Abstract
Aims/Objectives: Although recently approved treatments for IPF delay lung function decline, novel therapeutic options are needed. c-Jun N-terminal kinase (JNK), a stress-activated protein kinase, has been implicated in pulmonary fibrosis (PF) (Alcorn, 2009). In a previous study, CC-930, a first generation JNK inhibitor with a JNK2 bias, maintained stable FVC in subjects with IPF treated for 6 mos and decreased serum disease biomarkers (van der Velden, 2016). A study using mouse knockouts suggest JNK1, rather than JNK2, is the key JNK isoform in mediating PF (Alcorn, 2009).
Methods: CC-90001 is a selective JNK inhibitor 12.9-fold more potent for JNK1 inhibition than JNK2 in a cell-based model. In a phase 1b study in patients with PF, CC-90001 (100mg QD, 200mg QD and 400mg QD) was continuously administered over 12 wks.
Results: 16 subjects with PF (15 IPF; 1 RA-ILD) were treated with CC-90001, 100mg (n=3), 200mg (n=7) or 400mg (n=6). Fifteen subjects completed 12 wks of treatment. The most common AEs were GI in nature (all mild to moderate). Two of 3 subjects in the 100mg group had FVC declines at week 12 whereas 10 of 12 (83%) subjects in the combined 200/400mg groups had positive FVC changes at week 12. Mean FVC change from baseline in the combined 200/400mg groups was +168 ml (95% CI: +71 to +276). Plasma tenascin-C levels were reduced from a mean 717 at baseline to 585 ng/ml at week 12 (-132 ng/ml, 95% CI: -212 to -51).
Conclusions: CC-90001 was associated with an overall lack of FVC decline in the 200/400mg dose groups, trends in reduced tenascin-C, and acceptable safety over 12 wks of treatment in patients with PF. These data support further clinical development of CC-90001 in patients with IPF.
- Copyright ©the authors 2017
