Integrins and adhesion molecules as targets to treat inflammatory bowel disease

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ScienceDirect Integrins and adhesion molecules as targets to treat inflammatory bowel disease Ivana Bravata`1, Mariangela Allocca1, Gionata Fiorino1 and Silvio Danese1,2 Inflammatory bowel diseases (IBD) present a typically relapsingremitting behavior and are characterized by a disabling and progressive course. Anti-tumor necrosis factor (TNF)-a agents have drastically changed the therapeutic management of IBD. However, a significant proportion of patients does not have a primary response, some patients lose response overtime and/or experience side effects. Recently, anti-adhesion molecules were investigated and showed efficacy with a good safety profile. Vedolizumab was recently approved for both Crohn’s disease (CD) and ulcerative colitis (UC) and several other molecules are under evaluation in this field. Anti-adhesion molecules could represent a potential therapeutic option for future therapy in IBD. In this review we report the efficacy and safety of major antiadhesion drugs in active IBD patients. Addresses 1 IBD Center, Gastroenterology, IRCCS Humanitas, Rozzano, Milan, Italy 2 Humanitas University, Department of Biomedical Sciences, Rozzano, Milan, Italy Corresponding author: Danese, Silvio ([email protected])

Current Opinion in Pharmacology 2015, 25:67–71

gastrointestinal mucosa. Activated lymphocytes promote the release of pro-inflammatory cytokines which, in turn, up-regulate the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1), intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), that are present on endothelial cells [10–12]. Infiltration of leukocytes is regulated by the interactions with surface-expressed integrins. The major relevant components in IBD are a4b7 and a4b1. The a4b7 integrin mediates selectively the gut-homing of the CD4+ T lymphocytes, by binding to MAdCAM-1. MAdCAM-1 is characteristically expressed in gut-associated lymphoid tissue. During inflammation, its up-regulation promotes gut-homing adhesion, motility and migration of lymphocytes from the systemic circulation. The a4b1 integrin interacts with VCAM-1, by regulating lymphocytic migration in all organs, including the central nervous system. Finally, both integrins bind to ICAM-1. Recently, it has been evaluated the role of targeted therapy in the blockade of the interaction between adhesion molecules and T-cells. In Figure 1 represents the mechanism of action of anti-adhesion drugs.

This review comes from a themed issue on Gastrointestinal

Anti-integrins agents

Edited by Nathalie Vergnolle

Natalizumab

For a complete overview see the Issue

Natalizumab is an IgG4 not gut-selective antibody that binds to both a4b1 and a4b7 integrins. It was the first anti-integrin molecule that has proven effective in the induction and maintenance of remission in CD patients [13,14]. However, natalizumab treatment is associated with the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection, that is caused by the JC virus (JCV). In the postmarketing setting, natalizumab was responsible of about 450 cases of PML among 120 000 patients who experienced this treatment, with an estimated incidence of PML of 3.6/ 1000 patient/year. Hence in the European Union, natalizumab has not been approved for the treatment of CD patients.

http://dx.doi.org/10.1016/j.coph.2015.11.007 1471-4892/Published by Elsevier Ltd.

Introduction Inflammatory bowel diseases (IBD) present a typically relapsing-remitting behavior and are characterized by disabling and progressive course [1–4]. The advent of antitumor necrosis factor (TNF)-a therapy has drastically changed the therapeutic management of IBD. However, up to 40% of patients do not have a primary response, some patients lose response overtime [5–8], while some others experience intolerance up to serious side effects [9]. Recently, anti-adhesion molecules have been proven effective with a good safety profile. Some of them could represent a potential therapeutic option for future therapy in IBD.

