumarate, a LABA¹

·         PT003 (glycopyrronium/formoterol fumarate - 14.4/9.6 μg) is a fixed-dose dual bronchodilator in a pressurised metered-dose inhaler (pMDI), combining glycopyrronium, a LAMA, and formoterol fumarate, a LABA¹

 

ETHOS and the ATHENA clinical trial programme

ETHOS is a randomised, double-blinded, multi-centre, parallel-group, 52-week trial to assess the efficacy and safety of PT010 in symptomatic patients with moderate to very severe COPD and a history of exacerbation(s) in the previous year. Outcomes in the ETHOS trial included, as a primary endpoint, the rate of moderate or severe exacerbations.

 

ETHOS involved more than 8,500 patients who had experienced ≥1 moderate/severe exacerbation in the previous year and were receiving at least two inhaled maintenance treatments at entry into the trial.

 

ETHOS is part of AstraZeneca’s ATHENA Phase III clinical trial programme for PT010, which included more than 15,500 patients globally across 11 trials. The results of the earlier pivotal Phase III KRONOS trial were published in Lancet Respiratory Medicine.¹³

 

*ETHOS Primary and Key Secondary Endpoints

ETHOS Primary Endpoints1
Endpoint	Timepoint	Comparison/results
Rate of moderate or severe COPD exacerbations	Over 52 weeks	PT010 (320mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		Significant (p<0.001)1
		PT010 (320mcg budesonide dose) vs budesonide/formoterol fumarate
		Significant (p=0.003)1
		PT010 (160mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		Significant (p<0.001)1
		PT010 (160mcg budesonide dose) vs budesonide/formoterol fumarate
		Significant (p=0.002)1

 

ETHOS Secondary Endpoints.1,3
Endpoint	Timepoint	Comparison/results
Time to first moderate or severe COPD exacerbation	Over 52 weeks	PT010 (320mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		Significant (p=0.004)1
		PT010 (320mcg budesonide dose) vs budesonide/formoterol fumarate
		Significant (p=0.006)1
		PT010 (160mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		Significant (p=0.001)1
		PT010 (160mcg budesonide dose) vs budesonide/formoterol fumarate
		Significant (p=0.002)1
Rate of severe COPD exacerbations	Over 52 weeks	PT010 (320mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		Not significant (p=0.09)1
		PT010 (320mcg budesonide dose) vs budesonide/formoterol fumarate
		Significant (p=0.02)1
		PT010 (160mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		PT010 (160mcg budesonide dose) vs budesonide/formoterol fumarate
Time to death (all-cause mortality)	Over 52 weeks	PT010 (320mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		PT010 (320mcg budesonide dose) vs budesonide/formoterol fumarate
		PT010 (160mcg budesonide dose) vs glycopyrronium/formoterol fumarate
		PT010 (160mcg budesonide dose) vs budesonide/formoterol fumarate

 

AstraZeneca in Respiratory & Immunology  

Respiratory & Immunology is one of AstraZeneca’s three therapy areas and is a key growth driver for the Company.

 

AstraZeneca is an established leader in respiratory care, and its inhaled and biologic medicines reached more than 18 million patients in 2018. Building on 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 commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

 

AstraZeneca operates in five different locations in the UK, where around 8,300 employees work in research and development, manufacturing, supply, sales and marketing. We supply 40 different medicines to the NHS. The UK is also an important location for AstraZeneca’s clinical trials; in 2018, we undertook 201 trials in the UK, involving 376 centres and over 7,000 patients.

 

For more information, please visit www.astrazeneca.co.uk

 

References

1.     Rabe KF, Martinez FJ, Ferguson GT, et al. Inhaled Triple Therapy at Two Glucocorticoid Doses in Moderate-to-Very Severe COPD. NEJM 2020; published on June 24, 2020, at NEJM.org. DOI: 10.1056/NEJMoa191604. Available at: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1916046?articleTools=true [Last accessed: June 2020]

2.     GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available at: http://goldcopd.org [Last accessed: June 2020]

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12.  Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012; 67 (11): 957-63. Available at: https://thorax.bmj.com/content/67/11/957 [Last accessed: June 2020]

13.  Ferguson GT, Rabe KF, Martinez FJ, et al. Triple combination of budesonide/glycopyrrolate /formoterol fumarate using co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, randomised controlled trial. Lancet Respir Med. 2018; 6: 747–758. Available at: https://pubmed.ncbi.nlm.nih.gov/30232048/ [Last accessed: June 2020]