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JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers
Jos L J van der Velden1, Ying Ye2, James D Nolin1
1Department of Pathology, University of Vermont, Burlington, VT, USA.
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.
Insights
This study investigated the JNK inhibitor CC-930 for treating idiopathic pulmonary fibrosis (IPF). CC-930 showed potential in preclinical models and early human trials, with biomarker changes suggesting therapeutic effects in IPF patients.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Translational Research
Background:
- Lung remodeling and pulmonary fibrosis are severe conditions linked to chronic asthma and idiopathic pulmonary fibrosis (IPF).
- JNK enzyme activity is implicated in the fibrotic process within the lungs.
- No selective JNK inhibitor has been tested in translational lung fibrosis models or IPF patients.
Purpose of the Study:
- To evaluate the JNK inhibitor CC-930 in preclinical models of lung fibrosis.
- To assess the safety and pharmacodynamics of CC-930 in healthy volunteers.
- To investigate the efficacy and safety of CC-930 in patients with mild/moderate IPF.
Main Methods:
- CC-930 was tested in a mouse model of house dust mite-induced airway fibrosis.
- Phase I study in healthy volunteers assessed pharmacodynamics (e.g., UV-induced c-Jun phosphorylation).
- Phase II study involved 28 IPF patients in a dose-escalation, placebo-controlled trial followed by an open-label extension.
Main Results:
- CC-930 reduced fibrosis markers (collagen, MUC5B, MMP-7) in the preclinical model.
- In IPF patients, CC-930 showed a dose-dependent trend in reducing MMP-7 and SP-D plasma levels.
- Adverse events included elevated ALT/AST and upper respiratory infections; 46.4% discontinued due to AEs. Disease progression and FVC decline were observed in some patients.
Conclusions:
- JNK enzymatic activity is involved in pulmonary fibrosis.
- Systemic biomarkers can track IPF progression.
- CC-930 demonstrates potential as a novel therapeutic intervention for IPF, warranting further investigation.
