Pharmacology, efficacy and safety of JAK inhibitors in Crohn's disease

Abstract

Orally bioavailable inhibitors of the tyrosine kinases (TYKs), also referred to as Janus kinases (JAKs), are being evaluated for the treatment of patients with Crohn's disease (CD), ulcerative colitis (UC), and other chronic inflammatory disorders. To date, three JAK inhibitors have been tested in patients with moderate-to-severe CD: tofacitinib (pan-JAK inhibitor), filgotinib (JAK1 inhibitor) and upadacitinib (JAK1 inhibitor). Clinical development of tofacitinib was discontinued in CD because the primary endpoint of clinical remission in the phase II induction and maintenance trials was not met, although outcomes may have been influenced by trial design flaws and a high placebo rate was noted. In contrast, filgotinib did meet its primary endpoint of clinical remission at week 10 in the phase II FITZROY trial, in addition to several other clinically important secondary outcomes, spurring a subsequent larger phase III trial. Following promising results for upadacitinib in its phase II trial, larger phase III trials were also initiated to corroborate the efficacy results. Although JAK inhibitors appear to have an acceptable safety profile, higher rates of infections compared to placebo were noted. Overall, JAK inhibitors constitute a new promising class of drugs, given the efficacy signals observed in pivotal clinical trials in several chronic inflammatory diseases. Here we review the existing evidence on the pharmacology, safety and efficacy of JAK-STAT inhibitors that are currently under investigation for the treatment of patients with CD.

Keywords: Crohn’s disease; Inflammatory bowel disease; JAK-STAT; Janus kinase; Tyrosine kinase.