Vedolizumab , a monoclonal antibody that targets the α4β7 integrin, was approved by the FDA in May of 2014 for use in UC and Crohn’s disease. α4β7 integrin, a cell-surface glycoprotein variably expressed in circulating B and T lymphocytes, interacts with mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), its counter-receptor found preferentially in the intestinal vasculature [2]. By blocking the α4β7 integrin, vedolizumab mediates leukocyte trafficking to the gut [3]. The integrins found to be important for the gastrointestinal tract include α2β2, α4β1, and α4β7 [4]. They can, of course, be found in other organs as well besides the gut.

Vedolizumab is not the first anti-integrin approved for the treatment of IBD. Natalizumab, a monoclonal antibody that targets both the α4β1 and α4β7 integrins found in the gut, blocks trafficking not only in the gut but also the brain. α4β1 integrins are also involved in leukocyte trafficking in the brain [2]. Natalizumab was approved by the FDA in January 2008 for use in moderate to severe Crohn’s disease. Although efficacy data was compelling [5], reports of a 2.1 per 1000 risk of progressive multifocal leukoencephalopathy (PML) [6], a serious brain infection, relegated its use to second-line salvage therapy. The typical patient is low risk for PML (negative JC virus serology) and has failed TNF therapy [7].

In contrast to natalizumab, vedolizumab more selectively targets the α4β7 integrin receptor, found primarily in gut-specific lymphocytes. It does not target the α4β1 integrin, found in the gut and the brain [8]. Based on this gut-selective mechanism, the lack of reported cases of PML to date [9], and clinical trial data [2, 8], it was FDA approved as first-line therapy for the treatment of moderate to severe Crohn’s disease and ulcerative colitis. Specific monitoring for PML or JC virus serology is not required.

Phase III randomized controlled trials provide the evidence base demonstrating the efficacy of vedolizumab. GEMINI I enrolled patients with moderate to severe ulcerative colitis [2]. After induction, vedolizumab-treated patients had greater rates of response, remission, and mucosal healing at week 6 of the trial compared to placebo. These favorable data persisted at week 52 during the maintenance phase of the trial. The maintenance phase included an every 4 week and every 8 week arm, both which showed similar outcomes. There were no differences in adverse events among the groups and no cases of PML were identified.

GEMINI II enrolled patients with moderate to severe Crohn’s disease [8]. After induction, vedolizumab-treated patients achieved a statistical greater rate of remission at week 6, but missed the second co-primary endpoint, reduction in the Crohn’s Disease Activity Index by 100 points. However at week 52 in the maintenance trial, vedolizumab-treated patients had greater rates of clinical remission (primary endpoint) as well as other key outcomes (reduction in the CDAI by 100 points and steroid-free remission). No cases of PML were identified; however, the incidence of serious adverse events, infections, and serious infection was noted to be higher in the vedolizumab-treated group. These were not further elaborated in the manuscript and not seen in the ulcerative colitis clinical trial.

GEMINI III was an induction trial focusing on moderate-severe Crohn’s patients who failed TNF therapy [10]. Patients received vedolizumab at 0, 2, and 6 weeks and the primary outcome was measured at week 6. Although rates of remission between the vedolizumab-treated group and placebo were similar at week 6, rates of response were higher in the vedolizumab-treated group at this time point. The vedolizumab-treated group achieved greater rates of remission not at week 6 but several weeks after induction, at week 10. There were no d ifferences in adverse events in this induction trial and no cases of PML were identified.

Ertrolizumab is a monoclonal antibody with a dual anti-integrin mechanism of action. It blocks the β7 subunit of both the α4β7 and αEβ7 integrins, resulting potentially in a very novel mechanism of action compared to vedolizumab [11]. Besides inhibiting gut-specific α4β7 lymphocytes from homing and migrating to the gut, etrolizumab uniquely blocks the interaction between αEβ7 and E-cadherin [12]. The E-cadherin gene has been implicated in IBD through genome-wide association studies. Cadherins are important in preserving intestinal barrier function. Thus, etrolizumab can have an additional beneficial effect of controlling inflammation at the mucosal level by inhibiting αEβ7 lymphocytes from entering the epithelium [11, 13].

The data for etrolizumab will be informed by an extensive and novel phase III clinical trial program, for which studies are ongoing. In EUCALYPTUS, a phase II randomized controlled trial , etrolizumab showed to be an effective induction agent for moderate to severe UC [12]. More patients treated with etrolizumab were in remission at week 10 compared to placebo. Adverse events occurred at a similar frequency in the treated and placebo groups. Although no cases of PML were detected and its mechanism of action should not increase the risk of PML, this was a short-term induction study, thus requiring a larger and longer-term trial to more appropriately assess this outcome.

One milestone of this study was the finding of a 0% remission rate in the placebo group, thought to be in part to the use of central readers and entry criteria [11]. Another interesting post hoc exploratory analysis from the phase II study suggested a possible heterogeneity in treatment benefit or patients with varying αE concentration. The finding that baseline colonic αE expression could improve response to etrolizumab and that treatment reduced αE+ lymphocytes in the epithelium suggests that αEβ7+ lymphocytes contribute to the pathogenesis of UC and that specific blockade of these lymphocytes could provide a novel dual therapeutic approach to treatment [12]. These hypotheses, of course, will need further study and testing in the longer-term phase III trials.

The phase III trial program for etrolizumab includes at least eight studies, including one in Crohn’s disease, and is novel for several reasons. Besides using standardized centralized endoscopic scoring, it will also be the first phase III trials to perform head-to-head biologic comparison to anti-TNF therapy (infliximab in one trial, adalimumab in another).

