Empire-CF study: A phase 2 clinical trial of leukotriene A4 hydrolase inhibitor acebilustat in adult subjects with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterized by neutrophilic inflammation in the airways. Leukotriene B4 (LTB4) is a neutrophil chemoattractant and has been implicated in CF pathogenesis. Acebilustat, a novel, synthetic, small-molecule leukotriene A4 hydrolase inhibitor, reduces LTB4 production. We report findings from a randomized placebo-controlled trial of acebilustat in adult subjects with mild-to-moderate lung disease. METHODS: Subjects were randomized (1:1:1) to once-daily acebilustat 50 mg, 100 mg or placebo for 48 weeks, concomitantly with their current therapeutic regimen. Subjects were stratified by use of concomitant CF transmembrane conductance regulator (CFTR) modulators, baseline percent predicted forced expiratory volume in 1 second (ppFEV1) 50-75 and >75, and number of pulmonary exacerbations in the past year (1 or >1). Primary endpoints were the change from baseline in ppFEV1 and safety. Secondary endpoints included the rate of pulmonary exacerbations. RESULTS: Overall, 199 subjects were randomized and dosed (acebilustat 50 mg, n=67; acebilustat 100 mg, n=66; placebo, n=66). Baseline demographics and disease profile were well balanced among treatment groups. Acebilustat had no statistically significant effect on the primary endpoint of change in ppFEV1 at week 48 or the secondary endpoint pulmonary exacerbations. There was a trend towards reduced pulmonary exacerbations in subjects receiving acebilustat in pre-specified populations with ppFEV1>75 (35% rate reduction) and those on concomitant CFTR modulator therapy (20% rate reduction). Acebilustat was well tolerated. CONCLUSIONS: Acebilustat did not improve lung function. A trend towards reduced pulmonary exacerbations in subjects with an earlier stage of lung disease suggests a potential effect in this population.

EMPIRE-CF: A phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis - Study design and patient demographics.

Inflammation causes irreparable damage in the cystic fibrosis (CF) lung. Despite high standards of care and the advent of new therapies, inflammation continues to cause significant loss of lung function and morbidity. Acebilustat is a once-daily, oral molecule with anti-inflammatory activity through the inhibition of LTA4 hydrolase and modulation of LTB4. It has potential to reduce lung function decline and pulmonary exacerbations in patients with CF and is currently being tested in a Phase II multicenter, randomized, double-blind, placebo-controlled, parallel-group study (EMPIRE-CF). Strict inclusion criteria based on modeling of the Cystic Fibrosis Foundation Patient Registry data were selected to enrich the trial with patients most likely to benefit from chronic anti-inflammatory therapy that reduces lung function decline. 200 patients between 18 and 30 years of age, with an FEV1 percent predicted (pp) ≥50%, and ≥1 exacerbation in the past year have been enrolled. Patients are randomized 1:1:1 to placebo, acebilustat 50 mg or 100 mg for 48 weeks, taken concomitantly with their current standard of care, and stratified based on concomitant CFTR modulator use, baseline FEV1pp (50% to 75% and >75%), and number of exacerbations in the past year (1 or >1). The primary endpoints are absolute change from baseline in FEV1pp and safety outcomes. Secondary endpoints include rate of pulmonary exacerbations and time to first pulmonary exacerbation. Biomarkers of inflammation will also be assessed. EMPIRE-CF is expected to identify the optimal patient population, dose, duration and endpoints for future acebilustat trials, and widen understanding of the drug's efficacy in patients with CF.