Approval based on Phase III ETHOS trial which showed a statistically significant reduction in the rate of exacerbations compared with dual-combination therapies

WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca’s BREZTRI AEROSPHERE^TM (budesonide/glycopyrrolate/formoterol fumarate) has been approved in the US for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

The approval by the US Food and Drug Administration (FDA) was based on positive results from the Phase III ETHOS trial in which BREZTRI AEROSPHERE, a triple-combination therapy, showed a statistically significant reduction in the rate of moderate or severe exacerbations compared with dual-combination therapies glycopyrrolate/formoterol fumarate and PT009 (budesonide/formoterol fumarate). The approval was also supported by efficacy and safety data from the Phase III KRONOS trial.

Dr. Fernando J. Martinez, Chief of Division of Pulmonary and Critical Care Medicine at Weill Cornell Medicine and New York-Presbyterian Weill Cornell Medical Center, New York, US and Investigator in the ETHOS trial, said: “Preventing exacerbations is central to the management of chronic obstructive pulmonary disease. Even a single exacerbation can have a negative impact on a patient’s lung function and quality of life, and it can increase the risk of death. BREZTRI AEROSPHERE has demonstrated significant benefits in reducing exacerbations in patients suffering from COPD.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “BREZTRI AEROSPHERE has demonstrated a strong clinical profile compared with dual-combination therapies and offers a meaningful new treatment option for patients. Chronic obstructive pulmonary disease is a debilitating progressive condition and the fourth leading cause of death in the US. We look forward to discussing all-cause mortality data from the BREZTRI AEROSPHERE ETHOS trial with health authorities.”

Results from the Phase III ETHOS trial were published in The New England Journal of Medicine in June 2020 and results from the Phase III KRONOS trial were published in The Lancet Respiratory Medicine in September 2018. In both trials, the safety and tolerability of BREZTRI AEROSPHERE were consistent with the profiles of the dual comparators.

(Read more…)

BREZTRI AEROSPHERE is not indicated for the relief of acute bronchospasm or for the treatment of asthma in the US or other countries. BREZTRI AEROSPHERE is approved in Japan and China for patients with COPD and under regulatory review in the EU.

INDICATION

BREZTRI AEROSPHERE is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

LIMITATIONS OF USE

Not indicated for the relief of acute bronchospasm or for the treatment of asthma.

IMPORTANT SAFETY INFORMATION

• BREZTRI is contraindicated in patients who have a hypersensitivity to budesonide, glycopyrrolate, formoterol fumarate, or product excipients
• BREZTRI is not indicated for treatment of asthma. Long-acting beta₂-adrenergic agonist (LABA) monotherapy for asthma is associated with an increased risk of asthma-related death. These findings are considered a class effect of LABA monotherapy. When a LABA is used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. Available data do not suggest an increased risk of death with use of LABA in patients with COPD
• BREZTRI should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition
• BREZTRI is NOT a rescue inhaler. Do NOT use to relieve acute symptoms; treat with an inhaled short-acting beta₂-agonist
• BREZTRI should not be used more often than recommended; at higher doses than recommended; or in combination with LABA-containing medicines, due to risk of overdose. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs
• Oropharyngeal candidiasis has occurred in patients treated with orally inhaled drug products containing budesonide. Advise patients to rinse their mouths with water without swallowing after inhalation
• Lower respiratory tract infections, including pneumonia, have been reported following ICS. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap
• Due to possible immunosuppression, potential worsening of infections could occur. Use with caution. A more serious or fatal course of chickenpox or measles can occur in susceptible patients
• Particular care is needed for patients transferred from systemic corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer. Taper patients slowly from systemic corticosteroids if transferring to BREZTRI
• Hypercorticism and adrenal suppression may occur with regular or very high dosage in susceptible individuals. If such changes occur, consider appropriate therapy
• Caution should be exercised when considering the coadministration of BREZTRI with long-term ketoconazole and other known strong CYP3A4 Inhibitors. Adverse effects related to increased systemic exposure to budesonide may occur
• If paradoxical bronchospasm occurs, discontinue BREZTRI immediately and institute alternative therapy
• Anaphylaxis and other hypersensitivity reactions (eg, angioedema, urticaria or rash) have been reported. Discontinue and consider alternative therapy
• Use caution in patients with cardiovascular disorders, especially coronary insufficiency, as formoterol fumarate can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles
• Decreases in bone mineral density have been observed with long-term administration of ICS. Assess initially and periodically thereafter in patients at high risk for decreased bone mineral content
• Glaucoma and cataracts may occur with long-term use of ICS. Worsening of narrow-angle glaucoma may occur, so use with caution. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREZTRI long term. Instruct patients to contact a healthcare provider immediately if symptoms occur
• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if symptoms occur
• Use caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis or unusually responsive to sympathomimetic amines
• Be alert to hypokalemia or hyperglycemia
• Most common adverse reactions in a 52-week trial (incidence ≥ 2%) were upper respiratory tract infection (5.7%), pneumonia (4.6%), back pain (3.1%), oral candidiasis (3.0%), influenza (2.9%), muscle spasms (2.8%), urinary tract infection (2.7%), cough (2.7%), sinusitis (2.6%), and diarrhea (2.1%). In a 24-week trial, adverse reactions (incidence ≥ 2%) were dysphonia (3.3%) and muscle spasms (3.3%)
• BREZTRI should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors and tricyclic antidepressants, as these may potentiate the effect of formoterol fumarate on the cardiovascular system
• BREZTRI should be administered with caution to patients being treated with:
  • Strong cytochrome P450 3A4 inhibitors (may cause systemic corticosteroid effects)
  • Adrenergic drugs (may potentiate effects of formoterol fumarate)
  • Xanthine derivatives, steroids, or non-potassium sparing diuretics (may potentiate hypokalemia and/or ECG changes)
  • Beta-blockers (may block bronchodilatory effects of beta-agonists and produce severe bronchospasm)
  • Anticholinergic-containing drugs (may interact additively). Avoid use with BREZTRI
• Use BREZTRI with caution in patients with hepatic impairment, as budesonide and formoterol fumarate systemic exposure may increase. Patients with severe hepatic disease should be closely monitored

