AstraZeneca announces initiation of THARROS – a Phase III clinical trial investigating the potential of Breztri to improve cardiopulmonary outcomes in people with COPD

THARROS is the first-ever prospective trial to investigate the potential of an inhaled
triple therapy to reduce cardiopulmonary events, a key driver of mortality, in COPD

First patients dosed in ATHLOS Phase III trial assessing impact of Breztri on
integrated cardiopulmonary parameters associated with health status and survival in
patients with COPD

AstraZeneca today announced the initiation of a Phase III trial to investigate the potential effect of triple-combination inhaled therapy Breztri/Trixeo Aerosphere (budesonide/glycopyrronium/formoterol fumarate, or BGF) on severe cardiopulmonary outcomes, including death*, in people with chronic obstructive pulmonary disease (COPD) who also have elevated cardiopulmonary risk, irrespective of their exacerbation history.¹

Also, the first participants have been dosed in ATHLOS, a Phase III trial investigating AstraZeneca’s triple therapy BGF vs. ICS/LABA budesonide/formoterol fumarate (BFF) or placebo on cardiopulmonary parameters including hyperinflation and exercise endurance time, which are associated with health status and survival.²

COPD impacts 391 million people globally.³ The disease’s mechanisms elevate the risk of both pulmonary and cardiac events, including severe or fatal COPD exacerbations and cardiac events, which is termed cardiopulmonary risk.^4-8 This underlying risk is further increased after a COPD exacerbation and may remain elevated for up to a year following an exacerbation.^9-11 Just one COPD exacerbation doubles the risk of a heart attack and increases risk of hospitalisation and cardiopulmonary-related death.^5,12-14 Cardiopulmonary causes are the most common reasons for death in patients with COPD.^15,16

Fernando Martinez, MD, MS, Chief of the Division of Pulmonary and Critical Care Medicine at Weill Cornell Medicine and New York-Presbyterian Hospital, and International Co-ordinating Investigator in the THARROS trial said, “The 2024 GOLD Report highlights the treatment effect of non-pharmacologic interventions and inhaled triple combination therapies on mortality. The Report calls for a more proactive therapeutic approach to improve outcomes in COPD. If positive, the THARROS trial will provide critical evidence about the potential of single inhaler, triple combination therapy to reduce severe cardiopulmonary events and further advance treatment goals in COPD, including for patients with no history of exacerbations, for whom no evidence currently exists.”

David Berg MD, MPH, Associate Physician in Cardiovascular and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, US added: “Large outcomes trials have transformed the management of cardiovascular diseases by enhancing our understanding of the potentially broad impact of therapies targeting those diseases. Current evidence already supports a proactive treatment approach in COPD. Now THARROS is seeking to provide first-of-its-kind evidence to support a strategy of comprehensive cardiopulmonary risk reduction with a triple therapy.”

Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “We have an important and urgent mission to eliminate COPD as a leading cause of death. Even moderate COPD exacerbations are associated with increased risks of further lung events, severe cardiovascular complications, and have been shown to contribute to patients dying. With the first-of-its-kind THARROS study, we aim to demonstrate the potential of triple therapy to address cardiopulmonary risk.”

BGF is approved to treat COPD in 75 countries worldwide including the US, EU, China and Japan.

* The severe cardiopulmonary outcome measures investigated in THARROS include death from respiratory and cardiac causes.

COPD
COPD refers to a group of lung diseases, including chronic bronchitis and emphysema, that cause airflow blockage and breathing-related problems.¹⁷ It affects an estimated 391 million people around the world and is the third leading cause of death globally.^3,18

Breztri/Trixeo Aerosphere
Budesonide/glycopyrronium/formoterol fumarate (BFG) is a single-inhaler, fixed-dose triple-combination of formoterol fumarate, a LABA, glycopyrronium bromide, a LAMA, with budesonide, an ICS, and delivered in a pressurised metered-dose inhaler.

BGF is approved for patients with COPD under the brand name Trixeo Aerosphere in Europe and Breztri Aerosphere in Japan, China and the US.

