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JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers van der Velden, Jos L J; Ye, Ying; Nolin, James D; Hoffman, Sidra M; Chapman, David G; Lahue, Karolyn G; Abdalla, Sarah; Chen, Peng; Liu, Yong; Bennett, Brydon; Khalil, Nasreen; Sutherland, Donna; Smith, William; Horan, Gerald; Assaf, Mahmoud; Horowitz, Zebulun; Chopra, Rajesh; Stevens, Randall M; Palmisano, Maria; Janssen-Heininger, Yvonne M W; Schafer, Peter H

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

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Title
JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers
Creator
van der Velden, Jos L J; Ye, Ying; Nolin, James D; Hoffman, Sidra M; Chapman, David G; Lahue, Karolyn G; Abdalla, Sarah; Chen, Peng; Liu, Yong; Bennett, Brydon; Khalil, Nasreen; Sutherland, Donna; Smith, William; Horan, Gerald; Assaf, Mahmoud; Horowitz, Zebulun; Chopra, Rajesh; Stevens, Randall M; Palmisano, Maria; Janssen-Heininger, Yvonne M W; Schafer, Peter H
Publisher
Springer Berlin Heidelberg
Date Issued
2016-09-02
Description
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
Subject
Biomarkers; CC-930; Idiopathic pulmonary fibrosis; JNK; Matrix metalloproteinase 7; Surfactant protein D; Tenascin-C
Genre
Article
Type
Text
Language
eng
Date Available
2016-09-02
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0314107
URI
http://hdl.handle.net/2429/59055
Affiliation
Medicine, Faculty of; Non UBC; Medicine, Department of
Citation
Clinical and Translational Medicine. 2016 Sep 02;5(1):36
Publisher DOI
10.1186/s40169-016-0117-2
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s)
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)