Please see full Prescribing Information, including Patient Information. You may report side effects related to AstraZeneca products by clicking here.

Financial considerations

Under the terms of the past agreement to acquire Pearl Therapeutics Inc., AstraZeneca will make a $150m milestone payment upon US regulatory approval of BREZTRI AEROSPHERE for COPD. This is the final development and regulatory milestone under that agreement.

COPD

COPD is a progressive disease which can cause obstruction of airflow in the lungs resulting in debilitating bouts of breathlessness. It affects an estimated 384 million people and is the third leading cause of death globally. Improving lung function, reducing exacerbations and managing daily symptoms such as breathlessness are important treatment goals in the management of COPD. Even a single COPD exacerbation may be associated with a significant increase in the rate of decline in lung function, a significant deterioration in quality of life, and can significantly reduce life expectancy and increase the risk of mortality.

ETHOS, KRONOS and the ATHENA clinical trial program
ETHOS is a randomized, double-blinded, multi-center, parallel-group, 52-week trial to assess the efficacy and safety of BREZTRI AEROSPHERE in symptomatic patients with moderate to very severe COPD and a history of exacerbation(s) in the previous year. The primary endpoint was the rate of moderate or severe exacerbations.

KRONOS is a randomized, double-blinded, parallel-group, 24-week, chronic-dosing, multi-center trial to assess the efficacy and safety of BREZTRI AEROSPHERE in patients with moderate to very severe COPD regardless of whether or not they had an exacerbation in the previous year. The primary endpoints were lung function parameters.

ETHOS and KRONOS are part of AstraZeneca’s ATHENA Phase III clinical trial program for BREZTRI AEROSPHERE, which included more than 15,500 patients globally across 11 trials.

BREZTRI AEROSPHERE

BREZTRI AEROSPHERE^TM (budesonide/glycopyrrolate/formoterol fumarate) is a single-inhaler, fixed dose triple-combination of budesonide, an inhaled corticosteroid (ICS), with glycopyrrolate, a long-acting muscarinic antagonist (LAMA), and formoterol fumarate, a long-acting beta2-agonist (LABA), delivered in a pressurized metered-dose inhaler.

