Lym p h o c y t e H o m i n g A n t a g o n i s t s in t h e Tre a t m e n t o f I n f l a m m a t o r y Bowel Diseases Masayuki Saruta,
MD, PhD
a
, Konstantinos A. Papadakis, MD, PhDb,*
KEYWORDS Natalizumab Vedolizumab Etrolizumab Integrins Chemokine receptors Inflammatory bowel disease Ulcerative colitis Crohn disease KEY POINTS Inhibiting the interactions between adhesion molecules expressed on inflamed intestinal endothelium and lymphocyte integrins has proved to be a successful therapeutic strategy for the management of chronic inflammatory bowel disease (IBD). Targeting specifically the MAdCAM-1/a4b7 interactions with vedolizumab and, possibly, AMG 181 is likely to be effective and safe treatment approach for refractory IBD patients. Future studies need to address the use of these agents in the treatment of fistulizing Crohn disease phenotypes and extraintestinal manifestation of IBD. Subgroup analysis may identify genetic, serologic, and clinical parameters that may predict response to adhesion molecule inhibition and the best timing for therapeutic intervention. Combination therapeutic strategies with immunomodulators or even anti–tumor necrosis factor agents in a selective refractory group of IBD patients should also be entertained.
INTRODUCTION
Inflammatory bowel diseases (IBD) comprise a heterogeneous group of intestinal inflammatory disorders characterized by periods of disease exacerbation and remission, and are broadly classified into ulcerative colitis (UC) and Crohn disease (CD). Their pathogenesis is still unknown, but they are thought to develop as a result of a dysregulated immune response to certain gut bacterial antigens in the context of Financial Disclosure: None. a Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3 Chome-25-8 Nishishinbashi, Minato, Tokyo 105-0003, Japan; b Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA * Corresponding author. E-mail address: [email protected] Gastroenterol Clin N Am 43 (2014) 581–601 http://dx.doi.org/10.1016/j.gtc.2014.05.012 gastro.theclinics.com 0889-8553/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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genetic susceptibility, certain environmental triggers, and gut dysbiosis.1–3 Histopathologically, IBD is characterized by the extent and distribution of mucosal architectural abnormality, the cellularity of the lamina propria, and the cell types present, but with significant overlap between the 2 diseases.4 Disease activity can be reflected by neutrophil granulocyte infiltration and epithelial cell damage.4 Characteristics of disease that could interfere with response to medical therapy, whether to traditional medications or to biological agents (including adhesion molecule inhibitors), include early disease or long-standing disease, which could reflect differences in inflammatory cell infiltrate and their immunologic characteristics.4 Traditional therapies of IBD, such as 5-aminosalicylic acid, corticosteroids, and immunomodulators, have been shown to modulate the intestinal immune responses to some degree in a nonspecific manner.5,6 The introduction of biological agents for the treatment of IBD has targeted specific pathways of inflammation, including proinflammatory cytokines such as tumor necrosis factor (TNF)-a, with remarkable longterm beneficial effects that may alter the natural history of IBD.7 Such treatment approaches include the introduction of monoclonal antibodies targeting TNF-a, such as infliximab, adalimumab, certolizumab pegol, and golimumab.7,8 However, despite the remarkable effectiveness of these agents, they may lose efficacy over time or rarely produce treatment-related side effects. Therefore, alternative therapeutic agents with