Revefenacin: First Global Approval

Abstract

Revefenacin (YUPELRI™) inhalation solution, a long-acting muscarinic antagonist (i.e. an anticholinergic) developed by Theravance Biopharma and Mylan, is the first and currently the only once-daily, nebulized bronchodilator to be approved in the USA for the treatment of chronic obstructive pulmonary disease (COPD). In November 2018, based on results of three phase III trials, the US Food and Drug Administration granted market authorization to revefenacin for the maintenance treatment of patients with COPD. This article summarizes the milestones in the development of revefenacin leading to this first global approval.

<p>Long-Acting Muscarinic Antagonists Under Investigational to Treat Chronic Obstructive Pulmonary Disease</p>

“…12 As for REV pharmacokinetics (PK), peak plasma concentrations (C max ) of the drug and its active metabolite occur 14-41 min after nebulization, and the absolute bioavailability of orally administered REV is very low (<3%). 13 increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. 14 Cardiovascular safety of REV for nebulization has been assessed in randomized clinical trials.…”

Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

“…1 Revefenacin (YUPELRI R ) inhalation solution, delivered via standard jet nebulization, is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). [2][3][4] After inhaled administration, revefenacin is rapidly absorbed, with peak concentrations observed within 14 to 31 minutes after the start of nebulization. Absolute bioavailability after oral administration is low (<3%).…”

“…Absolute bioavailability after oral administration is low (<3%). 4 The primary metabolic pathway for revefenacin is via hydrolysis to form THRX-195518, 5 with only a minor contribution of cytochrome P450 enzymes. Results of binding studies at human recombinant M3 (hM3) muscarinic receptors show that THRX-195518 possesses modest muscarinic antagonistic activity but is 10-fold less potent than revefenacin and dissociates more rapidly from hM3 receptors.…”

“…Revefenacin is not anticipated to be subject to drug-drug interactions; however, its major metabolite (THRX-195518) is a substrate of organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3, and therefore coadministration of revefenacin with OATP inhibitors could lead to increased metabolite exposure. 4 Limited plasma accumulation (<1.6-fold) is observed for both revefenacin and THRX-195518 after multiple-dose (daily) inhaled administration. 4 This novel once-daily, lung-selective, long-acting muscarinic antagonist (LAMA), is predicted to have a low potential for adverse cardiovascular effects, including QT prolongation, as it does not inhibit the human ether-à-go-go (hERG)-related gene potassium channel at concentrations well above those observed clinically.…”

“…4 Limited plasma accumulation (<1.6-fold) is observed for both revefenacin and THRX-195518 after multiple-dose (daily) inhaled administration. 4 This novel once-daily, lung-selective, long-acting muscarinic antagonist (LAMA), is predicted to have a low potential for adverse cardiovascular effects, including QT prolongation, as it does not inhibit the human ether-à-go-go (hERG)-related gene potassium channel at concentrations well above those observed clinically. In HEK293 cells stably transfected with hERG cDNA, the hERG half-maximal inhibitory concentrations (IC 50 ) for revefenacin and THRX-195518 were 43 000-fold and 614 000-fold higher, respectively, than the maximum unbound plasma concentration (C max ) values in subjects receiving 700 µg of revefenacin (data on file, Theravance Biopharma US, Inc.).…”