title: JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers.
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.
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: Jos L J
authors: JL
authors: van der Velden
authors: Department of Translational Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors: Ying
authors: Y
authors: Ye
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: James D
authors: JD
authors: Nolin
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: Sidra M
authors: SM
authors: Hoffman
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: David G
authors: DG
authors: Chapman
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: Karolyn G
authors: KG
authors: Lahue
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: Sarah
authors: S
authors: Abdalla
authors: Clinical Research and Development, Celgene Corporation, Warren, NJ, USA.
authors: Peng
authors: P
authors: Chen
authors: Department of Translational Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors: Yong
authors: Y
authors: Liu
authors: Department of Inflammation Research, Celgene Corporation, San Diego, CA, USA.
authors: Brydon
authors: B
authors: Bennett
authors: Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors: Nasreen
authors: N
authors: Khalil
authors: Clinical Research and Development, Celgene Corporation, Warren, NJ, USA.
authors: Donna
authors: D
authors: Sutherland
authors: Clinical Research and Development, Celgene Corporation, Warren, NJ, USA.
authors: William
authors: W
authors: Smith
authors: Department of Translational Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors: Gerald
authors: G
authors: Horan
authors: Department of Translational Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors: Mahmoud
authors: M
authors: Assaf
authors: Clinical Research and Development, Celgene Corporation, Warren, NJ, USA.
authors: Zebulun
authors: Z
authors: Horowitz
authors: Department of Translational Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors: Rajesh
authors: R
authors: Chopra
authors: Clinical Research and Development, Celgene Corporation, Warren, NJ, USA.
authors: Randall M
authors: RM
authors: Stevens
authors: Department of Translational Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors: Maria
authors: M
authors: Palmisano
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: Yvonne M W
authors: YM
authors: Janssen-Heininger
authors: Department of Translational Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA. pschafer@celgene.com.
authors: Peter H
authors: PH
authors: Schafer
keywords: Biomarkers; CC-930; Idiopathic pulmonary fibrosis; JNK; Matrix metalloproteinase 7; Surfactant protein D; Tenascin-C