a different mode of action are urgently needed. Active IBD is characterized by the recruitment of large numbers of granulocytes, lymphocytes, and macrophages into the gastrointestinal mucosa.9 The recruitment of leukocytes to peripheral tissues is a highly coordinated, multistep process (Fig. 1). As they circulate at high speed through the postcapillary vessels, a highly coordinated sequential adhesion pathway is activated, which consists of the capture/tethering, rolling, activation, adhesion, and migration through the vascular wall, and eventual transmigration to the tissue.10 These infiltrating leukocytes may perpetuate the inflammatory process through the secretion of proinflammatory cytokines, further endothelial cell activation, and upregulation of adhesion molecules and enhancement of inflammatory cell recruitment. Further tissue damage may result from the release of proteases by the infiltrating leukocytes.9 The process of intestinal leukocyte infiltration is regulated by the expression of integrins and chemokine receptors on leukocytes, and adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on endothelial cells (see Fig. 1).11–13 Integrins comprise a family of a,b heterodimeric transmembrane receptors that are constitutively expressed and mediate the attachment of cells to the extracellular matrix (ECM), but can also take part in specialized cell-cell interactions.14,15 The integrin family consists of at least 24 different forms representing the combination of 18 a subunits and 8 b subunits.16 These integrins are expressed on the surface of leukocytes and require activation to bind their own specific ligand. The a subunit determines integrin ligand specificity, and the b subunit connects to the cytoskeleton and affects multiple signaling pathways.16 Integrins involved in the T-cell migration include leukocyte function–associated antigen 1 (LFA-1 or a2b2) and the 2 a4 integrins (a4b1 and a4b7).17 LFA-1 is expressed on neutrophils, and interacts with ICAM-1, which is expressed on leukocytes, dendritic cells, fibroblasts, epithelial cells, and endothelial cells.18,19 The a4b1 integrin is expressed on most leukocytes but not on neutrophils, and interacts with VCAM-1.20 The a4b7 integrin is expressed on the lymphocytes in the gut-associated lymphoid tissue, and interacts with MAdCAM-1.21 This ligand is expressed on endothelial venules in the small intestine and the colon, especially in the Peyer patches.22
Lymphocyte Homing Antagonists for IBD Treatment
Fig. 1. Adhesion molecules and chemokine receptors in the recruitment of immune cells in the intestinal endothelium. In the intestine, the adhesion molecule MAdCAM-1 functions as docking site for integrins a4b1 and a4b7 expressed by T cells.69 By contrast, the adhesion molecule VCAM-1 also acts as docking molecule for a4b1. Natalizumab inhibits a4 integrins, therefore blocking the adhesion of T cells to the entire intestinal mucosa and extramucosal tissues (eg, brain). Vedolizumab, an a4b7 integrin inhibitor, inhibits the adhesion of T cells to the intestinal mucosa only, and thus does not limit immune surveillance of the central nervous system while dampening the inflammatory response.69 In the endothelium of the small intestine, the chemokine CCL25 is constitutively expressed and upregulated during inflammation. It acts as a ligand for the chemokine receptor 9 (CCR9) on T cells. The inhibitor CCX282-B, or vercirnon, blocks the CCL25-CCR9 interaction, thus inhibiting T-cell adhesion to the small intestinal mucosa. Phase 3 trials of CCX282-B are currently on hold. ICAM, intercellular adhesion molecule; IL, interleukin; MAdCAM, mucosal addressin cell adhesion molecule; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.
Proinflammatory cytokines such as TNF-a and interleukin (IL)-1b upregulate the expression of gut-expressed adhesion molecules such as MAdCAM-1, ICAM-1, and VCAM-1. These adhesion molecules are overexpressed in IBD, especially in the active phase of the disease. Cultured supernatants from colonic biopsies taken from UC and CD patients induce upregulation of ICAM-1 and E-selectin,23 and there is increased expression of various endothelial adhesion molecules by immunohistochemistry from colonic biopsies in patients with IBD.24–26 Moreover, it has been shown that the proportion of venular endothelium within the lamina propria that expresses MAdCAM-1 at inflammatory foci associated with UC and CD is increased compared with normal tissues, and MAdCAM-1 is not detected in most normal or inflamed extraintestinal tissues, including those at other mucosal surfaces.22 Similarly, VCAM-1 is also overexpressed in the colonic IBD mucosa in comparison with normal controls by immunohistochemistry.24
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Saruta & Papadakis
PREVENTING LEUKOCYTE INFILTRATION BY BLOCKING ADHESION RECEPTORS
Inhibition of leukocyte trafficking to the gut mucosa during the inflammatory process in IBD has become the second major therapeutic target of biological agents after the introduction of anticytokine agents in the development of IBD therapeutics.13 Several critical steps outlined in Fig. 1 that are involved in the recruitment of inflammatory cells to the intestinal mucosa can be targeted for therapeutic purposes. The a4b7 integrin is highly expressed on a subpopulation of CD41CD45RA– memory T cells, which have been shown to preferentially home to the gut.27,28 The ligand mediating a4b7 T-cell gut-homing is MAdCAM-1, which is selectively expressed in the gut endothelium and is upregulated in the chronically inflamed small and large intestines of patients with IBD.22,29 The predominant targets of the novel biological agents in this group are the integrins a4b1, a4b7, and a2b2, which interact with VCAM-1, MAdCAM-1, and ICAM-1, respectively, to mediate the interactions between leukocytes and endothelial cells.12,13 The agents that target the integrins include the monoclonal antibodies natalizumab (antia4 integrin), vedolizumab (MLN-02, anti-a4b7 integrin), AMG181 (anti-a4b7 integrin), etrolizumab (RG7413, rhuMAb b7, anti-b7 integrin), which targets both a4b7 and aEb7, and PF-00547659 (anti-MAdCAM-1). AJM-300 (Ajinomoto Pharmaceuticals, Tokyo, Japan) is a small-molecule inhibitor of the a4 integrin subunit. Other molecules that aim to prevent leukocyte infiltration include alicaforsen (ISIS-2302), an antisense oligonucleotide against ICAM-1 messenger RNA. Vercirnon (CCX282-B, GSK1605786) is a small molecule that targets the chemokine receptor CCR9, the key chemokine receptor in the targeting of leukocytes to the intestinal mucosa (see Fig. 1, Table 1).30,31 CURRENT ANTIADHESION THERAPIES FOR IBD Antiadhesion Therapies for IBD Natalizumab
Natalizumab (Tysabri; Biogen-Idec, Cambridge, MA, USA) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody against a4 integrins.32 Previous randomized studies have suggested that natalizumab may be effective as induction therapy for patients with moderately to severely active CD.33–35 The first study of natalizumab was reported by Gordon and colleagues,34 and focused on the evaluation of the safety and efficacy of natalizumab in patients with mildly to moderately active CD. Ghosh and colleagues33 conducted a double-blind, placebo-controlled trial of natalizumab in 248 patients with moderate to severe CD. Patients were randomly assigned to receive 1 of 4 treatments: 2 infusions of placebo; 1 infusion of 3 mg natalizumab per kg body weight, followed by placebo; 2 infusions of 3 mg natalizumab per kg; or 2 infusions of 6 mg natalizumab per kg. The highest