J Stuart Elborn1, Michael W Konstan2, Jennifer L Taylor-Cousar3, Isabelle Fajac4, Alexander Horsley5, Sivagurunathan Sutharsan6, Shawn D Aaron7, Cori L Daines8, Ahmet Uluer9, Damian G Downey10, Vincenzina V Lucidi11, Sanjeev Ahuja12, Eric Springman12, John Mershon12, Ralph Grosswald12, Steven M Rowe13. 1. Faculty of Medicine Health and Life sciences Queens University School of Medicine, Belfast, UK. 2. Department of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies & Children's Hospital, Cleveland, OH, USA. 3. Departments of Medicine and Pediatrics, National Jewish Health, Denver, CO, USA. 4. Physiology Department, Cochin Hospital, APHP Centre, Paris, France; Université de Paris, Paris, France. 5. Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. 6. Division of Cystic Fibrosis, Department of Pulmonary Medicine, University Medicine EssenRuhrlandklinik, University of DuisburgEssen, Essen, Germany. 7. Ottawa Health Research Institute, Ottawa, Ontario, Canada. 8. Department of Pediatrics, University of Arizona, Tucson, AZ, USA. 9. Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 10. Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK. 11. Cystic Fibrosis Center, Children's Hospital and Research Institute, Bambino Gesu, Rome, Italy. 12. Celtaxsys, Inc., Atlanta, GA, USA. 13. Gregory Fleming James Cystic Fibrosis Research Center and Department of Medicine, University of Alabama at Birmingham, 1918 University Blvd, MCLM 804, Birmingham 35294, AL, USA. Electronic address: smrowe@uab.edu.
Abstract
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. Crown
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. Crown
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