Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD

Abstract

Background: Batefenterol is a novel bifunctional muscarinic antagonist β2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development.

Patients and methods: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0-6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose-response modeling, respectively, on day 42.

Results: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed.

Conclusion: Batefenterol 300 µg may represent the optimal dose for Phase III studies.

Keywords: bifunctional; bronchodilator; dose-response; dual-pharmacophore; muscarinic antagonist β2-agonist.

Conflict of interest statement

Disclosure The authors declare the following real/perceived conflicts of interest: C Crim, MLW, C Crawford, CB, and RC-S are GSK employees and hold shares in GSK; SH holds shares in GSK; EDB has received fees from Novartis, Cipla, Sanofi Regeneron, AstraZeneca, ALK, and Boehringer Ingelheim for advisory board membership, fees from Novartis for participation in speakers’ bureau, fees from Vectura and Actelion for consultancy work, fees from Cipla, Menarini, ALK, AstraZeneca, and Boehringer Ingelheim for lectures, and fees from ICON for participation on a study oversight steering committee, and his institution has received funding from Boehringer Ingelheim, Merck, Takeda, GSK, Hoffman le Roche, Actelion, Chiesi, Sanofi-Aventis, Cephalon, TEVA, Novartis, and AstraZeneca for participation in clinical trials. EMK has participated in advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca (Pearl), Forest, Novartis, Sunovion, Teva, and Theravance, has participated in medical advisory boards for Mylan and Oriel, and has performed consulting for Oriel and GSK. GJF’s institution has received funding from GSK for participation in clinical trials; KP and IS report no conflicts of interest in this work.

Figures

Figure 1

Schematic representation of the study. Abbreviations: UMEC/VI, umeclidium/vilanterol; V, visit.

Figure 2

CONSORT diagram. Note: Protocol-defined stopping criteria reached: all six patients who met criteria withdrew because of an ECG abnormality. Abbreviations: ECG, electrocardiogram; UMEC/VI, umeclidium/vilanterol.

Figure 3

Bayesian Emax model of the change from baseline in the WM FEV1 over 0–6 hours post-dose on day 42 (primary endpoint, ITT population). Abbreviations: ITT, intent-to-treat; UMEC/VI, umeclidinium/vilanterol; WM, weighted mean.

Figure 4

Posterior distribution plots for pairwise differences in the change from baseline in the WM FEV1 over 0–6 hours post-dose on day 42 (A) vs placebo and (B) vs UMEC/VI (ITT population). Notes: The vertical black lines represent 0, 50, 75, and 130 mL. (A) These plots show Bayesian probability distributions for comparisons between batefenterol treatment and placebo. The Bayesian probability for a treatment difference over 130 mL is almost 100% for the 150, 300, and 600 µg doses, because the probability density is to the right of the 130 mL line. (B) These probability plots show Bayesian probability distributions for comparisons between batefenterol and UMEC/VI. For example, in the fourth plot, the Bayesian probability for batefenterol 300 µg versus UMEC/VI is roughly centered around 0, so the probability of obtaining a treatment difference >0 mL is about 50%, indicating that the two treatments have comparable effects. Abbreviations: ITT, intent-to-treat; UMEC/VI, umeclidium/vilanterol; WM, weighted mean.

Figure 5

MMRM analysis of the change from baseline in the WM FEV1 over 0–6 hours post-dose on day 42 (ITT population). Abbreviations: BAT, batefenterol; ITT, intent-to-treat; MMRM, mixed models repeated measures; UMEC/VI, umeclidium/vilanterol; WM, weighted mean.