remission rate was 44% and the highest response rate was 71% at week 6 in the group given 2 infusions of 3 mg/kg. Patients with moderate to severe disease (Crohn Disease Activity Index [CDAI] scores 220 to 450) were enrolled in the phase 3 induction trial, Efficacy of Natalizumab as Active Crohn Therapy (ENACT-1) (N 5 905), and received 3 infusions of natalizumab (300 mg) or placebo over 8 weeks.35 Response was defined as a reduction of 70 or more points from week 0 in the CDAI score, whereas remission was defined as a CDAI score of less than 150 points. A clinical response at week 10 was observed in 56% of patients treated with natalizumab and 49% of patients with placebo (P 5 .051), and remission obtained at week 10 in 37% of natalizumab-treated patients and 30% of patients with placebo (P 5 .124). Although there were no significant differences among the 2 treatment groups, analysis in subgroups of patients,
Table 1 Selected leukocyte trafficking modulators for inflammatory bowel disease Description
Developer
Target
Indication
Clinical Status
Tysabri
Humanized IgG4 mAb
Biogen Idec (Cambridge, MA)
a4b1 integrin, a4b7 integrin
Multiple sclerosis, Crohn disease
Approved (FDA)
Entyvio
Humanized IgG1 mAb
Takeda Pharmaceuticals (Deerfield, IL)
a4b7 integrin
Crohn disease
Registration (in USA)
AMG-181
Fully human IgG2 mAb
AstraZeneca (London, UK)/Amgen (Thousand Oaks, CA)
a4b7 integrin
Crohn disease, ulcerative colitis
Phase 2
Etrolizumab (rhuMAb b7, RG7413)
Humanized IgG1 mAb
Genentech (South San Francisco, CA)
a4b7 integrin, aEb7 integrin
Ulcerative colitis
Phase 2
PF-00547659
Fully human IgG2k mAb
Pfizer (New York, NY, USA)
MAdCAM-1
Crohn disease, ulcerative colitis
Phase 2
AJM300
Oral small-molecule prodrug
Ajinomoto Pharmaceuticals (Tokyo, Japan)
a4 integrin
Ulcerative colitis, Crohn disease
Phase 2
Vercirnon (CCX282-B)
Oral small molecule
ChemoCentryx (Mountain View, CA)/GSK (Brentwood, Middlesex, UK)
CCR9
Crohn disease
Phase 3 (on hold)
Data sources: Company Web sites; PubMed. Abbreviations: FDA, Food and Drug Administration; IgG, immunoglobulin G; mAb, monoclonal antibody. Adapted from Sheridan C. First integrin inhibitor since Tysabri nears approval for IBD. Nat Biotechnol 2014;32:206; with permission.
Lymphocyte Homing Antagonists for IBD Treatment
Drug
585
586
Saruta & Papadakis
Fig. 2. Efficacy of Natalizumab in Crohn’s disease Response and Remission (ENCORE) trial. The primary end point was induction of response (70-point decrease from baseline Crohn’s Disease Activity Index [CDAI] score) at week 8 that was sustained through week 12. (A) Proportion of patients with a clinical response (70-point decrease from baseline CDAI score). The secondary end points were induction of remission (CDAI score
MD, PhD
a
, Konstantinos A. Papadakis, MD, PhDb,*
KEYWORDS Natalizumab Vedolizumab Etrolizumab Integrins Chemokine receptors Inflammatory bowel disease Ulcerative colitis Crohn disease KEY POINTS Inhibiting the interactions between adhesion molecules expressed on inflamed intestinal endothelium and lymphocyte integrins has proved to be a successful therapeutic strategy for the management of chronic inflammatory bowel disease (IBD). Targeting specifically the MAdCAM-1/a4b7 interactions with vedolizumab and, possibly, AMG 181 is likely to be effective and safe treatment approach for refractory IBD patients. Future studies need to address the use of these agents in the treatment of fistulizing Crohn disease phenotypes and extraintestinal manifestation of IBD. Subgroup analysis may identify genetic, serologic, and clinical parameters that may predict response to adhesion molecule inhibition and the best timing for therapeutic intervention. Combination therapeutic strategies with immunomodulators or even anti–tumor necrosis factor agents in a selective refractory group of IBD patients should also be entertained.
