REVIEW URRENT C OPINION
Therapy of inflammatory bowel disease: what to expect in the next decade David A. Leiman and Gary R. Lichtenstein
Purpose of review The increased understanding of the molecular mechanisms that are responsible for inflammatory bowel disease (IBD) has led to a wide range of potential therapeutic targets for this condition. Physicians treating individuals with Crohn’s disease and ulcerative colitis have a growing armamentarium of options to choose from in managing these patients. This article aims to summarize the relevant literature in the area of emerging therapy in IBD. Recent findings The widespread use of antitumor necrosis factor medications brought a landmark change in the treatment of IBD. More recently, several drugs have been shown to provide benefit in IBD in phase III studies by blocking other antiinflammatory pathways. The most likely new medications that will be available include vedolizumab for ulcerative colitis and ustekinumab for Crohn’s disease, which target cellular adhesion and inflammatory cell signaling, respectively. Other promising drugs focus on blockade of Janus kinase, inhibition of various chemokines, and biologic therapy such as hematopoietic stem cell transplants and mesenchymal cell infusions. Summary The growing understanding of the pathogenesis of IBD has led to new molecular targets for therapy. Over the next decade, the number of treatments available will grow, targeting cellular adhesion, protein regulation, inflammatory signal pathways, and immune tolerance. Keywords emerging therapy, inflammatory bowel disease, novel treatments
INTRODUCTION Scientific advances have led to an improved understanding of factors promoting and inhibiting the inflammation associated with inflammatory bowel disease (IBD). These advances have paved the pathway toward an array of exciting and complex new medical therapeutic targets. This review article highlights current and emerging therapies that will likely play an important role in the management of both Crohn’s disease and ulcerative colitis in the forthcoming years.
ANTITUMOR NECROSIS FACTOR In addition to the introduction of novel therapeutic agents, the next decade will invariably see the continued use and ‘fine-tuning’ of the current armamentarium of IBD therapy, especially antitumor necrosis factor (anti-TNF-a) medications that have become fundamental in treating both Crohn’s disease and ulcerative colitis. Since first approved in
1998, infliximab has been used for induction and maintenance of therapy in Crohn’s disease with and without fistulae [1–4]. This was followed by regulatory approval for use in ulcerative colitis [5]. Other TNF-a antagonist medications followed, with adalimumab approved first for induction and maintenance in Crohn’s disease and then in ulcerative colitis [6–10]; certolizumab pegol was then approved for induction and maintenance in Crohn’s disease, while golimumab was approved for ulcerative colitis [11,12]. Newer anti-TNF-a options have added to the
Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA Correspondence to Gary R. Lichtenstein, MD, Hospital of the University of Pennsylvania, Perelman School of Medicine, Division of Gastroenterology, University of Pennsylvania, 9th Floor Penn Tower, One Convention Avenue, Philadelphia, PA 19104-4283, USA. Tel: +1 215 349 8222; fax: +1 215 349 5915; e-mail:
[email protected] Curr Opin Gastroenterol 2014, 30:385–390 DOI:10.1097/MOG.0000000000000077
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammatory bowel disease
KEY POINTS Anti-TNF therapy will continue to be an important agent in the management of both Crohn’s disease and ulcerative colitis in the coming years. Novel therapies most likely to be available soon include vedolizumab for ulcerative colitis and ustekinumab for Crohn’s disease. New orally administered therapies may be available for both Crohn’s disease and ulcerative colitis in the future. Exciting drugs early in development continue to show promise, although much research is needed including large-scale trials before chemokine antagonists and stem cell therapy become available.
diversity of treatment but many patients still require other treatments during their disease course.
