Review Article

Predictors of Response to Vedolizumab and Ustekinumab in Inflammatory Bowel Disease

A. Barré; J.-F. Colombel; R. Ungaro

Disclosures

Aliment Pharmacol Ther. 2018;47(7):896-905. 

In This Article

Abstract and Introduction

Abstract

Background Increased knowledge of pathways involved in the pathogenesis of IBD has led to the development of new treatment options for Crohn's disease (CD) and ulcerative colitis (UC). Two new biological agents have been recently approved for IBD: vedolizumab and ustekinumab. They have different therapeutic targets (α4β7 integrin for vedolizumab and interleukin–12/23 pathways for ustekinumab) than the primary biological class, anti–tumour necrosis factor alpha (anti–TNF) agents. As the armamentarium for IBD increases in coming years, it will become important to understand factors associated with response in order to best position and personalise therapy.

Aim To summarise the current data on predictors of response to vedolizumab and ustekinumab in IBD patients.

Methods We conducted a comprehensive literature review. A PubMed search was performed using pre–defined key words and terms to identify relevant studies on predictors of response.

Results Patients with severe disease (by clinical activity and inflammatory biomarkers), or prior anti–TNF exposure are less likely to respond to vedolizumab. Ileocolonic disease, no prior surgery and uncomplicated phenotype were associated with better responses to ustekinumab in CD. Initial response seems to predict a better long–term maintenance in both therapies (P < 0.001). Contrary to anti–TNF therapies, immunogenicity appears to play less of a role in response.

Conclusion As the number of new biological therapies increase in IBD, identifying patients who are most likely to benefit from specific agents is of paramount importance to help best position IBD therapies.

Introduction

Biological agents have become the mainstay of therapy for moderate to severely active IBD. For many years, the only class of biologicals used in IBD treatment was anti–tumour necrosis factor alpha (anti–TNF) agents. However, 2 new biological drugs that target different inflammatory pathways have been recently approved for IBD: vedolizumab and ustekinumab.

Vedolizumab is a humanised monoclonal gut–selective antibody against α4β7 integrin and inhibits the trafficking of inflammatory cells to the intestine. Vedolizumab was efficacious at inducing and maintaining remission in three phase 3, randomised controlled trials (GEMINI) in Crohn's disease (CD) and ulcerative colitis (UC).[1–3] Vedolizumab was approved for the treatment of adult patients with moderate–to–severe UC or CD who have an inadequate response to, lose response to or are intolerant to conventional therapy (corticosteroids and immunomodulators) or anti–TNF therapy. In real–world cohorts from several groups from North America and Europe, primary response to vedolizumab was typically evaluated at week 14 after induction with rates of clinical remission and clinical response ranging between 24%–36% and 49%–64% in CD, and 23%–39% and 43%–57% in UC, respectively.[4–7] In longer term follow–up from the GEMINI trials, about 20% of both CD and UC patients who initially responded had discontinued vedolizumab because of lack of efficacy.[8,9] In real–world cohorts, vedolizumab therapy was stopped or optimised during the maintenance phase due to lack or loss of response in 36%–54% of IBD patients.[10–13]

Ustekinumab is a monoclonal IgG1 antibody against the p40 subunit of interleukin–12 (IL–12) and interleukin–23 (IL–23) that targets both the T–helper 1 and T–helper 17 pathways involved in the pathogenesis of CD. A large phase 2b (CERTIFI) and three pivotal phase 3 studies (UNITI) have shown that ustekinumab is effective as an induction and maintenance therapy for CD.[14,15] In 2016, ustekinumab was approved for the treatment of moderately to severely active CD in adults who have failed or were intolerant to treatment with immunomodulators or corticosteroids but never failed treatment with an anti–TNF, or who failed or were intolerant to treatment with one or more anti–TNF. In real–world observational studies, patients were treated off–label and received highly variable induction and maintenance dosing, thus limiting the generalisability of results. The rates of response were reported to be as high as 84% and remission rates as high as 35% at end of induction, with loss of response in around one–third of patients during maintenance.[16–21]

These 2 drugs appear to have a favourable safety profile and are well tolerated.[15,22] They provide alternative options other than anti–TNF therapy in the treatment of moderate to severe IBD. However, similar to anti–TNF agents, a significant number of patients do not respond to these drugs and their place relative to anti–TNF therapy (before or after) remains unclear. The purpose of this review is to summarise the current literature regarding the predictors of primary and secondary response to vedolizumab and ustekinumab in CD and UC adult patients, and to compare with the current predictors to anti–TNF, in order to identify patients who are most likely to benefit from these specific therapies.

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