Abstract
BackgroundLung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients.MethodsThe JNK inhibitor CC-930 was evaluated in the house dust mite-induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4-week, placebo-controlled, double-blind, sequential ascending-dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52-week open-label treatment-extension period.ResultsIn the preclinical model, CC-930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP-7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC-930 reduced c-Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC-930 dose-dependent trend in reduction of MMP-7 and SP-D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26–32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP-7, SP-D, and tenascin-C significantly correlated with change in FVC (% predicted).ConclusionsThese results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF.Trial registration ClinicalTrials.gov NCT01203943Electronic supplementary materialThe online version of this article (doi:10.1186/s40169-016-0117-2) contains supplementary material, which is available to authorized users.
Highlights
Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from dis‐ eases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF)
Increased Matrix metalloproteinases (MMP)-1 and Matrix MetalloProteinase-7 (MMP-7) protein concentrations were observed in the plasma, bronchoalveolar lavage fluid (BALF), and lung tissue of IPF patients, with MMP-7 concentrations negatively correlated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) [11]
house dust mite (HDM)‐induced lung remodeling The Jun N-terminal Kinase (JNK) inhibitor CC-930 had previously been tested in the mouse bleomycin-induced pulmonary fibrosis model, having shown a dose-dependent reduction in lung fibrosis scores [27]
Summary
Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from dis‐ eases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Occurring in older individuals, IPF is Multiple biomarkers have been proposed to be associated with IPF because they are expressed differentially in IPF patients compared with healthy individuals, are associated with survival of IPF patients, or play a known or hypothesized role in wound healing and/or the pulmonary fibrotic process [11]. SP-A and SP-D levels in serum are elevated in patients with IPF compared with healthy subjects and/or those with other interstitial lung diseases. Tenascin-C, an extracellular matrix protein expressed during wound healing, has been identified at elevated levels in the fibroblast foci and in the basement membrane regions under the epithelium of honeycomb lesions in the lungs of IPF patients [15]. Other proposed IPF biomarkers include Krebs von den Lungen-6 antigen (KL-6) [17], CCL-18 [18], monocyte chemotactic protein-1 (MCP-1; known as CC chemokine ligand 2) [19], tissue inhibitor of metalloproteinase-1 (TIMP-1) [20], and plasminogen activator inhibitor-1 (PAI-1) [21]
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