ANTIADHESION MOLECULES
&&
Natalizumab, a humanized IgG4 monoclonal antibody directed against the a4 integrin adhesion molecule involved in endothelial leukocyte migration, was initially approved by the Food and Drug Administration (FDA) for the treatment of multiple sclerosis [13], but its efficacy was demonstrated in Crohn’s disease for both induction and maintenance of remission [14,15]. Lingering concerns over its association with progressive multifocal leukoencephalopathy have led to a search for gut-specific antiintegrin action that would eliminate this risk. Drugs with selective effects in the a4b7 integrin and mucosal adhesion molecule (MadCAM-1) pathway were sought. The results of the subsequent GEMINI studies investigating vedolizumab for both induction and maintenance in ulcerative colitis and Crohn’s disease were published in 2013 [16 ,17 ]. In the Crohn’s disease study, 368 patients were randomized to vedolizumab or placebo. Disease activity was measured at week 6 by assessing the reduction of Crohn’s disease activity index (CDAI). Patients on vedolizumab had a statistically significant difference in clinical remission of 14.5 versus 6.8% in placebo (P ¼ 0.02) but no difference in CDAI100 response or reduction in mean C-reactive protein (CRP) levels. A second cohort was given open-label vedolizumab and a total of 461 responders from both cohorts continued in the maintenance portion of the trial; patients were randomized to receive drug every 4 or 8 weeks or placebo for 52 weeks. There was statistical significance in clinical remission, CDAI-100 response, and glucocorticoid-free remission at week 52 in the every 4 or 8-week group versus placebo (P < 0.001 and 0.004, respectively) [17 ]. &&
&&
&&
386
www.co-gastroenterology.com
A similarly designed study was conducted for vedolizumab in ulcerative colitis; 374 patients were randomised to either drug or placebo as part of induction. The response for week 6 was measured by the Mayo score and documented mucosal healing. During induction, 47.1% of the patients on vedolizumab versus 25.5% of the patients on placebo achieved remission (P < 0.001). A second cohort of patients received open-label vedolizumab and responders from both cohorts were included in the maintenance trial that evaluated clinical remission at week 52. Patients were randomized to receive drug every 4 or 8 weeks or placebo. A total of 41.8% maintained remission when receiving medication every 8 weeks compared with 44.8% who received drug every 4 weeks; patients on placebo had maintenance of remission at a rate of 15.9%. There was a statistically significant difference in maintenance of remission between patients who received drug every 8 weeks versus placebo (P < 0.001) and those receiving drug every 4 weeks versus placebo (P < 0.001) [16 ]. Based on these findings, the drug was approved for use in adults with moderate to severe ulcerative colitis and moderate to severe Crohn’s disease when one or more standard therapies (corticosteroids, immunomodulators, or tumor necrosis factor blocker medications) have not resulted in an adequate response [18]. Another adhesion molecule blocker, AJM300, which has broad a4 integrin antagonist properties, has been tested in patients with active Crohn’s disease. These data were published in a 2009 abstract, showing a significant decrease in CDAI between groups on higher doses as well as reduction in C-reactive protein [19]. Recently, the company developing AJM300 released data from a phase IIa study showing efficacy in the treatment of patients with ulcerative colitis [20]. It reports that 102 patients in 42 Japanese sites were studied to assess the primary end point of clinical response rate at 8 weeks post administration, with an intention to induce remission rates that were significantly higher in the AJM300 treatment group compared with patients receiving placebo. These preliminary studies suggest that AJM300 could provide an oral option for ulcerative colitis and Crohn’s disease, though further investigative studies are needed. Recently published data from the EUCALYPTUS trial, a phase II randomized, double-blind, placebocontrolled induction study to evaluate efficacy and safety in patients with refractory moderate-to-severe active ulcerative colitis, show promise for another molecule in the antiadhesion molecule family. Etrolizumab, which targets the b7 subunit, provides the advantage of not penetrating into the central nervous system. In EUCALYPTUS, 124 patients were Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammatory bowel disease therapy in the next decade Leiman and Lichtenstein