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 53 million patients in 2019. 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 (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal and 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 www.astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

US-40367 Last Updated 7/20

Contacts

Media Inquiries
Michele Meixell +1 302 885 2677

Brendan McEvoy +1 302 885 2677

Approval based on Phase III ETHOS trial which showed a statistically significant reduction in the rate of exacerbations compared with dual-combination therapies

WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca’s BREZTRI AEROSPHERE^TM (budesonide/glycopyrrolate/formoterol fumarate) has been approved in the US for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

The approval by the US Food and Drug Administration (FDA) was based on positive results from the Phase III ETHOS trial in which BREZTRI AEROSPHERE, a triple-combination therapy, showed a statistically significant reduction in the rate of moderate or severe exacerbations compared with dual-combination therapies glycopyrrolate/formoterol fumarate and PT009 (budesonide/formoterol fumarate). The approval was also supported by efficacy and safety data from the Phase III KRONOS trial.

Dr. Fernando J. Martinez, Chief of Division of Pulmonary and Critical Care Medicine at Weill Cornell Medicine and New York-Presbyterian Weill Cornell Medical Center, New York, US and Investigator in the ETHOS trial, said: “Preventing exacerbations is central to the management of chronic obstructive pulmonary disease. Even a single exacerbation can have a negative impact on a patient’s lung function and quality of life, and it can increase the risk of death. BREZTRI AEROSPHERE has demonstrated significant benefits in reducing exacerbations in patients suffering from COPD.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “BREZTRI AEROSPHERE has demonstrated a strong clinical profile compared with dual-combination therapies and offers a meaningful new treatment option for patients. Chronic obstructive pulmonary disease is a debilitating progressive condition and the fourth leading cause of death in the US. We look forward to discussing all-cause mortality data from the BREZTRI AEROSPHERE ETHOS trial with health authorities.”

Results from the Phase III ETHOS trial were published in The New England Journal of Medicine in June 2020 and results from the Phase III KRONOS trial were published in The Lancet Respiratory Medicine in September 2018. In both trials, the safety and tolerability of BREZTRI AEROSPHERE were consistent with the profiles of the dual comparators.

(Read more…)

BREZTRI AEROSPHERE is not indicated for the relief of acute bronchospasm or for the treatment of asthma in the US or other countries. BREZTRI AEROSPHERE is approved in Japan and China for patients with COPD and under regulatory review in the EU.

INDICATION

BREZTRI AEROSPHERE is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

LIMITATIONS OF USE

Not indicated for the relief of acute bronchospasm or for the treatment of asthma.

IMPORTANT SAFETY INFORMATION

• BREZTRI is contraindicated in patients who have a hypersensitivity to budesonide, glycopyrrolate, formoterol fumarate, or product excipients
• BREZTRI is not indicated for treatment of asthma. Long-acting beta₂-adrenergic agonist (LABA) monotherapy for asthma is associated with an increased risk of asthma-related death. These findings are considered a class effect of LABA monotherapy. When a LABA is used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. Available data do not suggest an increased risk of death with use of LABA in patients with COPD
• BREZTRI should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition
• BREZTRI is NOT a rescue inhaler. Do NOT use to relieve acute symptoms; treat with an inhaled short-acting beta₂-agonist
• BREZTRI should not be used more often than recommended; at higher doses than recommended; or in combination with LABA-containing medicines, due to risk of overdose. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs
• Oropharyngeal candidiasis has occurred in patients treated with orally inhaled drug products containing budesonide. Advise patients to rinse their mouths with water without swallowing after inhalation
• Lower respiratory tract infections, including pneumonia, have been reported following ICS. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap
• Due to possible immunosuppression, potential worsening of infections could occur. Use with caution. A more serious or fatal course of chickenpox or measles can occur in susceptible patients
• Particular care is needed for patients transferred from systemic corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer. Taper patients slowly from systemic corticosteroids if transferring to BREZTRI
• Hypercorticism and adrenal suppression may occur with regular or very high dosage in susceptible individuals. If such changes occur, consider appropriate therapy
• Caution should be exercised when considering the coadministration of BREZTRI with long-term ketoconazole and other known strong CYP3A4 Inhibitors. Adverse effects related to increased systemic exposure to budesonide may occur
• If paradoxical bronchospasm occurs, discontinue BREZTRI immediately and institute alternative therapy
• Anaphylaxis and other hypersensitivity reactions (eg, angioedema, urticaria or rash) have been reported. Discontinue and consider alternative therapy
• Use caution in patients with cardiovascular disorders, especially coronary insufficiency, as formoterol fumarate can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles
• Decreases in bone mineral density have been observed with long-term administration of ICS. Assess initially and periodically thereafter in patients at high risk for decreased bone mineral content
• Glaucoma and cataracts may occur with long-term use of ICS. Worsening of narrow-angle glaucoma may occur, so use with caution. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREZTRI long term. Instruct patients to contact a healthcare provider immediately if symptoms occur
• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if symptoms occur
• Use caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis or unusually responsive to sympathomimetic amines
• Be alert to hypokalemia or hyperglycemia
• Most common adverse reactions in a 52-week trial (incidence ≥ 2%) were upper respiratory tract infection (5.7%), pneumonia (4.6%), back pain (3.1%), oral candidiasis (3.0%), influenza (2.9%), muscle spasms (2.8%), urinary tract infection (2.7%), cough (2.7%), sinusitis (2.6%), and diarrhea (2.1%). In a 24-week trial, adverse reactions (incidence ≥ 2%) were dysphonia (3.3%) and muscle spasms (3.3%)
• BREZTRI should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors and tricyclic antidepressants, as these may potentiate the effect of formoterol fumarate on the cardiovascular system
• BREZTRI should be administered with caution to patients being treated with:
  • Strong cytochrome P450 3A4 inhibitors (may cause systemic corticosteroid effects)
  • Adrenergic drugs (may potentiate effects of formoterol fumarate)
  • Xanthine derivatives, steroids, or non-potassium sparing diuretics (may potentiate hypokalemia and/or ECG changes)
  • Beta-blockers (may block bronchodilatory effects of beta-agonists and produce severe bronchospasm)
  • Anticholinergic-containing drugs (may interact additively). Avoid use with BREZTRI
• Use BREZTRI with caution in patients with hepatic impairment, as budesonide and formoterol fumarate systemic exposure may increase. Patients with severe hepatic disease should be closely monitored

