CARDIOVASCULAR SAFETY OF REVEFENACIN FOR NEBULIZATION: A REVIEW OF RANDOMIZED CONTROLLED TRIAL DATA

Abstract

SESSION TITLE: Obstructive Lung Diseases 2 SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM PURPOSE: Revefenacin, a once-daily, lung-selective, long-acting muscarinic receptor antagonist in clinical development for the nebulized treatment of chronic obstructive pulmonary disease (COPD), produces sustained bronchodilation with limited systemic adverse events (AEs). As cardiovascular (CV) disease is highly prevalent in COPD patients, we evaluated CV safety data from 3 randomized trials of revefenacin, and a thorough QT study in healthy subjects. METHODS: CV safety data were assessed in a phase 1, placebo- and positive-controlled thorough QT study in healthy subjects receiving therapeutic (175 μg) and supratherapeutic (700 μg) inhaled single doses of revefenacin (Study 0136, N=48). The potential association between daily nebulized revefenacin 88 μg and 175 μg and CV safety was evaluated in patients with moderate to very severe COPD in 2 identical, 12-week, placebo-controlled, phase 3 trials (Study 0126, N=619; Study 0127, N=611), and an active-controlled, 52-week, phase 3 safety trial (Study 0128, N=699). An independent external clinical events committee (CEC) performed blinded review and adjudication of all prespecified major CV AEs (MACE) in studies evaluating COPD patients. RESULTS: Single doses of revefenacin did not have a clinically meaningful effect on cardiac repolarization (QTcF) in healthy subjects. No clinically meaningful changes in 12-lead ECG recordings were observed with up to 52 weeks of daily revefenacin 88 μg and 175 μg in patients with COPD. The incidences of prolonged QTcF interval (>450 msec) were similar in the placebo (4.9% and 5.8%), revefenacin 88 μg (6.3% and 4.9%) and revefenacin 175 μg (5.1% and 6.7%) arms of Studies 0126 and 0127, respectively. In Study 0128, the incidences of prolonged QTcF were similar in the revefenacin 175 μg (7.7%) and tiotropium (7.3%) groups, and slightly lower in the revefenacin 88 μg group (4.2%). No CV-related treatment-emergent AEs were reported with single-dose revefenacin at doses of 175 μg and 700 μg in healthy subjects. After CEC adjudication, there were 4 MACE in Study 0126 (2, 1, and 1 in the revefenacin 88 μg, revefenacin 175 μg, and placebo groups, respectively), zero MACE in Study 0127, and 26 MACE in Study 0128 (9, 10, and 7 in the revefenacin 88 μg, revefenacin 175 μg, and tiotropium groups, respectively). Only 1 of these MACE was considered related to revefenacin (atrial fibrillation in the revefenacin 175 μg group in Study 0128). CONCLUSIONS: Revefenacin for nebulization does not prolong QT interval. No increased risk of MACE was identified in clinical trials up to 52 weeks in duration. CLINICAL IMPLICATIONS: Once-daily revefenacin over periods of up to 1 year is associated with acceptable CV safety and, thus, may provide beneficial nebulized therapy for patients with COPD. DISCLOSURES: No relevant relationships by Chris Barnes, source=Web Response Consultant relationship with Theravance Biopharma Please note: >$100000 Added 03/09/2018 by Marie Borin, source=Web Response, value=Consulting fee Employee relationship with Theravance Biopharma Please note: >$100000 Added 03/08/2018 by David Bourdet, source=Web Response, value=Salary No relevant relationships by Borje Darpo, source=Web Response Advisory Committee Member relationship with Mylan Inc Please note: $1001 - $5000 Added 03/02/2018 by James Donohue, source=Web Response, value=Honoraria Removed 03/02/2018 by James Donohue, source=Web Response Advisory Committee Member relationship with Sunovion Pharmaceuticals Please note: $1001 - $5000 Added 03/02/2018 by James Donohue, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Mylan Inc Please note: $1001 - $5000 Added 03/02/2018 by James Donohue, source=Web Response, value=Consulting fee No relevant relationships by Gregory Feldman, source=Admin input Employee relationship with Theravance Please note: >$100000 Added 03/02/2018 by Srikanth Pendyala, source=Web Response, value=Salary Research funds to institution relationship with Astra Zeneca Please note: $20001 - $100000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Astra Zeneca Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Boerhinger Ingelheim Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Honoraria Advisory Committee Member relationship with Boerhinger Ingelheim Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Glaxo Smith Kline Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Clinical Event adjudication committee relationship with Pulmonx Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Sunovion Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Theravance Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Circassia Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee