Alimentary Pharmacology and Therapeutics

Review article: anti-adhesion therapies for inflammatory bowel disease T. Lobat on, S. Vermeire, G. Van Assche & P. Rutgeerts

Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.

Correspondence to: Dr P. Rutgeerts, Internal Medicine, Department of Gastroenterology, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] ac.be

Publication data Submitted 12 December 2013 First decision 31 December 2013 Resubmitted 8 January 2014 Accepted 8 January 2014 EV Pub Online 30 January 2014 This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.

SUMMARY Background A high proportion of patients with inflammatory bowel disease (IBD) do not achieve clinical remission with the current therapies including mesalazine (mesalamine), immunossupresants (IMS) and antibodies against tumour necrosis factor (anti-TNF). Moreover, IMS and anti-TNF involve a nonnegligible risk for infections and/or malignancies. The anti-adhesion molecules are one of the most interesting new treatments because of their gut-selectivity. Aim To review the physiopathology of the adhesion molecules and the current drugs targeting this mechanism. Methods We performed a literature review in PubMed and in clinicaltrials.gov using the terms ‘anti-adhesion molecules’, ‘inflammatory bowel disease’, ‘natalizumab’, ‘vedolizumab’, ‘AMG181’, ‘Etrolizumab’, ‘PF-00547659’, ‘AJM300’, ‘Alicaforsen’ and ‘CCX282-B’ up to November 2013. Results A total of eight drugs were found including those targeting the a4b1, a4b7 or aEb7 integrins as well as the ICAM-1 and MAdCAM-1 addressins and the chemokine receptor 9. The rationale for these drugs is the blockade of gut-homing T lymphocytes and the ones targeting the a4b7/MAdCAM-1 interaction presented the most promising results in luminal disease. Vedolizumab, an a4b7 antibody, has completed phase 3 trials with very positive results especially for ulcerative colitis. However, many questions remain unanswered such as the effect of these therapies in perianal disease and extraintestinal manifestations. Conclusions The blockade of the a4b7/MAdCAM-1 interaction and especially vedolizumab is an effective and safe gut-specific treatment for IBD. Further studies are needed to clarify the efficacy and safety of the other anti-adhesion drugs and to define the specific indications of these therapies in the different scenarios of IBD. Aliment Pharmacol Ther 2014; 39: 579–594

ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12639

579

n et al. T. Lobato INTRODUCTION Inflammatory bowel diseases (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) are chronic disorders involving mainly the gastrointestinal (GI) tract, although extraintestinal manifestations (EIM) can be present in up to 40% of patients.1 Environmental factors, gut dysbiosis, genetic susceptibility and an inappropriate immune response (IIR)2 seem to be important contributors to the pathogenesis of these multifactorial disorders. It is believed that CD and UC are two different diseases with overlapping phenotypes such as indeterminate colitis and isolated colonic CD. Most of the current therapies have focused on treating the IIR. The current drugs include corticosteroids (CS), 5-aminosalicylic acid (5-ASA), immunosuppressants (IMS) and antibodies against tumour necrosis factor (anti-TNF). Although CS are efficient for inducing remission, they do not maintain long-term remission. 5-ASA is an effective and well-tolerated treatment, for mild-to-moderate UC, but not for moderate or severe UC3 or CD.4 IMS such as thiopurines (azathioprine and mercaptopurine) or metrotexate (MTX) are slow-acting drugs that are not able to induce but to maintain remission. Thiopurines are indicated as maintenance treatment in CD, in CS resistant or CS-dependent disease and to prevent post-operative recurrence.5 In UC, thiopurines are indicated also as maintenance treatment, in CS-resistant or CS-dependent disease, in failures to 5-ASA, or in patients achieving remission after induction with ciclosporin.6 The indications for MTX are similar for UC as for CD, but the evidence is largely lacking, especially for UC. MTX may be effective in CD and UC that do not respond to thiopurines or in the case of nontolerance.7 Nonetheless, considerable rates of side effects are reported with thiopurines and MTX, including risk of malignancy with thiopurines.8 Ciclosporin is another IMS that is effective for the induction of remission in UC, but its use is difficult due to the need of monitoring its serum levels, and the drug carries a high rate of side effects.9 At present, anti-TNF treatment in IBD is carried out using monoclonal antibodies including infliximab (Remicade; Johnson & Johnson, Janssen Biotech, Inc., Horsham, PA, USA), adalimumab (ADM, Humira; AbbVie Inc., North Chicago, IL, USA), certolizumab (CZP, Cimzia; UCB Pharma, Brussels, Belgium) and golimumab (Simponi; Johnson & Johnson). Infliximab (IFX) is a chimeric monoclonal antibody (mAb) against TNF a and it was the first anti-TNF used in IBD. Its efficacy has been confirmed through different randomised

580

clinical trials for inducing and maintaining remission both in CD10 and in UC.11 ADM is a fully human mAb and has also demonstrated efficacy for induction and maintenance of remission in CD12 and more recently also in UC.13 CZP is a PEGylated Fab′ fragment of a humanised TNF inhibitor mAb, which is efficient for induction and maintenance treatment for CD.14, 15 Golimumab has recently been shown efficient for inducing and maintaining clinical remission in UC patients16 in two phase 2/3 multicentre, randomised, placebo-controlled, double-blind studies (Pursuit 1&2) in which more than 1000 UC patients were included. This subcutaneous (sc) administered anti-TNF antibody presents another treatment option for patients with UC whose disease is responsive to anti-TNF. Etanercept (Enbrel), a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kDa (p75) TNF receptor linked to the Fc portion of human IgG1 seems not effective to treat IBD, although it is efficacious to treat rheumatic diseases and psoriasis. Anti-TNFs are mostly used after CS and/or IMS failure, but also as first-line treatment in patients with a high-risk disease profile (e.g. extensive and fistulising CD in a young patient). The main limitation of anti-TNFs is that an important proportion of patients will be primary nonresponders, possibly due to a different pathophysiological mechanism driving the disease. According to a recent meta-analysis assessing efficacy of biological therapies in IBD,17 induction of remission rates for IFX (at weeks 10–12), ADM (at week 4) and CZP (at weeks 6–12) in CD are 45.3%, 24.2% and 24.7% respectively. In UC, the remission rates have been reported as 57.1%17and 17%18 for IFX (at weeks 6–12) and ADM (at week 6) respectively. Moreover, around 40% of primary responders lose response to the drug over time.19 This loss of response (LOR) can be caused by accelerated clearance of the drug especially upon formation of antibodies against the drug.19, 20 There are different ways to handle this LOR including interval shortening between doses or dose optimisation, addition of CS or IMS to reduce immunogenicity21, 22 or switch to another anti-TNF agent if high titres of anti-drug antibodies are present.23 In the GAIN trial,24 Sandborn et al. demonstrated that in CD patients intolerant or with LOR for IFX, 21% achieved remission with ADA at week 4, compared with 7% for placebo (P < 0.001). In the PRECISE-1 study,14 24% (24/98) of patients treated with CZP (previously treated with IFX) presented clinical response [defined as a decrease of

Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

Review: anti-adhesion therapies for inflammatory bowel disease ≥100 points in the Crohn’s Disease Activity Index (CDAI)] at week 6 and only 15% at both week 6 and week 26. These rates were not different for placebo groups. Anti-TNF strategies can also be associated with adverse events (AE) such as infusion reactions and increased rates of infections.25–28 It has been shown that thiopurines, anti-TNFs and combination of these agents carry an increased risk of nonmelanoma skin cancer and hepatosplenic T-cell lymphoma.29, 30 Besides, the chronic use of thiopurines is associated with an increased risk of non-Hodgkin’s lymphoma.25, 29 An important outcome parameter in the treatment of IBD is the need for surgery. In older studies, the cumulative proportion of patients undergoing surgery within the first 10–15 years of diagnosis was as high as 95% for CD31 and 25% for UC.32 In recent years, surgery rates seem to have decreased both for UC and for CD. In a recent Canadian population-based study between 1997 and 2009, Kaplan et al.33 reported a colectomy rate of 10% in UC patients within the first 10 years of diagnosis. During this period, they observed an increased use of IMS and IFX. Peyrin-Biroulet et al.34 followed a cohort of 296 CD patients diagnosed from 2000 and 2009 and reported a need of major surgery in 6.5%, 25.9% and 44.3% at 1, 5 and 9 years respectively. Interestingly, they also observed that long-term anti-TNF treatment together with noncomplicated inflammatory disease behaviour was protective for surgery, whereas the influence of AZA was less important. Despite this decrease, the proportion of patients going to surgery is still high and the long-term steroid-free remission rates with current therapies are far from optimal. There is still great need for improved therapy in IBD, such as new agents with different mode of action that allow inducing and maintaining remission. Several other anti-cytokine therapies are being tested including inhibition of IL-12 and IL-23 by blocking the p40 subunit (present in both IL-12 and IL-23) with the anti-p40 mAb Ustekinumab (Stelara; Centocor, Malvern, PA, USA).35 Instead of blocking one specific cytokine, a broader anti-inflammatory action can be achieved by interfering with an array of cytokine receptors. Tofacitinib (CP-690,550; Pfizer, New York, NY, USA) is a selective oral inhibitor of the Janus kinase (JAK) family of enzymes including JAK1 and JAK3, which mediate signal-transduction activity for multiple cytokines, many of them integral to lymphocyte activation, function and proliferation. Although this drug is already approved for the treatment of rheumatoid arthritis, studies in UC and CD are ongoing.36, 37 Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

One of the crucial pathways in the inflammatory cascade is the migration of leucocytes from the systemic circulation to the GI tract: molecules modulating T-cell trafficking to the gut are generally referred to as anti-adhesion molecules. In this review, we analyse the rationale for the treatments focused in adhesion molecules and the drugs that are currently being studied targeting these molecules.

RATIONALE FOR ANTI-ADHESION TREATMENTS IN IBD The main cell populations responsible for the adaptive immune response in the gut are antigen-presenting cells, which can be professional (dendritic cells) or not professional (epithelial cells), effector cells (effector T cells, granulocytes, natural killer, macrophages, etc.), regulatory T cells and mucosal B cells. T cells originate in the bone marrow and mature in the lymph nodes by differentiating into regulatory or effector cells. This occurs thanks to the activation by dendritic cells after they have recognised the antigen (Ag). The effector T cells have receptors that enable them to migrate to the inflamed tissue, mainly through the post-capillary venules. One of the crucial points of the IIR in IBD is the increased migration of T cells to the intestinal tract.38, 39 Leucocytes travel at high speed through the vascular tract, and to migrate to tissues such as the intestinal tract, there is a sequential adhesion system consisting of the capture/tethering, rolling, activation, adhesion and migration through the vascular wall.40 The capture of the T cells to the endothelium is mediated through the interaction between selectins (L-selectins expressed by leucocytes and P- and E-selectins that are found on the endothelium) and oligosaccharide moieties that act as ligands. This weak and transient interaction allows leucocytes first to slow their speed in the vascular flow and then to roll through the vascular wall by going from one selectin to another.41, 42 Secondary adhesion molecules are members of the integrin family, which are leucocyte cell-surface adhesion molecules that allow them to stop rolling and start migration/extravasation through the vascular wall. The expression of integrins is activated by chemokines, which are released by T cells.39 Intergrins involved in the T-cell migration are as follows: leucocyte function-associated antigen 1 (LFA-1 or a2b2) and the two a4-integrins (a4b7 and a1b7). The subunit a is implied in the specificity and the subunit b in signal pathways.43 For the migration of the leucocytes, these integrins bind to 581