Adhesion molecules The persistent inflammatory state in IBD is mediated by the migration of activated T cells from the blood to the www.sciencedirect.com

Vedolizumab

The demonstrated efficacy of this mechanism of action has led to the identification of molecules with a more acceptable safety profile. Vedolizumab is an IgG1 humanized monoclonal antibody gut-selective that inhibits the a4b7 integrin. Thanks to its gut-selectivity, vedolizumab presents a lower risk of systemic infections. Vedolizumab was evaluated in the GEMINI program that includes phase 3 trials conducted in IBD patients. Current Opinion in Pharmacology 2015, 25:67–71

68 Gastrointestinal

Figure 1

Leukocyte

AJM300 Natalizumab

AJM300 AMG181 Etrolizumab Natalizumab Vedolizumab

Etrolizumab

α4β1

α4β7

αEβ7

PF-00547659 VCAM-1

ICAM-1

ENDOTHELIAL CELLS

MAdCAM-1

E-CADHERIN

EPITHELIAL CELL Current Opinion in Pharmacology

Action mechanism of anti-adhesion drugs.

GEMINI I was composed of two randomized, placebocontrolled trials in which efficacy of vedolizumab was evaluated in active UC [15]. In the induction phase two cohorts of patients were enrolled: cohort 1 included 374 patients who were randomized to receive vedolizumab 300 mg, intravenously, or placebo at weeks 0 and 2; cohort 2 included 521 UC patients who received open-label vedolizumab. At week 6, patients in either cohorts with a response to vedolizumab, were randomized in the maintenance phase to receive vedolizumab (every 4 or 8 weeks) or placebo up to 52 weeks. Vedolizumab was effective in inducing clinical response at week 6 (47.1% in the vedolizumab group versus 25.5% in the placebo group; p < 0.001). At week 52, 41.8% and 44.8% of patients who continued to receive Vedolizumab every 8 or 4 weeks, respectively, were in clinical remission compared with 15.9% of patients switched to placebo ( p < 0.001). Authors concluded that vedolizumab was more effective than placebo as both induction and maintenance therapy for active UC with similar adverse events rates. Sandborn et al. [16] conducted a phase 3 placebo-controlled trial, in which Current Opinion in Pharmacology 2015, 25:67–71

vedolizumab was evaluated as induction and maintenance therapy in active CD patients (Gemini II). The study design was similar to Gemini I. Three hundred and sixty-eight patients were randomized to 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, 14.5% of the patients who received vedolizumab and 6.8% in placebo group were in clinical remission ( p = 0.02), while response rates were not significant different (31.4 vs 25.7%; p = 0.23). At week 52, 39% and 36.4% of the patients treated with vedolizumab every 8 weeks and every 4 weeks, respectively, showed a clinical remission ( p < 0.001; p = 0.004; respectively) compared with 21.6% assigned to placebo. Gemini III, a placebo-controlled, phase 3 trial was conducted on 416 active CD patients [17]. Patients were randomized to receive vedolizumab 300 mg or placebo and were observed for 10 weeks. The primary end point was clinical remission at week 6 in patients who had previously failed an anti-TNF. Vedolizumab was effective to induce clinical remission at week 10 compared with placebo (26.6% vs 12.1%; p = 0.001), www.sciencedirect.com

Integrins or adhesion molecules Bravata` et al. 69

while no significant difference was observed at week 6. Moreover, at week 6, vedolizumab was more effective than placebo to induce a CDAI-100 response (39.2% vs 22.3%; p = 0.001). Safety profile was similar among all groups. GEMINI LTS (URL: https://clinicaltrials.gov/ ct2/show/record/NCT00790933) is a 2-year extension ongoing open-label study in which the long-term safety and tolerability of vedolizumab are measured in patients with IBD who had participated in GEMINI trials. The GEMINI studies have demonstrated the effectiveness of vedolizumab in both UC and CD, with an acceptable safety profile. Therefore, in 2014, vedolizumab was approved as treatment of IBD patients who have failed to anti-TNF therapy or immunosuppressants or who are steroid-dependent. In approximately 3000 patients exposed to vedolizumab, there were no reported cases of PML. Therefore, vedolizumab does not seem to carry a significant risk of PML, even if post-marketing monitoring will be needed. Etrolizumab

