Emerging Treatments for COPD: Evidence to Date on Revefenacin

Figures & data

Table 1. Long acting bronchodilators currently available in the US market.

Currently available LABAs	Mode of delivery	Manufacturer	Comments
Salmeterol	Dry powder inhaler	GlaxoSmithKline	Approved in the US as Serevent diskus^®
Formoterol	Dry powder inhaler	Novartis	Approved in the US as Foradil aerosolizer
	Inhalation solution	Mylan	Approved in the US as Perforomist
Arformoterol	Inhalation solution	Sunovion	Approved in the US as Brovana
Indacaterol	Dry powder inhaler	Sunovion	Approved in the US as Arcapta
Olodaterol	Soft mist inhaler	Boehringer-Ingelheim	Approved in the US as Striverdi Respimat
Currently available LAMAs	Mode of delivery	Manufacturer	Comments
Tiotropium	Soft mist inhaler	Boehringer-Ingelheim	Approved in the US as Spiriva Respimat
Aclidinium	Dry powder inhaler	Astra-Zeneca	Approved in the US as Tudorza Pressair
Umeclidinium	Dry powder inhaler	GlaxoSmithKline	Approved in the US as Incruse ellipta
Glycopyrronium	Dry powder inhaler	Sunovion	Approved in the US as Seebri Neohaler
	Inhalation solution	Sunovion	Approved in the US as Lonhala Magnair
Revefenacin	Inhalation solution	Theravance and Mylan	Approved in the US as Yupelri™

Figure 1. Chemical structure of revefenacin.

Table 2. Clinical trials evaluating revefenacin.

