Journal List > Korean J Gastroenterol > v.71(2) > 1007772

Seo and Lee: Emerging Therapies: What Are Promising in the Near Future?

Abstract

The treatment of inflammatory bowel disease has evolved with the development of anti-TNF agents. In spite of long-term effectiveness, many patients do not respond or no longer responds to these drugs. Therefore, the development of new drugs that act on different inflammatory pathways has become necessary. Vedolizumab, a gut-specific biological agent, inhibits interaction α4β7 integrin with mucosal addressin cell adhesion molecule-1 without inhibiting systemic immune responses. Long-term vedolizumab therapy in patients with Crohn's disease and ulcerative colitis was safe and effective. Additionally, vedolizumab can be used in patients already failed an anti-TNF therapy. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23. Ustekinumab will be a clinically effective agent to use in medically-refractory Crohn's disease especially as a second line drug. Tofacitinib is an oral, small molecule that inhibits JAK1, JAK3 and in a lesser extent, JAK2. Perhaps the most attractive things of these JAK inhibitors is that they are given orally instead of parenterally. Early results showed that patients with moderately to severely active ulcerative colitis receiving tofacitinib were more likely to achieve remission at 8 weeks than those receiving placebo. However, these results have not been as robust in Crohn's disease. Much of the positioning will depend on the safety profile such as opportunistic infection and atherogenic risk. The challenges for the future are to determine the therapeutic drug monitoring-guided dose optimization, optimal timing and drug combinations to produce the most effective, and safest outcomes for IBD patients.

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Table 1.
Characteristics and Positioning of Vedolizumab, Ustekinumab and Tofacitinib in the Treatment of Inflammatory Bowel Disease
  Vedolizumab Ustekinumab Tofacitinib
Indication Moderate-to-severe UC and CD (second-line biologic agent in Korea) Moderate-to-severe CD Moderate-to-severe UC
Patient profiles 1. Concerns about infection and cancer 1. EIM 1. Intolerable injection side effects
2. Children a 2. Prefer oral medication over injectable administration
2. Uncontrolled heart failure, a history of lymphoma, or multiple sclerosis 3. Anti-TNF induced psoriaform lesions  
Route of administration and dosage in clinical trials IV induction (300 mg, q0–2–6w) and maintenance (300 mg q8w) IV or sc induction b (130 mg or 6 mg/kg), sc maintenance (90 mg q8w or q12w) Oral induction (10 mg BID) and maintenance (5 mg BID or 10 mg BID)
Induction of remission at week 6 or 8 1. 53.1% (anti-TNF naïve)/39.0% (anti-TNF failure) in UC 15.9% (130 mg)/20.9% (6mg/kg) in anti-TNF failure group 18.5% (10 mg BID)
2. 22.7% (anti-TNF naïve)/13.3% (anti-TNF failure) in CD 30.6% (130 mg)/40.2% (6 mg/kg) in conventional therapy failure group  
Sustained clinical remission who had a clinical response to induction therapy 1. 46.9% (anti-TNF naïve)/36.1% (anti-TNF failure) in UC at week 52 48.8% (90 mg q12w)/53.1% (90 mg q8w) at week 44 34.3% (5 mg BID), 40.6% (10 mg BID) at week 52
2. 48.9% (anti-TNF naïve)/27.7% (anti-TNF failure) in CD at week 52    
Mucosal healing 1. 41.9% (VDZ q8w)/47.5% (VDZ q4w) in anti-TNF failure group at week 52 Approximately one quarter (endoscopic or radiologic response; 51.6–76.0%) 1. 31.3% in OCTAVE 1, 28.4% in OCTAVE 2
2. 17–63% in CD 2. 37.4% (5 mg BID)/45.7% (10 mg BID) in OCTAVE sustain
Summary of clinical efficacy results 1. Highest as first-line agent for induction of remission and mucosal healing in moderate-to-severe UC Consistent benefit of induction regimens, irrespective of previous treatment or response to a TNF antagonist Similar efficacy in UC patients regardless of whether or not they have received prior anti-TNF therapy (highest second-line agent for induction of remission and mucosal healing in moderate-to-severe UC)
2. The effectiveness of VDZ in anti-TNFα-naive populations tended to be greater than that in anti-TNFα-experienced populations
Safety profile Favourable safety profile Contraindicated in patients with hypersensitivity and clinically important active infection (e.g. active TB) 1. Increased risk of herpes zoster
2. Risk of dyslipidemia

UC, ulcerative colitis; CD, Crohn's disease; EIM, extraintestinal manifestation; TNF, tumor necrosis factor; VDZ, vedolizumab.

a Pediatric CD patients; only case series of UST use are available

b Various dosage was used.

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