Etrolizumab is a humanized IgG1 monoclonal antibody, that binds to the b7 subunit of a4b7 and aEb7 integrins, blocking their ligands: MAdCAM-1 and E-cadherin, respectively. Etrolizumab targets the homing of the lymphocytes from systemic circulation, acting on a4b7– MAdCAM-1 interaction, and the presence of intraepithelial leucocytes, blocking the aEb7-E-cadherin interaction [18]. Etrolizumab was evaluated in a phase 1 trial, in 38 active UC patients compared with 10 patients treated with placebo [19]. The trial included two stages: a single ascending dose stage and a multiple dose stage. Etrolizumab was safe and well-tolerated in both studies, without dose-limiting toxicities, infusion or injection-site reactions. Two patients developed transient JCV viremia, but no clinical or radiographic findings of PML were observed. Evaluation of the pharmacokinetic profile indicated that etrolizumab could be administered as subcutaneous monthly injection. Recently, etrolizumab was evaluated as induction therapy in a phase 2 study [20]. One hundred and twenty-four refractory active UC patients were randomized to receive etrolizumab sc at 100 mg at weeks 0, 4 and 8; or 420 mg loadind dose at week 0 followed by 300 mg at weeks 2, 4 and 8; or placebo. At week 10, 20.5% of etrolizumab 100 mg group and 10.3% of Etrolizumab loading dose were in clinical remission versus no subject in placebo groups ( p = 0.004; p = 0.049; respectively). There were no differences in incidence of serious infections or of adverse events. Currently, efficacy and safety of etrolizumab, compared with adalimumab, infliximab or placebo, are under evaluation in phase 3 studies conducted in active UC patients (URL: http://clinicaltrials.gov/show/NCT02171429). AMG181

AMG 181 is a fully human IgG2 monoclonal antibody that, like vedolizumab, through its binding to a4b7 integrin, selectively blocks MAdCAM-1. AMG 181 was www.sciencedirect.com

investigated in 4 active UC patients (3 active drug, 1 placebo), compared with 68 healthy controls [21]. Results showed that AMG 181 had pharmacokinetics/ pharmacodynamics, safety, and effect profiles suitable for further testing in IBD. No serious adverse events were observed. AMG 181 is currently being evaluated in phase 2 trials in subjects with IBD (URL: http://clinicaltrials. gov/show/NCT01694485; URL: http://clinicaltrials.gov/ show/NCT01696396). AJM300

AJM300 is an orally administered, small molecule, a4integrin antagonist. It inhibits the interaction between a4b1and a4b7 integrins and VCAM-1 and MAdCAM-1, respectively, suggesting efficacy and safety profiles similar to those of natalizumab. Efficacy and safety of AJM300 in CD, were evaluated in a randomized, placebo-controlled trial (Takazoe M et al., abstract in Digestive Disease Week 2009, S1066). Seventy-one CD patients were randomized to receive AJM300 40, 120 or 240 mg 3 times daily, or placebo, for 8 weeks The primary endpoint, a CDAI score reduction from baseline at week 4 or later, was achieved in AJM 120 mg group, among those patients with a high CDAI at baseline ( p = 0.0485). There was no difference in clinical response among groups. There were no differences in adverse events between AJM300 and placebo groups. Efficacy of AJM300 was also evaluated in 102 active UC patients in a randomized, placebo-controlled, phase 2a trial (Watanabe M et al., abstract in DDW 2014, S82). At week 8, 62.7% of patients treated with AJM300, at a dosage of 960 mg 3 times daily, showed a clinical response compared with 25.5% in placebo group ( p = 0.0002). Clinical remission and mucosal healing were achieved in 23.5% and 58.8% in AMJ300 group versus 3.9% and 29.4% in the placebo group ( p = 0.0099; p = 0.0014; respectively). In the AJM300 group was osserved an increase in peripheral lymphocyte counts.

Anti-adhesion molecules PF-00547659

PF-00547659 is a human monoclonal antibody that selectively binds to MAdCAM-1, blocking its interaction with a4b7 integrin. Vermeire et al. conducted a randomized, placebo-controlled study, in which 80 patients with active UC were randomized to receive single or multiple doses of PF-00547659 compared with placebo [22]. Clinical and endoscopic response and remission rates were numerically higher in treated groups compared with placebo group, but no statistically significant differences were observed. No obvious drug-related adverse events were registered. OPERA and TURANDOT are two studies in progress in which PF-00547659 is evaluated as induction and maintenance therapy for active CD and UC, respectively (URL: https://clinicaltrials.gov/ct2/results?term=PF00547659&Search=Search). Recently, D’Haens et al. have presented the effects of PF-00547659 on cellular elements of the CSF (D’Haens G et al., abstract in ECCO Current Opinion in Pharmacology 2015, 25:67–71

