New Therapies for IBD: From the Bench to the Bedside
New Therapies for IBD: From the Bench to the Bedside
The mechanisms underlying the chronic intestinal inflammation that is a hallmark of inflammatory bowel diseases (IBD) are complex. Components of the pathological response include the adaptive and innate immune systems, as well as the intestinal epithelium and endothelium. Advances in the understanding of the roles of each of these components have resulted in the development of multiple biological agents that all represent an alternative to the use of current therapies in patients with refractory Crohn's disease or ulcerative colitis. This study systematically reviews the mechanisms of action, efficacy and safety of new and emerging therapies that are currently in clinical trials and discusses future directions in the treatment of IBD
The inflammatory bowel diseases (IBD) are characterised by chronic intestinal inflammation involving a pathological response in both the innate and adaptive immune systems. The pathogenesis of both types of IBD is caused by the interplay of many factors including genetic susceptibility, the external environment, infectious agents, the commensal enteric flora and immune system dysfunction. The diverse array of possible triggers and the complex immune response that results offers many therapeutic targets, which is reflected in the wide array of drugs for IBD that have been developed, are in development, or have failed to demonstrate efficacy.
The most popular approach to IBD has been to target the surplus or excessive activity of the adaptive immune system using biological agents such as monoclonal antibodies against tumour necrosis factor alpha (TNFα). However, although treatment with these anti-TNFα agents is successful in many patients, only a third or less will achieve remission and many of those who do will eventually lose their response. Because of this fact and the life-long nature of the disease, new therapies need to be developed. In addition to the inhibition of elements of the adaptive immune system, other approaches to the treatment of IBD address the apparent impairment of the innate immune system observed in patients with Crohn's disease (CD), boosting the innate immune system and blocking the infiltration of leucocytes into the intestinal mucosa. New molecules include either biological agents or small molecules, which both have advantages or not. Compared with small molecules, biological agents may seem more attractive because of the potency of action and their selectivity, which might include a limited or almost absence of off-target toxicity. However, their limitations are immunogenicity, extremely high costs and the long half life, which has to be taken into account in particular when they carry immunosuppressive activity.
This review comprehensively describes the mechanism of action, efficacy and safety of new biomolecules under development for CD and ulcerative colitis (UC). Table 1 and Table 2 and figures 1–3 summarise all the new treatments in development for IBD.
(Enlarge Image)
Figure 1.
Successful and unsuccessful therapeutic programs in inflammatory bowel disease. Green: programmes with a positive outcome. Orange: potentially effective or ongoing programmes. Red: programmes failed. IL, interleukin; TGF, transforming growth factor; INF, interferon; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; ICAM, intracellular cell adhesion molecule; MAdCAM, mucosal addressin cell adhesion molecule.
(Enlarge Image)
Figure 2.
The therapeutic pipeline in Crohn's disease. Drugs are categorised based on the mechanism of action. Purple symbols indicate oral drugs. JAK, janus kinase; IL, interleukin; CAM, cell adhesion molecule; TNF, tumor necrosis factor.
(Enlarge Image)
Figure 3.
The therapeutic pipeline in ulcerative colitis. Drugs are categorised based on the mechanism of action. Purple symbols indicate oral drugs. JAK, janus kinase; IL, interleukin; CAM, cell adhesion molecule.
An electronic search of English publications in the databases of PubMed up to August 2011 and Embase up to August 2011 was performed for the keywords: 'Crohn's disease', 'ulcerative colitis', 'inflammatory bowel disease', 'treatment', 'biological therapy', 'cytokine', 't cell', 'adhesion', 'growth factors', 'biomolecules'. Also a hand-search of abstracts from the yearly meetings of Digestive Disease Week and United European Gastroenterology Week between 2003 and 2011 was performed. In addition, clinical trials status was checked on http://www.clinicatrials.gov and new drug names were also searched and matched on google and on the website of the pharmaceutical companies developing new drugs.