Clinical trial	Sample size (n)	Endpoints studied	Results
Study 0059 and Study 0091 [21]	32 in 0059, 59 in 0091	Primary endpoint: Change from baseline in peak (0–6 hours) FEV1 in Study 0059, and trough FEV1 after the final dose (Day 7) in Study 0091	In Study 0059: Mean peak FEV1 was significantly higher (p < 0.001) for revefenacin and ipratropium as compared to placebo; differences seen were 176.8mL for 350μg revefenacin, 162.2mL for 700μg revefenacin and 190.6mL for ipratropium.
		Secondary endpoints: Area under the FEV1-time curve (FEV1 AUC) values from time 12–24 hours post dose and FEV1 AUC values from time zero to 24 hours post dose in both studies
			In Study 0091: Mean trough FEV1 on Day 7 was significantly higher (p < 0.006) for all revefenacin doses as compared to placebo, with differences ranging from 53.5mL (22μg dose) to 114.2mL (175μg dose).
			Revefenacin was seen to have long lasting (≥24hours) bronchodilator effect following nebulized administration.
NCT02040792 [22]	355	Primary endpoint: Change from baseline in D28 trough FEV1,	Revefenacin (88, 175 and 350 μg) significantly improved D28 trough FEV1 over placebo (187.4, 166.6 and 170.6 mL, respectively, all p < 0.001); the 44 μg dose produced a sub-therapeutic response. For doses ≥88 μg, D28 24 hours wm differences from placebo for FEV1 were numerically similar to respective trough FEV1 values, thus indicating a sustained bronchodilator effect of revefenacin for 24 hours post dose. Doses ≥88 μg reduced the average number of albuterol puffs/day by more than one puff/day. The 350 μg dose did not demonstrate additional efficacy over that seen with the 175 μg revefenacin. Revefenacin was generally well tolerated, with minimal systemic anti-cholinergic effects.
		Secondary endpoints: wm FEV1 over 0 to 24 hours Rescue medication (albuterol) use.
NCT02459080 (study 0126) and NCT02512510 (study 0127) [23, 24]	619 randomized (NCT02459080) and 611 randomized (NCT02512510)	Primary efficacy endpoint: Change from baseline in trough FEV1 (defined as the mean of the 23.25- and 23.75-hour spirometry assessments following the 84th dose) on day 85	Revefenacin (88 µg and 175 µg) improved day 85 baseline-adjusted mean trough FEV1 compared with placebo in both studies. In Study 0126, the placebo-adjusted LS mean increase in trough FEV1 was 79.2 mL for revefenacin 88 µg (p = 0.0003) and 146.3 mL for revefenacin 175 µg (p < 0.0001). In Study 0127, the LS mean increase in trough FEV1 with revefenacin was 160.5 mL (88 µg) and 147.0 mL (175 µg) (both p < 0.0001). Analysis of pooled Study 0126 and Study 0127 results revealed placebo-adjusted increases in trough FEV1 of 119.8 mL (88 µg) and 148.1 mL (175 µg), respectively; the 28.3 mL difference in trough FEV1 between the revefenacin 88 µg and 175 µg doses was not statistically significant (p = 0.088) Revefenacin increased OTE trough FEV1 by ≥ 100 mL compared with placebo in both studies. Analysis of pooled Study 0126 and Study 0127 results revealed placebo-adjusted increases in OTE FEV1 of 115.3 mL (88 µg) and 142.3 mL (175 µg). In addition, revefenacin increased trough FEV1 by ≥ 100 mL on days 15, 29, 57, 84 and 85 versus placebo at both the 88 µg and 175 µg dose Pooled study results revealed placebo-adjusted LS mean increases in peak FEV1 (0–2 hours after first dose) of 127.3 mL (88 µg) and 129.5 mL (175 µg) (both p < 0.0001).
		Secondary efficacy endpoints: OTE on trough FEV1 (defined as the inverse-variance weighted average of all the trough FEV1 assessments across days 15 through 85 [15, 29, 57 and 85]) and peak (maximum) FEV1 (0–2 hours post first dose) on day 1.
NCT03095456 [29]	207	207 subjects were enrolled and randomized to receive either YUPELRI (175 mcg once daily) or tiotropium once daily for 28 days. Efficacy assessments included FEV1) and FVC	In the intent-to-treat population, the YUPELRI group showed improvements in trough FEV1 and trough FVC on day 29 compared with tiotropium group; however, these differences did not reach statistical significance. In the prespecified analysis of subjects with severe to very severe COPD(FEV1 < 50% predicted), which included approximately 80% of the study population, YUPELRI demonstrated statistically significant improvements in trough FEV1 (p = 0.025) and FVC (p = 0.034) as compared to tiotropium. There were numerically fewer AEs observed in patients receiving YUPELRI (11.7%) compared to patients receiving tiotropium (37.5%).
NCT02518139 [30, 31]	1055	Randomized, active-controlled parallel group trial designed to evaluate the safety and tolerability of nebulized revefenacin (88 mcg or 175 mcg, inhaled once daily) over 52 weeks vs. Tiotropium (Spiriva^®) as the active comparator standard of care	Over 52weeks, both doses of revefenacin, as well as tiotropium, produced significant improvements (all p < 0.0003) from baseline in trough FEV1. The trough FEV1 profile (least squares mean change from baseline) for revefenacin 175 μg ranged from 52.3 to 124.3 mL and the trough FEV1 profile for tiotropium ranged from 79.7 to 112.8 mL. Rates of SAEs were 15.9% in the 88 mcg revefenacin group, 12.8% in the 175 mcg revefenacin group vs 16.3% in the tiotropium group COPD exacerbation or worsening was the most frequent AE in all groups (n = 280 [26.5%]), and occurred at a lower proportion in the revefenacin 175 μg group (97 events in 73 [21.8%] patients) than in the other two treatment groups (revefenacin 88 μg, 145 events in 107 [29.4%] patients; tiotropium, 137 events in 100 [28.1%] patients) All-cause mortality rates were low (0.27% in the 88 mcg revefenacin group, 0.30% in the 175 mcg revefenacin group vs. 0.28% in the tiotropium group

FEV₁, forced expiratory volume in one second; PIFR, peak inspiratory flow rate; AUC, area under curve; wm, weighted mean; OTE, overall treatment effect; LS, least squares; FVC, forced vital capacity; COPD, chronic obstructive pulmonary disease; AEs, adverse events; LABAs, long acting β-2 agonists; ICS, inhaled corticosteroids; SAE, serious adverse event.

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