NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 11 | FEBRUARY 2014

YEAR IN REVIEWIBD IN 2013

Enriching the therapeutic armamentarium for IBDSilvio Danese and Laurent Peyrin-Biroulet

In 2013, several new IBD drugs, including golimumab and vedolizumab, have been approved or completed successful programmes, showing efficacy in both Crohn’s disease and ulcerative colitis. In addition, classic IBD drugs have been formulated for colonic delivery, such as budesonide MMX®, which was recently approved for mild-to-moderate ulcerative colitis. Danese, S. & Peyrin-Biroulet, L. Nat. Rev. Gastroenterol. Hepatol. 11, 84–86 (2014); published online 24 December 2013; doi:10.1038/nrgastro.2013.246

The advent of anti-TNF agents dramati-cally changed the way we treat IBD that is refractory to standard medications (cortico-steroids, thiopurines or methotrexate), by achieving steroid-free remission, improving quality of life and reducing hospitalizations and surgeries. However, primary non-response, intolerance and loss of response are frequent for all available anti-TNF agents.1,2 In the context of more ambitious therapeutic goals, such as mucosal healing, deep remis-sion and histological healing, and evolv-ing therapeutic strategies based on tight monitor ing and rapid step-up approaches, new biologic agents are eagerly awaited. Building on the publication of studies on the biologic agents ustekinumab and tofacitinib in 2012, 2013 will stand out as a year of great success for the in troduction of new drugs for the t reatment of IBD.

TNF remains a key target in the treat-ment of IBD and the new anti-TNF agent golimumab has been shown to be very effective in patients who have moderately to severely active ulcerative colitis.3,4 In the SC induction study (PURSUIT-SC), patients with ulcerative colitis unresponsive to conventional treatment were randomly assigned to receive placebo or golimumab at two different doses given 2 weeks apart (400 mg followed by 200 mg, or 200 mg fol-lowed by 100 mg). At week 6, significantly more g olimumab-treated patients achieved response, remission and mucosal healing.3 In the subsequent maintenance study (PURSUIT-M), patients who responded to golimumab induction therapy were randomly assigned to receive golimumab (50 mg or 100 mg) or placebo every 4 weeks

for 52 weeks. At week 54, patients treated with golimumab achieved significant con-tinuous response, remission and mucosal healing compared with those who received placebo.4 Together, these studies bring a new treatment option to patients with ulcerative colitis, one that is effective, convenient and has a good safety profile. Golimumab has been approved by both the FDA and the European Medicines Agency (EMA), bring-ing the number of anti-TNF agents available for the treatment of ulcerative colitis to three (infliximab, ad alimumab and golimumab).

Among new biologic agents in the pipe-line for the treatment of IBD,5 several classes of compound seem promising. Vedolizumab is a humanized mono clonal antibody that specifically antagonizes α4β7 integrin, by inhibiting its binding to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1). MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. The α4β7 integrin is expressed on a subset of circulating white blood cells that have been shown to have a key patho-genic role in IBD. The binding specificity and selective antagonism of vedolizumab might ultimately confer an improved risk-to-benefit profile for patients with IBD. Indeed, the gut selectivity of vedolizumab is less likely to predispose patients to

systemic adverse events outside the gastro-intestinal tract, such as infection and/or neoplasia, than other biologic agents.6

Announced in early 2009, the GEMINI studies comprise a phase III programme evaluating the effect of vedolizumab on clinical response and remission along with the effect on mucosal healing in patients with ulcerative colitis, and long-term safety in patients with moderately to severely active Crohn’s disease or ulcerative colitis for whom treatment with at least one con-ventional therapy or a TNF antagonist had failed. The GEMINI programme consists of four separate studies: a placebo-controlle d induction and maintenance study in patients with ulcerative colitis (GEMINI I); a placebo-controlled induction and main-tenance study in patients with Crohn’s disease (GEMINI II); a placebo-controlled induction study in patients with Crohn’s disease with prior TNF antagonist failure (GEMINI III); and two open-label long-term safety studies in patients with either Crohn’s disease or ulcerative colitis (GEMINI LTS).

The findings from GEMINI I demon-strated that intravenous vedolizumab at a dose of 300 mg is highly effective at induc-ing and maintaining clinical remission and mucosal healing in patients with ulcerative colitis.7 Vedolizumab was also effective as induction therapy in patients with Crohn’s disease when considering clinical remission at week 6, but the difference between the active and placebo arms did not reach stat-istical significance when considering clini-cal response defined as a 100 point decrease of the Crohn’s disease activity index.8 The placebo effect (absence of evaluation of objective signs of inflammation, such as mucosal healing) and/or the fact that the studied population had Crohn’s disease of long duration and previous exposure to anti-TNF therapy is a possible explan-ation for these results. Importantly, patients with Crohn’s disease who had a response to induction therapy who continued to receive vedolizumab (rather than switching

‘‘…golimumab has been shown to be very effective [for] moderately to severely active ulcerative colitis…’’

‘‘…the gut selectivity of vedolizumab is less likely to predispose patients to systemic adverse events…’’

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YEAR IN REVIEW

to placebo) were successfully brought into remission at week 52. Vedolizumab was well tolerated in patients with either ulcer-ative colitis or Crohn’s disease. Approval of vedolizumab by the FDA and the EMA for both Crohn’s disease and ulcerative colitis is pending.

