Beyond Dual Bronchodilation – Triple Therapy, When and Why

Figures & data

Table 1 Pivotal Trials with Triple Therapy FDCs Approved for Maintenance Treatment of COPD versus Dual Bronchodilation

Study	Patients	Study Design	Therapy	Key Findings
Beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide
TRIBUTE^Citation52	Patients with a post-bronchodilator FEV1 <50% of the predicted normal value, ≥1 moderate-to-severe COPD exacerbation in the previous 12 months, CAT total score ≥10 and, who had used LABA/ICS, LAMA/ICS, LAMA/LABA, or LAMA monotherapy, but not triple therapy, for at least 2 months before screening	Multicentre, randomised, parallel-group, double-blind, double-dummy study over 52 weeks	BDP/FF/GB 200/12/25 μg twice daily in 764 patients IND/GB 85/43 μg once daily in 768 patients	Moderate-to-severe exacerbation rates were 0.50 per patient per year (95% CI 0.45 to 0.57) for BDP/FF/GB and 0.59 per patient per year (95% CI 0.53 to 0.67) for IND/GB BDP/FF/GB significantly reduced the rate of moderate or severe exacerbations compared with IND/GB (0.848 (95% CI 0.723 to 0.995; p = 0.043) The time to first moderate or severe exacerbation and the time to the first severe exacerbation were similar between the two treatment groups (hazard ratio 0.901, 95% CI 0.763 to 1.064, p = 0. 219; and 0.864, 95% CI 0.613 to 1.219, p = 0.405. respectively) Change in FEV1 and improvement in mean SGRQ total score from baseline were significantly better with BDP/FF/GB than with IND/GB Pneumonia occurred in 28 (4%) patients receiving BDP/FF/GB versus 27 (4%) patients receiving IND/GB
Fluticasone furoate/vilanterol/umeclidinium
IMPACT^Citation82	Patients with FEV1 < 50% of the predicted normal value and CAT ≥ 10 and ≥1 moderate or severe exacerbation in the previous year, or patients with FEV1 ≥50–<80% and CAT ≥10, and ≥2 moderate exacerbations in the past year or ≥1 severe exacerbation in the previous year	Multicentre, randomized, double-blind, parallel-group trial over 52 weeks	FLF/VI/UMEC 100/25/62.5 μg once daily in 4251 patients VI/UMEC 25/62.5 μg once daily in 2070 patients	Moderate-to-severe exacerbation rates were 0.91 per patient per year for FLF/VI/UMEC, and 1.21 per patient per year for VI/UMEC (rate ratio with triple therapy, 0.75; 95% CI 0.70 to 0.81; 25% difference; p < 0.001) The annual rate of moderate or severe exacerbations was lower with triple therapy, regardless of eosinophil level The annual rate of severe exacerbations was significantly lower with triple therapy than with VI/UMEC Change in FEV1 and improvement in mean SGRQ total score from baseline were significantly better with VI/UMEC The risk of clinician-diagnosed pneumonia was significantly higher with FLF/VI/UMEC than with VI/UMEC, as assessed in a time-to-first event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; p < 0.001)
Budesonide/formoterol fumarate/glycopyrronium bromide
KRONOS^Citation83	Patients with post-bronchodilator FEV1 ≥25–<80% of the predicted normal value, and CAT ≥10 despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening	Multicentre, randomised, double-blind, parallel-group trial over 24 weeks	BUD/FF/GB 320/9.6/18 μg twice daily in 640 patients FF/GB 9.6/18 μg twice daily in 627 patients	BUD/FF/GB did not significantly improve morning pre-dose trough FEV1 at week 24 versus FF/GB (13 mL, −9 to 36 mL; p=0·2375) BUD/FF/GB resulted in nominally significant improvements in SGRQ total score but not TDI focal score over 24 weeks versus FF/GB The rates of moderate or severe exacerbations with BUD/FF/GB were lower than with FF/GB for patients in both eosinophil subgroups (<150 cells/mm^3 or ≥150 cells/mm^3) Pneumonia incidence was low (<2%) and similar across treatments.
ETHOS^Citation51	Patients with post-bronchodilator FEV1 ≥25–<65% of the predicted normal value, CAT ≥10 and history of at least one moderate or severe COPD exacerbation (if their FEV1 was <50% of the predicted normal value) or at least two moderate or at least one severe COPD exacerbation (if their FEV1 was ≥50% of the predicted normal value) in the year before screening	Multicentre, randomized, double-blind, parallel-group trial over 52 weeks	BUD/FF/GB 320/9.6/18 μg twice daily in 2157 patients or 160/9.6/18 μg twice daily in 2137 patients, both using co-suspension delivery FF/GB 9.6/18 μg twice daily in 2143 patients using co-suspension delivery	The annual rates of moderate or severe exacerbations were 1.08 with BUD/FF/GB 320/9.6/18 μg, 1.07 BUD/FF/GB 160/9.6/18 μg, 1.42 with FF/GB Both triple-therapy regimens significantly prolonged the time to the first moderate or severe exacerbation as compared with FF/GB The incidence of confirmed pneumonia was 3.5% with BUD/FF/GB 160/9.6/18 μg, 4.5% with BUD/FF/GB 320/9.6/18 μg and 2.3% with FF/GB