70 Gastrointestinal

Table 1 Anti-adhesion molecules in IBD: current status Anti-adhesion molecules

Disease

Natalizumab Vedolizumab Etrolizumab AMG181 AJM300 PF-00547659

CD CD; UC CD; CD; CD;

UC UC UC UC

Target

Phase

a4b1; a4b7 a4b7 aEb7 a4b7 a4 MAdCAM-1

Approved a Approved Phase 3 Phase 2 Phase 2 Phase 2

Administration IV IV IV; SC IV; SC Oral IV; SC

IV: intravenous; SC: subcutaneous. In USA.

Schering-Plough, Abbott Laboratories, Merck & Co, UCB Pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Alpha Wasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson & Johnson. The other authors have no conflicts to declare.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:

a

2014, OP007). Twenty-four active CD patients underwent a lumbar puncture, and then they received 3 doses of PF-00547659, 225 mg every 4 weeks. Two weeks after the drug administration, a second lumbar puncture was performed in 12 patients. Lymphocytes count, evaluated by flow cytometry, was not affected by the administration of the highest dosage of PF-00547659. The TOSCA study underlines the gut-selectivity and the CNS-sparing mechanism of PF-00547659. In Table 1 it is reported the current status of anti-adhesion drugs.

 of special interest  of outstanding interest 1.

Peyrin-Biroulet L, Desreumaux P, Sandborn WJ, Colombel JF: Crohn’s disease: beyond antagonists of tumour necrosis factor. Lancet 2008, 372:67-81.

2.

Peyrin-Biroulet L, Cieza A, Sandborn WJ, Coenen M, Chowers Y, Hibi T, Kostanjsek N, Stucki G, Colombel JF: Development of the first disability index for inflammatory bowel disease based on the international classification of functioning, disability and health. Gut 2012, 61:241-247.

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Peyrin-Biroulet L: Disease-modifying anti-inflammatory bowel disease drugs (DMAIDs): the missing term in the literature. Am J Gastroenterol 2013, 108:859-860.

4.

Henriksen M, Jahnsen J, Lygren I, Sauar J, Kjellevold O, Schulz T, Vatn MH, Moum B: Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis 2006, 12:543-550.

5.

Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D’Haens G, Wolf DC, Kron M, Tighe MB, Lazar A, Thakkar RB: Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012, 142 257–265 e 251–253.

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7.

Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF: Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol 2008, 6:644-653.

8.

Amiot A, Peyrin-Biroulet L: Current, new and future biological agents on the horizon for the treatment of inflammatory bowel diseases. Therap Adv Gastroenterol 2015, 8:66-82.

9.

Lawrance IC, Radford-Smith GL, Bampton PA, Andrews JM, Tan PK, Croft A, Gearry RB, Florin TH: Serious infections in patients with inflammatory bowel disease receiving antitumor-necrosis-factor-alpha therapy: an Australian and New Zealand experience. J Gastroenterol Hepatol 2010, 25:1732-1738.

Conclusions IBD are chronic diseases with a global impact on health and quality of life. Currently available therapies are not able to control the disease in the long term in the majority of IBD patients. The anti-adhesion mechanism seems to represent a useful treatment option in IBD patients in the next future. The gut-selective integrin inhibitor vedolizumab has shown to be effective in UC and CD, both in naı¨ve and in patients who fail or are intolerant to anti-TNa therapy patients, with a very good safety profile. More anti-adhesion molecules, including etrolizumab and PF00547659, are now under evaluation and seem promising, enlarging the therapeutic alternatives for IBD patients. Many goals have been achieved, but further studies for particular settings of patients (such as prevention of postoperative recurrence, perianal CD, pregnant IBD patients) and head-to-head trials for the positioning of anti-adhesion molecules in the treatment algorithms are still needed.