Beside the novel biologic agents that are mainly developed for patients with mod-erate or severe disease, new drugs are also being investigated for the treatment of those with mild or moderate disease, trying to optimize old compounds with new colonic delivery systems. This scenario is relevant for a novel oral formulation of budesonide that uses Multi-Matrix System (MMX®, Cosmo Pharmaceuticals, Milan) technology to extend release to the colon. In a recent controlled trial, budesonide MMX® (9 mg once daily) was safe and more effective than placebo at inducing remission in patients with active, mild-to-moderate ulcerative colitis.9 Safety was comparable to that of placebo, supporting the lack of adverse effects recognized with systemic steroids. Budesonide MMX® has been approved by the FDA and in some European coun-tries for the treatment of mild or moderate u lcerative colitis.

In conclusion, the approval of new drugs, including biologic agents, will dramatically change our practice after 15 years using anti-TNF therapy. However, the launch

of these new biologic agents raises several questions. First, which biologic should be used as first-line therapy in patients who have refractory IBD? Second, when and how should biologic agents be switched? Only head-to-head trials can address which biologic agent to use first, because an indirect comparison across trials is not sufficient to guide decision-making. As no head-to-head trials have been conducted so far, the cost of treatment, convenience and satisfaction for the patient, route of admin-istration, and the safety and efficacy profile should all be considered when making clinical decisions.

When contemplating the issue of switch-ing biologic agents, some lessons can be learned from the treatment of rheumatoid arthritis, for which nine biologic agents have been approved. TNF inhibitors were the first biologic therapies approved for use in rheumatoid arthritis, followed by the T-cell co-stimulation inhibitor a batacept, the B-cell-depleting monoclonal anti-body rituximab, the IL-1 receptor blocker anakinra and the IL-6 receptor inhibitor tocilizumab. Before the advent of biologic agents that do not inhibit TNF, switching from one TNF inhibitor to another was common practice for patients with rheuma-toid arthritis whose disease was not respon-sive to a particular treatment; however, if more than one TNF inhibitor provides in adequate responses and/or similar toler-ability issues, switching to a different class of agent might provide a more effective option and is now recommended.

Overall, the findings of the studies pub-lished in 2013, as well as those of others published in recent years, offer hope that patients with IBD will benefit from the launch of new drugs by changing the course of their disease together with their daily life.

IBD Centre, Division of Gastroenterology, Humanitas Clinical and Research Centre, Via Manzoni 56, 20089 Rozzano, Milan, Italy (S. Danese). INSERM U954 and Department of Gastroenterology, Université de Lorraine, Vandoeuvre-lès-Nancy, France (L. Peyrin‑Biroulet). Correspondence to: S. Danese sdanese@hotmail.com

Competing interestsS. Danese declares associations with the following companies: Abbott Laboratories, Abbvie, Actelion, Alphawasserman, Astra Zeneca, Cellerix, Celltrion, Cosmo Pharmaceuticals, Merck & Co, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millenium Takeda, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Tigenix, UCB Pharma and Vifor. L. Peyrin-Biroulet declares associations with the following companies: Abbott, BMS, Boehringer-Ingelheim, Celltrion, Ferring, Genentech, HAC-pharma, Hospira, Janssen, Merck, Mitsubishi, Norgine, Pharmacosmos, Pilège, Shire, Takeda, Therakos, Tillots, UCB Pharma and Vifor. See the article online for full details of the relationships.

1. Nielsen, O. H. & Ainsworth, M. A. Tumor necrosis factor inhibitors for inflammatory bowel disease. N. Engl. J. Med. 369, 754–762 (2013).

2. D’Haens, G. R. et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am. J. Gastroenterol. 106, 199–212 (2011).

3. Sandborn, W. J. et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology http://dx.doi.org/ 10.1053/j.gastro.2013.05.048.

4. Sandborn, W. J. et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology http://dx.doi.org/10.1053/ j.gastro.2013.06.010.

5. Danese, S. New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 61, 918–932 (2012).

6. Cominelli, F. Inhibition of leukocyte trafficking in inflammatory bowel disease. N. Engl. J. Med. 369, 775–776 (2013).

7. Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).

8. Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 369, 711–721 (2013).

9. Travis, S. P. et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut http://dx.doi.org/10.1136/gutjnl-2012-304258.

‘‘…when and how should biologic agents be switched?’’

Key advances

■ A substantial proportion of patients with IBD are unresponsive and intolerant to anti-TNF agents, and novel drugs are needed to fill the unmet medical need

■ After many years of translational research, in 2013 several new agents have been shown to be effective for IBD3,4,6–8

■ Vedolizumab is a novel non-TNF inhibitor effective for the treatment of IBD6–8

■ Budesonide MMX® is not a biological agent, but a conventional steroid with a colonic delivery formulation that provides efficacy with a good safety profile9

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