randomized to two dose levels of drug (100 mg monthly subcutaneous or 300 mg monthly subcutaneous and loading dose of 420 mg subcutaneous between week 0 and 2) or placebo for three doses with demonstration of safety and efficacy [21 ]. Another agent, an anti-MadCAM-1 antibody (PF-00547659) showed encouraging results in a 12-week study of 80 patients with active ulcerative colitis with a primary end point for safety [22]. Antagonists of b7, such as AMG181, will also be studied more in the future. This suggests that the adhesion molecule pathway will continue to provide drug targets going forward. Many physicians anticipate that vedolizumab will gain regulatory approval for treatment of patients with ulcerative colitis soon. &
ANTIINTERLEUKIN 12/23 Interleukin-12 (IL-12) and IL-23 are proinflammatory cytokines involved in the pathophysiology of Crohn’s disease [23]. These molecules help to regulate type-1 helper T-cell responses and assist in the recruitment of macrophages. After initial lackluster results, ustekinumab, a fully human IgG1 monoclonal antibody to IL-12 and IL-23, demonstrated benefit when given subcutaneously to patients with moderate-to-severe active disease. The CERTIFI study, a phase IIb study, randomized 526 patients who were previously resistant to antiTNF-a therapy to receive either placebo or intravenous ustekinumab at doses of 1, 3, or 6 mg/kg. Clinical response based on CDAI scores was assessed at week 6. Only 23.5% of patients receiving placebo had response versus 36.6, 34.1, and 39.7%, respectively, for 1, 3, and 6 mg/kg of ustekinumab. These findings were only statistically significant for the 6 mg/kg group (P ¼ 0.005). In the maintenance phase of the study, patients who had a response to induction therapy and those who did not were rerandomized to either receive subcutaneous ustekinumab or placebo [24]. Response was assessed at week 22 and there was a statistically significant difference in clinical remission rates (41.7 versus 27.4%; P ¼ 0.03) and clinical response (69.4 versus 42.5%; P < 0.001). These findings are encouraging and potentially significant, presenting a nonsurgical approach to patients who previously had few medical options. In 2012, the FDA approved the drug for use in psoriatic arthritis, and phase III studies in Crohn’s disease are being conducted [25].
ANTAGONIST TO JANUS KINASE Although ustekinumab may eventually provide a medical option for patients with Crohn’s disease when anti-TNF therapy fails, its role for ulcerative colitis is not well established. Blockade of the Janus
kinase (JAK) has shown promise as an antiinflammatory approach in patients with autoimmune conditions such as psoriasis, and its use in ulcerative colitis may provide an alternative to surgery when current medications fail. The JAK family of tyrosine kinases mediates signal transduction for a variety of inflammatory cytokines including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [26 ]. Tofacitinib (CP-690550), an oral inhibitor of JAK 1, 2, and 3, was evaluated in patients with ulcerative colitis. In a phase II study, it was shown to significantly induce remission after 8 weeks compared with placebo. Although some safety concerns exist with respect to elevated levels of low-density lipoprotein cholesterol, we expect that this will be a matter of investigation over the next several years and has potential to be an alternative in the ulcerative colitis arsenal. &&
