Acebilustat

Fibrogenic carbon nanotubes (CNTs) induce the polarization of M1 and M2 macrophages in mouse lungs. Polarization of the macrophages regulates the production of proinflammatory and pro-resolving lipid mediators (LMs) to mediate acute inflammation and its resolution in a time-dependent manner. Here we examined the molecular mechanism by which multi-walled CNTs (MWCNTs, Mitsui-7) induce M1 polarization in vitro. Treatment of murine macrophages (J774A.1) with Mitsui-7 MWCNTs increased the expression of Alox5 mRNA and protein in a concentration- and time-dependent manner. The MWCNTs induced the expression of CD68 and that induction persisted for up to 3 days post-exposure. The expression and activity of inducible nitric oxide synthase, an intracellular marker of M1, were increased by MWCNTs. Consistent with M1 polarization, the MWCNTs induced the production and secretion of proinflammatory cytokines tumor necrosis factor-α and interleukin-1β, and proinflammatory LMs leukotriene B4 (LTB4) and prostaglandin E2 (PGE2). The cell-free media from MWCNT-polarized macrophages induced the migration of neutrophilic cells (differentiated from HL-60), which was blocked by Acebilustat, a specific leukotriene A4 hydrolase inhibitor, or LY239111, an LTB4 receptor antagonist, but not NS-398, a cyclooxygenase 2 inhibitor, revealing LTB4 as a major mediator of neutrophil chemotaxis from MWCNT-polarized macrophages. Knockdown of Alox5 using specific small hairpin-RNA suppressed MWCNT-induced M1 polarization, LTB4 secretion, and migration of neutrophils. Taken together, these findings demonstrate the polarization of M1 macrophages by Mitsui-7 MWCNTs in vitro and that induction of Alox5 is an important mechanism by which the MWCNTs promote proinflammatory responses by boosting M1 polarization and production of proinflammatory LMs.

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.

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.

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.

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.