INTRODUCTION
Inflammatory bowel diseases (IBD) comprise a heterogeneous group of intestinal inflammatory disorders characterized by periods of disease exacerbation and remission, and are broadly classified into ulcerative colitis (UC) and Crohn disease (CD). Their pathogenesis is still unknown, but they are thought to develop as a result of a dysregulated immune response to certain gut bacterial antigens in the context of Financial Disclosure: None. a Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3 Chome-25-8 Nishishinbashi, Minato, Tokyo 105-0003, Japan; b Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA * Corresponding author. E-mail address: [email protected] Gastroenterol Clin N Am 43 (2014) 581–601 http://dx.doi.org/10.1016/j.gtc.2014.05.012 gastro.theclinics.com 0889-8553/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
582
Saruta & Papadakis
genetic susceptibility, certain environmental triggers, and gut dysbiosis.1–3 Histopathologically, IBD is characterized by the extent and distribution of mucosal architectural abnormality, the cellularity of the lamina propria, and the cell types present, but with significant overlap between the 2 diseases.4 Disease activity can be reflected by neutrophil granulocyte infiltration and epithelial cell damage.4 Characteristics of disease that could interfere with response to medical therapy, whether to traditional medications or to biological agents (including adhesion molecule inhibitors), include early disease or long-standing disease, which could reflect differences in inflammatory cell infiltrate and their immunologic characteristics.4 Traditional therapies of IBD, such as 5-aminosalicylic acid, corticosteroids, and immunomodulators, have been shown to modulate the intestinal immune responses to some degree in a nonspecific manner.5,6 The introduction of biological agents for the treatment of IBD has targeted specific pathways of inflammation, including proinflammatory cytokines such as tumor necrosis factor (TNF)-a, with remarkable longterm beneficial effects that may alter the natural history of IBD.7 Such treatment approaches include the introduction of monoclonal antibodies targeting TNF-a, such as infliximab, adalimumab, certolizumab pegol, and golimumab.7,8 However, despite the remarkable effectiveness of these agents, they may lose efficacy over time or rarely produce treatment-related side effects. Therefore, alternative therapeutic agents with a different mode of action are urgently needed. Active IBD is characterized by the recruitment of large numbers of granulocytes, lymphocytes, and macrophages into the gastrointestinal mucosa.9 The recruitment of leukocytes to peripheral tissues is a highly coordinated, multistep process (Fig. 1). As they circulate at high speed through the postcapillary vessels, a highly coordinated sequential adhesion pathway is activated, which consists of the capture/tethering, rolling, activation, adhesion, and migration through the vascular wall, and eventual transmigration to the tissue.10 These infiltrating leukocytes may perpetuate the inflammatory process through the secretion of proinflammatory cytokines, further endothelial cell activation, and upregulation of adhesion molecules and enhancement of inflammatory cell recruitment. Further tissue damage may result from the release of proteases by the infiltrating leukocytes.9 The process of intestinal leukocyte infiltration is regulated by the expression of integrins and chemokine receptors on leukocytes, and adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on endothelial cells (see Fig. 1).11–13 Integrins comprise a family of a,b heterodimeric transmembrane receptors that are constitutively expressed and mediate the attachment of cells to the extracellular matrix (ECM), but can also take part in specialized cell-cell interactions.14,15 The integrin family consists of at least 24 different forms representing the combination of 18 a subunits and 8 b subunits.16 These integrins are expressed on the surface of leukocytes and require activation to bind their own specific ligand. The a subunit determines integrin ligand specificity, and the b subunit connects to the cytoskeleton and affects multiple signaling pathways.16 Integrins involved in the T-cell migration include leukocyte function–associated antigen 1 (LFA-1 or a2b2) and the 2 a4 integrins (a4b1 and a4b7).17 LFA-1 is expressed on neutrophils, and interacts with ICAM-1, which is expressed on leukocytes, dendritic cells, fibroblasts, epithelial cells, and endothelial cells.18,19 The a4b1 integrin is expressed on most leukocytes but not on neutrophils, and interacts with VCAM-1.20 The a4b7 integrin is expressed on the lymphocytes in the gut-associated lymphoid tissue, and interacts with MAdCAM-1.21 This ligand is expressed on endothelial venules in the small intestine and the colon, especially in the Peyer patches.22
Lymphocyte Homing Antagonists for IBD Treatment
Fig. 1. Adhesion molecules and chemokine receptors in the recruitment of immune cells in the intestinal endothelium. In the intestine, the adhesion molecule MAdCAM-1 functions as docking site for integrins a4b1 and a4b7 expressed by T cells.69 By contrast, the adhesion molecule VCAM-1 also acts as docking molecule for a4b1. Natalizumab inhibits a4 integrins, therefore blocking the adhesion of T cells to the entire intestinal mucosa and extramucosal tissues (eg, brain). Vedolizumab, an a4b7 integrin inhibitor, inhibits the adhesion of T cells to the intestinal mucosa only, and thus does not limit immune surveillance of the central nervous system while dampening the inflammatory response.69 In the endothelium of the small intestine, the chemokine CCL25 is constitutively expressed and upregulated during inflammation. It acts as a ligand for the chemokine receptor 9 (CCR9) on T cells. The inhibitor CCX282-B, or vercirnon, blocks the CCL25-CCR9 interaction, thus inhibiting T-cell adhesion to the small intestinal mucosa. Phase 3 trials of CCX282-B are currently on hold. ICAM, intercellular adhesion molecule; IL, interleukin; MAdCAM, mucosal addressin cell adhesion molecule; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.
