td-4208 and Pulmonary-Disease--Chronic-Obstructive

This article reviews the efficacy and safety of revefenacin, the first once-daily, long-acting muscarinic antagonist, when delivered via a standard jet nebulizer in patients with chronic obstructive pulmonary disease (COPD).. Revefenacin 175 µg is indicated for the maintenance treatment of patients with moderate to very severe COPD. Preclinical studies showed that revefenacin is a potent and selective antagonist with similar affinity for the different subtypes of muscarinic receptors (M1-M5). Furthermore, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose dependent and lasted longer than 24 hours, demonstrating a long duration of action. In phase 2 and 3 trials, treatment with revefenacin was demonstrated to result in statistical improvements in pulmonary function (≥100 mL, P < 0.05) vs placebo, including among patients with markers of more severe disease and those who received concomitant long-acting β-agonists or long-acting β-agonists together with inhaled corticosteroids. Revefenacin was also demonstrated to have efficacy similar to that of tiotropium. The clinical trial findings indicated no significant difference between revefenacin and tiotropium with regard to rates of adverse events. Overall, revefenacin was well tolerated, with COPD worsening/exacerbation, dyspnea, headache, and cough among the most common adverse events noted in the clinical trials.. Revefenacin treatment delivered via nebulization led to improvements in lung function in patients with COPD. It was also generally well tolerated, with no major safety concerns. Revefenacin provides a viable treatment option for patients with COPD and may be a suitable alternative for those with conditions that may impair proper use of traditional handheld inhalers.

Topics: Administration, Inhalation; Benzamides; Bronchodilator Agents; Carbamates; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States. Due to the substantial public health burden of COPD, there has been a lot of interest in developing new drug therapies, directed at improving the symptomatology and quality of life in COPD patients. Revefenacin is the first once daily nebulized long acting muscarinic antagonist for COPD treatment. It offers an advantage over other nebulized bronchodilators, as once daily administration may improve patient compliance. Revefenacin has a rapid onset of action, is long acting and significantly improves lung function (FEV1) in patients with COPD. It can play a major role in the management of COPD, especially in patients who have difficulty mastering inhaler techniques and those with low baseline FEV1 who may have difficulty generating flow with an inhaler. This manuscript is a review on revefenacin and outlines the pharmacologic profile and the clinical trials which have evaluated it's the efficacy and safety. The authors also discuss their own perspective on the potential role of revefenacin in COPD management.

Topics: Benzamides; Carbamates; Drug Administration Schedule; Forced Expiratory Volume; Humans; Medication Adherence; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Topics: Administration, Inhalation; Benzamides; Carbamates; Clinical Trials as Topic; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

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.

Topics: Administration, Inhalation; Adult; Aged; Benzamides; Bronchodilator Agents; Carbamates; Drug Approval; Humans; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; United States; United States Food and Drug Administration

Acetylcholine is the predominant parasympathetic neurotransmitter in the airways, and plays a key role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Muscarinic receptors are found in smooth muscle cells and submucosal glands. Binding of acetylcholine to muscarinic receptors could trigger bronchoconstriction. Muscarinic antagonists prevent acetylcholine from binding to its receptors and produce bronchodilation. Revefenacin is the first once-daily dosed nebulized long-acting muscarinic antagonist indicated for the maintenance treatment of patients with COPD. Areas covered: In this paper, the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy and safety of Revefenacin was introduced, and the evolution of muscarinic antagonists is also briefly described. Expert commentary: Revefenacin is a new M

Topics: Acetylcholine; Animals; Benzamides; Bronchodilator Agents; Carbamates; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life

Topics: Administration, Inhalation; Benzamides; Bronchodilator Agents; Carbamates; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

Replicate, 12-week, phase 3 trials (0126 and 0127) of once-daily nebulized revefenacin 175 μg vs placebo demonstrated significant bronchodilation and improvements in health status in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). This post hoc analysis evaluated improvement in patient-reported outcomes (PROs), including the St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Clinical COPD Questionnaire (CCQ) in both women and men.. Participants were pooled from the two 12-week studies (411 [51%] women and 401 [49%] men). Changes in PROs were assessed overall and separately in men and women.. Revefenacin improved SGRQ and CAT total scores from baseline in both studies; improvement in CCQ total score reached significance only in 0126. In pooled data, a greater proportion of patients achieved clinically meaningful response in SGRQ score (≥4-unit decrease from baseline) with revefenacin vs placebo (odds ratio, 1.5; 95% confidence interval, 1.1-2.1; P = 0.012). Clinically meaningful responses were also seen in CAT (≥2-unit decrease from baseline) and CCQ (≥0.4-unit decrease from baseline) scores with revefenacin vs placebo. When stratified by sex, improvements from baseline in SGRQ, CAT, and CCQ scores following revefenacin vs placebo reached statistical significance only in women.. Maintenance treatment with revefenacin improved health status in patients with moderate to very severe COPD; however, the effect was more pronounced for women than men.. GOV: NCT02459080; NCT02512510.

