Phase I Studies of Acebilustat: Biomarker Response and Safety in Patients with Cystic Fibrosis

Abstract

There is a significant unmet need for safe and effective anti-inflammatory treatment for cystic fibrosis. The aim of this study was to evaluate the safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis. Seventeen patients with mild to moderate cystic fibrosis were enrolled and randomized into groups receiving placebo or doses of 50 mg or 100 mg acebilustat administered orally, once daily for 15 days. Sputum neutrophil counts were reduced by 65% over baseline values in patients treated with 100 mg acebilustat. A modestly significant 58% reduction vs. placebo in sputum elastase was observed with acebilustat treatment. Favorable trends were observed for reduction of serum C-reactive protein and sputum neutrophil DNA in acebilustat-treated patients. No changes in pulmonary function were observed. Acebilustat was safe and well tolerated. The results of this study support further clinical development of acebilustat for treatment of cystic fibrosis.

Figure 1

Study timeline and biomarker data collection points. Black shaded areas with white text indicate biomarker test points used for analysis in relation to treatment period. BSL, baseline; SS, steady state; EOT, end of treatment; INT, interim.

Figure 2

Sputum white blood cell (WBC) and neutrophils counts at end of treatment. Sputum WBC (top) and neutrophil (bottom) counts taken at end of treatment (study day 16). Results are expressed as percentage of baseline value (bsln; mean ± SD) for each individual patient (shown as markers in the graphs). Analysis was performed in two ways: combined acebilustat‐treated group (50 mg and 100 mg) vs. placebo (left), and as separate dose groups placebo, 50 mg and 100 mg acebilustat (right).

Figure 3

Sputum DNA and elastase at end of treatment. Sputum DNA (top) and elastase (bottom) measures taken at end of treatment (study day 16). Results are expressed as percentage of baseline value (mean ± SD) for each individual patient (shown as markers in the graphs). Analysis was performed in two ways: combined acebilustat‐treated group (50 mg and 100 mg) vs. placebo (left), and as separate dose groups placebo, 50 mg and 100 mg acebilustat (right).

Figure 4

Longitudinal measures of bacterial colony‐forming unit (CFU) (left) and number of bacterial genera (right) for individual patients (represented by different markers in the graphs) receiving placebo (top), 50 mg acebilustat (middle) and 100 mg acebilustat (bottom).

Figure 5

Sputum bacterial colony‐forming unit (CFU) at end of treatment. Sputum bacterial CFU counts taken at end of treatment (study day 16). Results are expressed as percentage of baseline value (mean ± SD) for each individual patient (shown as markers in the graphs). Analysis was performed in two ways: combined acebilustat‐treated group (50 mg and 100 mg) vs. placebo (left), and as separate dose groups placebo, 50 mg and 100 mg acebilustat (right).

Figure 6

Lung function assessments at end of treatment. Percent predicted forced expiratory volume (FEV)1 (top) and lung clearance index (bottom) values taken at end of treatment (study days 15 and 14, respectively). Results are expressed as percentage of baseline value (mean ± SD) for each individual patient (shown as markers in the graphs). Analysis was performed in two ways: combined acebilustat‐treated group (50 mg and 100 mg) vs. placebo (left), and as separate dose groups placebo, 50 mg and 100 mg acebilustat (right).