Introduction

Tumor necrosis factor (TNF) antagonists have now become the cornerstone of therapy for moderately to severely active IBD. Considerable strides have been made towards the optimization of their use, through the early use of combination immunosuppressive therapy [1–3], or pro-active drug and disease monitoring with accompanying adjustments in therapy [4, 5]. Despite this, nearly a third of patients will be primary non-responders and another third will be secondary non-responders, leaving only a third of patients in clinical remission after 1 year of therapy [6]. Furthermore, these agents are not without risk and the off-target effect of TNF antagonists may result in serious and sometimes life-threatening adverse events [7, 8]. A need therefore remains for efficacious treatment options in these patients, with alternative mechanisms of action.

Anti-trafficking

Mucosal barrier dysfunction is felt to be one of the earliest, and potentially most important, events in the pathogenesis of IBD [5]. The occurrence of mucosal barrier dysfunction leads to the presentation of luminal bacterial antigens to the innate immune system and T cells which, under specific environmental circumstances, become activated. Once activated, T cells undergo proliferation and expansion in regional lymph nodes, eventually returning to the gut as mature antigen-differentiated lymphocytes. This process of proliferation, maturation, and release from regional lymph nodes has become the potential site of action for a new biologic agent, ozanimod.

Ozanimod

Ozanimod is a small molecule inhibitor that modulates the sphingosine 1-phosphate receptor (S1P), which is needed for activated lymphocytes to leave lymph nodes. By causing internalization of the S1P1R on lymphocytes so they are unable to respond to S1P expressed along the lymphatic endothelium, ozanimod effectively blocks downstream inflammatory processes by “trapping” lymphocytes at their earliest phase of trafficking. Treatment efficacy for ozanimod is largely limited to a phase 2 study of 186 UC patients [9•], where it was demonstrated that once daily dosing of ozanimod at 1 mg resulted in significantly higher rates of clinical remission and mucosal healing at 8 weeks (Table 1). Of importance, within this trial, the investigators looked at histologic remission as defined by the Geboes score (<2) and noted that the rates of histologic remission at week 8 (0.5 mg 14 %, 1.0 mg 22 %) were lower than endoscopic mucosal healing rates at week 8 (0.5 mg 28 %, 1.0 mg 34 %), but at week 32, these were more comparable (histologic remission 0.5 mg 23 %, 1.0 mg 31 %; endoscopic mucosal healing 0.5 mg 32 %, 1.0 mg 33 %). This, along with the overall increase in clinical remission rates and treatment effect size by week 32, would suggest that treatment efficacy is time dependent, and extended treatment may be associated with improved healing [9•]. Phase 3 trials in ulcerative colitis and phase 2 trials in Crohn’s disease are currently underway and should help to address this question.

Table 1 Phase 2 and 3 clinical trials in ulcerative colitis
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Anti-adhesion

Once activated lymphocytes have left lymph nodes to return to the gut as mature antigen-differentiated lymphocytes capable of secreting pro-inflammatory cytokines and chemokines, the next potential therapeutic target is inhibition of lymphocyte adhesion. This homing and adhesion require a dynamic interaction between surface ligands on leukocytes and adhesion molecules on the epithelial cell surface. Three molecules have been of particular interest for drug development in IBD and three new biologics are emerging as next-generation therapeutics.

Vedolizumab

Vedolizumab, a monoclonal antibody that targets the α4β7 integrin, was approved for use in UC and CD and is now widely used in routine practice [10•, 11•] (Tables 1 and 2). For UC, treatment outcomes in clinical practice have mirrored those seen in the RCT with rates of clinical remission after induction ranging from 24 to 36 % [12–15]. A multi-center cohort study has reported on long-term outcomes with vedolizumab in 114 moderately severely active UC patients, and the cumulative rates of clinical remission and mucosal healing at 6 months were observed to be 26 and 31 %, with corresponding rates at 12 months being 72 and 67 %, respectively [16]. Within this multi-center consortium, the single predictor identified for failing to achieve clinical remission with vedolizumab in UC was prior exposure to a TNF antagonist (hazard ratio (HR) 0.33, 95 % CI 0.18–0.61).

Table 2 Phase 2 and 3 clinical trials in Crohn’s disease
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For CD, rates of clinical remission after induction therapy in clinical practice have ranged from 24 to 31 %, with prior exposure to TNF antagonists (p = 0.011), prior hospitalization within the preceding 12 months (p = 0.015), and less severe disease (p = 0.019), being important predictors of treatment efficacy [12–15]. A multi-center cohort study has reported on long-term outcomes with vedolizumab in 212 moderately severely active CD patients, and the cumulative rates of clinical remission and steroid-free remission at 6 months were observed to be 18 %, with corresponding rates at 12 months being 34 % [17]. Within this multi-center consortium, individuals with prior exposure to TNF antagonists (HR 0.40, 95 % CI 0.20–0.81), those with more severe disease activity (HR 0.54, 95 % CI 0.31–0.95), those with active perianal disease at baseline (HR 0.49, 95 % CI 0.27–0.88), and those who were previous or current smokers (HR 0.47, 95 % CI 0.25–0.89) were less likely to achieve clinical remission. The impact of prior exposure to TNF antagonists on treatment efficacy in CD is further supported by a phase 3 RCT (GEMINI III) which demonstrated that rates of clinical remission at week 6 were not significantly different between vedolizumab and placebo among individuals with prior exposure to TNF antagonists (15.2 vs. 12.1 %, p = 0.433) [18•]. Rates of clinical remission were however significantly different at week 10 (26.6 vs. 12.1 %, p = 0.001), which would suggest that the time-dependent efficacy of vedolizumab is more pronounced among individuals with prior exposure to TNF antagonists [18•].

Etrolizumab

Etrolizumab, a monoclonal antibody that selectively binds the β7 subunit of the α4β7 and the αEβ7 integrins, has recently completed a phase 2 trial in UC [19]. In this small study of 124 UC patients, etrolizumab was demonstrated to be considerably more efficacious as compared to placebo for achieving clinical remission with induction therapy (Table 1). Although this would appear to be twice as efficacious as vedolizumab for induction of clinical remission, it should be noted that the study end-point for induction was week 10 compared to week 6 for vedolizumab. This is of importance as week 6 clinical remission rates between the placebo group (5 %), 100 mg etrolizumab group (10 %, p = 0.66), and the 300 mg etrolizumab group (8 %, p = 0.97) were not statistically significant. Furthermore, this study had no maintenance data, it used a modified intention-to-treat analysis, and it was a relatively small study with only 39 patients analyzed in each active treatment arm. Nonetheless, these data are quite promising and phase 3 trials in UC and CD are currently underway, including a head to head comparison against adalimumab.

Anti-MAdCAM-1

Another strategy to inhibit leukocyte adhesion is to block the adhesion molecule on endothelial cells as opposed to its integrin ligand. PF-00547659 is a monoclonal antibody that targets mucosal addressin cell adhesion molecule 1 (MAdCAM-1), and this drug has undergone phase 2 studies in both UC and CD. In UC, a phase 2 trial of 357 individuals demonstrated that PF-00547659 resulted in a significantly higher rate of remission and mucosal healing as compared to placebo, and this was most significant for the 22.5 and 75 mg dosing regimen [20] (Table 1). In CD, however, the phase 2 trial of 267 individuals failed to meet its primary end-point (Table 2). Despite this, there was a trend towards a higher response rate among individuals with an elevated baseline CRP and PF-00547659-treated individuals demonstrated a sustained dose-related reduction in soluble MAdCAM [21]. Given the trial was only 12 weeks in duration, and prior studies for anti-trafficking and anti-adhesion molecules have demonstrated a duration dependent efficacy that is more pronounced in CD as compared to UC, an extended duration study may be required to demonstrate a significant treatment effect size for this biologic in CD.

Anti-cytokine

Ustekinumab

Once activated lymphocytes return to the gut, they begin to secrete various cytokines and chemokines which are responsible for the local inflammatory micro-environment and cross-talk between immune cells. Beyond tumor necrosis factor-α, several other cytokines and cytokine pathways have now been implicated in the pathogenesis of IBD. An important pro-inflammatory cytokine pathway that induces Th1 and Th17 differentiation is IL-12 and IL-23, and a monoclonal antibody that targets this pathway through a common p40 subunit is ustekinumab. Within the phase 2b trial of CD patients who had failed prior TNF-antagonist therapy, ustekinumab resulted in a higher rate of maintaining clinical remission (41.7 vs. 27.4 %, p = 0.03) and steroid-free remission (30.6 vs. 17.8 %, p = 0.048) among patients who had responded to Ustekinumab induction therapy, as compared to placebo at week 22 [22]. Phase 3 trials have recently been completed in TNF-antagonist naïve and experience patients with promising results [23, 24] (Table 2). The improvement in clinical remission seen within these phase 3 induction trials was accompanied by improvements in biomarkers of inflammation (CRP, fecal calprotectin, fecal lactoferrin), and biochemical remission (normalization of CRP) was achieved in 21–26 %, 17–21 %, and 8–9 % of patients receiving 6 mg/kg of ustekinumab, 130 mg of ustekinumab, and placebo, respectively. In clinical practice, similar promising results have been seen with cohorts reporting a clinical benefit in over two thirds of patients after induction therapy, and the majority of these patients maintaining treatment response for up to 12 months [25, 26]. In these studies, the only significant predictor identified for achieving a clinical response with ustekinumab was the use of concomitant immunosuppressive therapy (odds ratio (OR) 5.43, 95 % CI 1.14–25.77), which is known to impact treatment outcomes with anti-cytokine biologics [3].

Mongersen

Transforming growth factor (TGF)-β1, another important cytokine linked to the pathogenesis of mucosal inflammation in IBD, is an immunosuppressive cytokine that negatively regulates T cell immune responses. It has been demonstrated that an inhibitor of TGF-β1, SMAD7, is overexpressed in CD patients and the inhibition of SMAD7 (disinhibition of TGF- β1) restores basal negative feedback loops on cytokine production [27]. Phase 2 trials for mongersen, an oral SMAD7 antisense oligonucleotide, have now been completed, and phase 3 trials are underway [28•] (Table 2). Although this trial demonstrated the largest treatment effect size ever seen in CD, it should be noted that the inclusion criteria were very strict in large part due to the fact that the active compound of mongersen is only released in the terminal ileum and proximal colon. Thus, the clinical efficacy and therapeutic benefit of this agent in patients with more extensive disease, penetrating or stricturing complications, and prior surgical resections remain to be determined.

Tofacitinib

Janus kinases (JAKs) are important mediators and regulators of cellular differentiation, immune cell function, and signaling pathways. By targeting JAKs, a common signaling pathway for several pro-inflammatory cytokines, therapeutic agents have the potential to inhibit both T and B cell functions, while preserving regulatory T cell function. Tofacitinib, an oral small molecule that inhibits JAK 1 and 3 (and JAK 2 at higher doses), has undergone phase 2 and 3 studies in UC. Phase 2 data demonstrated a significant treatment effect for tofacitinib with the 10-mg twice daily dosing being associated with maximum treatment effect size for clinical remission (38 %) and mucosal healing (28 %). Phase 3 data were recently presented and quite promising, with a significant treatment effect being demonstrated for both clinical and endoscopic remission [29, 30] (Table 1). It is worth noting that within one of the phase 3 induction trials (OCTAVE 1), the treatment effect size for clinical remission and mucosal healing were higher in the TNF-antagonist-exposed group (clinical remission 11 % and mucosal healing 18 %) as compared to the TNF-antagonist-naïve group (clinical remission 9 % and mucosal healing 13 %). This was not the case in the other phase 3 induction trial (OCTAVE 2) which followed more traditional outcomes for biologics and demonstrated a slightly higher treatment effect size in the TNF-antagonist naïve as compared to the TNF-antagonist exposed. Taken together, tofacitinib was efficacious in both groups and may potentially be more efficacious in TNF-antagonist-exposed patients. Furthermore, treatment effect was seen as early as 2 weeks suggesting a rapid onset of action for this biologic.

Clinical Considerations and Future Trends

Within this review, we have highlighted several novel therapeutic agents that are currently in the process of completing or have completed phase 2 and phase 3 clinical trials. As these agents come to market, several considerations will need to be made with regard to their integration and use. Perhaps, one of the most important is drug clearance, pharmacokinetics/pharmacodynamics, and the potential advantages of small molecule inhibitors. Small molecule inhibitors, such as ozanimod, tofacitinib, and mongersen, have a distinct advantage over parenterally administered biologics in that the small molecular weight of these agents allows for rapid uptake, steady-state concentrations, and reductions in the potential for immunogenicity. An example of this can be seen within the phase 3 induction studies for tofacitinib in UC, where a very similar rate of remission was seen among all four quartiles of plasma concentrations [31]. In contrast, within the phase 3 trials of ustekinumab in CD and the phase 3 trials of vedolizumab in UC, there was a clear exposure-response relationship for serum ustekinumab and vedolizumab concentrations and remission [32, 33]. Thus, small molecule inhibitors are potentially less likely to need concomitant immunosuppressive therapy to prevent immunogenicity, and may be more favorable in individuals with a higher baseline risk for enhanced drug clearance.

Another important consideration to be made when integrating these agents into practice is the latency of onset and time to maximal efficacy. Drugs that target lymphocyte migration, ozanimod, vedolizumab, and anti-MAdCAM-1 appear to have a more gradual onset of action, which is particularly more pronounced in CD as compared to UC. This is likely in part due to the inability of these to target local immune cell populations within sites of inflammation. In patients with more severe disease or those who are at an increased risk for immediate complications (i.e., colectomy for severe UC), anti-trafficking agents may be less effective in the short term, and anti-cytokine or anti-sense therapy may be more effective for achieving a rapid response and induction of remission. If anti-trafficking agents are to be used in these clinical settings, consideration will need to be given to concomitant administration of immunosuppressive agents or prolonged steroid tapers, to help bridge the latency of onset for treatment efficacy. Recently, the idea of combining biologics, particularly biologics with alternative mechanisms of action (i.e., infliximab + vedolizumab) has been entertained [34]. As we enter into an era of biosimilar therapy, which would make the TNF antagonist part of combination therapy more affordable, this approach may be given more consideration.

Conclusions

In summary, several therapeutic agents will soon be coming to market in both UC and CD. These agents have distinct biologic mechanisms and modes of drug delivery, which impact their overall efficacy, latency of treatment effect, and pharmacokinetic/pharmacodynamic profiles. Alongside, this evolution in our treatment armamentarium will need to identify better strategies for optimization of patient profiling and personalization of treatment decisions.