A Phase IIa Randomized Double-blind Placebo-controlled Two-way Cross-over Trial of the Effects of Repeat Doses of 50 mg AXP1275 Daily on the Asthmatic Response to a Pulmonary Allergen Challenge in Adults With Mild-to-Moderate Atopic Asthma

This is the first study in human patients with asthma that the sponsor is conducting in order to evaluate if there are signals that the investigational medication, AXP1275, may be a safe and effective treatment for asthma. The results of this study may help the sponsor to design additional studies.

开始日期2013-08-01

申办/合作机构

Axikin Pharmaceuticals, Inc.

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2015-09-01·5.1 Airway Pharmacology and Treatment

LATE-BREAKING ABSTRACT: A novel role for CCR3 in promoting airways hyperreactivity; Role for CCR3-muscarinic M3 receptor heterodimers

作者: Emma Moss ; Karen Bingham ; Mark Fitzgerald ; Gail Gauvreau ; Tracy Handel ; Stefen Boehme ; Taylor Gilliland ; Kevin Bacon ; Louis-Philippe Boulet ; Tai-Wei Ly ; Paul O'Byrne

We have developed a novel therapeutic inhibitor against the chemokine receptor CCR3 for allergic asthma that significantly inhibited the MCh PC 20 response in a Phase IIa trial in mild-to-moderate asthmatics. In vivo , AXP1275 had shown significant efficacy in reducing inflammatory mediators and cellular infiltrates in non-human primate models of allergic asthma, and, surprisingly, had also inhibited airways hyperreactivity and methacholine constriction responses (PC 150 ). In addition, inhibition was seen with ex-vivo carbachol (CCh)-induced constriction in human lung tissue. In order to discern pharmacologically-relevant mechanisms for inhibition of CCh-induced lung constriction by AXP1275, we have investigated the receptor pharmacology of CCR3 in human lung tissue. Immunohistochemically, CCR3 is present on epithelium and smooth muscle, and is co-localized with the muscarinic M3 receptor. In receptor transfectants, CCL11 and CCh cross-sensitize agonist-induced calcium mobilization, suggesting cooperativity between CCR3 and M3. AXP1275 and muscarinic receptor antagonists inhibit responses in a similarly-cooperative manner. Bioluminescence resonance energy transfer (BRET) assays demonstrated that CCR3 and M3 heterodimerize, and this was further supported by receptor co-immunoprecipitation assays. Receptor heterodimerization of CCR3 and M3 on non-leukocytic cells in vivo may provide a plausible explanation for the efficacy of CCR3-selective inhibitors on the hyperreactivity response in asthma.

2015-09-01·5.1 Airway Pharmacology and Treatment

LATE-BREAKING ABSTRACT: Inhibition of MAP3K19 - A novel therapeutic approach for treatment of IPF

作者: Kevin Bacon ; Stefen Boehme ; Tai Wei Ly

MAP3K19 (RC Kinase) is a novel nuclear kinase that is expressed in healthy lung by macrophages and type II epithelial cells, upregulated in IPF lungs, and commonly found in atypical epithelium adjacent to fibroblastic foci. Consistent with this cellular distribution, late-stage pre-clinical small molecule inhibitors of MAP3K19 caused significant reductions in inflammatory infiltrate, extra-cellular matrix deposition and hydroxyproline production in a murine xenograft model of IPF. In the murine bleomycin model, prophylactic or therapeutic oral administration of a MAP3K19 antagonist compound significantly decreased inflammation, fibrosis and collagen content. In contrast, Pirfenidone only significantly affected lung collagen levels. To understand the mechanism of action of specific MAP3K19 inhibitors, we examined whether the TGF-β signaling pathway was impacted. An examination of IPF patient-derived myofibroblast cell lines, primary human macrophages, and numerous MAP3K19+ human cell lines showed that inhibition of MAP3K19 resulted in a significant decrease in the nuclear accumulation of P-Smad-2 and P-Smad-3 upon TGF-β stimulation. Pirfenidone had minimal effects. Inhibition of MAP3K19 did not affect Smad-4 levels, and cytoplasmic levels of Smad-2 and Smad-3 were also unaffected. Inhibition of MAP3K19 also blocked TGF-β-induced gene transcription of various EMT molecules. Surprisingly, inhibition of MAP3K19 also inhibited TGF-β-induced nuclear translocation of Notch. These results suggest that MAP3K19 may act as a regulator of nuclear translocation of various signaling molecules involved in transcription, and provides a mechanism to explain how MAP3K19 inhibition may provide therapeutic benefit in IPF.

PLOS ONE3区 · 综合性期刊

MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction

3区 · 综合性期刊

ArticleOA

作者: Franz-Bacon, Karin ; Ludka, John ; Ly, Tai Wei ; DiTirro, Danielle N ; Boehme, Stefen A ; Bacon, Kevin B

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients.

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