n et al. T. Lobato specific ligands at the endothelium called addressins or adhesion molecules. The a2b2 integrin, expressed on neutrophils, interacts with intercellular adhesion molecule-1 (ICAM-1) that is expressed on leucocytes, dendritic cells, fibroblasts, epithelial cells and endothelial cells.44, 45 The a4b1 integrin is composed of one b1 chain and one a4 chain and is expressed on most leucocytes, but not on neutrophils. The a4b1 integrin binds to vascular cell adhesion molecule-1 (VCAM-1)46 and to components of the extracellular matrix such as fibronectin and thrombospondin. The third family is the a4b7 integrin, which is expressed on the lymphocytes that colonise the gut and gut-associated lymphoid tissues and interacts with the mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). The MAdCAM-1 ligand is expressed in the endothelial venules in the small intestine, in the Peyer’s patches and the colon, and the interaction with integrin a4b7 activates the migration of lymphocytes to Peyer’s patches.47, 48 Therefore, the interaction between a4b7 and MAdCAM-1 is gut-specific. This specificity was demonstrated by Picarella et al., when by neutralisation of anti-MAdCAM-1 or anti-a4b1 antibodies, they showed that the recruitment of leucocytes to the colon was reduced.49 Lastly, the aEb7 integrin is another member of the b7 integrin family that it is expressed only in mucosal intraepithelial T lymphocytes and that binds selectively to E-cadherin on epithelial cells.50 The expression of aEb7 is elevated in UC and CD in the active phase of the disease,51, 52 and the interaction of aEb7/ E-cadherin has been proposed to participate in the retention of T cells in the mucosal tissue.53

Tethering

Rolling

In addition to selectins and adhesion molecules, leucocytes also interact with chemokines through specific chemokine receptors (CCR). There are more than 50 different chemokines and in normal conditions, they attract the leucocytes when an infectious agent is present. However, they can also contribute to the amplification and perpetuation of the IIR occurring in IBD.40 Figures 1 and 2 summarise the mechanism of the main adhesion molecules and their blockade by the current drugs. Pro-inflammatory cytokines such as interleukine-1 and TNF54–56 upregulate the expression of ICAM-1 and MAdCAM-1. Treatment with IFX decreases the expression of ICAM-1.57 Increased ICAM-1 expression in CD is present not only in the mucosa but also in the submucosa and muscular layers,58 which could be implied in the transmural nature of CD. There is also evidence supporting the interaction between the a4-integrins of T cells and tissue ligands, including the matricellular protein thrombospondin, the cytokine-like matrix molecule osteopontin and metalloproteases.59–61 These interactions allow T cells to influence the function of dendritic cells or fibroblasts and therefore contribute to the amplification and maintenance of the inflammatory response. Aberrant homing of T cells may be involved in the pathogenesis of EIM. Salmi et al. showed that the reactive arthritis in IBD is mediated by gut-derived immunoblasts that bind to synovial vessels.62 It has also been demonstrated that in IBD patients with primary sclerosing cholangitis, there is an aberrant expression of MAdCAM-1 in the liver endothelium that enables the recruitment of T cells to the liver.63, 64

Integrin activation

Firm adhesion

Chemokinereceptor chemokines L-selectin Selectin-ligand MadCAM-1

Diapedesis

α4β7-integrin

MadCAM-1

CCX282-B PF-00547659

Natalizumab, Vedolizumab, Etrolizumab

Figure 1 | Mechanism of action of adhesion molecules in the intestinal endothelium and their blockage by anti-adhesion drugs. 582

Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

Review: anti-adhesion therapies for inflammatory bowel disease

Brain Bone marrow, skin...

Integrins

Leukocyte Gut

α4β7

Natalizumab

α4β1

αEβ7

Natalizumab

Etrolizumab

Vedolizumab AMG 181 Etrolizumab

PF-00547659

Addressins VCAM-1

Endothelial cell

E-cadherin

Epitelial cell

MAdCAM-1

Endothelial cell

Figure 2 | Systemic effects of blocking MAdCAM-1 addressin and a4b1, a4b7 or aEb7 integrins.

CURRENT ANTI-ADHESION THERAPIES FOR IBD Most anti-adhesion molecule therapies target the integrin family. The first drug developed was natalizumab, a mAb against a4 that is not gut-specific. Newer monoclonal antibodies targeting the a4b7 integrin (vedolizumab and AMG181) have been developed. Etrolizumab is a mAb against the b7 subunit. PF-547659 is a mAb against MAdCAM-1, the ligand for the a4b7 integrin. Alicaforsen reduces the expression of ICAM-1. Other small molecules under development are AJM300, which is an antagonist of a4 subunit and CCX282-B that selectively blocks the CCR9. We will discuss the clinical results with these therapies in UC and CD. Most relevant drugs are summarised in Table 1. Natalizumab Natalizumab (Antegren, Tysabri; Elan Pharma Ltd., Letchworth, UK and Biogen-Idec, Durham, NC, USA) is a recombinant humanised monoclonal IgG4 antibody against the integrin subunit a4 that blocks both a4b7 and a4b1. The a4b7/MAdCAM-1 interaction is gutspecific, whereas the a4b1-VCAM-1 interferes with the lymphocyte migration to the central nervous system (CNS).65–67 Natalizumab was the first anti-adhesion treatment developed in IBD and in parallel for multiple sclerosis. In a pilot placebo-controlled study, Gordon et al.68 showed that intravenous (iv) infusion of natalizumab at a dose of 3 mg/kg was superior to placebo in inducing clinical remission in 30 CD patients, with no Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