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; CAT, COPD assessment test; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; FLF, fluticasone furoate; GB, glycopyrronium bromide; IND, indacaterol; SGRQ, St George’s Respiratory Questionnaire; TDI, transition dyspnea index; UMEC, umeclidinium; VI, vilanterol.

Table 2 Pharmacological Characteristics of the ICSs, LABAs and LAMAs Included in Triple Therapy FDCs Approved for Maintenance Treatment of COPD

ICSs
	Relative Glucocorticoid Receptor Binding Affinity*	Lipophilicity (log P**)	Aqueous Solubility (μg mL^–1)	PPB (%)	Vss l	CL h^–1	F (%)
Beclomethasone dipropionate	53 (1345)	4.59 (3.27)	0.13 (15.5)	95.9	424	120	62^CFC 82^HFA 41°^ral
Budesonide	935	2.32	16	91.4	180	84	39^DPI 11°^ral
Fluticasone furoate	2989	4.17	0.03	99.7	608	65	15^DPI 1°^ral
LABAs

	β2-AR				β1-AR	β2/β1 ratio
	pKi	IA (% isoprenaline)	Onset of action (t1/2, min)	Duration of action (h)
Formoterol	8.06	95.0	5.9	0.93	6.10	130
Vilanterol	9.42	70.0	3.45	NA	NA	2400

LAMAs
	M3 mAChR				M1 mAChR		M2 mAChR		M3/M2 ratio
	pKi	Koff (h^−1)	Onset of action (t1/2, min)	Duration of action (h)	pKi	Koff (h^−1)	pKi	Koff (h^−1)
Glycopyrronium	9.28	0.11	8.72	6.1	9.77	NA	9.09	1.84	16.5
Umeclidinium	9.80	0.53	9.0	1.37	9.80	NA	9.82	4.44	8.7

Notes: *Glucocorticoid receptor binding affinity is relative to dexamethasone with dexamethasone affinity = 100. **Log P values are defined as the log₁₀ of the octanol/water partition coefficient. Sources¹⁶ and ³⁰.

Abbreviations: CL, plasma clearance; F, absolute bioavailability determined in healthy subjects; IA, intrinsic activity; K_off, dissociation rate; NA, not available in human tissue; pKi, the negative logarithm to base 10 of the equilibrium dissociation constant of a ligand determined in inhibition studies; PPB, plasma protein binding; Vss, volume of distribution at steady state; t_1/2, residence half-life.

Table 3 When to Prefer Triple Therapy FDCs Over Dual Bronchodilation

Immediate choice in

• Patients who present for the first time, and have severe airway obstruction (FEV1 <50%) and are symptomatic

• Patients who have had frequent (≥2) moderate or severe exacerbations (≥1 hospitalisation) in the previous year

• Patients who have peripheral eosinophilia (>300 cells·μL^−1)

• Patients with significant lung function decline

• Patients discharged from hospital after a COPD exacerbation.

Table 4 Future Research to Determine in Which Other Circumstances Triple Therapy is Preferable to Dual Bronchodilation

It must be determined

• Whether and when addition of an ICS to the LABA/LAMA combination provides real additional clinical value, regardless of a preventive effect on exacerbations;

• What kind of benefit it is;

• Which patients might benefit most from dual bronchodilation or triple therapy;

• Whether triple therapy may affect mortality in patients with COPD;

• Whether and when it is possible to de-escalate triple therapy maintaining the patient on dual bronchodilation therapy;

• Whether the blood eosinophil count is a real biomarker to be used when choosing triple therapy or dual bronchodilation or the increase in the eosinophil count is just an epimarker of other biological processes or even is causally related in the pathogenesis of a patient’s AECOPD risk;

• Whether LAMA/LABA combination therapy is preferred over triple therapy also because of the cost differences between the two treatments in real-life.

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