Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease

Abstract

A B S T R A C TBackground: Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 μg and 175 μg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 μg and 175 μg over 52 weeks of treatment. Methods: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 μg or 175 μg in a double-blind manner, or open-label active control tiotropium. Results: Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 μg, 272 [74.7%]; 175 μg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 μg (73 [21.8%]) than with 88 μg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 μg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 μg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 μg or tiotropium with a concurrent long-acting β-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 μg. Conclusions: Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD.

Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis

“…Revefenacin treatment was shown to improve FEV 1 and respiratory health outcomes in a 52-week study with results similar to tiotropium via HandiHaler ® [8]. Revefenacin was well tolerated for 52 weeks and has a safety profile that supports its long-term use in patients with COPD [9]. In addition, revefenacin was not associated with adverse cardiovascular events [10,11].…”

“…However, in patients with comorbid diabetes, it may be more appropriate to limit the use of ICS to the minority of patients with COPD who might benefit. There were no safety issues identified with the use of revefenacin in patients with cardiac risk factors [7,9]. In a preclinical study, revefenacin was shown to be a high-affinity competitive antagonist at human recombinant muscarinic acetylcholine receptors with kinetic functional selectivity for M 3 over M 2 muscarinic acetylcholine receptors [27].…”

Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials

“…11 Longterm safety of revefenacin in clinical trials was demonstrated in a 52 week, randomized, tiotropium-controlled, phase III safety and tolerability trial. 12 Revefenacin was well tolerated during the phase III trials and had a safety profile that supports its long-term use in patients with COPD. 11,12 Many patients with COPD require combination bronchodilator therapy for symptom management, and because more than 40% of patients in the phase III trials of revefenacin were taking concomitant LABA-containing therapy, we performed a prespecified subgroup analysis in this patient population to evaluate the efficacy and safety of revefenacin in combination with LABA-containing bronchodilators.…”

“…Inclusion and exclusion criteria for the three studies have been described previously. 11,12 For the 12-and 52-week studies, we enrolled patients aged at least 40 years with moderate to very severe COPD, a smoking history of at least 10 packyears, a postipratropium FEV 1 /forced vital capacity ratio <0.7, and a postipratropium FEV 1 <80% of predicted normal and >700 ml at screening. Patients with a substantially increased risk for cardiovascular events, such as myocardial infarction within the past 6 months, unstable or In the 12-week studies, up to 40% of patients were permitted concomitant use of LABA (LABA cap, controlled through stratification during randomization) with or without ICS.…”

Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis

“…There were no safety issues identified with the use of revefenacin in patients with cardiac risk factors [7,9]. In a preclinical study, revefenacin was shown to be a high-affinity competitive antagonist at human recombinant muscarinic acetylcholine receptors with kinetic functional selectivity for M 3 over M 2 muscarinic acetylcholine receptors [27].…”