differences in AE. In a double-blind, placebo-controlled phase 2 trial69 in 248 CD patients, natalizumab also achieved higher remission rates, as well as improved quality of life and decreased C-reactive protein levels. In this study, the dose of natalizumab at 6 mg/kg was not superior to 3 mg/kg. The efficacy of natalizumab to induce remission in CD was further evaluated in the ENACT-1 (Efficacy of Natalizumab as Active Crohn’s Therapy) and the ENCORE (Efficacy of Natalizumab in Crohn’s disease respOnse and Remission trial) trials. In ENACT-1,70 905 patients with active CD were randomised to natalizumab or placebo. Rates of response (56% and 49%, respectively; P = 0.05) and remission (37% and 30%, respectively; P = 0.12) for the drug and placebo at 10 weeks were similar. In the ENCORE trial,71 509 CD patients were randomised to natalizumab or placebo. Natalizumab was well tolerated and achieved superior response and remission rates than placebo at weeks 4, 8 and 12. Natalizumab also showed to be more effective than placebo to maintain remission in the ENACT-270 trial, with higher proportion of patients achieving sustained response (61% vs. 28%, P < 0.001) and remission (44% vs. 26%, P = 0.003) through week 36. Data evaluating the effectiveness of natalizumab in ulcerative colitis (UC) are scarce. Gordon et al.72 performed a pilot study where 10 patients with active UC defined by a Powell-Tuck activity score >4 received a single infusion of natalizumab (3 mg/kg). The primary endpoint was the decrease in Powell-Tuck score at 583

n et al. T. Lobato Table 1 | Current anti-adhesion molecules: manufacturers, targets and current status Disease Drug

Manufacturers

Target

Natalizumab Vedolizumab AMG181

Antegren (Tysabri); Elan (Biogen-Idec) a4 Millennium Pharmaceuticals a4b7 Amgen a4b7 b7

Admin CD

UC

iv iv iv/sc

Pilot study (+/ )† Phase 3 (+)‡ Phase 1 (ongoing) Phase 2 (discontinued)§ Phase 2 (+)

Etrolizumab Genentech (rhuMAb b7) PF-00547659 Pfizer

MAdCAM-1 iv/sc

AJM300 Alicaforsen CCX282-B

a4 ICAM-1 CCR9

Ajinomoto ISIS Pharmaceuticals ChemoCentryx Inc

iv/sc

Oral Oral Oral

Approved in USA* Phase 3 (+/ ) Phase 1 (ongoing) Phase 2 (discontinued)§ –

Phase 1 and 2 (ongoing) Phase Phase – Phase Phase 3 (+/ ) Phase Phase 3 (discontinued)¶ –

1 (+) 1 and 2 (ongoing) 1 (+/ ) 2 (+)

Admin, administration; UC, ulcerative colitis; CD, Crohn’s disease; iv, intravenous; sc, subcutaneous. * Approved only in US but not in other countries because of its risks to develop progressive multifocal leukoencephalopathy. † (+/ ), no clear benefit. ‡ (+), positive results. § Discontinued because of inaccuracy in study documents that require correction for future enrollees. ¶ The development programme was discontinued after a negative study where the primary endpoint was not met.

2 weeks post-infusion and this was achieved in 5/10 patients. The median C-reactive protein also decreased. The drug was well tolerated. Despite the efficacy of natalizumab to induce and maintain clinical remission in CD patients, its use is hampered due to its risk to develop progressive multifocal leukoencephalopathy (PML), an opportunistic and usually fatal brain infection that is caused by the reactivation of latent JC polyomavirus. The physiopathology of this infection is explained by the blockade of the a4b1/VCAM-1 interaction by natalizumab, resulting in a blockade of the migration of T cells to the CNS73 to avoid the infection of the JC present in the body. It has been shown that there are three risk factors for the development of PML: JC seropositivity, concomitant use of IS and the treatment duration with natalizumab.74, 75

Vedolizumab Vedolizumab (Millennium Pharmaceuticals, Cambridge, MA, USA) is a humanised IgG1 mAb against a4b7 integrin that interferes only with the a4b7/MAdCAM-1 interaction. It is therefore believed that the effect of vedolizumab will be limited to the GI tract (gut-selective) with no effect on the trafficking of lymphocytes to other organs including the CNS. The drug would not carry a risk of PML. In a phase I trial in 29 UC patients, Feagan et al. demonstrated that, after a single infusion of vedolizumab, 584

the inhibition of a4b7 integrin was superior to placebo in achieving clinical and endoscopic remission at 1 month.76 The first phase 2 trial was performed in UC patients na€ıve to biological therapy. It was a multicentre, double-blind, placebo-controlled study in 181 UC patients.77 Patients were randomised to receive vedolizumab 2 mg/kg, vedolizumab 0.5 mg/kg or placebo. Infusions were performed on days 1 and 29, and patients were followed up for up to 6 weeks with sigmoidoscopy performed at baseline and at weeks 4 and 6. The primary outcome was clinical remission at week 6. In both groups (0.5 and 2 mg/kg), clinical remission rates were significantly higher with vedolizumab than with placebo (33%, 32% and 14%, respectively; P = 0.03). The proportions of patients achieving endoscopic remission at week 6 were 28%, 12% and 8% for the 2 mg/kg dose, for the 0.5 mg/kg dose and placebo respectively (P = 0.007). There were no differences in AE between the vedolizumab groups and the placebo group. In a second phase 2, multicentre, double-blind, placebo-controlled study, 185 CD patients who had never been treated with biological therapy78 were randomised to receive vedolizumab 2 mg/kg, vedolizumab 0.5 mg/kg or placebo on days 1 and 29. At day 57, 37% and 30% of patients treated with 2 and 0.5 mg/kg of vedolizumab, respectively, achieved clinical remission as compared to 21% of patients receiving placebo (P = 0.04 Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

Review: anti-adhesion therapies for inflammatory bowel disease for 2 mg/kg vs. placebo). However, there was no significant difference in the proportion of patients achieving clinical response at day 57 among the three treatment groups (47%, 43% and 31% in the 2 mg/kg, 0.5 mg/kg and placebo groups respectively). The rates of AE were comparable in both groups and there were no cases of PML. Despite its efficacy, during these phase 2 studies,77, 78 up to 38% of the patients developed human anti-human antibody (HAHA). Moreover, a concentration superior to 1:125 was related to a lower clinical response to the drug due to a lower saturation of the a4b7 integrin. To prevent this, Millennium Pharmaceuticals developed a new formulation of vedolizumab that was tested in a dose-ranging study79 assessing doses of 2, 6 and 10 mg/kg. The results indicated that the concentration of the drug in serum increased proportionally as a function of dose and that vedolizumab maximally saturated a4b7 receptors on peripheral serum lymphocytes at all measurable serum concentrations. An open-label phase 2 study80 including UC and CD patients77, 78 further evaluated this new formulation at the same doses (2, 6 and 10 mg/kg), but with a more frequent dosing during induction (infusion at days 1, 15 and 40 instead of days 1 and 29 as in first phase 2 trials77, 78). The remission rates were 88% and 40% at day 491 in UC and CD patients respectively. In this study, only 4% of patients developed HAHA. The authors concluded that the combination of an improved manufacturing process, the higher doses and a more frequent dosing during induction might have contributed to the lower immunogenicity. More recently, vedolizumab has been assessed in phase 3 trials (Gemini I, II, III and LTS). Gemini I81 is a randomised, double-blinded, placebo-controlled, multicentre trial examining the efficacy of vedolizumab for induction and maintenance in moderate-to-severe UC. Clinical response was defined as a reduction in at least 3 points in the Mayo Clinic score (range 0–12, with higher scores indicating more active disease) and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Clinical remission was defined as Mayo Clinic score ≤2 and no subscore >1. In the induction phase, 374 patients (cohort 1) received 300 mg of vedolizumab or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2. Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group respectively (P > 0.001). In the study of maintenance, Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

the responders to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. At week 52, 41.8% of patients under vedolizumab every 8 weeks and 44.8% of patients receiving vedolizumab every 4 weeks were in clinical remission, compared to 15.9% from the placebo group (P > 0.001). The need for CS was reduced in vedolizumab groups, but not in the placebo group. The frequency of AE was similar in the vedolizumab and placebo groups. Gemini II82 was another randomised, double-blinded, placebo-controlled, multicentre trial analysing the efficacy of vedolizumab (at dose of 300 mg) as induction and maintenance therapy in patients with CD. Clinical remission was defined as the CDAI of ≤150 and CDAI-100 response as a decrease of ≥100-point decrease in the CDAI score. In the induction phase, 368 patients were randomised to receive vedolizumab or placebo at weeks 0 or 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2). At week 6, a total of 14.5% of the patients receiving vedolizumab and 6.8% of those receiving placebo were in clinical remission (P = 0.02), and 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (P = 0.23). In the maintenance trial, 461 patients with previous response to vedolizumab were randomised to receive placebo or vedolizumab every 8 or 4 weeks until week 52. At week 52, 39% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission, as compared with 21.6% assigned to placebo (P < 0.001 and P = 0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab were developed in 4% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently in patients from the vedolizumab group than for the placebo group. Vedolizumab was associated with a higher rate of serious AE (24.4% vs. 5.3%), infections (44.1% vs. 40.2%) and serious infections (5.5% vs. 3%). Gemini III83, 84 is a randomised, double-blinded, placebo-controlled multicentre study that has recently assessed the safety and efficacy of vedolizumab for the induction of clinical response and remission in 416 CD patients who previously failed to other treatments. Baseline CDAI was slightly higher in the vedolizumab than the placebo group (313.9 vs. 301.3; P = 0.015). Primary endpoint was clinical remission at week 6 in the prior anti-TNF failure group and this was not achieved by vedolizumab. However, the CDAI-100 response at 6 weeks and clinical remission rates at week 10 were 585

n et al. T. Lobato higher in the vedolizumab-treated patients. AE were reported in 56% of vedolizumab patients vs. 60% of placebo patients, and serious AE were reported in 6% vs. 8%, respectively, with no deaths. Vedolizumab has also shown to achieve a higher rate of CS-free remission at week 52 both in UC and in CD patients when compared with placebo.85 Regarding the safety data, an ongoing open-label extension study86 is currently assessing patients with moderate/ severe UC/CD who were na€ıve for vedolizumab or had participated in either a phase 2 or 3 vedolizumab trial. Recently, the AE were summarised by descriptive statistics for data collected through July 2012.87 The exposure to vedolizumab was ≥6, ≥12 and ≥24 months for 1534, 1149 and 502 patients respectively. Drug-related AE were similar for UC and CD (including headache, 6%; nasopharyngitis, 4%; nausea, 4%; arthralgia, 4%; upper respiratory infection, 3%; and fatigue, 3%). The serious infections and drug-related serious AE occurred in 4% and 2% of UC patients and in 7% and 5% of CD patients respectively. Malignancies were observed in 1; response as Mayo score decreases from baseline by ≥3 and ≥30% with rectal bleeding score decrease of ≥1 or absolute reading of 0 or 1; and mucosal healing (MH) as Mayo endoscopy subscore of ≤1. No antibodies anti-AMG181 were detected. PK and RO profiles were directly correlated, without apparent Tcm count elevation. Blinded evaluation showed that 3, 4 and 1 subjects achieved remission; 6, 6 and 2 subjects were in response; and 5, 5 and 1 subjects achieved MH at weeks 6, 12 and 28 respectively. The AE consisted on two early withdrawals due to colitis flare, which were assessed by the investigators as not related to the investigational product. Phase 1 multicentre trials are currently ongoing for UC and CD patients to evaluate safety, tolerability and clinical response to AMG181 (one of the phase 1 studies for UC has been already completed, but results are not published yet).91, 92 Phase 2 trials for UC and CD were suspended because of inaccuracy in study documents that require correction for future enrollees.93, 94 Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

