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Acebilustat is a new once-daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (Cmax) or exposure (AUC). In healthy volunteers, a shift in time to Cmax (Tmax) was observed after a high-fat meal, but there was no change in AUC. LTB4 production was reduced in the blood of both populations and in sputum from CF patients. Acebilustat did not induce CYP3A4. These results support continued clinical study of once-daily oral acebilustat in CF at doses of 50 and 100 mg. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis (CF) is characterized by neutrophilic inflammation in the airways. Leukotriene B4 (LTB 4 ) is a neutrophil chemoattractant and has been implicated in CF pathogenesis. Acebilustat, a novel, synthetic, small-molecule leukotriene A4 hydrolase inhibitor, reduces LTB 4 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 (ppFEV 1 ) 50-75 and >75, and number of pulmonary exacerbations in the past year (1 or >1). Primary endpoints were the change from baseline in ppFEV 1 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 ppFEV 1 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 ppFEV 1 >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., Competing Interests: Declaration of Competing Interest Dr. Aaron has nothing to disclose. Dr. Ahuja reports personal fees from Celtaxsys, Inc., during the conduct of the study; In addition, Dr. Ahuja has a patent PCT/US19/034810 pending, and a patent US16/427,571 pending. Dr. Daines has nothing to disclose. Dr. Downey reports and Honoraria from Vertex, Proteostasis and Chiesi. Dr. Elborn reports other from Celtaxsys, during the conduct of the study; grants and other from Corbus, grants from Novartis, grants from polyphor, outside the submitted work. Dr. Fajac reports grants from Celtaxsys, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants and personal fees from Proteostasis Therapeutics, grants and personal fees from Vertex Pharmaceuticals, outside the submitted work. Mr. Grosswald reports personal fees from Celtaxsys, Inc., during the conduct of the study; In addition, Dr. Grosswald has a patent PCT/US19/034810 pending, and a patent US16/427,571 pending. Dr. Horsley reports other from Celtaxys pharmaceuticals, during the conduct of the study; grants from NIHR, grants from CF Trust, grants from CF Foundation, personal fees from Vertex pharmaceuticals, personal fees from Mylan, outside the submitted work. Dr. Konstan reports personal fees from Celtaxsys, during the conduct of the study; grants and personal fees from Vertex Pharmaceuticals, personal fees from Chiesi, personal fees from Ionis Pharmaceuticals, grants and personal fees from Laurent Pharmaceuticals, grants and personal fees from Anthera, personal fees from Merck, personal fees from Paranta Biosciences, personal fees from Santhera, personal fees from pH Pharma, grants and personal fees from Cystic Fibrosis Foundation, grants from National Institutes of Health, grants and personal fees from AzurRx, personal fees from Kala Pharmaceuticals, outside the submitted work. John Mershon has nothing to disclose. Dr. Rowe reports grants from Celtaxsys, during the conduct of the study; grants and personal fees from Novartis, grants and personal fees from Bayer, grants from Translate Bio, non-financial support from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants, personal fees and other from Synedgen/Synspira, grants from Eloxx, grants from Celtaxsys, grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc, personal fees from Renovion, grants and personal fees from Arrowhead, grants and other from Ionis, grants from Astra Zenica, outside the submitted work. Dr. Springman reports personal fees from Celtaxsys, Inc., during the conduct of the study; In addition, Dr. Springman has a patent PCT/US19/034810 pending, and a patent US16/427,571 pending. Dr. Sutharsan reports personal fees personal Proteostasis Therapeutics, personal fees from Novartis Pharma GmbH, personal fees from Vertex Pharmaceuticals Incorporated, personal fees from Teva GmbH, personal fees from Chiesi GmbH, outside the submitted work; . SS has served as an investigator in clinical trials for Galapagos NV, Proteostasis, Celtaxsys, Flatley Discovery Lab, Novartis and Vertex. Dr. Taylor-Cousar reports grants and personal fees from Celtaxys, during the conduct of the study; grants and personal fees from Gilead, grants from N30, grants and personal fees from Vertex, grants and personal fees from Proteostasis, grants from Bayer, personal fees from Novartis, personal fees from Genentech, personal fees from Protalix, personal fees from Santhera, personal fees from 4DMT, personal fees from Polarean Imaging, personal fees from Insmed, personal fees from Abbvie, outside the submitted work; and Service on the CF TDN Clinical Research Executive CommitteeÐervice as the Chair of the ATS Clinical Problems Assembly Program Committee. Dr. Uluer has served in an advisory capacity with Vertex and Eloxx but these relationships are in no way associated with the work submitted in this manuscript, (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