PF-00547659 is a monoclonal IgG2 antibody directed against mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) [14]. MAdCAM-1, found in the endothelium of venules, preferentially binds leukocytes expressing α4β7 receptor integrins in the gut and results in migration of lymphocytes from the bloodstream into the intestine and promotion of the inflammatory cascade locally [15]. Thus, while PF-00547659 is similar to vedolizumab and etrolizumab in that it prevents migration of α4β7-expressing lymphocytes from migrating to the gut, it works quite differently by blocking the effector receptor in the intestinal vasculature (MAdCAM-1) as opposed to its α4β7 integrin ligand on the lymphocytes [1].

Phase III clinical trials using this molecule are reportedly planned. TURANDOT, a phase II randomized controlled trial, enrolled patients with moderate to severe ulcerative colitis [14]. This induction study achieved its primary endpoint, clinical remission at week 12. There was no increased incidence of infection, including in MAdCAM-1 bearing tissues (gastrointestinal tract, nasal tissue, spleen, bladder, uterus, and lung). There were no cases of PML in this short-term induction study. Even though mechanistically there is low concern for PML, nonetheless this question is best addressed in longer-term studies. TURNADOT II is the open-label long-term treatment study which is ongoing but no longer recruiting. The estimated completion date is December 2017.

OPERA I, a phase II randomized controlled clinical trial, enrolled patients with moderate to severe Crohn’s disease [16]. This induction study missed its primary endpoint, a reduction of 70 points in the CDAI at week 12, and this was attributed to a high placebo response rate. A statistically significant difference in response to those with an elevated CRP (above 18) suggested that perhaps better identifying those with true inflammation would help in trial design. There were no cases of PML in this short-term induction study. OPERA II is a phase II open-label long-term treatment study that completed in July 2016.

The central nervous system is constitutively devoid of MAdCAM-1; thus the strategy of blocking MAdCAM-1 should not result in cases of PML. As corroborating data that this strategy should not be associated with PML, the TOSCA study performed up to two lumbar punctures in 24 patients with Crohn’s who received PF-00547659 after failing TNF therapy [17]. The results showed no change in the CSF lymphocytes, supporting a CNS-sparing mechanism with this drug.

Ozanimod is a small molecule inhibitor with a different strategy than other leukocyte anti-trafficking strategies discussed above. Instead of inhibiting circulating lymphocytes from entering injured/inflamed tissue through blockade of the α4β7 integrin or its counter-receptor, MAdCAM-1, ozanimod effectively traps lymphocytes at the earliest phase of trafficking [1]. Besides the novel mechanism of action, this drug is also novel in that it is an oral medication.

Ozanimod traps lymphocytes through internalization and degradation of the sphingosine-1-phosphate receptor (S1P) found on the lymphocytes [18]. Without the S1P receptor, the lymphocyte is unable to respond to S1P expressed along the lymphatic endothelium, a necessary step for activated lymphocytes to leave the lymph nodes. The arrest of lymphocytes in the lymph nodes leads to a reversible reduction of circulating lymphocytes in the blood.

There are five S1P subtypes (S1P1 through S1P5), responsible for regulating multiple immunologic and cardi ovascular effects [18]. S1P1–3 are expressed ubiquitously, S1P4 is generally confirmed to lymphoid cells and tissues, and S1P5 is predominantly located in the central nervous system [19, 20]. Ozanimod blocks two of these subtypes, primarily subtype 1 but also subtype 5. Blockade of subtypes 2, 3, and 4 is associated with cardiovascular issues (bradycardia, second-degree AV block), elevated aminotransferases, and macular edema. Blockade of subtypes 1 and 5 in patients with multiple sclerosis showed reduction in brain lesions with minimal effect on heart rate and liver enzymes [18].

A phase III randomized controlled trial is underway in UC. TOUCHSTONE, a phase II randomized controlled trial, recruited patients with moderate to severe UC [18]. This study achieved its primary induction primary endpoint, clinical remission at 8 weeks over placebo. It also achieved its primary maintenance endpoint, clinical remission at week 32 [18]. Treatment with ozanimod at the highest-dose group reduced circulating lymphocytes by 49% with no significant side effects. Even so, the study was deemed as preliminary by the authors [18]. The reasons were size of the study (around 65 patients per group) and insufficient duration to establish clinical efficacy or assess safety. A phase II study in Crohn’s disease is ongoing but not recruiting patients. Estimated completion date is September 2018.

Activated lymphocytes , if allowed to leave the lymph node and enter the gut, will participate in the local and dysregulated inflammatory cascade that includes various cytokines [1]. The traditional anti-cytokine strategy in IBD had been to target tumor necrosis factor α. New data show this is not the only potentially successful target.

Ustekinumab , a monoclonal antibody that targets interleukins IL12 and IL23, was approved by the FDA in September 2016 for use in moderate to severe Crohn’s disease. Genome-wide association studies have shown an association between the IL12/IL23 pathway and CD, and the IL12/IL23 pathway is an important driver of inflammation in adaptive immune responses [21, 22]. Ustekinumab, an interleukin inhibitor, blocks the p40 subunit of IL12 and IL23 and prevents their interaction with the IL12Rb1 receptor on the surface of T cells, natural killer cells, and antigen-presenting cells. The result is inhibition of IL12- and IL23-mediated cell signaling, activation, and cytokine production [22, 23].