Abstract
Background: Urotensin II (U-II) is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma.Methods: Safety, tolerability, and pharmacokinetics (PK) of single doses of GSK1440115 (1–750 mg) were assessed in a Phase I, placebo controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a two-period, single-blind crossover study and treated with single doses of 750 mg GSK1440115 or placebo and given a methacholine challenge.Results: Administration of GSK1440115 was safe and well-tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50 mg dose. In the presence of food at the 750 mg dose, the time to maximal concentration was between 2 and 6 h and the terminal half-life was short at approximately 2 h. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for ≥3 h (between 4 and 7 h post-dose). There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics.Conclusion: While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population.
Highlights
Asthma is characterized by blockage, narrowing, or constriction of airways resulting in breathing difficulties with symptoms such as coughing, wheezing, shortness of breath, or rapid breathing, and chest tightness
urotensin II (U-II) receptor expression has been localized to rat airway smooth muscle cells where it functions as a growth factor (Chen et al, 2004; Zhang et al, 2012)
A total of 12 subjects with asthma were randomized and treated in the Phase Ib study with similar demographics in both treatment groups (750 mg GSK1440115 or placebo; Table 1)
Summary
Asthma is characterized by blockage, narrowing, or constriction of airways resulting in breathing difficulties with symptoms such as coughing, wheezing, shortness of breath, or rapid breathing, and chest tightness. It is a chronic disease affecting over 20 million Americans and is either allergic (non-intrinsic triggered by inhaled allergens) or non-allergic (triggered by intrinsic factors). There has been increasing evidence for U-II’s role in regulating respiratory physiology It is highly expressed in the lung (Zhang et al, 2002; Qi et al, 2004), which is a major source of U-II in humans (Russell et al, 2003). Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma
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