Pharmacodynamic biomarkers of drug action in patients treated for pulmonary fibrosis


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.


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.



Horan G, Ye Y, Adams M, et al. Safety, Pharmacokinetics, and Antifibrotic Activity of CC-90001 (BMS-986360), a c-Jun N-Terminal Kinase Inhibitor, in Pulmonary Fibrosis. (2023) Clinical Pharmacology in Drug Development, DOI: 10.1002/cpdd.129

Proteomic analyses also provided insight into the antifibrotic effects of CC-90001. Most of the circulating proteins modulated by CC-90001 in this study have known functions in tissue and ECM remodeling, cellular adhesion and invasion, fibrosis, or inflammation.

Horan et al. (2023)

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