Abstract and Introduction
Abstract
The mechanisms underlying the chronic intestinal inflammation that is a hallmark of inflammatory bowel diseases (IBD) are complex. Components of the pathological response include the adaptive and innate immune systems, as well as the intestinal epithelium and endothelium. Advances in the understanding of the roles of each of these components have resulted in the development of multiple biological agents that all represent an alternative to the use of current therapies in patients with refractory Crohn's disease or ulcerative colitis. This study systematically reviews the mechanisms of action, efficacy and safety of new and emerging therapies that are currently in clinical trials and discusses future directions in the treatment of IBD
Introduction
The inflammatory bowel diseases (IBD) are characterised by chronic intestinal inflammation involving a pathological response in both the innate and adaptive immune systems. The pathogenesis of both types of IBD is caused by the interplay of many factors including genetic susceptibility, the external environment, infectious agents, the commensal enteric flora and immune system dysfunction. The diverse array of possible triggers and the complex immune response that results offers many therapeutic targets, which is reflected in the wide array of drugs for IBD that have been developed, are in development, or have failed to demonstrate efficacy.
The most popular approach to IBD has been to target the surplus or excessive activity of the adaptive immune system using biological agents such as monoclonal antibodies against tumour necrosis factor alpha (TNFα). However, although treatment with these anti-TNFα agents is successful in many patients, only a third or less will achieve remission and many of those who do will eventually lose their response. Because of this fact and the life-long nature of the disease, new therapies need to be developed. In addition to the inhibition of elements of the adaptive immune system, other approaches to the treatment of IBD address the apparent impairment of the innate immune system observed in patients with Crohn's disease (CD), boosting the innate immune system and blocking the infiltration of leucocytes into the intestinal mucosa. New molecules include either biological agents or small molecules, which both have advantages or not. Compared with small molecules, biological agents may seem more attractive because of the potency of action and their selectivity, which might include a limited or almost absence of off-target toxicity. However, their limitations are immunogenicity, extremely high costs and the long half life, which has to be taken into account in particular when they carry immunosuppressive activity.
This review comprehensively describes the mechanism of action, efficacy and safety of new biomolecules under development for CD and ulcerative colitis (UC). Table 1 and Table 2 and figures 1–3 summarise all the new treatments in development for IBD.
(Enlarge Image)
Figure 1.
Successful and unsuccessful therapeutic programs in inflammatory bowel disease. Green: programmes with a positive outcome. Orange: potentially effective or ongoing programmes. Red: programmes failed. IL, interleukin; TGF, transforming growth factor; INF, interferon; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; ICAM, intracellular cell adhesion molecule; MAdCAM, mucosal addressin cell adhesion molecule.
(Enlarge Image)
Figure 2.
The therapeutic pipeline in Crohn's disease. Drugs are categorised based on the mechanism of action. Purple symbols indicate oral drugs. JAK, janus kinase; IL, interleukin; CAM, cell adhesion molecule; TNF, tumor necrosis factor.
(Enlarge Image)
Figure 3.
The therapeutic pipeline in ulcerative colitis. Drugs are categorised based on the mechanism of action. Purple symbols indicate oral drugs. JAK, janus kinase; IL, interleukin; CAM, cell adhesion molecule.
An electronic search of English publications in the databases of PubMed up to August 2011 and Embase up to August 2011 was performed for the keywords: 'Crohn's disease', 'ulcerative colitis', 'inflammatory bowel disease', 'treatment', 'biological therapy', 'cytokine', 't cell', 'adhesion', 'growth factors', 'biomolecules'. Also a hand-search of abstracts from the yearly meetings of Digestive Disease Week and United European Gastroenterology Week between 2003 and 2011 was performed. In addition, clinical trials status was checked on http://www.clinicatrials.gov and new drug names were also searched and matched on google and on the website of the pharmaceutical companies developing new drugs.