Revefenacin: A Once-Daily, Long-Acting Bronchodilator For Nebulized Treatment Of COPD

Figures & data

Table 1 Commonly Used Long-Acting Anticholinergics For Maintenance Treatment Of COPD¹

LAMA	Inhaler Type^a	Mode Of Delivery/Frequency	Duration Of Action
Aclidinium bromide	DPI, MDI	Oral inhalation/twice daily	12 hrs
Glycopyrrolate	DPI, nebulizer	Oral inhalation/twice daily^b Nebulizer/twice daily	12–24 hrs
Tiotropium bromide	DPI, SMI	Oral inhalation/once daily	24 hrs
Umeclidinium bromide	DPI	Oral inhalation/once daily	24 hrs

Notes: ^aNot all formulations are available in all countries.¹ bGlycopyrrolate is approved for once-daily dosing in some countries.^2,3

Abbreviations: DPI, dry powder inhaler; LAMA, long-acting muscarinic antagonist; MDI, metered-dose inhaler; SMI, soft-mist inhaler.

Figure 1 Structural formulas of once-daily LAMAs.^19–21

Abbreviation: LAMA, long-acting muscarinic antagonist.

Table 2 Summary Of Trials Evaluating Efficacy And Safety Of Revefenacin

Trial Identifier/Publication	Phase	Trial Design	Population	Dosing	Efficacy/Safety
U1111-1120-8290; NCT3064113^Citation25	Phase II	Randomized, double-blind, placebo- and ipratropium-controlled, crossover, single-dose study	Moderate to severe COPD	Single dose of 350 or 700 μg	Significant change in peak FEV1 (0–6 hrs) vs placebo Significant improvement in trough FEV1 vs placebo AEs generally mild; few antimuscarinic AEs
NCT1704404^Citation25	Phase II	Randomized, double-blind, placebo-controlled, 5-way crossover, multidose study	Moderate to severe COPD	22, 44, 88, 175, 350, or 700 μg once daily for 7 days	Significant improvement in mean trough FEV1 on Day 7 vs placebo Rapid onset and sustained bronchodilator effect for 24 hrs AEs generally mild; few antimuscarinic AEs
NCT2109172^Citation26	Phase II	7-day, randomized, double-blind, placebo-controlled, crossover study	Moderate to severe COPD	44 μg twice-daily or 175 μg once daily	Improvement in weighted mean (0–24 hrs) change from baseline FEV1 with both doses vs placebo Well tolerated with no major safety concerns
NCT2040792^Citation27	Phase II	28-day, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study	Moderate to severe COPD	44, 88, 175, or 350 μg once daily	Significant improvement in mean trough FEV1 vs placebo ≥100 mL increase in FEV1 in >80% of patients within 4 hrs postdose Effective dose: ≥88 μg Bronchodilation sustained for 24 hrs Well tolerated, with few antimuscarinic AEs
NCT2459080, NCT2512510^Citation28	Phase III	12-week, replicate, randomized, double-blind, placebo-controlled, multiple-dose, parallel-group studies	Moderate to very severe COPD	88 or 175 μg once daily	Significant improvement in day 85 mean trough FEV1 vs placebo Significant improvement in OTE trough FEV1 and peak FEV1 vs placebo 175-μg dose more effective than 88 μg Well tolerated, with no major safety concerns
NCT2518139^Citation29	Phase III	52-week, randomized, partially double-blind, tiotropium-controlled, parallel-group safety study	Moderate to very severe COPD	REV 88 or 175 μg or TIO 18 μg once daily	AEs comparable across treatments Fewer exacerbations with REV 175 μg vs REV 88 μg and TIO Fewer serious AEs with REV 175 μg vs REV 88 μg and TIO
NCT3095456^Citation30	Phase III	28-day, randomized, double-blind, double-dummy, tiotropium-controlled study	Moderate to very severe COPD; PIFR <60 L/min	REV 175 μg or TIO 18 μg once daily	Significant improvements in trough FEV1 and forced vital capacity in patients with FEV1 <50% predicted vs TIO Subgroups with lower PIFR cut points (33–56 L/min) had a more pronounced effect

Abbreviations: AE, adverse event; OTE, overall treatment effect; PIFR, peak inspiratory flow rate; REV, revefenacin; TIO, tiotropium.