CHEMOKINE ANTAGONISTS Novel oral agents also may be available for patients with Crohn’s disease in the future based on early research on the blockade of certain chemokines. Chemokines bind to G-protein-coupled transmembrane receptors and are involved in the recruitment and migration of leukocytes into intestinal mucosa under both normal and inflamed conditions [27]; they also play a role in the pathogenesis of IBD [28]. Aberrant expression of the chemokine receptor 9 is found in the small intestine and may be expressed in the colon as well, suggesting a potential target for the therapy of Crohn’s disease. The orally administered inhibitor of chemokine receptor 9, CCX282-B or vercirnon, was evaluated in a randomized, double-blind, placebo-controlled study of 436 patients with large or small bowel Crohn’s disease [29 ]. The study evaluated both induction and maintenance of remission, with primary end points of clinical response at weeks 8 and 52, respectively. The patients received doses of 250 mg daily, 250 mg twice daily, or 500 mg daily. During the 12-week induction period, the clinical response was highest in the group that was given 500 mg once daily at 61 versus 47% in the placebo group (P ¼ 0.039). At the end of the maintenance phase (week 52), 47% of patients on CCX282-B were in remission, compared with 31% on placebo (P ¼ 0.012). Although not statistically significant, the trend suggests that there may be a benefit in a subset of the population having Crohn’s disease. Ongoing phase III trials will aim to further evaluate this novel potential therapeutic. Chemokine antagonists are also being explored for use in ulcerative colitis. Indeed, interferon g-inducible protein-10 (IP-10) is a chemokine that
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-gastroenterology.com
387
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammatory bowel disease
is involved with inflammatory cell migration and is overexpressed in colonic tissue and the plasma of patients with ulcerative colitis [30]. An 8-week phase II clinical proof-of-concept trial was carried out in 109 North American and European patients with moderately-to-severely active ulcerative colitis to test an inhibitor of IP-10 called BMS-936557 (formerly, MDX-1100). Patients were randomized to intravenous drug (10 mg/kg at weeks 0, 2, 4, and 6) or placebo and evaluated for induction of remission at day 57. No statistically significant difference was seen in clinical response, remission, or mucosal healing. However, in the patients achieving highest plasma concentrations, there was a statistically significant difference in all three end points (87.5% for the highest tertile versus 37.0% for placebo; P < 0.001) [31 ], reinforcing enthusiasm for further investigation of chemokine antagonists. Another molecule in this class to watch for in the future includes interferon-g IP-10 (CXCL-10), which mediates T-cell recruitment and activity modulating other cell functions such as epithelial and endothelial cells [32]. However, it is likely that these agents will require significant further investigation before they will be readily available for use in the management of IBD. &
LONG-RANGE OPTIONS There are several therapeutic options at early stages of study, but still they have shown promise in both the Crohn’s disease and the ulcerative colitis.
Antiinterleukin-6/Tocilizumab IL-6 is a cytokine secreted by a variety of immune and nonimmune cells that functions to stimulate the immune response and is involved in the acute-phase response. Tocilizumab is a humanized monoclonal antibody that blocks both membrane-bound and soluble IL-6 receptor [33]. A small randomized controlled pilot trial of 36 patients with active Crohn’s disease treated with tocilizumab showed encouraging results [34]. Patients received biweekly infusions of either drug or placebo at 8 mg/kg and after 12 weeks there was a statistically significant difference in clinical response (80 versus 31%; P ¼ 0.019). These findings need to be confirmed in a larger clinical trial. Other drugs in this class that will continue to be tested include BMS-945429 and PF-04236921, which are fully human antibodies to IL-6 [35,36].
Laquinimod Laquinimod is a novel orally administered synthetic agent that has been studied for use in multiple sclerosis and explored as a potential agent in Crohn’s disease. It acts as an immunomodulator 388
www.co-gastroenterology.com
but does not seem to lead to immunosuppression, primarily acting to direct T cells into an antiinflammatory phenotype [37] and downregulating proinflammatory cytokines. In a phase IIa multicenter, sequential cohort randomized controlled exploratory trial of 180 patients with moderately-toseverely active Crohn’s disease, clinical remission, clinical response, and intestinal inflammation (based on fecal calprotectin levels) were assessed. Patients were given doses of 0.5, 1, 1.5, or 2 mg/day of laquinimod for 8 weeks or placebo. In this study, patients on the lowest dosage of laquinimod have the greatest benefit in clinical remission (48.3 versus 15.9% with placebo, no P-value reported), clinical response (55.2 versus 31.7% with placebo, no P-value reported), and more than 50% reduction in fecal calprotectin (38.9 versus 13.6% with placebo, no P-value reported). These data represent early findings and warrant further investigation [38 ]. &
HMPL-004 HMPL-004 (Andrographis paniculata extract) is a plant derivative that has been shown to have several antiinflammatory properties that work by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells, TNF-a, and IL-1b [39]. It has known efficacy in murine colitis models and, therefore, has been evaluated in patients with ulcerative colitis [40 ]. A double-blind, randomized placebo-controlled trial was conducted over 8 weeks to evaluate its efficacy in 224 patients with mild-to-moderate ulcerative colitis at daily doses of 1.2 g, 1.8 g, or placebo. There was a statistically significant response seen in patients treated at high dose of A. paniculata, with 60% of patients achieving clinical response compared with 40% receiving placebo (P ¼ 0.018). However, it has not yet been tested in patients with more severe disease and, therefore, may represent an alternative to traditional mesalamine compounds in the future, with unclear utility in patients with refractory disease. &
Stem cell therapy Case reports suggesting that IBD could be cured through stem cell transplants raised hopes for a paradigm-shifting therapy [41,42]. This led to the investigation of both hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) as therapeutic options in Crohn’s disease. The use of HSC has been reserved for the most refractory Crohn’s disease cases and has shown some degree of success. It is believed that HSC exert effects through ‘resetting’ the immune system, although this requires a cytotoxic conditioning regimen prior to transplant [41]. Two case series Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammatory bowel disease therapy in the next decade Leiman and Lichtenstein
of patients treated with autologous HSC transplant had success rates of 80 and 91%, with cohorts of 10 and 24 patients, respectively [43,44]. In the only randomized controlled trial investigating autologous stem cell transplant, 45 patients with severe Crohn’s disease were randomized to receive either cytotoxic conditioning followed by autologous cell infusion or conditioning alone [45 ]. Early results demonstrated a greater reduction in CDAI in the transplanted patients (324 to 161) compared with conditioning alone (351 to 272), but no P-value was reported. While these findings highlight some of the potential benefits, there are substantial risks. Separating the potential benefit of HSC transplant versus the risk of the conditioning cytotoxic regimen alone is crucial but still an unresolved issue. It is believed that MSC, which can be derived from both bone marrow and adipose tissue, work through two mechanisms to be both immunosuppressive and antiinflammatory [41]. In patients with IBD, MSC therapy has been tested for treatment of fistulizing disease and luminal disease. Early phase I and phase II studies of feasibility described fistula closure with local injection of MSC along with fibrin glue [46,47]. These successes were followed by investigations of injecting peripherally expanded MSC into a fistulous tract [48]. In the study of 10 patients, seven had complete sustained closure (P < 0.01) on magnetic resonance imaging and reduction in Crohn’s disease and perianal disease activity indices (P < 0.01 for both). Treating luminal Crohn’s disease with MSC seems promising based on recent data. A phase II open-label, multicenter, nonrandomized study of 16 refractory Australian patients with Crohn’s disease who had failed anti-TNF therapy investigated the benefit of sequential MSC infusions, which were given 1 week apart over 4 weeks [49 ]. The primary outcome of clinical response was evaluated at day 42 and showed success in 80% (P < 0.0001) of the patients, with improvement in secondary outcomes of clinical remission and endoscopic score in 53 and 47%, respectively. The use of stem cell therapy offers great promise, including a potential cure for patients with IBD. However, it comes with significant potential risk and with scant data for use in the setting of ulcerative colitis. These early reports of success will continue to prompt deeper investigation into the utility of both HSC and MSC. &&
&&
CONCLUSION The future holds potential for new and effective therapies for patients with IBD. Multiple agents acting via novel mechanisms are being explored
and developed to increase our existing therapeutic armamentarium. It is likely that the next decade will see some of these drugs come to market. As we gain a greater understanding of the microbiome and its role in the pathogenesis of IBD, there will be many new opportunities for even more options, including antibiotics, fecal transplant, probiotics, and nonimmunosuppressive agents. Acknowledgements None. Conflicts of interest D.A.L. has no financial disclosures or conflicts of interest to report. G.R.L. reports consulting for and/or receiving financial compensation from Abbott Corporation/Abbvie, Alaven, Bristol-Myers Squibb, Elan, Ferring, Hospira, Jansen Orthobiotech, Luitpold/American Regent, Millennium Pharmaceuticals, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Prometheus Laboratories, Inc., Salix Pharmaceuticals, Santarus, Shire Pharmaceuticals, Takeda, UCB, and Warner Chilcotte.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. D’Haens G, Deventer SV, Hogenzand RV, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999; 116:1029– 1034. 2. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359:1541– 1549. 3. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340:1398– 1405. 4. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350:876–885. 5. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462– 2476. 6. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130:323–333. 7. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007; 56:1232–1239. 8. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007; 132:52–65. 9. 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; 60:780–787. 10. 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; 142:257–265. 11. Schreiber S. Certolizumab pegol for the treatment of Crohn’s disease. Therap Adv Gastroenterol 2011; 4:375–389. 12. 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. 13. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348:15–23.
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
389
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammatory bowel disease 14. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005; 353: 1912–1925. 15. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial. Gastroenterology 2007; 132:1672–1683. 16. 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. This trial of Crohn’s disease showed statistically significant reduction in clinical remission during induction but not for objective measures of inflammation. These findings suggest that there may be more efficacy in ulcerative colitis than Crohn’s disease for vedolizumab. 17. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and && maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369:711– 721. This trial aimed at patients with ulcerative colitis showing a highly statistically significant measure of induction and maintenance of remission. It is the basis for FDA priority review of the drug. 18. Food and Drug Administration. FDA approves Entyvio to treat ulcerative colitis and Crohn’s disease. 2013. 19. Takazoe M, Watanabe M, Kawaguchi T, et al. Oral alpha-4 integrin inhibitor (AJM300) in patients with active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2009; 136:A181. 20. Ajinomoto Pharmaceuticals. PIIa Clinical Study Results of AJM300 in Ulcerative Colitis: Oral a4 integrin inhibitor was demonstrated to be effective in treatment of inflammatory bowel disease for the first time in the world. http:// www.ajinomoto-seiyaku.co.jp/newsrelease/2013/1106e.pdf. [Accessed 2 February 2014] 21. Vermeire S, O’Byrne S, Williams M, Mansfield J. Differentiation between & etrolizumab (rhuMAb beta7) and placebo in the Eucalyptus phase II randomized double-blind placebo-controlled induction study to evaluate efficacy and safety in patients with refractory moderate-to-severely active ulcerative colitis. Gastroenterology 2013; 144:S-36. Etrolizumab is a targeted anticellular adhesion molecule that does not cross the blood–brain barrier and has demonstrated safety in the treatment of ulcerative colitis. 22. Vermeire S, Ghosh S, Panes J, et al. The mucosal addressin cell adhesion molecule antibody PF-00547659 in ulcerative colitis: a randomised study. Gut 2011; 60:1068–1075. 23. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008; 135:1130– 1141. 24. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012; 367: 1519–1528. 25. ClinicalTrials.gov: National Institutes of Health, 2014. http://clinicaltrials.gov/ ct2/show/NCT01369342 and http://clinicaltrials.gov/ct2/show/NCT 01369355. [Accessed 29 January 2014] 26. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase && inhibitor, in active ulcerative colitis. N Engl J Med 2012; 367:616–624. This trial explores a novel targeted pathway to treat ulcerative colitis. These positive results represent a potential novel oral antiinflammatory approach. 27. Walters MJ, Wang Y, Lai N, et al. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease. J Pharmacol Exp Ther 2010; 335:61–69. 28. Papadakis KA, Prehn J, Moreno ST, et al. CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn’s disease. Gastroenterology 2001; 121:246–254. 29. Keshav S, Vanasek T, Niv Y, et al. A randomized controlled trial of the efficacy & and safety of CCX282-B, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn’s disease. PloS One 2013; 8: e60094. The results of this trial only show a trend toward significance but form the basis for future studies. 30. Torres J, Danese S, Colombel JF. New therapeutic avenues in ulcerative colitis: thinking out of the box. Gut 2013; 62:1642–1652.
390
www.co-gastroenterology.com
31. Mayer L, Sandborn WJ, Stepanov Y, et al. Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study. Gut 2014; 63:442–450. In this study, a subgroup of patients with high serum concentrations of the antibody had a statistically significant difference in clinical response, remission, or mucosal healing. 32. Antonelli A, Ferrari SM, Giuggioli D, et al. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 2014; 13:272–280. 33. Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology 2009; 136:1182–1197. 34. Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a human antiinterleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 2004; 126:989–996. 35. Mease P, Strand V, Shalamberidze L, et al. A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate. Ann Rheum Dis 2012; 71:1183–1189. 36. Ho RJ, Chien JY. Drug delivery trends in clinical trials and translational medicine: growth in biologic molecule development and impact on rheumatoid arthritis, Crohn’s disease, and colitis. J Pharm Sci 2012; 101:2668– 2674. 37. Preiningerova J. Oral laquinimod therapy in relapsing multiple sclerosis. Expert Opin Investig Drugs 2009; 18:985–989. 38. D’Haens GR, Colombel J-F, Sandborn W, et al. 90 safety and efficacy of & laquinimod in inducing clinical and biochemical improvement in active Crohn’s disease: results of an exploratory trial. Gastroenterology 2013; 144:S-21. In this study, the patients on low-dose laquinimod had clinical remission and response as well as objective reductions in fecal calprotectin. 39. Michelsen KS, Wong MH, Ko B, et al. HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses. Inflamm Bowel Dis 2013; 19:151–164. 40. Sandborn WJ, Targan SR, Byers VS, et al. Andrographis paniculata extract & (HMPL-004) for active ulcerative colitis. Am J Gastroenterol 2013; 108:90– 98. In this study, patients with mild-to-moderate disease benefited from treatment. 41. van Deen WK, Oikonomopoulos A, Hommes DW. Stem cell therapy in inflammatory bowel disease: which, when and how? Curr Opin Gastroenterol 2013; 29:384–390. 42. Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn’s disease after allogeneic marrow transplantation. Gastroenterology 1998; 114:433– 440. 43. Cassinotti A, Onida F, Annaloro C, et al. P362 autologous haematopoietic stem cell transplantation without CD34þ cell selection for refractory Crohn’s disease: the Milan experience after 5 years. J Crohn’s Colitis 2012; 6:S153– S154. 44. Burt RK, Craig RM, Milanetti F, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood 2010; 116:6123–6132. 45. Hawkey C, Allez M, Ardizzone S, et al. OC-014 clinical and endoscopic && improvement following hematopoietic stem cell transplantation vs mobilisation alone in Crohn’s disease. Gut 2013; 62 (Suppl 1):A6. This study shows that patients receiving HSC did better than immunosuppressive conditioning alone. These results suggest that HSC may have a role in treating severe, refractory patients with Crohn’s disease. 46. Garcia-Olmo D, Herreros D, Pascual I, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 2009; 52:79–86. 47. Garcı´a-Olmo D, Garcı´a-Arranz M, Herreros D, et al. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 2005; 48:1416–1423. 48. Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrowderived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut 2011; 60:788–798. 49. Forbes GM, Sturm MJ, Leong RW, et al. A phase 2 study of allogeneic && mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin Gastroenterol Hepatol 2014; 12:64–71. This study of MSC shows promise in the treatment of luminal Crohn’s disease. Endoscopic scores improved in nearly half of the patients. &
Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.