New biologics and small molecules in inflammatory bowel disease: an update

Abstract

Inflammatory bowel disease (IBD) is a spectrum of immune-mediated inflammatory disorders with a complex multifactorial pathogenesis, where different pathways may predominate in different individuals. This complexity will most likely require a panoply of drugs targeting different pathways if one wants to treat to steroid-free sustained remission and mucosal healing. Presently, the mainstay of medical management of IBD is based on 5-aminosalicylates, corticosteroids, thiopurines, methotrexate, antitumor necrosis factor, anti-alpha4 beta7 (α4β7) integrin and anti-interleukin (IL)-12/IL-23 therapies. The discovery of new pathways involved in the pathogenesis of IBD resulted in new drugs targeting Janus kinase/signal transducers and activators of transcription, IL-6, spingosine-1-phosphate, and phosphodiesterase 4, among others. These new therapies might result in more advantageous safety profiles. Several of these new drugs have already been successfully tested in other inflammatory disorders, such as psoriasis or rheumatoid arthritis. In this review, evidence from phase II and phase III randomized controlled clinical trials in patients with IBD involving new biologicals and small molecules are summarized.

Keywords: Crohn’s disease; JAK inhibitor; S1P modulator; anti-integrin; biologicals; inflammatory bowel disease; small molecules; therapy; ulcerative colitis.

Figure 1.

The JAK-STAT signaling pathway is involved in several processes. This figure was made with Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com. The presence of the ligand leads to receptor dimerization. Subsequently, JAK transphosphorylation takes place which allows for STAT recruitment and phosphorylation. Once phosphorylated, STATs will make dimers, which will translocate and promote transcription in the nucleus. Different JAK combinations will lead to different effects. Several JAK inhibitors are being studied in inflammatory bowel disease. EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; P, phosphorylated; STAT, signal transducer and activator of transcription protein; TPO, thrombopoietin.

Figure 2.

S1P mechanisms of action. This figure was made with Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com. (a) S1P binds to five known receptors (S1P1, S1P2, S1P3, S1P4, and S1P5), each promoting distinct functions; (b) dendritic cells migrate to lymph nodes and present antigens to T cells. The binding of S1P to the S1P receptors promotes the egress of activated T cells from the lymph nodes to the lymph, following the S1P gradient. S1P modulators block this binding, resulting in a decrease of circulating blood lymphocytes. Ozanimod blocks the binding of S1P to receptor S1P1 and S1P5. Etrasimod selectively blocks receptor S1P1. DC, dendritic cell; NK cell, natural-killer cell; S1P, sphingosine-1-phosphate; TC, T cell; T_H17, T-helper cell 17.