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Next generation of small molecules in inflammatory bowel disease
  1. Pablo Olivera1,2,
  2. Silvio Danese3,
  3. Laurent Peyrin-Biroulet2
  1. 1Gastroenterology Section, Department of Internal Medicine, Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina
  2. 2INSERM U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France
  3. 3Humanitas University, IBD Center, Milan, Italy
  1. Correspondence to Professor Laurent Peyrin-Biroulet, INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Lorraine University, Allée du Morvan, Vandoeuvre-lès-Nancy F-54511, France; peyrinbiroulet{at}gmail.com

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Introduction

Inflammatory bowel disease (IBD) encompasses two major entities: ulcerative colitis (UC) and Crohn's disease (CD).1 Both are chronic, progressive, disabling conditions that require lifelong medical treatment in most cases. IBD has a major impact on the patient's health-related quality of life,2 and the treatment-related costs place a significant burden on healthcare systems.3

Historically, the medical management of IBD has been based on the use of several small-molecule drugs (SMDs), including corticosteroids, immunomodulators (such as azathioprine, 6-mercaptopurine and methotrexate) and aminosalicylates.4 The introduction of biologic anti-tumour necrosis factor-α (TNF-α) agents in the first few years of this century has revolutionised the clinical management of IBD. In parallel, treatment goals have shifted from symptomatic control towards more objective endpoints (such as mucosal healing and deep remission) associated with better long-term outcomes.5 ,6 Over the past 20 years, drug research in the field of IBD has focused on the development of new, large-molecule biologics; hence, several anti-TNF-α monoclonal antibodies (including infliximab,7 ,8 adalimumab,9 ,10 certolizumab pegol,11 ,12 and golimumab)13 and, most recently, antibodies with other targets (such as vedolizumab14 ,15 and ustekinumab)16 have become available in clinical practice.

However, monoclonal antibodies have limitations in terms of efficacy, safety and cost. First, the available biologics are only moderately efficacious17 since up to 30% of patients show a lack of improvement after induction therapy with anti-TNF drugs (ie, primary non-response).18 Furthermore, a significant proportion of patients (between 13% and 25% per year)19–21 may develop a loss of response to anti-TNF agents over time (ie, secondary non-response).20 ,21 This loss of response may be due to pharmacodynamic, pharmacokinetic and/or immunogenic factors.22 Combination therapy is the best way to prevent the formation of antibodies,23 which …

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