Contributorship Ivana Bravata`, Mariangela Allocca and Gionata Fiorino reviewed the literature, Ivana Bravata` drafted the manuscript, Mariangela Allocca and Silvio Danese critically revised the manuscript. All the authors approved the final version of the manuscript.

10. Lobaton T, Vermeire S, Van Assche G, Rutgeerts P: Review article: anti-adhesion therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2014, 39:579-594. 11. Brand S: Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut 2009, 58:1152-1167.

Conflict of interest

12. Strober W, Fuss IJ: Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011, 140:1756-1767.

Gionata Fiorino served as a consultant and a member of Advisory Boards for MSD, Takeda Pharmaceuticals and Janssen Pharmaceuticals; Silvio Danese has served as a speaker, consultant and advisory board member for

13. Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, Spehlmann ME, Rutgeerts PJ, Tulassay Z, Volfova M et al.: Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial. Gastroenterology 2007, 132:1672-1683.

Current Opinion in Pharmacology 2015, 25:67–71

www.sciencedirect.com

Integrins or adhesion molecules Bravata` et al. 71

14. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S et al.: Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005, 353:1912-1925. 15. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF,  Sandborn WJ, Van Assche G, Axler J, Kim HJ, Danese S et al.: Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013, 369:699-710. Report results from a phase 3 clinical trial testing vedolizumab versus placebo in active ulcerative colitis. This study highlights that vedolizumab was effective as both induction and maintenance therapy compared with placebo.

19. Rutgeerts PJ, Fedorak RN, Hommes DW, Sturm A, Baumgart DC, Bressler B, Schreiber S, Mansfield JC, Williams M, Tang M et al.: A  randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. Gut 2013, 62:1122-1130. In this phase 1 study the safety and pharmacology of etrolizumab was evaluated in patients with moderate to severe UC. Patients were enrolled in a single ascending dose stage and in a multiple dose stage. Etrolizumab was safe and well-tolerated in both studies, without dose-limiting toxicities, infusion or injection-site reactions.

16. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, Lukas M, Fedorak RN, Lee S, Bressler B et al.: Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013, 369:711-721.

20. Vermeire S, O’Byrne S, Keir M, Williams M, Lu TT, Mansfield JC,  Lamb CA, Feagan BG, Panes J, Salas A et al.: Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014, 384:309-318. This is a phase 2 study in which etrolizumab is evaluated as induction therapy in refractory active UC patients. Results show that etrolizumab was significantly able to induce clinical remission compared with placebo.

17. Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ,  Sy R, D’Haens G, Ben-Horin S, Xu J, Rosario M et al.: Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 2014, 147 618–627 e 613. In this trial vedolizumab was evaluated in a cohort of active CD patients who had previously failed an anti-TNF. Vedolizumab was effective to induce clinical remission at week 10 compared with placebo, even if the primary endpoint was not achieved.

21. Pan WJ, Kock K, Rees WA, Sullivan BA, Evangelista CM, Yen M,  Andrews JM, Radford-Smith GL, Prince PJ, Reynhardt KO et al.: Clinical pharmacology of AMG 181, a gut-specific human antialpha4beta7 monoclonal antibody, for treating inflammatory bowel diseases. Br J Clin Pharmacol 2014, 78:1315-1333. This is the first-in-human study conducted in healthy subjects and subjects with active UC in which AMG181 was evaluated. Despite the small sample, AMG181 showed an acceptable safety, tolerability profile and effect profiles.

18. Stefanich EG, Danilenko DM, Wang H, O’Byrne S, Erickson R, Gelzleichter T, Hiraragi H, Chiu H, Ivelja S, Jeet S et al.: A humanized monoclonal antibody targeting the beta7 integrin selectively blocks intestinal homing of T lymphocytes. Br J Pharmacol 2011, 162:1855-1870.

22. Vermeire S, Ghosh S, Panes J, Dahlerup JF, Luegering A, Sirotiakova J, Strauch U, Burgess G, Spanton J, Martin SW et al.: The mucosal addressin cell adhesion molecule antibody PF00547,659 in ulcerative colitis: a randomised study. Gut 2011, 60:1068-1075.

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Current Opinion in Pharmacology 2015, 25:67–71