JAK inhibition in inflammatory bowel disease

Abstract

Current available treatments for inflammatory bowel disease (IBD) have some limitations and new options are needed. Several new molecules are being tested for the treatment of IBD and other immune-mediated inflammatory diseases. Among them, Janus kinase (JAK) inhibitors seem to have the lead, since tofacitinib has received regulatory approval in 2012 for the treatment of rheumatoid arthritis, and also it has shown a favorable risk-benefit ratio in phase 3 studies for ulcerative colitis, both in anti-TNF naïve and anti-TNF experienced patients. Other compounds with JAK inhibitory activity are also being tested with promising results. Areas covered: This review discusses the molecular aspects of the JAK-STAT pathway, which gives rationale for the use of JAK inhibitors in immune-mediated inflammatory diseases, especially in IBD. Different compounds with JAK inhibitory activity are presented, and relevant efficacy and safety data in IBD and other conditions are discussed. Expert commentary: It would not be surprising that in a foreseeable future many new orally administrated drugs will be available. This enhanced armamentarium will probably pose new dilemmas, in terms of drug positioning, escalation and de-escalation strategies, and combination therapy.

Tofacitinib in the Management of Ulcerative Colitis Refractory to Anti-TNF and Anti-Integrin Therapies

“…TOFA (CP-690,550) is an oral small-molecule drug (SMD) with a molecular weight of 312.3 Da. It inhibits JAK1, JAK3, and, to a lesser extent, JAK2 (13)(14)(15) . This inhibition ends up blocking signals for several inflammatory cytokines such as interleukin (IL)-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21 and interferon-gama, among others (13)(14)(15) .…”

“…It inhibits JAK1, JAK3, and, to a lesser extent, JAK2 (13)(14)(15) . This inhibition ends up blocking signals for several inflammatory cytokines such as interleukin (IL)-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21 and interferon-gama, among others (13)(14)(15) . These cytokines are involved in the pathogenesis of IBD and play a role in many immune signaling routes including lymphocyte activation, function, and proliferation (12)(13)(14)(15) .…”

“…This inhibition ends up blocking signals for several inflammatory cytokines such as interleukin (IL)-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21 and interferon-gama, among others (13)(14)(15) . These cytokines are involved in the pathogenesis of IBD and play a role in many immune signaling routes including lymphocyte activation, function, and proliferation (12)(13)(14)(15) . The initial favorable results of TOFA in a phase II multicenter randomized trial in UC, prompted a phase III program (OCTAVE) investigating the efficacy and safety of induction and maintenance therapy in patients with moderately to severely active UC (8,9) .…”

“…The drug is currently being investigated for the treatment of psoriasis and IBD (12)(13)(14)(15) . TOFA (CP-690,550) is an oral small-molecule drug (SMD) with a molecular weight of 312.3 Da.…”

Exposure–Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended‐Release Formulation

“…The JAKs are a family of four intracellular tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2) that play central roles in innate and adaptive immunity . Inhibition specifically of JAK1 blocks the signaling of several pro‐inflammatory cytokines (e.g., interleukin (IL)‐2, IL‐6, IL‐7, and IL‐15, among others) that seem to play a role in the pathogenesis of CD …”