Topics: Benzamides; Bronchodilator Agents; Female; Forced Expiratory Volume; Health Status; Humans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive

Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV. Revefenacin demonstrated significant improvements in FEV. Revefenacin showed significantly greater improvements in FEV. Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Time Factors

Revefenacin is a long-acting muscarinic antagonist that was recently approved for the nebulized treatment of chronic obstructive pulmonary disease (COPD). Although shorter duration studies have documented the efficacy of revefenacin in COPD, longer-term efficacy has not been described. In a recent 52-week safety trial, revefenacin was well tolerated and had a favorable benefit-risk profile. Here we report exploratory efficacy and health outcomes in patients receiving revefenacin 175 μg or 88 μg daily during the 52-week trial.. In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 175 μg or 88 μg in a double-blind manner, or open-label active control tiotropium.. Over the 52-week treatment period, both doses of revefenacin, as well as tiotropium, elicited significant (all p < 0.0003) improvements from baseline in trough forced expiratory volume in 1 s (FEV. Significant sustained improvements from baseline in trough FEV. NCT02518139 ; Registered 5 August 2015.

Topics: Aged; Benzamides; Bronchodilator Agents; Carbamates; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzamides; Bronchodilator Agents; Carbamates; Case-Control Studies; Cholinergic Antagonists; Disease Progression; Drug Therapy, Combination; Drug Tolerance; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Safety; Severity of Illness Index; Tiotropium Bromide; Vital Capacity

The cardiovascular safety of revefenacin, an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive lung disease (COPD), was evaluated in phase 3 trials in patients with moderate to very severe COPD. No clinically meaningful changes in 12-lead electrocardiogram recordings were observed with up to 52 weeks of once-daily revefenacin 88 or 175 μg. In a pooled analysis of Studies 0126 and 0127, the incidence of prolonged QT interval corrected for heart rate using the Fridericia correction formula (QTcF; >450 msec) for revefenacin 88 μg (n = 23, 5.6%) and revefenacin 175 μg (n = 23, 5.9%) was similar to that for placebo (n = 22, 5.3%). In Study 0128, the incidence of prolonged QTcF was similar in the revefenacin 175 μg (n = 25, 7.7%) and tiotropium (n = 26, 7.3%) groups and lower in the revefenacin 88 μg (n = 15, 4.2%) group. There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 μg, and revefenacin 175 μg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 μg, revefenacin 175 μg and tiotropium groups, respectively). In Study 0128, only one MACE was considered possibly/probably related to revefenacin (atrial fibrillation in the revefenacin 175 μg group). Thus, revefenacin may provide beneficial nebulized therapy for patients with COPD without further elevating their risk of cardiovascular events.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Tiotropium Bromide

Revefenacin (TD-4208) is a potent, lung-selective, long-acting muscarinic antagonist currently in development as a once-daily nebulized therapy for chronic obstructive pulmonary disease (COPD). We evaluated the pharmacodynamics (bronchodilator activity), pharmacokinetics (PK) and safety of single- and multiple-dose administrations of revefenacin in two clinical trials (Study 0059 and Study 0091) in patients with moderate to severe COPD.. In Study 0059, 32 patients were randomized to receive a single dose of revefenacin (350 or 700 μg), active control ipratropium (500 μg) or placebo inhalation solution administered via standard jet nebulizer in a double-blind, crossover fashion. In Study 0091, 59 patients were randomized to receive once-daily inhalations of revefenacin (22, 44, 88, 175, 350 or 700 μg) or placebo for 7 days in a double-blind, incomplete block, five-way crossover design. The primary efficacy endpoint was change from baseline in peak (0-6 h) forced expiratory volume in 1 s (FEV. Revefenacin demonstrated a rapid onset and sustained duration of bronchodilator action in both studies. In Study 0059, mean peak FEV. Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure.

Topics: Administration, Inhalation; Aged; Benzamides; Bronchodilator Agents; Carbamates; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Spirometry; Time Factors

Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration-time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies.. Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22-700 μg in 935 patients (488 men, 447 women; age 41-88 years) were analyzed using nonlinear mixed-effects modeling.. Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration-time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518.. None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease.. ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510.

Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

Topics: Benzamides; Bronchodilator Agents; Carbamates; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

In chronic obstructive pulmonary disease (COPD), inhaled long-acting antimuscarinic agents (LAMA) are effective maintenance therapies used across all severity stages of the disease. Most of them are administered via dry powder inhalers, but these devices require a potent inspiratory flow which cannot be effectively achieved by patients with advanced disease. In such patients, inhaled therapy via nebulization might be an option.. Revefenacin is a LAMA that was specifically formulated for once daily nebulization and which was authorized by the FDA as a maintenance therapy for COPD. In phase II and III clinical studies discussed in this review, revefenacin demonstrated its rapid onset of action and sustained effect on lung function on both a short- and long-term basis.. Nebulized revefenacin with once daily use does not require any particular effort of administration and hence can be used by patients with severe airways obstruction or by those having milder cognitive deficits. Further studies are needed, however, to better document the long-term cardiovascular safety and its ability to reduce the exacerbation rate.

Topics: Benzamides; Carbamates; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive