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Current Opinion in Gastroenterology Therapy of Inflammatory Bowel Disease: What to Expect in the Next Decade David A. Leiman, Gary R. Lichtenstein Disclosures Curr Opin Gastroenterol Abstract and Introduction Abstract 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. 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-α) 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-α 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-α options have added to the 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 α4 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 α4β7 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 = 0.02) but no difference in CDAI-100 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] 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 α4 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, placebo-controlled 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 β7 subunit, provides the advantage of not penetrating into the central nervous system. In EUCALYPTUS, 124 patients were 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 β7, 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 anti-TNF-α 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 = 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 = 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 lowdensity 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 = 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 = 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 γ-inducible protein-10 (IP-10) is a chemokine that 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-γ 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 = 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 IL6.[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 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-to-severely 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-lightchain-enhancer of activated B cells, TNF-α, and IL-1β.[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 = 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 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.