Trials in Progress: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Trials of a Nebulized Long-Acting Muscarinic Antagonist (Revefenacin) in Study Participants With Moderate to Very Severe COPD

Abstract

SESSION TITLE: Airways 1 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM PURPOSE: Revefenacin (pINN), a novel nebulized long-acting muscarinic antagonist (LAMA) in development for chronic obstructive pulmonary disease (COPD), produces sustained bronchodilation with minimal systemic anticholinergic effects. A 28-day phase 2b study in participants with COPD demonstrated that doses of 88 and 175 µg, administered once daily, produced clinically relevant changes compared with placebo across a range of endpoints. To establish efficacy and safety for this dose range, 2 identical 12-week phase 3 efficacy trials in participants with COPD are in progress; the trial methodology and select characteristics of the participants enrolled to-date are presented here. METHODS: In these double-blind, parallel-group replicate studies (study 1, NCT02459080; study 2, NCT02512510), participants with moderate-to-very severe COPD are randomized (1:1:1) to 3 treatment groups (revefenacin 88 µg or 175 µg or matched placebo, administered once daily via a standard jet nebulizer) for 12 weeks. The primary endpoint is 24-hour trough forced expiratory volume in 1 second (FEV1) on day 85. Secondary endpoints include use of rescue medication, health outcomes, safety, and pharmacokinetic assessments. Up to 40% of participants are allowed to receive concomitant inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) combination therapy, resulting in the following comparisons: revefenacin vs placebo and ICS/LABA/revefenacin vs ICS/LABA/placebo. RESULTS: As of March 18, 2016, 889 of 1236 participants (mean age, 64 years; 51% male; 48% current smokers) have been enrolled in these replicate studies; these participants have moderate-to-very severe COPD (post-ipratropium % predicted FEV1 median [range]: 55.6 [19.2-79.9]% and baseline FEV1 median [range]: 1.27 [0.44-3.24] L), with 33% of participants classified as GOLD category D. Approximately 38% of participants are receiving concomitant therapy with ICS/LABA (90% bid ICS/LABA and 10% qd ICS/LABA). Diabetes, pulmonary hypertension, ischemic heart disease, and gastroesophageal reflux disease are key comorbidities in this patient population. CONCLUSIONS: These 2 replicate phase 3 trials in participants with moderate-to-very severe COPD are expected to provide pivotal efficacy and safety data for nebulized once-daily revefenacin as monotherapy, and in conjunction with ICS/LABA therapy, over a dosing period of 12 weeks. CLINICAL IMPLICATIONS: Revefenacin, a novel nebulized LAMA, is in development as a once-daily maintenance treatment for COPD. Assuming positive results and a favorable regulatory review, revefenacin may become the first once-daily nebulized bronchodilator for the maintenance treatment of COPD. DISCLOSURE: Srikanth Pendyala: Employee: Dr. Pendyala is an employee of Theravance Biopharma US, Inc. Chris Barnes: Employee: Dr. Barnes is an employee of Theravance Biopharma US, Inc. Edmund Moran: Employee: Dr. Moran is an employee of Theravance Biopharma US, Inc. Brett Haumann: Employee: Dr. Haumann is an employee of Theravance Biopharma UK, Ltd Edward Kerwin: Consultant fee, speaker bureau, advisory committee, etc.: Consultant and medical advisor for Theravance Biopharma, Consultant fee, speaker bureau, advisory committee, etc.: Medical advisor for Mylan, Consultant fee, speaker bureau, advisory committee, etc.: Consultant and medical advisor for Amphastar, Consultant fee, speaker bureau, advisory committee, etc.: Consultant and medical advisor for AstraZeneca, Consultant fee, speaker bureau, advisory committee, etc.: Speakers bureau for Boehringer-Ingelheim, Consultant fee, speaker bureau, advisory committee, etc.: Speakers bureau for Forest, Consultant fee, speaker bureau, advisory committee, etc.: Consultant and medical advisor for Novartis, Consultant fee, speaker bureau, advisory committee, etc.: Consultant for Pearl, Consultant fee, speaker bureau, advisory committee, etc.: Medical advisor for Sunovion, Other: Received travel reimbursement from Teva The following authors have nothing to disclose: Krishna Pudi The presentation will discuss clinical trials for revefenacin, a new drug entity currently under investigation for the treatment of patients with chronic obstructive pulmonary disease (COPD).