The Lancet Respiratory Medicine publishes first Phase III trial for PT010 triple combination therapy in moderate to very severe chronic obstructive pulmonary disease

AstraZenecaAstraZeneca today announced publication of results from the KRONOS Phase III trial which evaluated the efficacy and safety of triple combination therapy PT010 (budesonide/ glycopyrronium/formoterol fumarate) versus dual combination therapies Bevespi Aerosphere (glycopyrronium/formoterol fumarate), Symbicort Turbuhaler (budesonide/formoterol fumarate) and PT009 (budesonide/formoterol fumarate) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) regardless of whether or not they had an exacerbation in the prior year.(1)

The KRONOS trial met eight of the nine primary lung function endpoints and, in a key secondary endpoint, PT010 showed a statistically significant 52% reduction in the rate of moderate or severe COPD exacerbations compared with Bevespi Aerosphere in a patient population that was not required to have had an exacerbation in the previous 12 months. PT010 also demonstrated reductions in the rate of moderate or severe COPD exacerbations versus PT009 and Symbicort (18% and 17% respectively), which were numerically but not statistically significant improvements. The incidence of adjudicated pneumonia was low and comparable in all treatment arms.(1) Further details on the primary endpoints are outlined below.

The data were presented today at the European Respiratory Society (ERS) International Congress 2018 in Paris, France, and published in The Lancet Respiratory Medicine.(1)

Dr Colin Reisner, Head of Respiratory, Global Medicines, said: "We are encouraged by the results of the KRONOS trial which demonstrate PT010's efficacy in improving lung function and its potential value as a triple combination therapy for patients with COPD. Importantly, PT010 also halved the rate of moderate or severe exacerbations compared to glycopyrronium/formoterol fumarate and we look forward to the ETHOS exacerbation trial results in 2019 to further characterise PT010."

Gary Ferguson, Professor of the Pulmonary Research Institute of Southeast Michigan, Livonia, Michigan and lead author of the KRONOS trial publication, said: "Preventing exacerbations is a priority in the management of COPD because they are known to have an impact on lung function and mortality, and patients are at risk even if they haven't had an exacerbation in the previous 12 months. The KRONOS trial demonstrated that PT010 reduces the risk of an exacerbation versus LAMA/LABA combination therapy in symptomatic COPD patients regardless of whether or not they’ve had an exacerbation in the previous year."

There were no new or unexpected safety or tolerability signals for PT010 in the KRONOS trial, and the adverse events profile was consistent with that observed in previous trials. The most frequently reported adverse events were nasopharyngitis, upper respiratory tract infection, COPD, bronchitis, muscle spasms, dysphonia, hypertension, dyspnoea, back pain and nausea. The incidence of adjudicated pneumonia was low and comparable among PT010 (1.9%), Bevespi Aerosphere (1.6%), PT009 (1.9%) and Symbicort Turbuhaler (1.3%).

AstraZeneca anticipates making the first regulatory submissions for PT010 in the second half of 2018.

About COPD

Chronic obstructive pulmonary disease (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 people worldwide(3) and is predicted to be the third leading cause of death by 2020.(2) Improving lung function, reducing exacerbations and managing daily symptoms such as breathlessness are important to the management of COPD.(2)

COPD exacerbations significantly impair quality of life and are linked to disease progression, accelerated decline in lung function, increased hospitalisations and mortality.(4) Even one severe exacerbation carries an increased risk of mortality.(5)

About PT010 and the Aerosphere portfolio

PT010 is a single inhaler, fixed-dose triple combination therapy of budesonide, an inhaled corticosteroid (ICS) with glycopyrronium, a long-acting muscarinic agonist (LAMA), and formoterol fumarate, a long-acting beta2-agonist (LABA). It is being developed using AstraZeneca's Aerosphere Delivery Technology. Aerosphere Delivery Technology is also the platform for the approved medicine Bevespi Aerosphere.

About KRONOS and the ATHENA clinical trial programme

KRONOS is a randomised, double-blind, parallel-group, 24-week, chronic-dosing, multi-centre trial to assess the efficacy and safety of PT010. The trial compared PT010 to Bevespi Aerosphere (glycopyrronium/formoterol fumarate 14.4/9.6µg pMDI), Symbicort Turbuhaler (budesonide/formoterol fumarate 400/12µg) and PT009 (budesonide/formoterol fumarate 320/9.6µg using Aerosphere Delivery Technology in a pressurised metered-dose inhaler (pMDI). Patients were given two inhalations twice a day of PT010, Bevespi Aerosphere, Symbicort Turbuhaler or PT009. KRONOS involved approximately 1,900 patients with moderate to very severe COPD. Around three-quarters of patients (74%) had not reported an exacerbation in the previous 12 months.

In the KRONOS trial, eight of the nine primary comparisons were met, including two non-inferiority endpoints to support PT009 as a comparator. The Lancet Respiratory Medicine publication reports on six of the primary comparisons in the trial. The primary and secondary endpoints and treatment comparisons in the KRONOS trial differed according to regional regulatory requirements.(1)

ATHENA is AstraZeneca's Phase III clinical trial programme for PT010, which includes more than 15,500 patients globally across 11 trials.(6,7,8,9) The four key trials are ETHOS, KRONOS, TELOS and SOPHOS. ETHOS, TELOS and SOPHOS include low and high doses of ICS and stratification of patients by eosinophil levels as part of randomisation, for PT010 and PT009 respectively.(7,8,9)

About Symbicort

Symbicort is a combination formulation containing budesonide, an ICS, and formoterol, a LABA, in a single inhaler. Symbicort is approved in approximately 120 countries to treat COPD either as Symbicort Turbuhaler or Symbicort pMDI. Indications differ by country/region and the respective prescribing information or Summary of Product Characteristics (SmPC) should be consulted.

About Bevespi Aerosphere

Bevespi Aerosphere is a fixed-dose dual bronchodilator combining glycopyrronium, a long-acting muscarinic agonist (LAMA), and formoterol fumarate, a long-acting beta2-agonist (LABA). Bevespi Aerosphere is the first and only LAMA/LABA with Aerosphere Delivery Technology. Results from an imaging trial have shown that Bevespi Aerosphere effectively delivers medicine to both the large and small airways. Aerosphere Delivery Technology is also the platform for potential new medicines including PT010.

About AstraZeneca in Respiratory Disease

Respiratory disease is one of AstraZeneca's main therapy areas, and the Company has a growing portfolio of medicines that reached more than 18 million patients in 2017. AstraZeneca’s aim is to transform asthma and COPD treatment through inhaled combinations at the core of care, biologics for the unmet needs of specific patient populations, and scientific advancements in disease modification.

The Company is building on a 40-year heritage in respiratory disease and AstraZeneca’s capability in inhalation technology spans pressurised metered-dose inhalers and dry powder inhalers, as well as the Aerosphere Delivery Technology. The Company also has a growing portfolio of respiratory biologics including Fasenra (anti-eosinophil, anti-IL-5rɑ), now approved for severe eosinophilic asthma and in development for severe nasal polyposis, and tezepelumab (anti-TSLP), which is in Phase III trials and achieved its Phase IIb primary and secondary endpoints. AstraZeneca’s research is focused on addressing underlying disease drivers focusing on the lung epithelium, lung immunity and lung regeneration.

About 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. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

1. 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; Sep 16. [Epub ahead of print] https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30327-8/fulltext
2. GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. [Online]. Available at: http://goldcopd.org. Last accessed: January 2018.
3. Adeloye D, Chua S, Lee C, et al; Global Health Epidemiology Reference Group (GHERG). Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health. 2015;5(2): 020415.
4. Halpin MG. D, Miravitlles M, Metzdorf N, Celli B. Impact and prevention of severe exacerbations of COPD: a review of the evidence. International Journal of COPD; 2017; 12: 2891-2908
5. Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax 2012; 67 (11): 957-963
6. Clinicaltrials.gov. A Randomized, Double-Blind, Parallel-Group, 24-Week, Chronic-Dosing, Multi-Center Study to Assess the Efficacy and Safety of PT010, PT003, and PT009 Compared With Symbicort® Turbuhaler® (Kronos) (KRONOS). [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT02497001. Last accessed: August 2018.
7. Clinicaltrials.gov. Study to Assess the Efficacy and Safety of PT010 Relative to PT003 and PT009 in Subjects With Moderate to Very Severe COPD (ETHOS). [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT02465567 Last accessed: August 2018.
8. Clinicaltrials.gov. Study to Assess Efficacy and Safety of PT009 Compared to PT005, PT008, and Symbicort® Turbuhaler® on Lung Function Over 24-Weeks in Subjects With Moderate to Very Severe COPD (TELOS). [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT02766608. Last accessed: August 2018.
9. Clinicaltrials.gov. A Study to Assess the Efficacy and Safety of PT009 Compared to PT005 on COPD Exacerbations Over a 52-Week Period in Subjects With Moderate to Very Severe COPD (SOPHOS). [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT02727660. Last accessed: August 2018.

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