Review: anti-adhesion therapies for inflammatory bowel disease Etrolizumab Etrolizumab, also known as rhuMAb b7 (Genentech, San Francisco, CA, USA), is a humanised monoclonal IgG1 antibody targeting the integrin subunit b7. By blocking the subunit b7, Etrolizumab has then a double effect: the a4b7/MAdCAM-1 blockade that inhibits lymphocyte trafficking to the gut and the aEb7/E-cadherin blockade that results in inhibition of retention of leucocytes in the intraepithelial lining of the gut. Studies in murine animal models95 showed that rhuMAb b7 selectively blocks the lymphocyte homing to the gut without affecting lymphocyte trafficking to nonmucosal tissues. The safety and pharmacology of etrolizumab has been evaluated in UC patients in a phase 1, double-blind randomised, placebo-controlled study.96 In a single ascending dose stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg iv, 3.0 mg/kg sc or placebo) was administered 4:1 (n = 25) in each cohort. In a multiple-dose stage, new patients received monthly etrolizumab [0.5 mg/kg sc (n = 4), 1.5 mg/kg sc (n = 5), 3.0 mg/kg sc (n = 4), 4.0 mg/kg intravenous (n = 5)] or placebo (n = 5).There were no infusion or injection site reactions. Headache was the most common AE, and antibodies anti-etrolizumab were observed in two patients. At day 71, clinical response was observed in 12/18 patients and clinical remission in 3/18 among patients treated with etrolizumab, compared with 4/5 and 1/5 placebo patients, respectively. In a phase 2 study, 198 UC patients were randomised to receive etrolizumab sc (at 100 or 300 mg dose) or placebo. Clinical remission rates at week 10 were significantly superior in the etrolizumab groups both at 100 and at 300 mg doses than in the placebo group (21%, 10% and 0% respectively). Interestingly, in a subanalysis considering only anti-TNF na€ıve patients, clinical remission at week 10 was 25% and 43.4% for 300 and 100 mg, respectively, whereas in patients with previous failure to one anti-TNF, these rates were only of 4% and 4.5% respectively.97 Endoscopic remission was also higher in etrolizumab groups. The drug was generally well tolerated, and AE rates were comparable for placebo and etrolizumab groups. The drug is currently being studied in a phase 2 open-label extension trial.98 PF-547659 PF-00547659 (anti-MAdCAM-1, Pfizer, New York, NY, USA) is a monoclonal IgG2 antibody directed against MAdCAM-1. The role of MAdCAM-1 in the intestinal inflammatory response has been previously demonstrated in animal models49, 99 where the inhibition of MAdCAM-1 resulted in improvement of the colitis in Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

mice. In humans, only a multicentre randomised, double-blind placebo-controlled study has been performed,100 where 80 patients with active UC were treated during 4 weeks with PF-00547659, with single or multiple doses of 0.03–10 mg/kg iv/sc, or placebo. The efficacy analyses were based on the Mayo score and the endoscopic response at weeks 4 and 12. Responder/ remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively, with combined doses of PF-00547659 compared with 32%/11% and 21%/0%, respectively, with placebo. However, differences were not statistically significant. Endoscopic and biological response (measured by the decrease in FC) was also higher in the group treated with PF-00547659 than with placebo. The drug was well tolerated. In conclusion, the drug showed positive efficacy results and a short-term safety profile. The safety of the drug is currently being assessed in a multicentre, phase 1, open-label study with CD or UC patients who are anti-TNF inadequate responders (TOSCA).90 In this study, the effect of the drug is evaluated on the cerebrospinal fluid (CSF) lymphocytes, and the primary endpoint is the per cent change from baseline (pre-treatment) in absolute lymphocyte count in CSF in subjects with CD or UC after receiving 3 monthly doses of PF-00547659. Other secondary endpoints are the presence of AE, of anti-drug antibodies and of injection-site reactions. The estimated study completion date is on April 2016. Besides, the drug is being assessed in phase 2 trials for UC and CD.101–104

AJM300 AJM300 (Ajinomoto Co., Inc., Kawasaki, Japan) is an orally active small molecule that is an antagonist to the a4 integrin. In an animal model, Sugiura et al.105 demonstrated that the oral treatment with AJM300 inhibited the lymphocyte homing to the gut dosedependently, increasing the peripheral lymphocyte count and preventing the development of experimental colitis in mice. Takazoe et al.106 performed the only clinical trial in humans where 71 CD patients were randomised to receive placebo, oral AJM300 40, 120 or 240 mg during 8 weeks. The primary efficacy endpoint was the decrease in CDAI score from baseline to final evaluation at week 4 or later. Secondary efficacy endpoint was clinical response, defined by a decrease of at least 70 points in the CDAI. At week 4, the decreases of CDAI in AJM300 groups (40 mg: 19.9  74.1, 120 mg: 25.5  61.3, 240 mg: 21.6  84.9) were higher than placebo group (5.2  71.0), but differences were not statistically significant. The drug was well tolerated. 587

n et al. T. Lobato Further studies with a larger number of patients are necessary to clarify the effects of this drug. Because of the mode of action of this molecule, it might be associated with an increased risk of PML.

Alicaforsen Alicaforsen (ISIS 2302; ISIS Pharmaceuticals, Carlsbad, CA, USA) is a 20-base ICAM-1 anti-sense oligonucleotide that specifically reduces ICAM-1 mRNA and protein expression. In a pilot study107 in 20 CD patients, alicaforsen administered in 13 infusions during 26 days showed a higher clinical remission rate than placebo (47% vs. 20%) and was well tolerated. However, in two other multicentre studies with larger cohorts, results were negative. On the one hand, Yacyshyn et al.108 performed a double-blind, placebo-controlled trial including 299 patients with active, steroid-dependent CD, and they were randomised to receive placebo vs. ISIS 2302 (2 mg/kg intravenously three times a week) for 2 or 4 weeks during months 1 and 3, with steroid withdrawal attempted by week 10. The study failed to achieve the primary endpoint, with equivalent rates of steroid-free remission for the 2- and 4-week ISIS 2302 groups (20.2% and 21.2%) and the placebo group (18.8%). In this study, however, the steroid-free remission was highly correlated with exposure (P = 0.0064). Another dose-interval, multicentre, placebo-controlled trial was conducted in 75 CD steroid-dependent patients109 also with the endpoint of steroid-free remission at week 14. This was only achieved by 3.3% (2/60) patients treated with ISIS 2302. One of the possible explanations for these negative results was that the drug could not go into the intestinal tissue. In this context, van Deventer et al.110 evaluated the safety and efficacy of an enema formulation of alicaforsen in phase 2 randomised, placebo-controlled, double-blind, escalating dose multicentre study in 40 patients with mild to moderately active distal ulcerative colitis [disease activity index (DAI) of 4–10]. Patients were assigned to four dosing cohorts of 10 patients each (eight active, two placebo). Each patient received 60 mL of alicaforsen enema (with 0.1, 0.5, 2 or 4 mg/mL of alicaforsen or placebo) once daily for 28 consecutive days. Safety and efficacy were evaluated up to 6 months after initiation of dosing. At day 29, alicaforsen enema resulted in dose-dependent improvement in DAI (overall P = 0.003). Alicaforsen 4 mg/mL improved DAI by 70% compared with the placebo response of 28% (P = 0.004). The drug was well tolerated with no major safety issues identified. The systemic and local bioavailability of alicaforsen enema, as well as its activity when administered once daily, was assessed in UC patients in 588