Please see full Prescribing Information, including Patient Information. You may report side effects related to AstraZeneca products by clicking here.

Financial considerations

Under the terms of the past agreement to acquire Pearl Therapeutics Inc., AstraZeneca will make a $150m milestone payment upon US regulatory approval of BREZTRI AEROSPHERE for COPD. This is the final development and regulatory milestone under that agreement.

COPD

COPD is a progressive disease which can cause obstruction of airflow in the lungs resulting in debilitating bouts of breathlessness. It affects an estimated 384 million people and is the third leading cause of death globally. Improving lung function, reducing exacerbations and managing daily symptoms such as breathlessness are important treatment goals in the management of COPD. Even a single COPD exacerbation may be associated with a significant increase in the rate of decline in lung function, a significant deterioration in quality of life, and can significantly reduce life expectancy and increase the risk of mortality.

ETHOS, KRONOS and the ATHENA clinical trial program
ETHOS is a randomized, double-blinded, multi-center, parallel-group, 52-week trial to assess the efficacy and safety of BREZTRI AEROSPHERE in symptomatic patients with moderate to very severe COPD and a history of exacerbation(s) in the previous year. The primary endpoint was the rate of moderate or severe exacerbations.

KRONOS is a randomized, double-blinded, parallel-group, 24-week, chronic-dosing, multi-center trial to assess the efficacy and safety of BREZTRI AEROSPHERE in patients with moderate to very severe COPD regardless of whether or not they had an exacerbation in the previous year. The primary endpoints were lung function parameters.

ETHOS and KRONOS are part of AstraZeneca’s ATHENA Phase III clinical trial program for BREZTRI AEROSPHERE, which included more than 15,500 patients globally across 11 trials.

BREZTRI AEROSPHERE

BREZTRI AEROSPHERE^TM (budesonide/glycopyrrolate/formoterol fumarate) is a single-inhaler, fixed dose triple-combination of budesonide, an inhaled corticosteroid (ICS), with glycopyrrolate, a long-acting muscarinic antagonist (LAMA), and formoterol fumarate, a long-acting beta2-agonist (LABA), delivered in a pressurized metered-dose inhaler.

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 53 million patients in 2019. 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 (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal and 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 www.astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

US-40367 Last Updated 7/20

Contacts

Media Inquiries
Michele Meixell +1 302 885 2677

Brendan McEvoy +1 302 885 2677