Blocking JNK Pathway May Ease Lung Fibrosis in IPF Patients, Study Suggests

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Blocking a particular pathway — called c-Jun N-terminal Kinase (JNK) — may reduce lung remodeling and fibrosis, researchers said in a multi-part study reporting the effects of a JNK inhibitor in a mouse model and, subsequently, in a clinical trial involving patients with idiopathic pulmonary fibrosis (IPF).

The study, “JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers,” was published in the journal Clinical and Translational Medicine. 

The trial was stopped early because a risk/benefit analysis did not justify its continuation, but the report’s authors saw evidence that led them to conclude the studies, taken together, “illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support … the potential clinical benefit of this novel intervention in IPF.”

IPF induces lung remodeling and fibrosis, changes that could cause serious damage to patients’ airways. Previous preclinical studies suggested that a cellular pathway, the JNK pathway, is activated in IPF and contributes to the pulmonary fibrotic process.

In fact, fibrosis promoted by the transforming growth factor β1 (TGF-β1) is blocked by inhibiting JNK activation. TGF-β1 transforms human lung fibroblasts into myofibroblasts that produce collagen and other extracellular matrix components, contributing to fibrosis. Despite the link between JNK and the fibrotic process, how inhibiting JNK via a selective drug warrants further investigation in IPF.

Researchers investigated the effects of the JNK inhibitor CC-930 in three different settings: a mouse model, the dust mite-induced fibrotic airway model; a Phase 1 healthy volunteer study, to evaluate the effect of CC-930 on JNK activity after UVB irradiation of human skin; and a Phase 2 multi-center, placebo-controlled, double-blind study with patients with mild or moderate IPF.

In the Phase 2 trial (NCT01203943), patients were randomly assigned to three sequential dose cohorts: CC-930 50 mg (one a day, cohort 1); CC-930 100 mg (one a day, cohort 2); and CC-930 100 mg (twice a day, cohort 3). Eligible patients were randomly allocated to receive placebo (two patients) or CC-930 (eight patients) for four weeks in each cohort. Patients who completed this ascending-dose phase were eligible to enter the open-label treatment-extension phase. This second part intended to run for an additional 52 weeks, but was terminated early.

In the preclinical mouse model, researchers observed that CC-930 treatment reduced the expression of several markers of fibrosis — including collagen, airway mucin, and matrix metalloproteinase-7 (MMP-7) — in the lungs, bronchoalveolar lavage fluid, and serum. In the Phase 1 study, CC-930 administration impaired JNK activation induced by UV radiation to the skin.

In the Phase 2 trial in patients, researchers found that CC-930 reduced the expression of fibrosis markers in a dose-dependent manner. Treatment was associated with adverse effects, however, including increased expression of markers of liver damage (alanine transaminase and aspartate aminotransferase), and upper respiratory tract infection (21.4% of the patients). A total of 13 patients (46.4%) experienced adverse events that led to treatment discontinuation.

FVC (% predicted; forced vital capacity, a measure of lung function) remained stable in treated patients through 32 weeks, but then began to decline. But no conclusions could be drawn, the research team said, because a control group was lacking in the extension study.

The researchers concluded that these results support a potential involvement of the JNK pathway during pulmonary fibrosis, and a possible therapeutic role for JNK inhibitors such as CC-930. They also suggested that analyzing the expression of several markers in patients’ blood be a way of monitoring disease progression in IPF patients.

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