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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®)., Methods: This was a randomized, double-blind, double-dummy, 28-day Phase 3b study in patients with COPD enrolled based on sPIFR. The primary endpoint was trough forced expiratory volume in 1 second (FEV 1 ) on Day 29 for revefenacin for nebulization versus tiotropium HandiHaler® DPI., Results: We enrolled 206 patients with mean (standard deviation) age, 65 (8) years; percent predicted FEV 1 , 37 (16)%; PIFR, 45 (12) L/min. In the intent-to-treat (ITT) population, revefenacin improved trough FEV 1 from baseline; however, the difference versus tiotropium was not significant (least squares [LS] mean difference [standard error], 17.0 [22.4] mL, P=0.4461). In a prespecified analysis of patients with FEV 1 < 50% predicted, revefenacin produced an LS mean difference (95% confidence interval [CI]), 49.1 (6.3-91.9) mL in trough FEV 1 and 103.5 (7.7-199.3) mL in forced vital capacity versus tiotropium. Revefenacin produced >100 mL increase in FEV 1 in 41.6% versus 34.4% of patients with tiotropium in ITT and 41.4% versus 25.7% of patients in FEV 1 < 50% predicted populations., Conclusions: Revefenacin did not produce significant improvements in FEV1 versus tiotropium in the ITT population, but increased trough FEV 1 in patients with FEV 1 < 50% predicted and sPIFR. Clinical Trial Registration (www.Clinicaltrials.gov): Study 0149 (NCT03095456)., Competing Interests: DAM has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc, Grifols SA, Sunovion Pharmaceuticals Inc., Theravance Biopharma, Inc., and Trevi and is on the speaker’s bureau for AstraZeneca, Boehringer Ingelheim, and Sunovion Pharmaceuticals Inc. JAO has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc, Mylan Inc, Reckitt Benckiser Group plc, Sunovion Pharmaceuticals Inc., and Theravance Biopharma, Inc. EJM and GDC are employees of Theravance Biopharma US, Inc. CNB and SP were employees of Theravance Biopharma US, Inc. at the time this study was conducted., (JCOPDF © 2019.)

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. The primary endpoint was 24-hour trough forced expiratory volume in 1 second (FEV 1 ) on day 85. Secondary efficacy endpoints included overall treatment effect (OTE) on trough FEV 1 and peak FEV 1 (0-2 hours after first dose). Safety assessments included treatment-emergent adverse events., Results: At day 85, revefenacin 88 µg and 175 µg improved trough FEV 1 versus placebo in Study 0126 (by 79 mL [ p =0.0003] and 146 mL [ p <0.0001]) and Study 0127 (by 160 mL and 147 mL; both p <0.0001). Compared with placebo, pooled data of revefenacin 88 µg and 175 µg increased OTE trough FEV 1 by 115 mL and 142 mL (both p <0.001) and increased peak FEV 1 by 127 mL and 129 mL (both p <0.0001). Revefenacin 175 µg demonstrated greater improvements in FEV 1 in concomitant long-acting beta2-agonist patients and in more severe patients than revefenacin 88 µg. Adverse events were minor., Conclusion: Revefenacin, administered once daily for 12 weeks to patients with moderate to very severe COPD, demonstrated clinically significant improvements in trough FEV 1 and OTE FEV 1 . Revefenacin was generally well tolerated with no major safety concerns., Competing Interests: GTF has received grants, served on advisory boards, received consulting fees and/or received speaking fees from AstraZeneca, Boehringer Ingelheim, Circassia, Forest, GlaxoSmithKline, Innoviva, Meda, Mylan, Novartis, Pearl Therapeutics, Sanofi, Sunovion, Theravance Biopharma and Verona. GF and KKP have nothing to declare. CNB, EJM, BH, SP and GC are employees of Theravance Biopharma US, Inc. Mylan Inc., (Canonsburg, Pennsylvania) and Theravance Biopharma US, Inc., (South San Francisco, California) funded medical writing support., (JCOPDF © 2019.)