BREZTRI Triple Therapy COPD Clinical Trial Data

KRONOS Study: No required history of exacerbations*
ETHOS Study: Required history of exacerbations*
Additional Data

BREZTRI Reduced Exacerbations vs Dual Therapies

KRONOS Primary Endpoints^1,2

In a 24-week study, BREZTRI demonstrated a significant improvement in FEV₁ AUC_0-4 vs ICS/LABA (116 mL; P<0.0001) and an improvement in change from baseline in morning predose trough FEV₁ vs LAMA/LABA (13 mL; P=0.2375) at Week 24.

THE ONLY TRIPLE THERAPY^‡ TO DEMONSTRATE BETTER BREATHING, FAST^1-5

*Moderate or severe.

^†KRONOS Study: Patients (N=1902) were not required to have a history of moderate or severe exacerbations in the year prior to screening.²

^‡Fixed-dose combination: ICS/LAMA/LABA.²

KRONOS: Study Design^2,6

A 24-week, Phase 3, randomized 2:2:1:1, double-blind, multicenter, parallel-group trial of 1902 patients with moderate to very severe COPD, comparing BREZTRI MDI 320/18/9.6 mcg (n=640), GLY/FORM MDI 18/9.6 mcg (n=627), BUD/FORM_(A) 320/9.6 mcg (n=316), and open-label BUD/FORM DPI 400/12 mcg (n=319), each administered BID. Patients were 40-80 years of age, with a smoking history of ≥10 pack-years and symptomatic COPD while receiving ≥2 inhaled maintenance therapies, with no requirement for a moderate or severe exacerbation(s) in the previous year. Primary endpoints were FEV₁ AUC_0-4 for BREZTRI vs BUD/FORM_(A) and change from baseline in morning predose trough FEV₁ for BREZTRI vs GLY/FORM MDI at Week 24. Secondary endpoints included the rate of moderate or severe COPD exacerbations.² Moderate exacerbations were defined as those leading to treatment with systemic corticosteroids and/or antibiotics, and severe exacerbations as those resulting in hospitalization or death.⁶

AUC_0-4=area under the curve from 0 to 4 hours; BID=twice daily; BUD=budesonide; BUD/FORM_(A)=budesonide/formoterol fumarate Aerosphere; COPD=chronic obstructive pulmonary disease; DPI=dry powder inhaler; FEV₁=forced expiratory volume in 1 second; FORM=formoterol fumarate; GLY=glycopyrrolate; ICS=inhaled corticosteroid; LABA=long-acting beta₂-adrenergic agonist; LAMA=long-acting muscarinic antagonist; MDI=metered-dose inhaler; mITT=modified intent-to-treat; RR=rate ratio.

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ETHOS Primary Endpoint^1,2

In a 52-week study, BREZTRI significantly reduced the annual rate of moderate or severe COPD exacerbations by 24% vs LAMA/LABA (RR=0.76; P<0.0001) and by 13% vs ICS/LABA (RR=0.87; P=0.0027). Annual rate estimate: BREZTRI 1.08; LAMA/LABA 1.42; ICS/LABA 1.24.^1,2

All-Cause Mortality—Observational Data

Ethos Secondary Endpoint | Final retrieved data set

Time to All-Cause Mortality (Over 52 Weeks)³

ETHOS COPD Clinical Trial Data Graph Showing Time to All-Cause Mortality Over 52 Weeks

Figure adapted from Martinez FJ, et al. Am J Respir Crit Care Med. 2021;203(5):553-564.³

Due to nonsignificant results on endpoints higher in the testing hierarchy, these results are observational in nature, and any comparisons between treatment arms should be interpreted with caution.

No drug has been proven to reduce all-cause mortality in patients with COPD.

The analysis of time to death from any cause over 52 weeks was performed in the ITT population with the use of a treatment policy estimand, which included all observed data from the patients regardless of whether they continued to receive their assigned treatment. The effect of ICS withdrawal on these data is unknown.

*Moderate or severe.

ETHOS Study Design²

A 52-week, Phase 3, randomized 1:1:1:1, double-blind, multicenter, parallel-group trial of 8588 patients with moderate to very severe COPD, comparing BREZTRI MDI 320/18/9.6 mcg (n=2157), BUD/GLY/FORM MDI 160/18/9.6 mcg (n=2137), GLY/FORM MDI 18/9.6 mcg (n=2143), and BUD/FORM_(A) 320/9.6 mcg (n=2151), each administered BID. Patients were 40-80 years of age, with a smoking history of ≥10 pack-years and symptomatic COPD while receiving ≥2 inhaled maintenance therapies, and had a history of ≥1 moderate or severe exacerbation(s) in the previous year. The primary endpoint was the annual rate of moderate or severe COPD exacerbations, and secondary endpoints included the annual rate of severe COPD exacerbations and time to death (all cause). Moderate exacerbations were defined as those leading to treatment with systemic corticosteroids and/or antibiotics, and severe exacerbations as those resulting in hospitalization or death.

BID=twice daily; BUD=budesonide; BUD/FORM_(A)=budesonide/formoterol fumarate Aerosphere; CI=confidence interval; COPD=chronic obstructive pulmonary disease; FORM=formoterol fumarate; GLY=glycopyrrolate; ICS=inhaled corticosteroid; ITT=intent-to-treat; LABA=long-acting beta₂-adrenergic agonist; LAMA=long-acting muscarinic antagonist; MDI=metered-dose inhaler; RR=rate ratio.

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KRONOS Primary Endpoints^1,2

ETHOS Primary Endpoint^1,3

LUNG DEPOSITION BETWEEN BREZTRI AND TRELEGY^1,4,5

There are no head-to-head comparisons of the in vivo lung deposition of currently approved FDC triple therapies for COPD. Data do not imply superior efficacy or safety of one drug over the other. Data are descriptive only.

Study Design:

In silico 3D airway models of patients with COPD (N=20) were used to evaluate the total lung deposition (large and small airways) for each component of fixed-dose triple-therapy combinations currently approved for the treatment of COPD, when administered at an inspiratory flow rate of 30 L/min and at 60 L/min. Total lung deposition in patients with moderate to very severe COPD, as a percentage of delivered dose, was evaluated using FRI, an in silico computational fluid dynamics method, for 2 actuations of BREZTRI pMDI 160/9.0/4.8 μg and 1 actuation of Trelegy DPI 100/62.5/25 μg. Dosages for BREZTRI and Trelegy^® reflect US equivalent of the globally used formulation applied to this study.

Limitations of Use⁴:

This study used FRI to compare/assess in silico lung deposition with 3 single-inhaler, triple-therapy combinations when administered at a low inspiratory flow rate
Different formulations of inhaled medicines, even those delivered via the same device type, can have different total and regional lung deposition characteristics

BREZTRI showed over 50% deposition in the large and small airways⁴

Representative deposition visualization (% delivered dose) of a 3D airway model of the same participant.

BREZTRI Vs Trelegy Lung Deposition Comparison In Large and Small Airways

Total lung deposition* for all 3 components of ICS/LABA/LAMA.⁴

Trelegy Ellipta^® (fluticasone furoate/umeclidinium/vilanterol) is a registered trademark of the GlaxoSmithKline group of companies.

3D=three-dimensional; AUC_0-4=area under the curve from 0 to 4 hours; COPD=chronic obstructive pulmonary disease; DPI=dry powder inhaler; FDC=fixed-dose combination; FRI=functional respiratory imaging; ICS=inhaled corticosteroid; LABA=long-acting beta₂-adrenergic agonist; LAMA=long-acting muscarinic antagonist; pMDI=pressurized metered-dose inhaler; RR=rate ratio.

EXACERBATION RATES BEFORE AND AFTER INITIATING BREZTRI

Study Design⁶:

This was an observational, retrospective, multicenter study in Spain involving 718 patients with COPD who initiated treatment with BREZTRI at the discretion of a physician in routine clinical practice. The objective was to describe the occurrence and severity of exacerbations (primary endpoint) in patients taking dual therapy, single-, or multiple-inhaled triple therapy in the 12 months prior to BREZTRI initiation compared with the 12 months after BREZTRI initiation. Patients were a mean of 70.2 years of age, 70.6% were male; 41.1% were on dual therapy, with 15.6% on ICS/LABA and 25.5% on LABA/LAMA; 49.6% of patients were on triple therapy, with 20.5% on SITT and 29.1% on MITT; 6.0% of patients were treatment naïve; 66% of patients had experienced an exacerbation of any severity.* Mean FEV₁ at initiation was 1.31 L.

Limitations⁶:

Results may not be generalizable to US clinical practice. Conclusions from these data are limited by the retrospective design, lack of control arm, and treatment options according to local label and routine practice in Spain. Patients from the US were not included in this study
There are no head-to-head clinical studies evaluating BREZTRI and SITT or MITT
Key clinical variables (spirometry, eosinophils) were inconsistently available over time, which constrains assessment of lung function trajectories and phenotype-driven effects
Patients were identified from 20 Spanish hospital centers and likely had more severe, complex COPD, with specialist follow-up. Findings may not generalize to milder patients
Concurrent interventions were not captured and could contribute to outcome changes. Site-to-site practice variability may also affect results
Exacerbations were classified using record-based criteria (ER visits, OCS/antibiotics, hospitalization duration). Misclassification or under-capture of events managed outside hospital systems is possible

MEAN ANNUALIZED RATE OF TOTAL EXACERBATIONS FOR PATIENTS WITH ≥1 EXACERBATION^6*

Mean Annual Exacerbation Rate Comparison for COPD Patients Treated with BREZTRI

Results are descriptive only, and definitive conclusions cannot be made. There are no head-to-head clinical studies evaluating BREZTRI and SITT or MITT.