Figure 2 Peak FEV₁ treatment difference from placebo in single-dose (A) and multi-dose 7-day (B) trials. Peak FEV₁ is the highest value obtained between 0 and 6 hrs after the first dose. *p<0.001. Data are least squares mean±95% confidence interval treatment difference from placebo. Dotted line indicates minimal clinically important difference.³¹

Notes: Reproduced from Quinn D, Barnes CN, Yates W, et al Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): results of two randomized, double-blind, phase 2 studies. Pulm Pharmacol Ther. 2018;48:71–79. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.²⁵ 

Figure 3 Sustained increase in trough FEV₁ for 85 days in two randomized, double-blind, placebo-controlled Phase III trials in patients with moderate to severe COPD (pooled data from NCT2459080 and NCT2512510; N=1,255). Dotted line indicates minimal clinically important difference.³¹

Notes: Reproduced with permission from Ferguson GT, Feldman G, Pudi KK, et al. Improvements in lung function with nebulized revefenacin in the treatment of patients with moderate to very severe COPD: results from two replicate phase III clinical trials. Chronic Obstr Pulm Dis. 2019;6(2):154–165. doi:10.15326/jcopdf.6.2.2018.0152.²⁸ *p<0.0001 vs placebo.
Abbreviations: LS, least squares; REV, revefenacin; SE, standard error.

Figure 4 Placebo-adjusted changes from baseline at day 85 trough FEV₁ in patients with COPD who received once-daily revefenacin (88 and 175 μg) for nebulization.²⁸ *p<0.001 vs placebo. Day 85 trough FEV₁ was the average of values obtained at 23.25 and 23.75 hrs following the 84th dose. Dotted line indicates minimal clinically important difference.³¹

Notes: Reproduced with permission from Ferguson GT, Feldman G, Pudi KK, et al. Improvements in lung function with nebulized revefenacin in the treatment of patients with moderate to very severe COPD: results from two replicate phase III clinical trials. Chronic Obstr Pulm Dis. 2019; 6(2):154–165. doi:10.15326/jcopdf.6.2.2018.0152.²⁸
Abbreviations: LS, least squares; OTE, overall treatment effect; REV, revefenacin; SE, standard error.

Table 3 Incidence (n, %) Of Treatment-Emergent AEs Reported In ≥2% Patients^a Receiving Revefenacin 175 μg Once Daily In Phase II And III Clinical Trials

	Quinn et al 2018^Citation25 (N=37)	Pudi et al 2017^Citation27 (N=71)	Ferguson et al 2019^Citation28		Donohue et al 2019^Citation29 (N=335)
			Study 0126 (N=198)	Study 0127 (N=197)
Study design	7-day, 5-way crossover, multidose Phase II study	28-day, dose-ranging Phase II study	12-week, replicate Phase III studies		52-week, randomized Phase III safety study
Any AE	17 (45.9)	22 (31.0)	101 (51.0)	102 (51.8)	242 (72.2)
SAEs	0	2 (2.8)	10 (5.1)	5 (2.5)	43 (12.8)
AEs leading to drug interruption or discontinuation	1 (2.7)	5 (7.0)	-	-	41 (12.2)
Antimuscarinic effects	0	0	4 (2.0)	-	7 (2.1)
Headache	4 (10.8)	-	8 (4.0)	8 (4.1)	13 (3.9)
Dyspnea	2 (5.4)	3 (4.2)	4 (2.0)	8 (4.1)	13 (3.9)
Cough	2 (5.4)	3 (4.2)	7 (3.5)	10 (5.1)	25 (7.5)
COPD exacerbation	-	-	21 (10.6)	21 (10.7)	73 (21.8)
[as SAE]			[4 (2.0)]	-	[8 (2.4)]
Pneumonia [as SAE]	-	-	-	-	[1 (0.3)]
Back pain	1 (2.7)	2 (2.8)	-	7 (3.6)	-
Oropharyngeal pain	2 (5.4)	-	4 (2.0)	-	-
Hypertension	-	-	-	4 (2.0)	-
Dizziness	-	-	-	4 (2.0)	-
Upper respiratory tract infection	-	-	-	10 (5.1)	20 (6.0)
Urinary tract infection	-	-	-	-	11 (3.3)
Nasopharyngitis	0	-	6 (3.0)	9 (4.6)	26 (7.8)
Bronchitis	-	-	-	-	17 (5.1)
Sinusitis	-	-	5 (2.5)	4 (2.0)	-
Rash	2 (5.4)	-	-	-	-
Nausea	1 (2.7)	-	-	-	-
Death	-	-	0	0	1 (0.3)

Note: ^a≥5% in Donohue et al 2019.²⁹

Abbreviations: -, not reported or incidence <2%; AE, adverse event; SAE, serious adverse event.

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