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. 2016 Dec;5(1):36.
doi: 10.1186/s40169-016-0117-2. Epub 2016 Sep 2.

JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers

Jos L J van der Velden  1 , Ying Ye  2 , James D Nolin  1 , Sidra M Hoffman  1 , David G Chapman  1 , Karolyn G Lahue  1 , Sarah Abdalla  1 , Peng Chen  3 , Yong Liu  2 , Brydon Bennett  4 , Nasreen Khalil  5 , Donna Sutherland  3 , William Smith  3 , Gerald Horan  2 , Mahmoud Assaf  2 , Zebulun Horowitz  3 , Rajesh Chopra  2 , Randall M Stevens  3 , Maria Palmisano  2 , Yvonne M W Janssen-Heininger  1 , Peter H Schafer  6
Affiliations

JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers

Jos L J van der Velden et al. Clin Transl Med. 2016 Dec.

Abstract

Background: Lung 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.

Methods: The 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.

Results: In 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).

Conclusions: These 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 NCT01203943.

Keywords: Biomarkers; CC-930; Idiopathic pulmonary fibrosis; JNK; Matrix metalloproteinase 7; Surfactant protein D; Tenascin-C.

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Figures

Fig. 1
Fig. 1
C-Jun phosphorylation in HDM-challenged mice and the impact of CC-930 or vehicle control. a Schematic depicting the time course of HDM exposure and CC-930 administration. For instillation, 50 µg HDM or PBS as the vehicle control was administered intranasally once for 5 days over 3 weeks at the days indicated via the top arrows. Vehicle control (0.5 % CMC/0.25 % Tween 80) or CC-930 (100 mg/kg) was administered twice daily on the days indicated via the bottom arrows. Mice were euthanized 72 h after the last challenge. b Lung tissue was homogenized from PBS or HDM-challenged mice for assessment of phospho-c-Jun. Equal amounts of protein (20 μg for phosho-c-jun, 5 μg for actin) were separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) and subjected to Western blot analysis for phospho-c-Jun and actin. Band intensity was determined and expressed as a ratio of phosphorylation to total protein (actin). Data shown represent mean ± SEM from two independent experiments (PBS: n = 10; HDM alone: n = 10; HDM + vehicle control: n = 11; HDM + CC-930: n = 11). *P < 0.05 (analysis of variance) versus PBS. † P < 0.05 versus the HDM group
Fig. 2
Fig. 2
Effect of CC-930 or vehicle on HDM-induced mucus metaplasia. a Periodic acid-Schiff staining of airway mucus in mice exposed to PBS, HDM alone, HDM + vehicle, or HDM + CC-930 (magnification: 200×). Quantification of mRNA levels for b MUC5AC and c MUC5B in lung tissue homogenates by q-PCR after PBS or HDM exposure. d MUC5B immunofluorescent (red) and club cell secretory protein (green) staining of mouse lungs exposed to PBS, HDM alone, HDM + vehicle, or HDM + CC-930. Nuclei were stained using DAPI (blue) (magnification: 200×). Data shown represents mean ± SEM from two independent experiments (PBS: n = 10; HDM alone: n = 10; HDM + vehicle control: n = 11; HDM + CC-930: n = 11). *P < 0.05 (analysis of variance) versus PBS
Fig. 3
Fig. 3
Impact of CC-930 or vehicle on HDM-induced fibrotic airway remodeling. a Histopathological analysis of Masson’s trichrome-stained airway sections in mice exposed to PBS, HDM alone, HDM + vehicle, or HDM + CC-930 (magnification: 200×). Assessment of total collagen content by b sircol and c hydroxyproline assay in the upper right lobe of mice after PBS, HDM alone, HDM + vehicle, or HDM + CC-930 exposure. Assessment of mRNA abundance of d collagen 1A1 and e collagen 4, collagen 5, and mRNA abundance was normalized to β-actin. Results are expressed as fold change compared with PBS-exposed mice and reflect mean ± SEM from two independent experiments (PBS: n = 10; HDM alone: n = 10; HDM + vehicle control: n = 11; HDM + CC-930: n = 11). *P < 0.05 (analysis of variance) versus PBS. † P < 0.05 compared with the HDM group
Fig. 4
Fig. 4
HDM-induced MMP-7 protein and gene expression is attenuated by CC-930. a MMP-7 immunohistochemistry staining of mouse lungs exposed to PBS, HDM alone, HDM + vehicle, or HDM + CC-930 (magnification: 200×). b Evaluation of total MMP-7 protein in BALF and c serum measured by the enzyme-linked immunosorbent assay and d mRNA expression of MMP-7 in lung homogenates measured by q-PCR mice after PBS or HDM exposure. Data shown represents mean ± SEM from two independent experiments (PBS: n = 10; HDM alone: n = 10; HDM + vehicle control: n = 11; HDM + CC-390: n = 11). *P < 0.05 (analysis of variance) versus PBS. † P < 0.05 versus the HDM + vehicle group
Fig. 5
Fig. 5
Median change from baseline in a plasma MMP-7, b surfactant protein D, and c tenascin-C in all treatment groups throughout the 56-week study
Fig. 6
Fig. 6
Median change from baseline in a plasma MMP-7 concentration at week 4 versus CC-930 dose and b MMP-7 versus CC-930 exposure (AUC0−τ) predicted from the population pharmacokinetic model. a The dose was reduced from 100 mg BID to 100 mg QD within the first 4 weeks for one patient due to a protocol amendment
Fig. 7
Fig. 7
Mean change from baseline in FVC over time in idiopathic pulmonary fibrosis patients treated with CC-930. a FVC percent predicted and b FVC in milliliters. a Defined as the last measurement on or before the day of the first dose of study drug. b 4 weeks post-treatment visit. The follow-up visit appears as a separate study week in the figure, with a dotted line connecting the last visit where subjects’ received drug to the follow-up visit. c Relative to the day of the first dose of study drug
Fig. 8
Fig. 8
Correlation of a plasma MMP-7, b surfactant protein D, and c tenascin-C concentration with changes in FVC percent of predicted
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