*A moderate exacerbation was defined as requiring ambulatory treatment with systemic corticosteroids and/or antibiotics and/or presentation to the ER for ≤24 hours. A severe exacerbation was defined as an exacerbation that led to hospitalization for longer than 24 hours.

^†Subgroup analysis was stratified by two main groups, SITT and dual therapy, which was defined as either ICS/LABA or LAMA/LABA.

^‡Comprised other prescription maintenance inhaler and rescue medications: ICS/LABA and/or LAMA/LABA, SABA, SAMA, SABA/SAMA, LAMA. Six percent of patients were treatment-naïve at start of BREZTRI therapy.

^§Patients in the SITT group were either on Trelegy Ellipta or beclometasone/glycopyrrolate/formoterol fumarate, which is not an approved product in the US.

Trelegy Ellipta^® (fluticasone furoate/umeclidinium/vilanterol) is a registered trademark of the GlaxoSmithKline group of companies.

AUC_0-4=area under the curve from 0 to 4 hours; CI=confidence interval; COPD=chronic obstructive pulmonary disease; ER=emergency room; ICS=inhaled corticosteroid; LABA=long-acting beta₂-adrenergic agonist; LAMA=long-acting muscarinic antagonist; MITT=multiple-inhaler-triple therapy; OCS=oral corticosteroid; pMDI=pressurized metered-dose inhaler; RR=rate ratio; SABA=short-acting beta-agonist; SAMA=short-acting muscarinic antagonist; SITT=single-inhaler triple therapy.

Mechanism of Action

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Important Safety Information

BREZTRI is contraindicated:
- For the primary treatment of status asthmaticus or other acute episodes of asthma or COPD requiring intensive measures
- In patients who have a hypersensitivity to budesonide, glycopyrrolate, formoterol fumarate or product excipients
Long-acting beta₂-adrenergic agonist (LABA) monotherapy for asthma is associated with an increased risk of serious asthma-related events. These findings are considered a class effect of LABA monotherapy. When a LABA is used in a 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 use 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 or asthma, 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
Monitor growth in pediatric patients
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 (incidence ≥ 2%) are:
- COPD: upper respiratory tract infection, pneumonia, back pain, oral candidiasis, influenza, muscle spasms, urinary tract infection, cough, sinusitis, and diarrhea
- Asthma: nasopharyngitis, pneumonia, and headache
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

INDICATIONS

BREZTRI AEROSPHERE 160 mcg/9 mcg/4.8 mcg is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients.

BREZTRI AEROSPHERE 160 mcg/18 mcg/4.8 mcg is indicated for the maintenance treatment of asthma in adult and pediatric patients 12 years of age and older.

LIMITATIONS OF USE

Not indicated for the relief of acute bronchospasm.

Please see full Prescribing Information, including Patient Information and Instructions for Use.

You may report side effects related to AstraZeneca products.

Important Safety Information
+

References

1. BREZTRI AEROSPHERE^® (budesonide, glycopyrrolate, and formoterol fumarate) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2026.
2. Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multi-centre, phase 3 randomised controlled trial. Lancet Respir Med. 2018;6(10):747-758.
3. Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol inhalation powder) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2023.
4. Papi A, Wise, RA, Jackson DJ, et al. Budesonide-glycopyrronium-formoterol fumarate dihydrate in uncontrolled asthma (KALOS and LOGOS): twin multicentre, double-blind, double-dummy parallel-group, randomised, phase 3 trials. Lancet Respir Med. 2026;14(4):350-362. doi:10.1016/S2213-2600(25)00457-6
5. Trimbow^® U.S. (beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate) [prescribing information]. Cary, NC: Chiesi USA, Inc; 2026.
6. Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir Med. 2018;6(suppl):1-23. https://doi.org/10.1016/s2213-2600(18)30327-8
7. Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111-124. https://www.tandfonline.com/doi/full/10.1081/COPD-200053377
8. Data on file, REF-296305, AZPLP.

1. BREZTRI AEROSPHERE^® (budesonide, glycopyrrolate, and formoterol fumarate) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2026.
2. Rabe KF, Martinez FJ, Ferguson GT, et al; ETHOS Investigator. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very severe COPD. N Engl J Med. 2020;383(1):35-48.
3. Martinez FJ, Rabe KF, Ferguson GT, et al; Reduced all-cause mortality in the ETHOS trial of budesonide/glycopyrrolate/formoterol for chronic obstructive pulmonary disease: a randomized, double-blind, multicenter, parallel-group study. Am J Respir Crit Care Med. 2021;203(5):553-564.

