Batefenterol (GSK961081)

Population Pharmacokinetics and Pharmacodynamics of GSK961081 (Batefenterol), a Muscarinic Antagonist and β2-Agonist, in Moderate-to-Severe COPD Patients: Substudy of a Randomized Trial

GSK961081 (batefenterol) is a novel bifunctional molecule composed of a muscarinic antagonist and a β2-agonist. The aims of this substudy were (1) to characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of GSK961081 in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD); and (2) to investigate the relationship between systemic exposure to GSK961081 and key cardiac-related safety parameters. Three once-daily doses (100, 400, and 800 μg) and three twice-daily doses (100, 200, and 400 μg) of GSK961081 DISKUS were investigated. A two-compartment disposition PK model with first-order absorption adequately described the plasma GSK961081 concentration-time data. An empirical maximum-effects PD model adequately described the forced expiratory volume in 1 s (FEV1) response relationship with the covariate baseline FEV1 on day 1. No clear relationships between GSK961081 plasma drug levels and cardiac-related safety parameters were apparent. The PK and PD models will be used to guide the dose selection and development of GSK961081 in patients with COPD.

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

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 ?g, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 ?g 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 E_max 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 ?g were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed.
Conclusion: Batefenterol 300 ?g may represent the optimal dose for Phase III studies.

Open-Label, Randomized, 6-Way Crossover, Single-Dose Study to Determine the Pharmacokinetics of Batefenterol (GSK961081) and Fluticasone Furoate When Administered Alone or in Combination

To investigate the pharmacokinetics of inhaled batefenterol (BAT) and fluticasone furoate (FF) given alone or in combination via ELLIPTA? dry powder inhaler (DPI-E), and BAT monotherapy via DISKUS? DPI (DPI-D). In this open-label, 6-way crossover study, 48 healthy subjects were randomized to 1 of 6 treatment sequences, comprising 6 single-dose treatment regimens: (1) BAT 1200 μg via DPI-D; (2) BAT 1200 μg via DPI-E without a lactose-filled second strip; (3) BAT 1200 μg via DPI-E with a lactose-filled second strip; (4) BAT/FF 1200/300 μg via DPI-E; (5) FF 300 μg via DPI-E with a lactose-filled second strip; and (6) BAT/FF 900/300 μg via DPI-E. Pharmacokinetic data were analyzed using noncompartmental methods. Plasma BAT area under the curve (AUC) and maximum plasma concentration (Cmax ) were similar for all treatments containing BAT 1200 μg (geometric least-squares means [GLSM] ratio, 0.90-1.06). Plasma FF AUC and Cmax were reduced following BAT/FF 1200/300 μg and 900/300 μg versus FF 300 μg monotherapy (GLSM ratio, 0.62-0.77). BAT 1200 μg administered via DPI-E, alone or in combination with FF, resulted in similar systemic exposure versus BAT administered by DPI-D. FF exposure was reduced when administered in combination with BAT compared with FF alone.

Discovery of (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl)piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate (TD-5959, GSK961081, batefenterol): first-in-class dual pharmacology multivalent muscarinic antagonist and β? agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD)

Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by 1. Herein we describe the subsequent lead optimization of both muscarinic antagonist and β2 agonist activities, through modification of the linker motif, to achieve 24 h duration of action in a guinea pig bronchoprotection model. Concomitantly we targeted high lung selectivities, low systemic exposures and identified crystalline forms suitable for inhalation devices. This article culminates with the discovery of our first clinical candidate 12f (TD-5959, GSK961081, batefenterol). In a phase 2b trial, batefenterol produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Pharmacokinetics and pharmacodynamics of GSK961081, a novel inhaled muscarinic antagonist β2 -agonist, and fluticasone propionate administered alone, concurrently and as a combination blend formulation in healthy volunteers

Objective: To investigate the pharmacokinetics and pharmacodynamics of inhaled GSK961081 and fluticasone propionate (FP) given alone, concurrently and as a combination blend formulation.
Methods: The study was double-blind, double-dummy, four-way crossover. Twenty-four healthy volunteers took single doses of the following in randomized order: (1) GSK961081 800 ?g; (2) FP 500 ?g; (3) GSK961081 800 ?g and FP 500 ?g as a blend formulation; and (4) GSK961081 800 ?g and FP 500 ?g concurrently via separate inhalers. The eLung breathing simulator was also used for the in vitro characterization of the formulations.
Results: There was no pharmacokinetic interaction when GSK961081 and FP were administered concurrently. Mean Cmax and AUC(0-t) of GSK961081 were lower (?20%) and mean Cmax and AUC(0-t) of FP were higher (two fold) following GSK961081/FP blend formulation compared to concurrent or the individual components alone. There was an increase in the FP in vitro ex-throat dose for the GSK961081/FP blend from the eLung breathing simulator. Serum cortisol suppression was greater with GSK961081/FP blend, with lower (?10%) cortisol levels than after GSK961081 + FP concurrent or FP alone.
Conclusion: GSK961081/FP blend formulation was associated with an increase in FP systemic exposure and greater serum cortisol suppression.