Revefenacin Area Under the Curve Spirometry in Patients with Moderate to Very Severe COPD.

Purpose: Several lung function endpoints are utilized in clinical trials of inhaled bronchodilators for chronic obstructive pulmonary disease (COPD). Trough forced expiratory volume in 1 second (FEV) is a commonly reported endpoint in COPD trials and can be complemented by area under the FEV vs time curve (FEV AUC), which provides information on duration and consistency of bronchodilation over a dosing interval. Revefenacin, a once-daily bronchodilator, significantly improved lung function in patients with COPD when measured by trough FEV in two replicate Phase 3 trials.

Clinical Burden of Chronic Obstructive Pulmonary Disease in Patients with Suboptimal Peak Inspiratory Flow.

Introduction: Many patients with chronic obstructive pulmonary disease (COPD) may derive inadequate benefit from dry powder inhalers (DPIs) because of suboptimal peak inspiratory flow (sPIF).

Objectives: To assess the clinical burden of COPD by characterizing the clinical characteristics of participants with sPIF against medium-low resistance DPIs versus those with optimal PIF (oPIF) from two phase 3 clinical trials.

Methods: Baseline data were collected from two randomized, controlled, phase 3 trials (NCT03095456; NCT02518139) in participants with moderate-to-severe COPD.

Efficacy and safety of an inhaled pan-Janus kinase inhibitor, nezulcitinib, in hospitalised patients with COVID-19: results from a phase 2 clinical trial.

Background: The inhaled lung-selective pan-Janus kinase inhibitor nezulcitinib had favourable safety and potential efficacy signals in part 1 of a phase 2 trial in patients with severe COVID-19, supporting progression to part 2.

Methods: Part 2 was a randomised, double-blind phase 2 study (NCT04402866). Hospitalised patients aged 18-80 years with confirmed symptomatic COVID-19 requiring supplemental oxygen (excluding baseline invasive mechanical ventilation) were randomised 1:1 to nebulised nezulcitinib 3 mg or placebo for up to 7 days with background standard-of-care therapy (including corticosteroids).

A phase 2 multiple ascending dose study of the inhaled pan-JAK inhibitor nezulcitinib (TD-0903) in severe COVID-19.

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

Background: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD.

Methods: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks.

Safety and Efficacy of Revefenacin and Formoterol in Sequence and Combination via a Standard Jet Nebulizer in Patients with Chronic Obstructive Pulmonary Disease: A Phase 3b, Randomized, 42-Day Study.

Although no nebulized, dual mechanism, long-acting bronchodilator is currently marketed, with the approval of once-daily long-acting muscarinic antagonist (LAMA) revefenacinefenacin, it is theoretically possible to deliver a LAMA and long-acting beta2-agonist via standard jet nebulizer. The primary and secondary objectives of our study were to characterize the safety profile of revefenacin administered sequentially before or in combination with formoterol, via standard jet nebulizer in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, 42-day trial (NCT03573817), patients received revenacin 175 µg (n=63) or placebo (n=59), followed by formoterol 20 µg in the morning and formoterol alone in the evening formoterol 21 days via standard jet nebulizer (sequential administration).

Maintained therapeutic effect of revefenacin over 52 weeks in moderate to very severe Chronic Obstructive Pulmonary Disease (COPD).

Background: 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.

Nebulized Versus Dry Powder Long-Acting Muscarinic Antagonist Bronchodilators in Patients With COPD and Suboptimal Peak Inspiratory Flow Rate.

Background: Patients with chronic obstructive pulmonary disease (COPD) and suboptimal peak inspiratory flow rate (sPIFR) may not benefit optimally from dry powder inhalers (DPI) because of inadequate inspiratory flow. Nebulized bronchodilators may provide a better alternative. We compared bronchodilation with the long-acting muscarinic antagonist (LAMA) revefenacin for nebulization versus the DPI LAMA tiotropium, in patients with COPD and sPIFR (< 60 L/min against the resistance of Diskus®).

Data on the safety and tolerability of revefenacin, in patients with moderate to very severe chronic obstructive pulmonary disease.

This article contains information on the experimental design and methods on how the safety and tolerability data concerning patients with moderate to very severe chronic obstructive pulmonary disease (COPD) were obtained. This is in addition to our original research article. [1] We have also provided information on the clinical laboratory tests that were conducted.

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.

Background: 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.

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.

Background: Revefenacin, a novel, lung-selective, long-acting muscarinic antagonist, has been developed for nebulized therapy for chronic obstructive pulmonary disease (COPD). We present the results of replicate Phase III efficacy and safety studies of revefenacin in patients with moderate to very severe COPD.

Methods: In 2 double-blind, parallel-group studies, (Study 0126 and Study 0127), patients ≥ 40 years old were randomized to revefenacin 88 μg, revefenacin 175 μg or placebo administered once daily by standard jet nebulizer for 12 weeks.

A 28-day, randomized, double-blind, placebo-controlled, parallel group study of nebulized revefenacin in patients with chronic obstructive pulmonary disease.

Background: Revefenacin is a once-daily long-acting muscarinic antagonist (LAMA) in clinical development for the treatment of patients with chronic obstructive pulmonary disease (COPD). In a dose-ranging study, nebulized once-daily revefenacin had a long duration of action in patients after 7 days' administration of doses up to 700 μg. In this multiple-dose study, the bronchodilation efficacy and adverse events profile were characterized in patients administered nebulized revefenacin once daily for 28 days.

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.

Background: 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.

Methods: 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.

Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.

A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs.

Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.

A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination.

A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD.

A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer.

Exploring the positional attachment of glycopeptide/beta-lactam heterodimers.

Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams.

A multivalent approach to drug discovery for novel antibiotics.

The design, synthesis and antibacterial activity of novel glycopeptide/beta-lactam heterodimers is reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, A and B respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams.