2015-10-26 17:45:00 2015-10-26 19:15:00 Europe/Riga Gut-Selective Biologic Therapy for Ulcerative Colitis: Lessons from Science and Practice This event begins at 17:45, Barcelona time, Monday October 26, 2015. http://www.takedaibd.com Fira de Barcelona Room B2 Barcelona, Spain www.takedaibd.com

Gut-Selective Biologic Therapy for Ulcerative Colitis

Lessons From Science and Practice

26 October 2015
Fira de Barcelona
Room C1
Barcelona Spain


Axel Dignass, MD, PhD

Director, Dept of Medicine
Agaplesion Markus Hospital, Goethe–University
Frankfurt am Main, Germany

Treatment Goals in Ulcerative Colitis: Clinical Remission and Beyond

Therapeutic goals for patients with UC are not only to achieve symptomatic relief and induce clinical remission, but also to prevent further disease flares and maintain clinical remission. A broad armamentarium of medical therapies for the treatment of UC has been approved and licensed, and can be used according to the principles of evidence-based medicine for the induction and maintenance of remission in patients with moderate–severe UC. Among these therapies are various mesalazine formulations, systemic and topical corticosteroids, various immunosuppressants like thioguanines and calcineurin inhibitors, and biologics such as anti–TNF blockers and the anti-integrin antibody. As a significant portion of UC patients may become dependent on glucocorticoids to control symptoms, steroid sparing is also an important treatment goal in the management of UC. Due to the chronic nature of UC, long-term disease control has to be achieved with consideration of the risk-benefit profile of a medication, and thus the safety of a treatment option has gained significant importance.

Biological therapy with the anti-TNF antibodies infliximab, adalimumab, and golimumab, and the gut-selective anti-integrin antibody vedolizumab has added significantly to the range of available treatments for moderate–severe UC in the past decade. In clinical trials, all of these biologics have demonstrated good tolerability and clinical benefits in inducing and maintaining remission, including steroid-free remission. For example, treatment with infliximab has shown a clinical response rate up to 69% at Week 8 and a steroid-free remission rate of 26% at Week 54 in patients who failed conventional therapies.1 Vedolizumab has shown a 47% clinical response rate at Week 6 and a 45% steroid-free remission rate at Week 52 in a more refractory patient population, including those who had failed anti-TNF or conventional therapies.2

Treatment targets in UC are currently evolving to include other outcomes, such as mucosal healing and patient-reported remission.3 There is increasing evidence to suggest that achieving mucosal healing and reduction in endoscopic disease activity may correlate with better long-term outcomes, such as prolonged clinical remission and lower risk of hospitalizations, colectomy, and dysplasia.4,5 Patient-reported remission has recently been proposed as one of the treatment targets in the care of patients with IBD, with the goal of improving health-related quality of life and physical/emotional disability, and ultimately getting the patient's life back to normal.6

With the emergence of these potential new therapeutic goals in UC, many unanswered questions remain: What are the optimal treatment goals for an individual patient? How do we define these goals and when and how do we assess if a given treatment achieves them? How do we achieve therapeutic goals with well tolerated and effective treatment, and monitor treatment success with affordable, reliable, and safe procedures? Will achieving these new goals ultimately change the disease course of UC? Answers to these questions, it is hoped, will improve our understanding of evidence-based treatment goals in UC and guide their potential application in routine clinical practice.

1 Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.
2 Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699-710.
3 Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324-38.
4 Lichtenstein GR, Rutgeerts P. Importance of mucosal healing in ulcerative colitis. Inflamm Bowel Dis. 2010;16:338-46.
5 Frøslie KF, Jahnsen J, Moum BA, Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007; 133:412-22.
6 Williet N, Sandborn WJ, Peyrin-Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2014;12:1246-56.e6.

Britta Siegmund, MD

Director, Dept of Gastroenterology, Infectious Diseases, and Rheumatology
Charité–Universitätsmedizin Berlin, Germany

First-line Biologic Options for the Treatment of Ulcerative Colitis

Several biologic agents have received regulatory approval for the treatment of UC. Adalimumab, golimumab, and infliximab are all TNF-α blockers. Vedolizumab has a different mechanism of action; it specifically recognizes the α4β7 integrin receptor and selectively blocks gut lymphocyte trafficking. How to choose a first-line biologic among systemic anti-TNFs and gut-selective vedolizumab to achieve and maintain clinical remission is an important clinical question, but challenging to answer due to the lack of head-to-head trials of biologic agents.

The parameters to consider for determining the first biologic treatment for our patients with moderate–severe UC, based on clinical data, literature search, and personal experience, will be discussed. These parameters include patient comorbidities and preference, disease severity, previous treatments, and, most importantly, the benefit-risk profile of each biologic.

In terms of efficacy, indirect comparison of results from pivotal phase 3 trials shows that anti-TNFs and vedolizumab appear largely comparable in their ability to induce and maintain clinical remission, taking into consideration different trial populations and analyses.1-6 Systemic reviews and network meta-analyses have reported similar results, with some variations in comparative efficacy between biologic agents depending on the methodology and trials included in each meta-analysis.7,8 Compared with anti-TNFs, vedolizumab does not seem to be associated with systemic immunosuppression, as shown in pivotal trials.1-6,9 The safety of vedolizumab is being further assessed in the ongoing GEMINI long-term safety study.

Patient comorbidities and preference may also affect decision-making regarding the choice of first-line biologic agent. Applying the recommended screening for latent tuberculosis, active hepatitis B/C virus, or other infections, before biologic treatment not only minimizes treatment-related adverse events, but also helps in determining the best biologic to use.10 Patient preference may be influenced by drug administration route, schedule, infusion time, or "unpleasant" infusion reactions or injection-site reactions.

Other parameters to consider are safety of dose escalation, previous treatments and response to previous treatments, and efficacy and safety of combining biologics with corticosteroids or immunomodulators for early intervention.

By focusing on these parameters in detail, benefit-risk evidence for each biologic will be obtained, which will then result in practical guidelines on the use of biological agents in patients with moderate–severe UC.

1 Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.
2 Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60:780–7.
3 Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:85–95.
4 Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257–65.e1–3.
5 Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:96–109.e1.
6 Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699-710.
7 Danese S, Fiorino G, Peyrin-Biroulet L, et al. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis. Ann Intern Med. 2014;160:704-11.
8 Vickers AD, Mody RR, Bergman A, et al. Comparative efficacy of biologics in the treatment of moderately to severely active ulcerative colitis (UC): a systematic review and network meta-analysis. Gastroenterology. 2015;148:S-272. Abstr Sa1257.
9 Entyvio [summary of product characteristics]. Taastrup, Denmark: Takeda Pharma A/S; 2014.
10 Chebli JM, Gaburri PD, Chebli LA, et al. A guide to prepare patients with inflammatory bowel diseases for anti-TNF-α therapy. Med Sci Monit. 2014;20:487-498.

William Sandborn, MD

Chief, Division of Gastroenterology
University of California, San Diego
La Jolla, USA

Real-world Experience With Gut-Selective Therapy in Ulcerative Colitis

In the GEMINI I clinical trial, vedolizumab has demonstrated efficacy and a good tolerability profile in the induction and maintenance of remission in patients with moderate-severe UC.1 Because inclusion criteria used in randomized controlled trials and procedures in a research setting may not readily reflect everyday clinical practice, however, the question remains if the treatment effect of vedolizumab is similar in a real-life setting.

During tonight's presentation, I will discuss our clinical experience on the use of vedolizumab in UC based on a recent analysis we conducted from a well-characterized large multicenter consortium.2 In addition, I will present and summarize other real-world studies of vedolizumab so that we can have a holistic view of how this gut-selective therapy has been used in clinical practice since its approval a little over a year ago.3-10

In our analysis, only half of the UC patients would have qualified for the GEMINI I trial and the majority had failed multiple anti-TNF therapies, indicating these real-world patients had complex phenotypes and highly refractory diseases. Despite these characteristics, UC patients who were treated with vedolizumab achieved high response, remission, and mucosal healing rates, and the rates increased over time.2 Similar results were observed in other studies of vedolizumab from multiple tertiary/referral centers across the USA and Europe.3-10 When reviewing these real-world studies, we noticed the trend that vedolizumab therapy seems to have comparable short term efficacy and safety to those seen in the pivotal trials.1-10

In addition to efficacy and safety, I will discuss some practical considerations for the use of vedolizumab, including its dosing, steroid sparing, concomitant medications, monitoring of therapeutic response, and appropriate patients. The overall outlook for patients newly diagnosed with UC, their perspective on receiving a well tolerated and effective gut-selective drug, and other unanswered questions that may be addressed with real-world studies will also be reviewed.

1 Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699-710.
2 Dulai P, Singh S, Narula N, et al. Vedolizumab for moderate to severely active inflammatory bowel disease: a multi-center U.S. consortium. Presented at the American College of Gastroenterology Annual Scientific Meeting, Honolulu, HI, 16-21 October, 2015. P1755.
3 Morganstern B, Singh N, Targan S, et al. Single-center experience of vedolizumab in patients with inflammatory bowel disease: does age matter? Gastroenterology. 2015;148;S-250. Abstr Sa1182.
4 Lucci MB, Collins E, Cao B, et al. Initial vedolizumab cohort: patient characteristics and clinical response. Gastroenterology. 2015;148;S-255. Abstr Sa1198.
5 Christensen B, Goeppinger SR, Colman RJ, et al. Vedolizumab in the treatment of IBD: the University of Chicago experience. Gastroenterology. 2015;148;S-866. Abstr Tu1350.
6 Stevens BW, Shelton E, Sauk J, et al. Efficacy of vedolizumab as induction therapy in refractory IBD patients following multiple anti-TNF therapy failures. Gastroenterology. 2015;148;S-869. Abstr Tu1359.
7 Vivio E, Kanuri ND, Dey N, et al. Vedolizumab efficacy and safety in a tertiary care IBD clinical practice. Gastroenterology. 2015;148;S-871. Abstr Tu1369.
8 Oppenheim S, Wasan SK, Noronha A, et al. A retrospective review of response rates and risk of complications among inflammatory bowel diseases patients treated with vedolizumab. Gastroenterology. 2015;148;S-872. Abstr Tu1371.
9 Eriksson C, Almer S, Björk JA, et al. Vedolizumab in inflammatory bowel disease, the first experience from the Swedish IBD Registry (SWIBREG). Gastroenterology. 2015;148;S-871. Abstr Tu1368.
10 Shelton E, Allegretti JR, Stevens B, et al. Efficacy of vedolizumab as induction therapy in refractory IBD patients: a multicenter cohort. Inflamm Bowel Dis. 2015 Aug 17. [Epub ahead of print.]