an open-label study.111 Fifteen subjects received nightly enemas of alicaforsen (240 mg) during 6 weeks. Concentrations of the intact oligonucleotide in mucosal colonic tissue biopsies were orders of magnitude higher than those observed in plasma. A 46% reduction in mean DAI and a 33% rate of remission as defined by complete MH were observed at the end of treatment. In none of the studies, alicaforsen showed more AE when compared with placebo group except for mild injection-site reactions and increases in activated partial thromboplastin time. Altogether, alicaforsen has shown conflicting data for CD patients and promising results in UC patients, although studies with a larger number of patients are needed. It has been proposed that this lack of efficacy is due to the nondominant role of ICAM-1 expression in the inflammatory response that occurs in IBD.38, 112

CCX282-B (GSK-1605786) Some chemokines receptors are expressed on lymphocytes in the circulation such as the chemokine receptor 9 (CCR9) and, together with the adhesion molecules, are necessary for the T-cell migration to the GI tract. CCX282-B (Vercinon, GSK-1605786, Traficet-ENTM or anti-CCR9, ChemoCentryx Inc., CA, USA and GlaxoSmithKline, London, UK) is an orally bio-available small molecule that selectively blocks the human CCR9 receptor. In a first animal model, CCR9 demonstrated to be involved in murine ileitis and the blockade of this receptor achieved improvement of ileitis.113 In another animal model, CCX282-B demonstrated for the first time to block selectively CCR9 with clear therapeutic benefit on the intestinal inflammation.114 In IBD patients, a multicentre, double-blind, placebo-controlled, parallel group phase 2 study called PROTECT-1 (Prospective Randomized Oral-Therapy Evaluation in CD)115 has been performed to evaluate the safety and efficacy of CCX282-B. Participants included 436 CD patients who received placebo or CCX282-B (250 mg once daily, 250 mg twice daily or 500 mg once daily) during 12 weeks. Afterwards, they received 250 mg CCX282-B twice daily, open-label, until week 16. Subjects who had a clinical response (defined as a ≥70-point drop in CDAI) at week 16 were randomly assigned to placebo or CCX282-B (250 mg, twice daily) groups until week 52. Primary endpoints were clinical response at week 8 and sustained clinical response at week 52. The response rates at week 8 were similar between groups: 49% in the placebo group, 52% in the group receiving CCX282-B 250 mg once daily, 48% in the group receiving Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

Review: anti-adhesion therapies for inflammatory bowel disease CCX282-B 250 mg twice daily and 60% in the group receiving CCX282-B 500 mg once daily. However, at week 52, 47% of subjects under CCX282-B were in remission, compared to 31% under placebo (OR = 2.01; P = 0.012). The drug was well tolerated. Recently, CCX282-B has been evaluated in adult subjects with moderately-to-severely active CD through a phase 3 randomised, double-blind, placebo-controlled study to assess the efficacy and safety of two doses (500 mg once daily and 500 mg twice daily) of the drug as compared to placebo up to 12 weeks. Unfortunately, the development programme was discontinued after a negative study where the primary endpoint was not met.116

DISCUSSION The drugs discussed in this review all aim at blocking the migration of effector T lymphocytes to the gut. Although it is not yet established which therapy is the most efficacious and safest, the inhibition of the a4b7/ MAdCAM-1 interaction seems to be the most promising approach. Among the molecules targeting this interaction, vedolizumab has been widely studied, with very positive results in UC patients both for induction and for maintenance of remission. Results for CD have been more modest especially for the induction phase, while the drug seems more effective at long term in patients achieving initial response. It has been suggested that because of the systemic and transmural condition of the disease, the induction therapy may need to be longer in CD than in UC and also that the severe disease activity at baseline of the CD patients included in the study might have been a confounder.82 New studies evaluating the possible predictors for better response to vedolizumab among CD patients would help to select which patients would benefit most from this therapy. The other drugs targeting the a4b7/MAdCAM-1 interaction include AMG 181, etrolizumab and PF-00547659, but are still being evaluated in phase 1 and 2 studies. In addition to alter the migration of T cells to the gut, the anti-adhesion molecules have potentially other beneficial effects in the physiopathology of IBD. On the one hand, etrolizumab antagonises the retention of leucocytes within the intestinal mucosa by blocking the aEb7/ E-cadherin interaction. On the other hand, the presence of adhesion molecules in the submucosa layers58 as well as the interaction of integrins with tissue ligands59–61 might interfere with the function of dendritic cells and fibroblasts. Nonetheless, it is not yet clear what subtypes of lymphocytes are targeted with this therapy and whether it is beneficial to arrest also migration of B cells Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