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 FEV 1 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 FEV 1 pp (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 FEV 1 pp 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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Acebilustat is a new once-daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (C max ) or exposure (AUC). In healthy volunteers, a shift in time to C max (T max ) was observed after a high-fat meal, but there was no change in AUC. LTB4 production was reduced in the blood of both populations and in sputum from CF patients. Acebilustat did not induce CYP3A4. These results support continued clinical study of once-daily oral acebilustat in CF at doses of 50 and 100 mg., (© 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: We sought to define the risks facing octogenarians undergoing contemporary percutaneous coronary interventions (PCIs)., Background: The procedural risks of PCI for octogenarians have not been well established., Methods: We compared the clinical characteristics and in-hospital outcomes of 7,472 octogenarians (mean age 83 years) with those of 102,236 younger patients (mean age 62 years) who underwent PCI at 22 National Cardiovascular Network (NCN) hospitals from 1994 through 1997., Results: Octogenarians had more comorbidities, more extensive coronary disease and a two- to fourfold increased risk of complications, including death (3.8% vs. 1.1%), Qwave myocardial infarction (1.9% vs. 1.3%), stroke (0.58% vs. 0.23%), renal failure (3.2% vs. 1.0%) and vascular complications (6.7% vs. 3.3%) (p < 0.001 for all comparisons). Independent predictors of procedural mortality in octogenarians included shock (odds ratio [OR] 5.4, 95% confidence interval [CI] 3.3 to 8.8), acute myocardial infarction (OR 3.2, 95% CI 2.3 to 4.4), left ventricular ejection fraction (LVEF) <35% (OR 2.9, 95% CI 2.1 to 3.9), renal insufficiency (OR 2.8, 95% CI 2.0 to 3.8), first PCI (OR 2.3, 95% CI 1.7 to 3.3), age >85 years (OR 2.1, 95% CI 1.5 to 2.7) and diabetes mellitus (OR 1.5, 95% CI 1.1 to 2.0). For elective procedures, octogenarian mortality varied nearly 10-fold, and was strongly influenced by comorbidities (0.79% mortality with no risk factors vs. 7.2% with renal insufficiency or LVEF <35%). Despite similar case-mix, PCI outcomes in octogenarians improved significantly over the four years of observation (OR of 0.61 for death/myocardial infarction/stroke in 1997 vs. 1994; 95% CI 0.45 to 0.85)., Conclusions: Risks to octogenarians undergoing PCI are two- to fourfold higher than those of younger patients, strongly influenced by comorbidities, and have decreased in the stent era.

Objectives: The purpose of this study was to evaluate characteristics and outcomes of patients age > or =80 undergoing cardiac surgery., Background: Prior single-institution series have found high mortality rates in octogenarians after cardiac surgery. However, the major preoperative risk factors in this age group have not been identified. In addition, the additive risks in the elderly of valve replacement surgery at the time of bypass are unknown., Methods: We report in-hospital morbidity and mortality in 67,764 patients (4,743 octogenarians) undergoing cardiac surgery at 22 centers in the National Cardiovascular Network. We examine the predictors of in-hospital mortality in octogenarians compared with those predictors in younger patients., Results: Octogenarians undergoing cardiac surgery had fewer comorbid illnesses but higher disease severity and surgical urgency than younger patients. Octogenarians had significantly higher in-hospital mortality after cardiac surgery than younger patients: coronary artery bypass grafting (CABG) only (8.1% vs. 3.0%), CABG/aortic valve (10.1% vs. 7.9%), CABG/mitral valve (19.6% vs. 12.2%). In addition, they had twice the incidence of postoperative stroke and renal failure. The preoperative clinical factors predicting CABG mortality in the very elderly were quite similar to those for younger patients with age, emergency surgery and prior CABG being the powerful predictors of outcome in both age categories. Of note, elderly patients without significant comorbidity had in-hospital mortality rates of 4.2% after CABG, 7% after CABG with aortic valve replacement (CABG/AVR), and 18.2% after CABG with mitral valve replacement (CABG/MVR)., Conclusions: Risks for octogenarians undergoing cardiac surgery are less than previously reported, especially for CABG only or CABG/AVR. In selected octogenarians without significant comorbidity, mortality approaches that seen in younger patients.

