Tofacitinib: A Small Molecule for Biologic-Refractory Crohn’s Disease?

Excerpt

Since the treatment of chronic inflammatory diseases was revolutionized with the introduction of the therapeutic monoclonal antibody (biologic) infliximab in 1994 [1], several newer agents targeting various pathways were subsequently introduced. One of these, tofacitinib, a small molecule Janus kinase and Signal Transducer and Activator of Transcription (JAK-STAT) inhibitor, the first oral treatment for inflammatory bowel disease (IBD) to be approved in several decades, showed safety and efficacy in the treatment of ulcerative colitis (UC), receiving FDA and EMA approvals [2]. However, a phase 2b study in Crohn’s disease (CD) failed to demonstrate a significant benefit [3], with the study failing to meet its primary endpoints. Notably, for the induction phase, clinical remission (CD activity index (CDAI) < 150) at week 8, was observed in 36.7% (95 CI [26.8–47.5]), 43.5% (95 CI [32.8–54.7]) and 43.0% (95 CI [32.4–54.2]) in the placebo, and the tofacitinib 5 mg and 10 mg twice daily groups, respectively. Differences were not significant between the placebo group and the tofacitinib-treated groups. Even though the primary endpoint was not met in this study, secondary endpoints did suggest a potential benefit in patients with CD. For example, mean decreases from baseline in CDAI score at week 8 were significantly larger with both tofacitinib doses (p < 0.05) compared with placebo. At week 8, mean decreases from baseline C-reactive protein (CRP) concentration were significantly greater with tofacitinib 5 and 10 mg twice daily (p < 0.001) compared with placebo. Notably, > 70% of the trial population had been previously exposed to anti-TNF biologics, a factor that negatively impacts the subsequent efficacy of subsequent biologics and other anti-inflammatory drugs [4]. …