THARROS
THARROS is a randomised, multi-centre, double-blind, parallel-group trial to investigate the effect of budesonide/glycopyrronium/formoterol fumarate (BGF) on cardiopulmonary outcomes in COPD patients. Approximately 5,000 COPD patients with cardiopulmonary risk, aged 40-80 years old, will be randomised to receive either fixed-dose triple combination therapy, BGF, or a dual bronchodilator therapy glycopyrronium/formoterol fumarate. The trial uses a novel composite endpoint combining respiratory and cardiac outcomes: the primary endpoint in the THARROS trial is time to first severe cardiac event, severe COPD exacerbation, or cardiopulmonary death.¹

ATHLOS
ATHLOS is a randomised, multi-centre, double-blind, three-treatment, three-period, cross-over study to investigate the effect of budesonide/glycopyrronium/formoterol fumarate vs budesonide/formoterol fumarate (an ICS/LABA) or placebo on isotime inspiratory capacity (IC) and exercise endurance time in participants with COPD who have exertional breathlessness despite treatment with monotherapy or dual COPD maintenance therapy. This study will include 180 patients aged 40-80 years.²

AstraZeneca in Respiratory & Immunology
Respiratory & Immunology, part of AstraZeneca BioPharmaceuticals is a key disease area and growth driver to the Company.

AstraZeneca is an established leader in respiratory care with a 50-year heritage and a growing portfolio of medicines in immune-mediated diseases. The Company is committed to addressing the vast unmet needs of these chronic, often debilitating, diseases with a pipeline and portfolio of inhaled medicines, biologics and new modalities aimed at previously unreachable biologic targets. Our ambition is to deliver life-changing medicines that help eliminate COPD as a leading cause of death, eliminate asthma attacks and achieve clinical remission in immune-mediated diseases.

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 social media @AstraZeneca

References

1. ClinicalTrials.gov. A Study Evaluating the Efficacy of Budesonide, Glycopyrronium and Formoterol Fumarate Metered Dosed Inhaler on Cardiopulmonary Outcomes in Chronic Obstructive Pulmonary Disease (THARROS). Accessible at: https://clinicaltrials.gov/study/NCT06283966?term=NCT06283966&rank=1 [last accessed: March 2024] 

2. ClinicalTrials.gov. A Study to Evaluate the Effect of Budesonide, Glycopyrronium, Formoterol Fumarate (BGF) Metered Dose Inhaler (MDI), Budesonide and Formoterol Fumarate (BFF) MDI and Placebo MDI on Exercise Parameters in Participants with Chronic Obstructive Pulmonary Disease (COPD). (ATHLOS). Accessible at: https://classic.clinicaltrials.gov/ct2/show/NCT06067828 [last accessed: March 2024]

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6. Watz H, Tetzlaff K, Magnussen H, et al. Spirometric changes during exacerbations of COPD: A post hoc analysis of the WISDOM trial. Respir Res. 2018;19(1):251.   

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8. Swart K, Baak B, Lemmens L, et al. Risk of cardiovascular events after an exacerbation of chronic obstructive pulmonary disease: results from the EXACOS-CV cohort study using the PHARMO Data Network in the Netherlands. Respiratory Research. (2023) Vol 24: 293.   

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10. Halpin DMG, Decramer M, Celli BR, et al. Effect of a single exacerbation on decline in lung function in COPD. Respiratory Medicine 2017; 128: 85-91.     

11. Vogelmeier CF, et al. Increased risk of severe cardiovascular events following exacerbations of COPD: a multi-database cohort study [Poster]. Presented at the European Respiratory Society Congress 2023 (9-13 September).    

12. Whittaker H, Rubino A, Mullerova H, et al. Frequency and Severity of Exacerbations of COPD Associated with Future Risk of Exacerbations and Mortality: A UK Routine Health Care Data Study. Int J Chron Obstruct Pulmon Dis. 2022;17:427-437.    

13. Rothnie KJ, Müllerová H, Smeeth L, Quint JK. Natural History of Chronic Obstructive Pulmonary Disease Exacerbations in a General Practice-based Population with Chronic Obstructive Pulmonary Disease. Am J Resp Crit Care Med. 2018;198(4): pp.464-471.    

14. HO TW, Tsai YJ, Ruan SY, et al. In-hospital and one-year mortality and their predictors in patients hospitalized for first-ever chronic obstructive pulmonary disease exacerbations: A nationwide population-based study. PLOS ONE. 2014;9 (12): e114866.

15. García-Sanz MT, Cánive-Gómez JC, Senín-Rial L, et al. One-year and long-term mortality in patients hospitalized for chronic obstructive pulmonary disease. J Thorac Dis. 2017; 9 (3): 636‐645. doi:10.21037/jtd.2017.03.34.    

16. Mannino DM, Doherty DE, Buist AS. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med. 2006;100: pp.115-122.     

17. GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024. [Online]. Available at: https://goldcopd.org/2024-gold-report/ [Last accessed: March 2024]  

18. WHO Fact Sheet. The Top 10 Causes of Death. Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death [Last accessed: March 2024]