Proinflammatory cytokines such as TNF-a and interleukin (IL)-1b upregulate the expression of gut-expressed adhesion molecules such as MAdCAM-1, ICAM-1, and VCAM-1. These adhesion molecules are overexpressed in IBD, especially in the active phase of the disease. Cultured supernatants from colonic biopsies taken from UC and CD patients induce upregulation of ICAM-1 and E-selectin,23 and there is increased expression of various endothelial adhesion molecules by immunohistochemistry from colonic biopsies in patients with IBD.24–26 Moreover, it has been shown that the proportion of venular endothelium within the lamina propria that expresses MAdCAM-1 at inflammatory foci associated with UC and CD is increased compared with normal tissues, and MAdCAM-1 is not detected in most normal or inflamed extraintestinal tissues, including those at other mucosal surfaces.22 Similarly, VCAM-1 is also overexpressed in the colonic IBD mucosa in comparison with normal controls by immunohistochemistry.24
583
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Saruta & Papadakis
PREVENTING LEUKOCYTE INFILTRATION BY BLOCKING ADHESION RECEPTORS
Inhibition of leukocyte trafficking to the gut mucosa during the inflammatory process in IBD has become the second major therapeutic target of biological agents after the introduction of anticytokine agents in the development of IBD therapeutics.13 Several critical steps outlined in Fig. 1 that are involved in the recruitment of inflammatory cells to the intestinal mucosa can be targeted for therapeutic purposes. The a4b7 integrin is highly expressed on a subpopulation of CD41CD45RA– memory T cells, which have been shown to preferentially home to the gut.27,28 The ligand mediating a4b7 T-cell gut-homing is MAdCAM-1, which is selectively expressed in the gut endothelium and is upregulated in the chronically inflamed small and large intestines of patients with IBD.22,29 The predominant targets of the novel biological agents in this group are the integrins a4b1, a4b7, and a2b2, which interact with VCAM-1, MAdCAM-1, and ICAM-1, respectively, to mediate the interactions between leukocytes and endothelial cells.12,13 The agents that target the integrins include the monoclonal antibodies natalizumab (antia4 integrin), vedolizumab (MLN-02, anti-a4b7 integrin), AMG181 (anti-a4b7 integrin), etrolizumab (RG7413, rhuMAb b7, anti-b7 integrin), which targets both a4b7 and aEb7, and PF-00547659 (anti-MAdCAM-1). AJM-300 (Ajinomoto Pharmaceuticals, Tokyo, Japan) is a small-molecule inhibitor of the a4 integrin subunit. Other molecules that aim to prevent leukocyte infiltration include alicaforsen (ISIS-2302), an antisense oligonucleotide against ICAM-1 messenger RNA. Vercirnon (CCX282-B, GSK1605786) is a small molecule that targets the chemokine receptor CCR9, the key chemokine receptor in the targeting of leukocytes to the intestinal mucosa (see Fig. 1, Table 1).30,31 CURRENT ANTIADHESION THERAPIES FOR IBD Antiadhesion Therapies for IBD Natalizumab
