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

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca today announced the initiation of a Phase III trial to investigate the potential effect of triple-combination inhaled therapy BREZTRI 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 hospitalization 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.

BREZTRI AEROSPHERE^® (budesonide/glycopyrronium/formoterol fumarate) 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

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.

Please see full BREZTRI Prescribing Information, including Patient Information.

You may report side effects related to AstraZeneca products.

Notes

COPD

COPD refers to a group of lung diseases, including chronic bronchitis and emphysema, that cause airflow blockage and breathing-related problems.¹⁷ Affecting an estimated 16 million Americans, COPD is the third leading cause of death due to chronic disease and the sixth overall leading cause of death in the US.^18,19

BREZTRI AEROSPHERE^®

BREZTRI AEROSPHERE (budesonide/glycopyrronium/formoterol fumarate) 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 pressurized metered-dose inhaler. BREZTRI AEROSPHERE is approved to treat COPD in more than 50 countries worldwide including the US, EU, China and Japan, and is currently being studied in Phase III trials for asthma.

THARROS

THARROS is a randomized, multi-center, 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 randomized 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 randomized, multi-center, 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.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization 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. For more information, please visit www.astrazeneca-us.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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