Background
Current approved treatments for idiopathic pulmonary fibrosis (IPF) have tolerability concerns and limited efficacy. A team from Bristol Myers Squibb have reported on their findings from a phase 1b clinical trial for the c-Jun N-terminal kinase inhibitor, CC-90001. The drug was found to be generally safe and well tolerated, and treatment was associated with improvements in clinical features of lung function. A pharmacodynamic investigation of patient samples was also run, using five different Olink® Target 96 panels to measure plasma proteomics before and during drug treatment.
Outcome
Proteomic analysis was carried out on samples taken at day 1, week 12, and week 16. A total of 63 proteins were significantly changed in the 400 mg dose cohort at week 12, and 46 of these showed a fold-reduction of greater than 0.25. Several markers were downregulated in a dose-dependent manner from 200 to 400 mg of CC-90001, including mesenchymal markers and regulators of epithelial–mesenchymal signaling that were previously shown to be modulated by the drug in vitro (e.g., RET and TNFRSF19). Other drug-responsive proteins identified included circulating mediators previously shown to be upregulated in IPF (OSM, CXCL5). Most of the drug-responsive proteins identified in this study have known functions in tissue and ECM remodeling, cellular adhesion and invasion, fibrosis, or inflammation. Together with preclinical findings, the proteomic data support a mechanism whereby JNK inhibition promotes tissue remodeling, resulting in rapid decreases in serum fibrosis biomarkers and concomitant increases in lung function.