or suppressor T cell besides effector T cells. Therefore, mechanistic studies analysing the effects of these therapies on the composition of the inflammatory infiltrate in CD and UC are greatly needed. The concomitant use of IMS or anti-TNF with these new molecules needs also to be assessed to know if any combination is more effective than the use of anti-adhesion therapies on mono-therapy. Some studies54–56 in IBD patients have shown that anti-TNF downregulate the expression of adhesion molecules and therefore that anti-TNF and anti-adhesion drugs could eventually have a synergic effect. However, no clinical trial has evaluated this aspect yet. In this context, it is important to focus the research not only on the efficacy but also on the safety of the concomitant use of anti-adhesion therapies and other treatments such as IMS or anti-TNF. Because of the selective action in the gut, we could expect a safer profile than with other combinations of the current therapies, but prospective controlled trials are needed to confirm it. This gut-selectivity might theoretically limit the effect of the drug in perianal disease and EIM, although the role of the anti-adhesion therapies in these scenarios is unknown. Some of the EIM are parallel to the luminal disease activity and therefore their management consists on the control of the underlying disease.117, 118 It has been suggested that activated gut-homing lymphocytes travel to other tissues such as synovial vessels to contribute to the inflammatory process, although in this case, the adhesion molecules involved in the extravasation to the synovial tissue (mainly CD44) are different from those of the gut (mainly a4b7).62 Some data suggest that gut mucosal T-cell lines from patients with ankylosing spondylitis present an increased expression of aEb7.119 Interestingly, spondyloarthropathy patients present upregulation of the E-cadherin/catenin complex in their inflamed bowel mucosa.120 Adhesion molecules involved in the skin-homing lymphocytes (mainly cutaneous lymphocyte antigen and aLb2) are also different from those involved in the gut.121 In contrast, in inflammatory liver diseases associated with IBD, it has been shown that the endothelial hepatic portal endothelium also expresses MAdCAM-1 receptors where the T cells expressing a4b7 can bind.63, 64 In this context, the anti-adhesion molecules can hypothetically have an effect in liver diseases driven by this pathway. Taken together, more data about the physiopathology of EIM, as well as studies assessing the effect of anti-adhesion in EIM, are necessary. Lastly, some methodological aspects from the trials performed with anti-adhesion molecules need to be carefully analysed: the variability in the assessment time-points, 589

n et al. T. Lobato endpoints and subpopulations included in each study. The assessment points at short term vary from 4 to 12 weeks with clinical response rates that range from 30% to 70% according to different studies. As for the endpoints, most of the studies include only clinical remission (although with different definitions for it), whereas in some studies, biological or endoscopic remissions are also included. As endoscopic remission has demonstrated to have a prognostic value both in CD and in UC, it is mandatory to include it as a regular endpoint. Regarding the population characteristics, data about the previous medication and, above all, subanalysis in previous anti-TNF failures, are extremely relevant because the efficiency of the drug varies among the different subpopulations. Because of the high rate of failures of anti-TNF, new drugs that are efficient in this subpopulation are urgently needed. In fact, this might currently be the main role of these anti-adhesion drugs: to ‘rescue’ patients who already failed to conventional therapy. Nonetheless, due to their gut-selectivity, it might happen that anti-adhesion molecules can be able to rescue only anti-TNF failure patients with luminal disease, and not those with perianal disease or EIM. Potentially, they could also be indicated as first-line treatment, but comparative studies with anti-TNF are needed before they have such indication. Moreover, expression studies comparing patients under anti-TNF therapies vs. patients starting anti-adhesion molecules drugs will also shed light in the mechanism responsible for a response (or nonresponse) in a given patient. In conclusion, anti-adhesion molecules addressed to a4b7-MAdCAM-1 interaction, and specially vedolizumab, are an efficient and safe alternative treatment for IBD patients refractory to the current therapies. Many questions such as the consequences of anti-adhesion molecules in the composition of the inflammatory infiltrate, their role in perianal disease and EIM and the effect of concomitant treatment still need to be answered. In future, clinical data from comparative studies with the new and the convectional drugs are needed. In addition, a set of genetic, serologic and/or biological

data (through a biomarker panel) could allow the clinician to choose the most suitable drug and/or combination of drugs in each patient. Lastly, the most challenging research remains the one based on the etiopathogenic pathways of IBD, which would lead to the ‘curative’ treatment for IBD.

AUTHORSHIP Guarantor of the article: Triana Lobaton. Author contributions: Research and data collection, interpretation of data, and writing of the draft manuscript: Triana Lobaton. Data collection and critical revision of the manuscript: Severine Vermeire. Editing figures and critical revision of the manuscript: Gert Van Assche. Design of the body manuscript and critical revision of the manuscript: Paul Rutgeerts. All authors approved the final version of the manuscript. ACKNOWLEDGEMENTS Declaration of personal interests: None. Declaration of funding interests: Triana Lobaton was kindly supported by a grant from the Institut d’ Investigacio Biomedica de Bellvitge (IDIBELL). Severine Vermeire receives financial support for research from UCB Pharma, MSD and Abbvie, lecture fees from Abbvie, Merck, Ferring, UCB Pharma and Centocor, and consultancy from UCB Pharma, AstraZeneca, Ferring, Abbvie, Merck, Ferring, Shire and Pfizer. Gert Van Assche receives financial support for research from Abbvie and Ferring, lecture fees form Janssen-Cilag, Merck and Abbvie and consultancy from PDL BioPharma, UCB Pharma, Sanofi-Aventis, Abbvie, Ferring, Novartis, Biogen Idec, Janssen Biologics, NovoNordisk, Zealand Pharma A/S, Millenium/Takeda, Shire, Novartis and BMS. Paul Rutgeerts receives financial support for research from UCB Pharma, Abbvie, Janssen Biologics, Merck and Prometheus, lecture fees from Abbvie and Merck, and consultancy from Amgen, Merck, UCB Pharma, Genentech, BMS, Abbvie, Janssen Biologics, Millenium, Neovacs, Actogenics and Prometheus.

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Aliment Pharmacol Ther 2014; 39: 579-594 ª 2014 John Wiley & Sons Ltd

Review article: anti-adhesion therapies for inflammatory bowel disease.

A high proportion of patients with inflammatory bowel disease (IBD) do not achieve clinical remission with the current therapies including mesalazine ...
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