Natalizumab (Tysabri; Biogen-Idec, Cambridge, MA, USA) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody against a4 integrins.32 Previous randomized studies have suggested that natalizumab may be effective as induction therapy for patients with moderately to severely active CD.33–35 The first study of natalizumab was reported by Gordon and colleagues,34 and focused on the evaluation of the safety and efficacy of natalizumab in patients with mildly to moderately active CD. Ghosh and colleagues33 conducted a double-blind, placebo-controlled trial of natalizumab in 248 patients with moderate to severe CD. Patients were randomly assigned to receive 1 of 4 treatments: 2 infusions of placebo; 1 infusion of 3 mg natalizumab per kg body weight, followed by placebo; 2 infusions of 3 mg natalizumab per kg; or 2 infusions of 6 mg natalizumab per kg. The highest remission rate was 44% and the highest response rate was 71% at week 6 in the group given 2 infusions of 3 mg/kg. Patients with moderate to severe disease (Crohn Disease Activity Index [CDAI] scores 220 to 450) were enrolled in the phase 3 induction trial, Efficacy of Natalizumab as Active Crohn Therapy (ENACT-1) (N 5 905), and received 3 infusions of natalizumab (300 mg) or placebo over 8 weeks.35 Response was defined as a reduction of 70 or more points from week 0 in the CDAI score, whereas remission was defined as a CDAI score of less than 150 points. A clinical response at week 10 was observed in 56% of patients treated with natalizumab and 49% of patients with placebo (P 5 .051), and remission obtained at week 10 in 37% of natalizumab-treated patients and 30% of patients with placebo (P 5 .124). Although there were no significant differences among the 2 treatment groups, analysis in subgroups of patients,
Table 1 Selected leukocyte trafficking modulators for inflammatory bowel disease Description
Developer
Target
Indication
Clinical Status
Tysabri
Humanized IgG4 mAb
Biogen Idec (Cambridge, MA)
a4b1 integrin, a4b7 integrin
Multiple sclerosis, Crohn disease
Approved (FDA)
Entyvio
Humanized IgG1 mAb
Takeda Pharmaceuticals (Deerfield, IL)
a4b7 integrin
Crohn disease
Registration (in USA)
AMG-181
Fully human IgG2 mAb
AstraZeneca (London, UK)/Amgen (Thousand Oaks, CA)
a4b7 integrin
Crohn disease, ulcerative colitis
Phase 2
Etrolizumab (rhuMAb b7, RG7413)
Humanized IgG1 mAb
Genentech (South San Francisco, CA)
a4b7 integrin, aEb7 integrin
Ulcerative colitis
Phase 2
PF-00547659
Fully human IgG2k mAb
Pfizer (New York, NY, USA)
MAdCAM-1
Crohn disease, ulcerative colitis
Phase 2
AJM300
Oral small-molecule prodrug
Ajinomoto Pharmaceuticals (Tokyo, Japan)
a4 integrin
Ulcerative colitis, Crohn disease
Phase 2
Vercirnon (CCX282-B)
Oral small molecule
ChemoCentryx (Mountain View, CA)/GSK (Brentwood, Middlesex, UK)
CCR9
Crohn disease
Phase 3 (on hold)
Data sources: Company Web sites; PubMed. Abbreviations: FDA, Food and Drug Administration; IgG, immunoglobulin G; mAb, monoclonal antibody. Adapted from Sheridan C. First integrin inhibitor since Tysabri nears approval for IBD. Nat Biotechnol 2014;32:206; with permission.
Lymphocyte Homing Antagonists for IBD Treatment
Drug
585
586
Saruta & Papadakis
Fig. 2. Efficacy of Natalizumab in Crohn’s disease Response and Remission (ENCORE) trial. The primary end point was induction of response (70-point decrease from baseline Crohn’s Disease Activity Index [CDAI] score) at week 8 that was sustained through week 12. (A) Proportion of patients with a clinical response (70-point decrease from baseline CDAI score). The secondary end points were induction of remission (CDAI score