Background: Increasingly over the past several years, patients have returned after coronary surgery for reoperative procedures, and the experience has become substantial. In this report, we describe immediate- and long-term outcomes after reoperative coronary artery bypass graft surgery., Methods and Results: The source of data was the clinical database at Emory University. The surgical procedure and statistical methods were standard. Data were collected prospectively and entered into a computerized database. Follow-up was by letter, telephone, or hospital records documenting additional events resulting in readmission. In-hospital correlates of survival were determined by logistic regression, and long-term correlates were determined by Cox model analysis. There were 2030 patients with a mean age of 61 and a mean of 7.8 +/- 4.1 years since the first surgery. The mean ejection fraction was close to 50%, and the majority had three-vessel or left main disease. Urgent or emergency surgery was required in 16.6%. The internal mammary was used in 60.1%. Q-wave myocardial infarctions occurred in just over 5%. Neurological events increased from 1.2% at less than age 50 to 4.1% at more than age 70. The hospital mortality increased from 5.7% at less than age 50 to 10% at more than age 70, with an overall rate of 7.0%. Mortality was 5.7% for elective, 10.9% for urgent, and 16.4% for emergency cases. Angina was noted at follow-up in 41.3%. Urgent or emergency surgery, reduced ejection fraction, hypertension, older age, and female sex were univariate and multivariate correlates of in-hospital death. Diabetes was a univariate correlate only. Five- and 10-year survival rates were 76% and 55%, respectively. Five- and 10-year myocardial infarction-free survival rates were 63% and 40%, respectively. By 12 years, few patients were free of cardiac events. The univariate and multivariate correlates of long-term mortality were older age, reduced ejection fraction, hypertension, diseased vessels, presence of diabetes, congestive failure, and emergency surgery, with a strong trend for female sex. The use of the internal mammary artery was not a correlate for long-term mortality., Conclusions: Patients undergoing reoperative procedures have higher mortality initially and at long term than patients undergoing a first procedure. Expected mortality based on covariates may help in the decision of whether to perform reoperative coronary artery bypass graft surgery.

Background: Although patients with diabetes mellitus constitute an important segment of the population undergoing coronary angioplasty, the outcome of these patients has not been well characterized., Methods and Results: Data for 1133 diabetic and 9300 nondiabetic patients undergoing elective angioplasty from 1980 to 1990 were analyzed. Diabetics were older and had more cardiovascular comorbidity. Insulin-requiring (IR) diabetics had diabetes for a longer duration and worse renal and ventricular functions compared with non-IR subjects. Angiographic and clinical successes after angioplasty were high and similar in diabetics and nondiabetics. In-hospital major complications were infrequent (3%), with a trend toward higher death or myocardial infarction in IR diabetics. Five-year survival (89% versus 93%) and freedom from infarction (81% versus 89%) were lower, and bypass surgery and additional angioplasty were required more often in diabetics. In diabetics, only 36% survived free of infarction or additional revascularization compared with 53% of nondiabetics, with a marked attrition in the first year after angioplasty, when restenosis is most common. Multivariate correlates of decreased 5-year survival were older age, reduced ejection fraction, history of heart failure, multivessel disease, and diabetes. IR diabetics had worse long-term survival and infarction-free survival than non-IR diabetics., Conclusions: Coronary angioplasty in diabetics is associated with high success and low complication rates. Although long-term survival is acceptable, diabetics have a higher rate of infarction and a greater need for additional revascularization procedures, probably because of early restenosis and late progression of coronary disease. The most appropriate treatment for these patients remains to be determined.