1. BREZTRI AEROSPHERE^® (budesonide, glycopyrrolate, and formoterol fumarate) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2026.
2. Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir Med. 2018;6(10):747-758.
3. Rabe KF, Martinez FJ, Ferguson GT, et al; ETHOS Investigators. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very severe COPD. N Engl J Med. 2020;383(1):35-48.
4. Singh D, Roche N, Wu L, et al. In silico lung deposition profiles of three single-inhaler triple therapies in patients with COPD using functional respiratory imaging. Int J Chron Obstruct Pulmon Dis. 2025;20:2103-2116. https://doi.org/10.2147/COPD.S510214
5. Trelegy Ellipta (fluticasone furoate/umeclidinium, and vilanterol inhalation powder) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2023.
6. Alcázar-Navarrete B, González-Gangols JM, Corregidor-García C, Fitas F, Sánchez-Covisa J; ORESTES group. Real-world outcomes in patients with COPD initiating budesonide/glycopyrronium/formoterol fumarate dehydrate in Spain: ORESTES study. Adv Ther. 2025;42(11):5708-5726. https://doi.org/10.1007/s12325-025-03361-x

Explore the Efficacy of BREZTRI for COPD

BREZTRI Reduced Exacerbations vs Dual Therapies

KRONOS Primary Endpoints^1,2

THE ONLY TRIPLE THERAPY^‡ TO DEMONSTRATE BETTER BREATHING, FAST^1-5

KRONOS: Study Design^2,6

ETHOS Primary Endpoint^1,2

All-Cause Mortality—Observational Data

Time to All-Cause Mortality (Over 52 Weeks)³

ETHOS Study Design²

BREZTRI Primary Endpoints

KRONOS Primary Endpoints^1,2

ETHOS Primary Endpoint^1,3

FRI Observational Lung Deposition

LUNG DEPOSITION BETWEEN BREZTRI AND TRELEGY^1,4,5

Study Design:

Limitations of Use⁴:

BREZTRI showed over 50% deposition in the large and small airways⁴

ORESTES: Retrospective Observational Analysis

EXACERBATION RATES BEFORE AND AFTER INITIATING BREZTRI

Study Design⁶:

Limitations⁶:

MEAN ANNUALIZED RATE OF TOTAL EXACERBATIONS FOR PATIENTS WITH ≥1 EXACERBATION^6*

Important Safety Information

IMPORTANT SAFETY INFORMATION

INDICATIONS

LIMITATIONS OF USE

Important Safety Information
+

References

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Explore the Efficacy of BREZTRI for COPD

BREZTRI Reduced Exacerbations vs Dual Therapies

KRONOS Primary Endpoints1,2

THE ONLY TRIPLE THERAPY‡ TO DEMONSTRATE BETTER BREATHING, FAST1-5

KRONOS: Study Design2,6

BREZTRI Reduced the Rate of Moderate or Severe Exacerbations vs LAMA/LABA and ICS/LABA1,2

better breathing fast with BREZTRI

ETHOS Primary Endpoint1,2

KRONOS Primary Endpoints1,2

ETHOS Primary Endpoint1,3

LUNG DEPOSITION BETWEEN BREZTRI AND TRELEGY1,4,5

Study Design:

Limitations of Use4:

BREZTRI showed over 50% deposition in the large and small airways4

EXACERBATION RATES BEFORE AND AFTER INITIATING BREZTRI

Study Design6:

Limitations6:

MEAN ANNUALIZED RATE OF TOTAL EXACERBATIONS FOR PATIENTS WITH ≥1 EXACERBATION6*

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Important Safety Information

IMPORTANT SAFETY INFORMATION

INDICATIONS

LIMITATIONS OF USE

Important Safety Information +

References

About

Access & Resources

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KRONOS Primary Endpoints^1,2

THE ONLY TRIPLE THERAPY^‡ TO DEMONSTRATE BETTER BREATHING, FAST^1-5

KRONOS: Study Design^2,6

BREZTRI Reduced
the Rate of
Moderate or Severe
Exacerbations vs LAMA/LABA and ICS/LABA^1,2

ETHOS Primary Endpoint^1,2

KRONOS Primary Endpoints^1,2

ETHOS Primary Endpoint^1,3

LUNG DEPOSITION BETWEEN BREZTRI AND TRELEGY^1,4,5

Limitations of Use⁴:

BREZTRI showed over 50% deposition in the large and small airways⁴

Study Design⁶:

Limitations⁶:

MEAN ANNUALIZED RATE OF TOTAL EXACERBATIONS FOR PATIENTS WITH ≥1 EXACERBATION^6*

Important Safety Information
+