SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans

Abstract

What is already known about this subject: Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans.

What this study adds: SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects.

Aims: To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects.

Methods: Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers.

Results: Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses.

Conclusions: SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.

Figure 1

Study design for the single dose human healthy volunteer ozone challenge

Figure 2

SB-656933 concentration–time profiles after administration of single doses in human healthy volunteers. 933 2 mg (▾); 933 10 mg (-------); 933 50 mg (♦); 933 150 mg (•); 933 400 mg (▪); 933 800 mg (▴); 933 1100 mg (◂)

Figure 3

Individual dose-normalized C_max and AUC(0,∞) vs. dose following administration of single doses of SB-656933

Figure 4

Peak CD11b expression (measured as mean fluorescence signal, MSF 0–9 h) relative to placebo adjusted for unstimulated control (±95% CI), on peripheral blood neutrophils following stimulation of whole blood with 30 nm CXCL1

Figure 5

The period adjusted geometric mean for the change in CD11b expression (MSF) relative to control (30 nm–0 nm CXCL1) on peripheral blood neutrophils over time by treatment. Plocebo (▾); 933 2 mg (-------); 933 10 mg (♦); 933 50 mg (•); 933 150 mg (▪); 933 400 mg (▴); 933 800 mg (◂); 933 1100 mg (+)

Figure 6

Time course of population predicted CXCl-1 induced CD11b inhibition, expressed as % baseline, for 30 nm concentration of CXCL1, simulated for proposed doses 50 mg (-------) and 150 mg (—) SB-656933 in the single dose ozone challenge study, overlaid with the target pharmacological range obtained from pre-clinical acute lung inflammation models

Figure 7

The adjusted geometric mean (±95% CI) for leucocyte counts in sputum following ozone challenge. Plocobo (♦); 933 50 mg (+); 933 150 mg (◂)

Figure 8

The adjusted geometric mean (±95% CI) for myeloperoxidase (MPO) in sputum supernatant following ozone challenge

Figure 9

Median (IQR) peripheral blood neutrophil counts over time in the FTIH study over the dose range 2–1100 mg of SB-656933. IQR: interquartile range. Plocebo (▾); 933 2 mg (-------); 933 10 mg (♦); 933 50 mg (•); 933 150 mg (▪); 933 400 mg (▴); 933 800 mg (◂); 933 1100 mg (+)